Multi-module keying systems and methods include a chassis. A first module slot and a second module slot are located on the chassis. A keying device is movably coupled to the chassis and includes a first keying member that is located adjacent the first module slot and a second keying member that is located adjacent the second module slot. The keying device is configured to move in response to a first keyed module being positioned in the first module slot such that the first keyed module engages the first keying member. The movement of the keying device positions the second keying member adjacent the second module slot to restrict modules that may be positioned in the second module slot to second keyed modules. The systems and methods allow the second module slot to be keyed for second keyed modules based on the first keyed module positioned in the first module slot.

The present disclosure relates generally to information handling systems, and more particularly to a keying system for information handling systems that are configured to couple to multiple different modules.
As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option is an information handling system (IHS). An IHS generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes. Because technology and information handling needs and requirements may vary between different applications, IHSs may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in IHSs allow for IHSs to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, IHSs may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
Some IHSs are configured to couple to multiple different modules to enable different functionality of the IHS. For example, some switch IHSs may be mounted to either the front or back of an IHS rack, and the switch IHSs cooling system may be configurable to adjust the airflow direction in the switch IHS so that air is drawn from a "cool" side of the IHS rack (e.g., the side of the IHS rack to which other IHSs in the IHS rack do not expel heated air) and expelled out of a "hot" side of the IHS rack (e.g., the side of the IHS rack to which other IHSs in the IHS rack expel heated air). To enable this configurability, the switch IHS may include fan module slots that allow for the coupling of different type fan modules: a first type of fan module that provides airflow in a first direction, and a second type of fan module that provides airflow in a second direction. However, problems can arise when different types of fan modules are coupled to the switch IHS in the fan module slots at the same time. For example, if a user couples fan module(s) of the first type in one or more first fan module slots in the switch IHS, and fan module(s) of the second type in one or more second fan module slots in the switch IHS, those different type fan modules will provide airflow in different directions and prevent cooling air from properly cooling the switch IHS components (e.g., the first type fan module(s) will draw air into the switch IHS from a first side of the IHS rack, and the second type fan modules will expel that air out of the switch IHS and back to the first side of the IHS rack before it reaches the switch IHS components.)
Accordingly, it would be desirable to provide an improved multi-module coupling system.


The invention is a prefabricated door assembly for installation in a roughed-in door frame. The assembly includes a pair of vertically extending door jambs having interengaging casings and a header unit spanning the upper ends of the door jambs. The header unit includes a header board or jamb having interengaging horizontal casings. Both horizontal and vertical casings have pin nails protruding from their tongue portions which engage the jambs lightly during transport and installation prior to final nailing in place. The assembly also includes L-shaped brackets affixed to the upper outer corners which join and fasten the vertical and horizontal jambs together. The assembly may be packaged as a kit, which may include hinges, shims and/or shimming hardware.

1. Field of the Invention.
This invention relates, in general, to a prefabricated door frame kit designed for easy shipping, handling, storage, and installation. More specifically, this invention relates to prefabricated door frames constructed to self-align to fit out-of-plumb walls, warped doors, or varying wall thicknesses, while minimizing separation of joints.
2. Description of the Related Art.
Prefabricated door assemblies have been built in order to eliminate the need for skilled craftsmen to custom-build door frame and door systems at construction sites. Unitary construction of these prefabricated door assemblies has proved cumbersome, inefficient to ship, and difficult to install into imperfect roughed-in framing. Sklar (U.S. Pat. Nos. 3,250,049 and 3,338,008) and J. H. Parker (U.S. Pat. No. 3,239,978) disclose knock-down prefabricated door assemblies, which are relatively easy to transport to construction sites and which fit into openings that vary somewhat in size and shape. McKann (U.S. Pat. No. 5,345,722) discloses a plastic door frame, with first and second inside sections having a frictionally-engaging slot and tongue system for adjustment to varying wall thicknesses. Winston (U.S. Pat. No. 5,365,708) discloses jambs comprising two members, having L-shaped shoulders, which fit together to allow expansion of the jamb width.
G.L. Barr (U.S. Pat. No. 4,166,346) adds to a prefabricated door assembly refinements intended to maintain the tightness and integrity of the joints and of the connection of the door assembly to the door frame. Barr discloses tongue and groove connection of casings to jambs, and a connection between side and head jambs that provides an outward-biasing of the side jambs.
What is still needed is a prefabricated door frame assembly designed for easy installation that results in high quality appearance and tight-fitting joints, in spite of imperfections and irregularities in the rough-framing, jambs, or door.

Self-aligning prefabricated door frame assembly


A method of forming a conductive pattern on a metallic frame for manufacturing a stack frame for electrical connections is disclosed. In one embodiment, a recess is formed in the metallic frame and a conductive element is bonded in the recess to make a stack frame for electrical connections. In another embodiment, the process can be performed on both top surface and bottom surface of metallic frame to make another stack frame for electrical connections. In yet another embodiment, a package structure and a manufacturing method of forming a conductive pattern on a lead frame for electrical connections are disclosed.

I. Field of the Invention
The present invention relates to a packaging structure, and in particularly, to a metallic frame for packaging and making electrical connections.
II. Description of the Prior Art
Lead frame is a material for IC package and can be in variety of forms such as QFP, TSOP, SOT or SOJ. The molded semiconductor devices are constructed by assembling and interconnecting a semiconductor device to a lead frame. The structure is often molded with plastic material. A lead frame is made by a metal ribbon with a paddle (also known as a die paddle, die-attach tab, or island) for attaching a semiconductor device thereto and a plurality of leads arranged in a manner such that the leads do not overlap the paddle on which the semiconductor device is to be mounted.
Conventionally, lead frame is used for die bond of an IC chip. The process flow includes many stages which are wire bond, molding of IC chip, and the tests after trimming or forming. Various products can be made by integrating or packaging the lead frame with other devices such as inductors or capacitors. It's one of the main packaging processes in the industry due to its easiness, maturity and better reliability. However, such kind of conventional process has many disadvantages including: a. higher cost and more development works of molding devices; b. poor capability in area design which is only in the form of plane so that product size doesn't shrink; and c. lacking of modular capability as it is only good for packaging a single device.
Accordingly, the present invention proposes a stack frame and its manufacturing method to overcome the above-mentioned disadvantages.

Stack frame for electrical connections and the method to fabricate thereof


A surgical instrument (e.g., endocutter, grasper, cutter, staplers, clip applier, access device, drug/gene therapy delivery device, and energy device using ultrasound, RF, laser, etc.) may benefit from having a plurality of hydraulically actuated subsystems (e.g., severing, stapling, articulation, locking/unlocking, lockout enabling/disabling, grasping, etc.) supplied with hydraulic power from a trigger actuated rotary pump (e.g., lobe pump, rotary gear pump, internal rotating gear pump, flexible vane rotor pump, rotary vane pump). Thereby, an available amount of mechanical advantage available at a firing trigger may be optimally distributed to various end effector components, perhaps sequenced by an electroactive polymer or piezoelelectrically actuated function switch block.

Endoscopic and laparoscopic surgical instruments are often preferred over traditional open surgical devices since a smaller incision tends to reduce the post-operative recovery time and complications. The use of laparoscopic and endoscopic surgical procedures has been relatively popular and has provided additional incentive to develop the procedures further. In laparoscopic procedures, surgery is performed in the interior of the abdomen through a small incision. Similarly, in endoscopic procedures, surgery is performed in any hollow viscus of the body through narrow endoscopic tubes inserted through small entrance wounds in the skin.
Laparoscopic and endoscopic procedures generally require that the surgical region be insufflated. Accordingly, any instrumentation inserted into the body must be sealed to ensure that gases do not enter or exit the body through the incision. Moreover, laparoscopic and endoscopic procedures often require the surgeon to act on organs, tissues and/or vessels far removed from the incision. Thus, instruments used in such procedures are typically long and narrow while being functionally controllable from a proximal end of the instrument.
Significant development has gone into a range of endoscopic surgical instruments that are suitable for precise placement of a distal end effector at a desired surgical site through a cannula of a trocar. These distal end effectors engage the tissue in a number of ways to achieve a diagnostic or therapeutic effect (e.g., endocutter, grasper, cutter, staplers, clip applier, access device, drug/gene therapy delivery device, and energy device using ultrasound, RF, laser, etc.).
Known surgical staplers include an end effector that simultaneously makes a longitudinal incision in tissue and applies lines of staples on opposing sides of the incision. The end effector includes a pair of cooperating jaw members that, if the instrument is intended for endoscopic or laparoscopic applications, are capable of passing through a cannula passageway. One of the jaw members receives a staple cartridge having at least two laterally spaced rows of staples. The other jaw member defines an anvil having staple-forming pockets aligned with the rows of staples in the cartridge. The instrument includes a plurality of reciprocating wedges which, when driven distally, pass through openings in the staple cartridge and engage drivers supporting the staples to effect the firing of the staples toward the anvil.
An example of a surgical stapler suitable for endoscopic applications is described in U.S. Pat. No. 5,465,895, which advantageously provides distinct closing and firing actions. Thereby, a clinician is able to close the jaw members upon tissue to position the tissue prior to firing. Once the clinician has determined that the jaw members are properly gripping tissue, the clinician can then fire the surgical stapler with a single firing stroke, thereby severing and stapling the tissue. The simultaneous severing and stapling avoids complications that may arise when performing such actions sequentially with different surgical tools that respectively only sever or staple.
Generally, a single closing stroke followed by a single firing stroke is a convenient and efficient way to perform severing and stapling. However, in some instances, it would be desirable for multiple firing strokes to be required. For example, surgeons are able to select from a range of jaw sizes with a corresponding length of staple cartridge for the desired length of cut. Longer staple cartridges require a longer firing stroke. Thus, a hand-squeezed trigger to effect the firing is required to exert a larger force for these longer staple cartridges in order to sever more tissue and drive more staples as compared to a shorter staple cartridge. It would be desirable for the amount of force to be lower and comparable to shorter cartridges so as not to exceed the hand strength of some surgeons. In addition, some surgeons not familiar with the larger staple cartridges may become concerned that binding or other malfunction has occurred when an unexpectedly higher force is required.
In U.S. Pat. No. 6,905,057, a multiple firing stroke handle for an endoscopic surgical stapling and severing instrument succeeds in reducing these firing forces by advancing a firing mechanism during each squeeze of the firing trigger, mechanically coupling this firing motion through a pawl into a linked rank. In addition to reducing the force required to squeeze the firing trigger, the linked rack stows into a pistol grip of the handle to advantageously reduce the length of the handle as compared to a rigid rack.
In U.S. Pat. Nos. 6,755,338 and 6,830,174, an alternative approach has been proposed with a trigger driven master hydraulic piston and cylinder arrangement in an instrument handle that transmits fluid pressure through a shaft to a slave cylinder to hydraulically actuate an end effector. Incorporating several small and flexible hydraulic lines into such an instrument benefits from the internal pressures being balanced and not requiring a complex support structure and sheathing as perhaps a mechanical beam would, especially through an articulating shaft.
While such hydraulically actuated surgical instruments may support multiple axis articulation, simplified fabrication, and reduced size, design limitations persist. In particular, the fluid transferred from a hydraulic master cylinder in the handle is received in a corresponding slave cylinder in the end effector. Thus, the tuned volume of fluid transferred and the internal pressure imparted to this fluid are constrained by the available volume in the end effector. In addition, with increased internal pressures to obtain effective actuation with a reduced fluid volume, dynamic seals between the hydraulic piston and cylinder are challenged. Avoiding leaks with tighter seals, however, increases the internal frictional resistance that the surgeon must overcome in actuating the instrument.
Consequently, a significant need exists for an improved surgical stapling instrument that uses multiple firing strokes to hydraulically actuate an end effector.

Rotary hydraulic pump actuated multi-stroke surgical instrument


This invention relates to novel haloenol lactone compounds. These compounds have the following general structure:

This invention relates to novel haloenol lactone compounds. These compounds are useful for the specific measurement of particular isoenzymes of glutathione S-transferase. The measurement of glutathione S-transferase isoenzymes has importance in diagnostic medicine. The compounds of the invention are also useful for treatment of drug resistance in cancer and for preventing herbicide resistance in plants.
Glutathione S-transferase enzymes (GST enzymes) are a superfamily of enzymes that play an important role in the metabolism of a variety of organic compounds, including chemotherapeutic drugs, carcinogens, environmental pollutants and other harmful foreign compounds. GST enzymes have been reported to be present in a wide variety of species including bacteria, yeast, plants, nematodes, insects, birds, fish and mammals.
GST enzymes catalyze the conjugation of glutathione to a variety of different organic compounds. The glutathione thiolate anion serves as a nucleophile in the enzyme catalyzed reaction to attack electrophilic carbon, nitrogen, sulfur or oxygen atoms of a substrate molecule. See Beckett, et al. (1993) Adv. Clin. Chem. 30:281-380 for a detailed description of specific GST-catalyzed reactions.
There are a large number of GST isoenzymes in all mammalian species. These isoenzymes are encoded by four different families of GST genes, which have been designated alpha, mu, pi and theta. The GST isoenzymes from all four families are cytosolic enzymes and are dimers with a submit molecular weight of about 26 kDa. There are multiple isoenzyme forms in both the alpha and mu GST families, and these enzymes are located primarily in the liver. The pi family of GST isoenzymes are found in the liver as well as in a large number of other tissues. Thus far, only one or two isoenzymes in the pi family have been identified. The theta family of GST enzymes has only recently been isolated from liver and it is unknown how many isoenzymes exist in this family. In addition, a microsomal GST enzyme has recently been identified that is apparently structurally unrelated to the above described cytosolic enzymes. See Beckett, et al., supra for a more detailed description of GST isoenzymes.
Many cancers treated with chemotherapeutic drugs develop resistance to the particular chemotherapeutic drugs used in treatment. Furthermore, overexpression of GST enzymes is an important cellular mechanism involved in the development of drug resistance by tumor cells. Isoenzymes from both the alpha and pi GST families play a role in the development of resistance to chemotherapeutic drugs. For example, overexpression of alpha GST isoenzymes has been implicated in drug resistance to alkylating agents such as chlorambucil and cyclophosphamide. In addition, the pi GST isoenzymes have been shown to be involved in the development of drug resistance to a variety of other chemotherapeutic agents such as adriamycin, vinblastine, actinomycin D and colchicine.
Herbicide resistance in weeds has emerged as a significant problem in agriculture. Furthermore, overexpression of GST enzymes in plant cells is an important mechanism for development of herbicide resistance. In particular, overexpression of GST enzymes appears to be involved in the development of resistance to chloracetanalides, thiocarbamates, and to triazines such as atrazine.
As described above, GST isoenzymes have medical importance due to their role in mediating drug resistance in cancer patients. In addition, the measurement of GST isoenzymes in vitro also has importance in diagnostic medicine. For example, the measurement of the pi isoenzyme of GST in tissue specimens is useful in pathology for the detection and diagnosis of a variety of different tumors. In addition, measurement of the alpha form of GST in blood is useful for the detection and monitoring of a variety of different forms of liver disease. (See Beckett, et al., supra for a detailed description of the clinical applications of GST isoenzyme measurements.
There is a need for selective inhibitors of GST isoenzymes for treatment of drug resistance in cancer patients. There is also a need for GST isoenzyme inhibitors to be used with herbicides to prevent herbicide resistance in plants. In addition, there is a need for selective inhibitors of GST isoenzymes to be used in the in vitro diagnostic testing for the measurement of specific forms of GST isoenzymes. These and other needs are addressed by the present invention.
The invention provides for novel haloenol lactone compounds. The invention also provides for pharmaceutical compositions containing a pharmaceutically acceptable carrier and an amount of a haloenol compound of the invention that is effective in inhibiting a GST enzyme in an animal. For example, the animal can be a mammal.
The invention also provides for methods of inhibiting a GST enzyme in an animal. These methods involve the administration of a pharmaceutically acceptable carrier and an amount of a haloenol compound of the invention which is effective for inhibiting a GST enzyme in the animal. The animal can be, for example, a mammal.
In addition, the invention provides for methods of inhibiting a GST enzyme in a plant cell by contacting the plant cell with an amount of a haloenol lactone of the invention that is effective for inhibiting the GST in the plant cell. The haloenol lactone can be applied to the plant cell along with an herbicide. The herbicide can be, for example, a triazine, a chloroacetanalide, or a thiocarbamate herbicide.
The invention also provides for methods of detecting a GST isoenzyme in a biological specimen. These methods involve the measurement of GST enzyme activity in the presence and absence of an amount of a haloenol lactone of the invention that is effective to inhibit a GST isoenzyme. The GST isoenzyme can be, for example, GST pi or GST alpha isoenzyme.

Inhibition of glutathione transferase by haloenol lactones

Abstract: in which Ar is an aryl group and Y is a haloenol lactone moiety.

Abstract: The compounds of the invention are useful for the specific measurement of particular isoenzymes of glutathione S-transferase. Measurement of glutathione S-transferase isoenzymes has importance in diagnostic medicine. The compounds of the invention are also useful for treatment of drug resistance in cancer and for preventing herbicide resistance in plants.

The Regents of the University of California


A packet switch of the type in which packets received in the switch are stored in memory until they are output. In the switch fabric of the switch, packets are serially received in input shift registers wide enough to store an entire packet, output in parallel to memory which is as wide as the input shift register, moved in parallel in the memory, and output in parallel to an output shift register. The bus connecting the input shift registers, the output shift register, and the memory is as wide as the input shift register, but does not cross the boundaries of the semiconductor chips making up the switch fabric, thus avoiding the electrical problems of very wide buses. In the disclosed implementation, there are 14 input lines and 14 output lines. A switch memory is associated with each output line and receives packets from all 14 input lines, accepting only those destined for the output line associated with the input line. Each switch memory includes a controller, memory and a communications interface for the controller, and a set of switch memory VLSI devices. Each switch memory VLSI device includes a first shift register for receiving slices of the packet and a bus, a memory, and a second shift register for outputting the slices. The bus, the memory, and the second shift register are as wide as the first shift register.

1. Field of the Invention
The invention concerns packet switching generally and packet switching in very high-speed networks in particular.
2. Description of the Prior Art
Increasingly, devices communicate with each other by sending packets of digital data. As shown in FIG. 1, a packet (P 113) is a sequence of bits which one device sends another. Packets generally have two parts: a message (MSG 115), which is the sequence of bits which make up the actual message which is being sent, and a header (HDR 117), which contains control information which the communications system over which the packet is sent uses in transferring the message. At a minimum, header 117 will contain destination (D 119), a value which indicates the destination to which the message is directed. Header 117 may also contain information such as the length of message 115, the type of message 115, or the source of message 115. The manner in which destination 119 indicates the destination will depend on the kind of communications system over which the message is sent. For example, destination 119 may specify the address of the device which is to receive the packet in the network or it may specify a virtual circuit which is currently connecting the source of the packet with its destination.
One way of sending packets between devices is by means of a switched network. A switched network is made up of nodes connected by incoming and outgoing links. A packet switch at each node of the network receives packets on its incoming links, determines from destination 119 where each packet is going, and switches the packet to the outgoing link which will take it to its destination.
FIG. 1 shows a prior-art packet switch 101. Packet switch 101 receives packets from a number of input links at input ports (IP) 107(0 . . . n), switches the packets in switch fabric (SF) 103, and outputs them to output links at output ports (OP) 109(0 . . . n). In most common kinds of prior-art packet switches, switching fabric 103 includes memory 105. Memory 105 contains at a minimum an output queue (OQ) 111 for each output port 109. Switch fabric 103 does the switching by placing each packet received on an input port 107 onto the tail of output queue 111 for output port 109 for the output link which will take the packet to its destination. As switch fabric 103 adds incoming packets 113 to the tails of the output queues, it takes outgoing packets 113 from the heads of the output queues 111 and provides them to output ports 109 corresponding to the queues 111.
A problem with packet switches in modern networks is the switch is often unable to keep up with the speed at which the links can operate. For example, a glass fiber link can operate at speeds of 1 Gigabyte/second. If the switch cannot keep up with that speed, that is, unless the switch can handle simultaneous inputs from a number of links operating at that speed, the network will not be able to use the full capacity offered by the links, but will instead be limited by the rate at which the switches can transfer packets from one link to another. A survey of architectures for fast packet switches may be found in Fouad A. Tobagi, "Fast Packet Switch Architectures for Broad-band Integrated Services Digital Networks", Proceedings of the IEEE, vol. 78, No. 1, January, 1990.
A particularly troublesome area in designing packet switches of the type of packet switch 101 is the limitations that memory 105 places on operating speed. Modern packet switches are of course made up of integrated circuits; in particular, memory 105 is made up of a number of off-the-shelf dynamic RAM integrated circuits. Memory 105 must be both large and fast; however, off-the-shelf dynamic RAM integrated circuits are either large and slow or small and fast. For example, current CMOS memories of 256 Kbits have a cycle time of 35 ns, while those of 4 Mbits have a cycle time of 200 ns. Worse, the product of memory size with cycle time has remained remarkably constant over generations of memory technologies.
If switch 101 is to operate at the necessary speed, enough fast memory integrated circuits must be provided so that memory 105 is wide enough to store an entire packet in a single row of the memory, so that the entire packet can be written to or read from memory 105 in a single operation. Further, the packet must be carried to and from the memory by a bus which is as wide as the memory. However, as a bus becomes wider, it also becomes slower. The large number of parallel lines increases distortion and skew in the data signals, and the bus cycle time must be increased to counteract these effects. Further, crosstalk between the many data lines increases the noise level, so that larger bus drivers and more sensitive receivers are required. As a result of all of these factors, the speed advantages gained by a wide memory 105 are limited by the slowness of the bus which connects the memory integrated circuits making up memory 105 to the remaining integrated circuits making up switch fabric 103 and switch 101 cannot provide provide the gigabytes/second transfer rate which is needed.
It is an object of the high-speed packet switch disclosed in this patent application to overcome the foregoing problems and limitations of prior-art packet switches.


An electronic device includes: a display panel configured to display an image; an input sensor on the display panel and comprising a first sensing electrode and a second sensing electrode that is electrically insulated from the first sensing electrode, the input sensor being configured to sense a first input in a first mode and to sense a second input in a second mode; and an input device configured to provide the second input to the input sensor, wherein at least one of the first or second sensing electrodes comprises: a main mesh pattern in a crossing area in which the first and second sensing electrodes cross each other; and a sub mesh pattern in a non-crossing area on which the first and second sensing electrodes do not cross each other and which has a size different from that of the main mesh pattern.

Aspects of some embodiments of the present disclosure herein relate to an electronic device.
Multimedia electronic devices such as televisions, mobile phones, tablet computers, navigation systems, game consoles, and the like are utilized to display images. Such electronic devices may include input sensors, which are capable of providing a touch-based input mechanism to allow users to relatively easily input information or commands intuitively and conveniently in addition to a usual input manner such as buttons, keyboards, mouses, and the like.
The input sensor may sense a touch or pressure input using a user's body. There is an increasing demand for using an active pen for fine touch input for a user who is familiar with information input using a writing instrument or a specific application program (for example, application program for sketching or drawing).
The above information disclosed in this Background section is only for enhancement of understanding of the background and therefore the information discussed in this Background section does not necessarily constitute prior art.


A computer-implemented method of controlling the creation of a printed document includes the steps of: retrieving print information for generating a print job, said print information specifying characteristics of a document to be printed; retrieving at least one attribute of a print finishing device, said attribute defining a constraint imposed on the print job for printing said document, when the printed document is processed in said print finishing device; and generating a print job based on said print information and said constraint. In one example, retrieving said at least one attribute of a print finishing device includes establishing a communication link to said print finishing device and prompting the print finishing device to transmit the at least one attribute. Said communication link can be established and used on-line at the time of generating the print job or in advance.

Generally, printing systems are known which go from a simple desktop printer to a large format digital press which is able to produce any commercial print job and digitally print any size application, including pocket folders, multiple-page brochures, posters, and large lay-flat books, for example. Fully or half-automated digital printers, such as HP Indigo Digital Press, for example, enable highly-efficient imposition of jobs and support a large media range, including different sizes, weight and quality of printing papers, including coated, colored, metallic and other specialty papers and cardboard etc.
These and other printers often operate in combination with a print finishing device which may be integrated or separate from the printer as such. A print finishing device performs any type of post-processing of a printed document, such as cutting, stapling, folding, perforation, margin trim, creasing, coating, bookbinding and the like. Examples of print finishing devices are Duplo DC-645 and Lasermax Page Ready, without being limited thereto. Print finishing devices are fully or half-automated machines which can operate according to different selectable configurations and allow to perform different pre-programmed finishing jobs, such as stapling a predetermined number of pages, creasing, cutting and folding printed pages to a predetermined format, etc. Different print finishing jobs may require different impositions of the printed document.
It is known to provide an image with a finishing mark which can be extracted to determine the type of finishing which is required for the printed document. It is also known to incorporate commands into a print job for determining which finishing operations shall be performed on the print run. The printing device can select a finishing device that can perform all or a maximum of the demands.

Method and system for generating a print job


A bismuth-213 generator comprising an insoluble composition having the general formula Zr(Phosponate)x(HPO4)2−x.nH2O, wherein x is between 0 and 2; and n is the number of waters of hydration; and wherein cations of radioactive isotopes selected from radium, actinium and combinations thereof are immobilized on the composition. The value of x may be between about 0.2 and about 1. The phosphonate may be n-phosphonomethyl-miniodiacetic acid (PMIDA), wherein x may be between about 0.1 and about 1.9. The phosphonate may be one or more phosphonate having the formula:H2O3P—(CH2)a—N—((CH2)bCO2H)—((CH2)cCO2H),wherein a, b, and c are numbers from 1 to 3 that may or may not be equal. The value of x may also be between about 0.1 and 1.9.

1. Field of the Invention
The present invention relates to radionuclide generators, ion exchange materials for radionuclide generators and methods of making these materials.
2. Description of the Related Art
The use of alpha-emitting radionuclides in the treatment of specific forms of cancers has become increasingly of interest in recent years. Alpha particles are far more effective in the destruction of cancer cells than gamma or beta particles due to their greater linear energy transfer (LET) rates. Bismuth-213 (213Bi) has been identified as an important radioisotope for use in this new field of radiomedicine.
In order for an isotope to be used in medical applications, the isotope should be of high purity to avoid introduction of undesirable radioactive isotopes into the body that would deliver an unnecessary dose to sensitive areas of the body such as the bone marrow. 213Bi is produced as a daughter product in the decay of 229Th, which is itself a daughter product of the decay of 233U. 213Bi has a short half-life of only about 45 minutes, which means that it rapidly decays away once introduced into the body. This also means that the isotope should be supplied in the form of a generator in which a suitable parent isotope is immobilized on an ion exchange material so that the 213Bi can be eluted when required. 225Ac is a parent isotope of choice that can be immobilized and shipped to medical facilities. The 229Th decay series that includes 213Bi is shown in FIG. 1.
Alpha particles are extremely destructive towards conventional organic ion exchange resins, which leads to limited generator life, bleed of undesirable 225Ac into the 213Bi product and the possible release of pyrogens into the aqueous phase during 213Bi elution.
Therefore, there is a need for a radionuclide generator, such as a 213Bi generator, that has improved stability against alpha particles and other forms of ionizing radiation. It would be desirable if the generator provided high separation and high stability in order to yield a solution with substantially no parent isotope and no by products of generator decomposition.


A pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:

The present invention relates to dosage forms for controlled onset and sustained release of active ingredients for human or animal use.
The goal of any drug delivery system is to provide an effective therapeutic amount of a drug to a targeted site in the body to obtain quickly, and then maintain, the desired drug concentration. The two most important aspects of drug delivery are spatial placement and temporal delivery of a drug. Spatial placement relates to the targeting of a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue.
Sustained release drug delivery systems are designed in an attempt to satisfy the spatial placement and temporal delivery of a drug. Sustained release drug delivery systems include any drug delivery system that achieves slow release of a drug over an extended period of time. If these sustained release drug delivery systems can provide some control of drug release in the body, whether this be of a temporal or spatial nature, or both, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered to be a controlled release drug delivery system.
Some therapeutic programs require that the dose of a drug be administered in a time varying pattern of delivery such as a drug free interval followed by a sustained release of the drug for an extended period of time. The science of chronotherapeutics relies on the practice of delivering an effective therapeutic amount of a drug to the desired site of action at the most appropriate time period for a particular disease condition. For example, the greatest incidence of cardiovascular disorders including angina, stroke, heart attack, etc., typically occur during the early morning hours when blood pressure is rising in response to an animal""s natural circadian rhythm. This rise in blood pressure, which occurs at waking, requires a dosage form that is administered upon retiring which dosage form delivers its drug before waking but after a drug free interval during sleep. This time varying pattern or controlled onset of drug delivery provides the required therapy at the appropriate time, thereby substantially lessening the instance of a waking elevated blood pressure.
It is well known in the prior art to provide dosage forms that deliver their contents at a desired rate after a predetermined time delay. Applicant is aware of two such controlled onset and sustained release drug delivery systems currently on the market namely, Verelan(copyright) PM by Schwarz Pharma and Covera-HS(trademark) by G.D. Searle and Co. Verelan(copyright) PM is a verapamil hydrochloride capsule formulation utilizing the proprietary CODAS(trademark) (Chronotherapeutic Oral Drug Absorption System) technology, developed by Elan Corporation PLC and which technology is based on U.S. Pat. No. 4,863,742. U.S. Pat. No. 4,863,742 relates to a controlled absorption verapamil containing pellet formulation for oral administration comprising: (i) a core of (a) a powder mixture containing verapamil or a salt thereof and an organic acid, and (b) a polymeric material containing a major proportion of a water soluble polymer and a minor proportion of a water insoluble polymer, the core comprising layers of the powder mixture and the polymeric material superimposed one upon the other; and (ii) a multi-layer membrane surrounding the core and containing a major proportion of a film-forming, water insoluble polymer and a minor proportion of a film forming water soluble polymer; the release of the verapamil from the pellet being substantially independent of pH and at a rate allowing controlled absorption thereof over a 24 hour period following oral administration.
The individual pellets formulated according to U.S. Pat. No. 4,863,742 may be filled into hard or soft gelatin capsules or may be compressed into tablets. The pellets in the formulation may consist of a blend of pellets formulated to provide various release rates of verapamil. Upon ingestion, the hard or soft gelatin capsules dissolve immediately, thus releasing the individual pellets into the gastrointestinal tract. Likewise, upon ingestion, the compressed tablets are designed to fall apart immediately, thus releasing the individual pellets into the gastrointestinal tract.
The Verelan(copyright) PM capsule formulation, which is based on the teachings of U.S. Pat. No. 4,863,742, is a controlled onset sustained release drug delivery system designed for bed time administration, which incorporates a 4 to 5 hour delay in drug delivery. The Verelan(copyright) PM capsule formulation initiates the release of verapamil hydrochloride 4 to 5 hours after ingestion and results in a maximum plasma concentration (Cmax) of verapamil hydrochloride in the morning hours. The pellet filled, hard gelatin capsules provide for extended release of verapamil hydrochloride in the gastrointestinal tract. The delay is introduced by the level of non-enteric release controlling polymer applied to the verapamil hydrochloride loaded beads. The release controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the verapamil hydrochloride diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the verapamil hydrochloride. The rate of release is essentially independent of pH, posture, and gastrointestinal motility in fed or fasting conditions.
The formulation disclosed in U.S. Pat. No. 4,863,742 and thus the currently marketed Verelan(copyright) PM capsule formulation, has several limitations. In the acidic environment of the stomach (pH 1 to 3) where the verapamil is water soluble, the gastric fluid diffuses through the permeable membrane of each pellet, dissolves the verapamil, and diffuses out through the permeable membrane of each pellet with the dissolved verapamil. The purpose of the organic acid is purportedly to maintain an acidic micro-environment in the pellet core to keep the verapamil soluble, even when the pellet is introduced into the alkaline environment of the lower gastrointestinal tract. Thus, when the pellets descend through the stomach into the alkaline environment of the lower gastrointestinal tract (pH 5 to 7), the verapamil purportedly continues to be dissolved because of the purported continued presence of the organic acid in the core which organic acid maintains the acidity of the micro-environment (assuming the acid has not diffused out). Fluid entering the pellet from the lower gastrointestinal tract (even though more basic) is purportedly neutralized by the presence of the organic acid and the relatively low pH maintained so that the verapamil can purportedly remain in its more soluble state in the maintained acidic micro-environment. Thus, the verapamil purportedly continues to dissolve and diffuse through the multi-layer permeable membrane into the lower gastrointestinal tract.
The difficulty of the approach used in the formulation disclosed in U.S. Pat. No. 4,863,742 and thus the approach used in the Verelan(copyright) PM capsule formulation, is two-fold. Firstly, the organic acid is soluble. Therefore, the organic acid dissolves and diffuses out from the core through the multi-layer permeable membrane as the pellets pass through the gastrointestinal tract. Secondly, the organic acid is subject to neutralization as a result of its contact with the alkaline environment of the lower gastrointestinal tract, where the effectiveness of the organic acid is most needed. At the time when only a percentage of the original amount of verapamil is present in the core, there is a stronger need for solubilization because the less product inside the core, the higher the osmotic pressure needed to permit the verapamil to be pushed out. However, at that point, the quantity of organic acid has had time to diffuse out and another quantity of organic acid has had time to be neutralized. Thus, the organic acid concentration is lower and the system loses its ability to adequately acidify the micro-environment within the pellet surrounded by the multi-layer permeable membrane, becoming less effective when it is more and more needed. As a result of this phenomena, the pellets formulated in accordance with U.S. Pat. No. 4,863,742 and thus the Verelan(copyright) PM capsule formulation does not reliably release verapamil at a sustained rate.
Covera-HS(trademark) is a verapamil hydrochloride tablet formulation utilizing the proprietary OROS(copyright) (Oral Osmotic) technology developed by Alza Corporation and which technology is based on U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338. U.S. Pat. No. 5,160,744 relates to a dosage form for the delayed-delivery of a drug, wherein the dosage form comprises: (a) a first composition comprising the drug verapamil and a poly(ethylene oxide), said poly(ethylene oxide) comprising means for changing from a nondispensable viscosity to a dispensable viscosity when contacted by fluid that enters the dosage form; (b) a second composition comprising a polymeric composition that imbibes fluid and expands, whereby the second composition pushes the first composition from the dosage form; (c) a wall that surrounds the first and second compositions, said wall permeable to the passage of fluid present in the environment of use and comprises a polymeric composition that hydrates slowly when contacted by fluid that enters the wall; (d) at least one exit mans in the wall for delivering the drug from the dosage form; and, wherein the dosage form is characterized by: (e) a delayed-drug interval for delivering verapamil up to 4.5 hours provided by (a), (b) and (c) operating in combination as a unit to provide the delayed-drug interval.
U.S. Pat. Nos. 5,190,765 and 5,252,338 relate to a dosage form for the delayed-delivery of a drug to a fluid environment of use, wherein the dosage form comprises: (a) drug composition comprising a calcium channel blocker drug, and a polymer comprising a molecular weight up to 1,000,000 and a rate of hydration in the presence of fluid that enters the dosage form to change from a non-dispensable phase to a dispensable phase; (b) a push composition that imbibes fluid and expands, whereby the push composition pushes the calcium channel blocker drug composition from the dosage form; (c) a wall that surrounds the drug and push compositions, said wall comprising a semi-permeable cellulose polymer composition permeable to the passage of fluid present in the environment of use, and a different cellulose polymer comprising a 8,500 to 4,000,000 molecular weight for slowing the rate of fluid passage through the semi-permeable cellulose polymer composition of the wall; (d) at least one exit means in the wall for delivering the drug from the dosage form; and wherein the dosage form is characterized by: (e) a subcoat for the delayed-delivery of drug, which subcoat comprises a hydroxyalkylcellulose polymer possessing a 8,500 to 4,000,000 molecular weight that surrounds the drug and push composition and is positioned between the inside surface of the wall and the drug and push composition; and characterized further by: (f) a delayed-delivery of 30 minutes to 7 hours is provided by (1) the polymer in the drug composition, (2) the polymer in the wall composition and (3) the polymer in the subcoat operating in conjunction, whereby through the combined operations of (1), (2) and (3) a delayed-delivery of the calcium channel blocker drug is provided by the dosage form.
U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338 all relate generally to dosage forms for the controlled drug delivery of a drug, wherein osmotic pressure is employed as the driving force to generate a constant release of the drug from the dosage form provided a constant osmotic pressure is maintained. The dosage forms comprise a semi-permeable membrane, permeable to the passage of exterior fluid and substantially impermeable to the passage of drug, the semi-permeable membrane surrounding and forming a compartment comprising a drug layer and an osmotic layer and, at least one preformed passageway in the membrane communicating with the drug layer in the compartment and the exterior of the dosage form. Typical materials for forming the semi-permeable membrane are cellulose esters, cellulose ethers and cellulose ester-ethers. When the dosage form is exposed to water or any fluid in the body, water is imbibed into the dosage form in a tendency towards osmotic equilibrium due to the osmotic pressure difference. The volume flow rate of water into the dosage form is determined by the osmotic pressure gradient across the membrane and the permeability, area and thickness of the membrane. The drug is pumped out of the dosage form through the orifice at a controlled rate, the rate of which is determined by the volume flow rate of water into the dosage form and the concentration of the drug inside the dosage form.
The Covera-HS(trademark) tablet formulation, which is based on the teachings of U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338, is a controlled onset sustained release drug delivery system designed for bedtime dosing, incorporating a 4 to 5-hour delay in drug delivery. The Covera-HS(trademark) tablet formulation initiates the release of verapamil hydrochloride 4 to 5 hours after ingestion and results in a maximum plasma concentration (Cmax) of verapamil hydrochloride in the morning hours. The delay is introduced by a layer between the active drug core and the outer semi-permeable membrane. As water from the gastrointestinal tract enters the tablet, the delay coating is solubilized and released. As tablet hydration continues, the osmotic layer expands and pushes against the drug layer, releasing verapamil hydrochloride through precision laser drilled orifices in the outer membrane at a constant rate. This controlled rate of drug delivery in the gastrointestinal lumen is independent of posture, pH, and gastrointestinal motility in fed or fasting conditions. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.
The formulations disclosed in U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338 and thus the currently marketed Covera-HS(trademark) tablet formulation, has several limitations. The semi-permeable membrane that surrounds the drug and push compositions is permeable to the passage of the external fluid but is substantially impermeable to the passage of the drug. Delivery of the drug is purported to be essentially constant. However, the release rate of the drug from the dosage form is constant only until the concentration of the drug inside the dosage form falls below saturation. Thereafter, the osmotic gradient decreases across the membrane and the release rate of the drug from the dosage form gradually declines to zero. As a result, the formulations disclosed in U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338 and thus the currently marketed Covera-HS(trademark) tablet formulation does not reliably release verapamil at a sustained rate. As well, upon ingestion, the semi-permeable membrane maintains its physical and chemical integrity during gastrointestinal transit and is eliminated in the feces as an insoluble shell. The osmotically active agents may lack the ability to imbibe sufficient fluid for the maximum self-expansion needed for urging all of the drug from the dosage form. Therefore, due to the nature of the osmotic drug delivery system, some of the drug remains in the insoluble, inflexible shell and is thus not available for the desired absorption and effect. In addition, the formulations may be manufactured with solvents (used to dissolve cellulose ester polymers in the semi-permeable membrane) that are not environmentally friendly, expensive and also require expensive manufacturing processes that need explosion proof equipment and laser guns to drill holes on the surface of the dosage forms. Furthermore, these processes may be unhealthy and may even be harmful to the employees involved in manufacturing these products. The residual solvents remaining in these products may also cause adverse side effects among users of these products.
It is accordingly one object of the present invention to provide a novel and improved pharmaceutical composition for delivering an active ingredient or a plurality of active ingredients from the pharmaceutical composition at a sustained rate after a desired time delay or a controlled onset of release while avoiding the disadvantages of the prior art compositions.
It is a further object of the present invention is to provide pharmaceutical compositions that begin to release active ingredients from the pharmaceutical compositions at a predetermined time delay or controlled onset after administration of the pharmaceutical compositions and which continue releasing the same active ingredients from the pharmaceutical compositions at a predetermined release rate such that the blood levels achieved by such pharmaceutical compositions provide a significant therapeutic benefit to patients suffering from various disease states.
It is yet another object of the present invention to provide a method for administering active ingredients to a patient in need of therapy by administering a pharmaceutical composition which provides a time delay of between about 30 minutes to 6 hours in the delivery of the active ingredient.
It is yet another object of the present invention to provide a method for producing a delayed therapeutic effect of between about 30 minutes to 6 hours in a patient in need of therapy.
It is yet another object of the present invention to provide a method of preparing a pharmaceutical composition for controlled onset and sustained release of an active ingredient.
It is yet another object of the present invention to provide a pharmaceutical composition that delivers an active ingredient selected from the group consisting of very soluble active ingredients, freely soluble active ingredients, soluble active ingredients, sparingly soluble active ingredients, slightly soluble active ingredients, very slightly soluble active ingredients and practically insoluble, or insoluble active ingredients in a controlled and sustained rate to a patient in need of therapy with a controlled onset of between about 30 minutes and 6 hours.
It is yet another object of the present invention to provide a pharmaceutical composition that delivers glipizide (insoluble drug) in a controlled and sustained rate to a patient in need of glipizide therapy with a controlled onset of about 2 hours.
It is yet another object of the present invention to provide a pharmaceutical composition that delivers verapamil HCl (soluble drug) in a controlled and sustained release rate to a patient in need of verapamil therapy with a controlled onset of about 2 hours.
Further and other objects of the invention will become apparent to those skilled in the art from reading the following summary of the invention and the preferred embodiments described and illustrated herein.
In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and
(ii) a functional coating membrane surrounding said core.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a functional coating membrane surrounding said core; and
(iii) a top coating membrane surrounding said functional coating membrane.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core; and
(iii) a functional coating membrane surrounding said seal coating membrane.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane, and
(iv) a top coating membrane surrounding said functional coating membrane.
In an embodiment of the present invention, the active ingredient in the core is dispersed as a solid in a matrix comprising the hydrophilic carrier, the hydrodynamic diffusion enhancer, and the optional conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof.
In an embodiment of the present invention, the core is in a form selected from the group consisting of a tablet, a caplet, a sphere, a spheroid, a granule, a pellet or the like, which form allows for coating.
In an embodiment of the present invention, the pharmaceutical composition is a finished dosage form selected from the group consisting of a tablet, a caplet, a capsule, a sphere, a spheroid, a pellet, a troche, a cachet, a pill or the like in all sizes, shapes and colours.
In an embodiment of the present invention, the core is developed such that the release rate of the active ingredient from the uncoated core is faster than the release rate of the active ingredient from the finished dosage form (coated core). The ratio of hydrophilic carrier to hydrodynamic diffusion enhancer and to the optional conventional pharmaceutically acceptable excipients is optimized to obtain the desired release rate of the active ingredient from the core.
In an embodiment of the present invention, the active ingredient is any ingredient that provides a significant therapeutic benefit to humans or animals when released from the pharmaceutical compositions in a controlled onset and sustained release profile.
Preferably, the active ingredients which are suitable for use in the pharmaceutical compositions of the present invention are selected from the group consisting of very soluble drugs, freely soluble drugs, soluble drugs, sparingly soluble drugs, slightly soluble drugs, very slightly soluble drugs and practically insoluble, or insoluble drugs. According to Remington: The Science and Practice of Pharmacy, 19th Edition, ed. Alfonso R. Gennaro, Vol. 1, Table 1, p. 195, Mack Publishing Company, Easton, Pa. 18042, the above-mentioned descriptive terms for solubility are defined. Specifically, very soluble means that less than 1 part of solvent is required to dissolve 1 part of solute. Freely soluble means that from 1 to 10 parts of solvent are required to dissolve 1 part of solute. Soluble means that from 10 to 30 parts of solvent are required to dissolve 1 part of solute. Sparingly soluble means that from 30 to 100 parts of solvent are required to dissolve one part of solute. Slightly soluble means that from 100 to 1000 parts of solvent are required to dissolve one part of solute. Very slightly soluble means that from 1000 to 10,000 parts of solvent are required to dissolve 1 part of solute. Practically insoluble, or insoluble means that more than 10,000 parts of solvent are required to dissolve 1 part of solute.
Preferably, the active ingredients which are suitable for use in the pharmaceutical compositions of the present invention are selected from the group consisting of anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, oxaprozin, prednisone and prednisolone; coronary dilator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate; peripheral vasodilator drugs such as naftidrofuryl oxalate, cyclandelate and nicotinic acid; anti-infective drugs such as erythromycin, cephalexin, naldixic acid, clarithromycin, cefuroxime, cefaclor, cefprozil, zidovudine, acyclovir, ofloxacin, ciprofloxacillin, azithromycin and flucloxacillin sodium; psychotropic and/or an antianxiety drugs such as fluazepam, diazepam, amitryptaline, doxepine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipremine, clorazepate, estazolam, lorazepam, alprazolam, bupropion, fluoxetine, buspirone, clonazepam, sertaline, zolpidem, desmethylimipramine, lithium carbonate, lithium sulfate and methylphenidate; central stimulant drugs such as isoproterinol, amphetamine sulphate and amphetamine hydrochloride; antihistamine drugs such as chlorpheniramine, bropheniramine, fexofenadine, loratidine and diphenhydramine; laxative and/or antidiarrheal drugs such as bisacodyl, magnesium hydroxide, loperamide, diphenoxylate, and dioctyl sodium sulfosuccinate; decongestant drugs such as phenylpropanolamine and pseudoephedrine; vitamin substances such as alphatocopherol, thiamin, pyridoxine and ascorbic acid; antacids such as aluminum trisilicate, aluminum hydroxide, cimetidine, ranitidine, famotidine, omeprazole and nizatidine; gastrointestinal sedatives such as propantheline bromide and metoclorpramide; cerebral vasodilators such as soloctidilum, naftidrofuryl oxalate, co-dergocrine mesylate, papaverine and pentoxifylline; anti-anginal drugs such as isosorbide dinitrate, pentaerythritol tetranitrate, verapamil, nifedipine, diltiazem, and glyceryl trinitrate; antiarrythmics such as verapamil, nifedipine, diltiazem, disopyramide, bretylium tosylate, quinidine sulfate, quinidine gluconate and procainamide; antihypertensives such as methyldopa, captopril, hydralazine, propranolol, labetalol, sotalol, terazosin, enalapril, lisinopril, quinalapril, benazepril, ramipril, clonidine, fosinopril, felodipine, immodipine and amlodipine; vasoconstrictors such as ergotamine; substances which influences blood coagulability such as protamine sulfate and epsilon aminocaproic acid; hypnotics such as dichloral phenazone, nitrazepam and temazepam; antinauseants such as chlorpromazine and promethazine theoclate; anticonvulsants such as sodium valproate, phenytoin sodium, divalproex sodium and carbamezipine; neuromuscular drugs such as dentrolene sodium; hypoglycemic agents such as diabenese, insulin, glyburide, glipizide and troglitazone; drugs used in treating thyroid gland disorders such as thyroxin, triiodothyronine and propylthiouracil; diuretics such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone, triampterene and indapamide; uterine relaxant medications such as ritodrine; appetite suppressants such as asphenteramine, diethylproprion hydrochloride and fenfluramine hydrochloride; erythropoietic substances such as folic acid, calcium gluconate and ferrous sulphate; antiasthmatic drugs such as aminophylline, theophylline, orciprenaline sulphate, terbutaline sulphate, albuterol and salbutamol; expectorants such as carbocisteine and guaiphenesin; cough suppressants such as noscapine, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone and dextromethorphan; antiuricemic drugs such as allopurinol, probenecid and sulphinpyrazone; antiseptics such as cetylpyridinium chloride, tyrothricin and chlorhexidine; antilipidimic or anticholesterol agents such as lovastatin, gemfibrozil, simvastatin and pravastatin; pharmaceutically acceptable salts thereof and combinations thereof. Any active ingredient from a very soluble drug to a practically insoluble or insoluble drug would be a suitable active ingredient for the present invention and the active ingredients discussed above are used as examples only.
In an embodiment of the present invention, the hydrophilic carrier is one or more hydrophilic polymeric excipients in any desired ratio to provide a desired release profile of the active ingredient from the pharmaceutical composition.
Preferably, the hydrophilic carrier is a homopolysaccharide or a heteropolysaccharide, preferably selected from the group consisting of xanthan gum, locust bean gum, propylene glycol ester, galactomannan, glucomannan, guar gum, gum acacia, gum tragacanth, alkali metal carageenates, alginates, cellulose alkyl carboxylates, carboxymethyl cellulose, carboxyethyl cellulose, alkali metal salts of cellulose alkyl carboxylates, sodium carboxymethyl cellulose, carboxypolymethylene, hydroxypropyl methylcelluloses, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, polyethylene glycols and polyethylene oxides, gellan gum, alginate salts, natural polysaccharides, gum arabica, etc. and combinations thereof. Some examples of polyethylene glycols and polyethylene oxides commercially available are those under the tradename Polyox(copyright) (Union Carbide, Danbury, Conn.). Any polymeric material that can hydrate and gel in the presence of water would be a suitable hydrophilic carrier for the pharmaceutical compositions of the present invention.
Preferably, the hydrophilic carrier is hydroxypropyl methylcellulose, preferably having a viscosity between about 5 cps and 100,000 cps, a hydroxypropoxyl content between about 7 and 12%, a methoxyl content between about 19 and 30%.
The molecular weight of the hydrophilic carrier is selected based on the solubility of the active ingredient. Low molecular weight grade hydrophilic carriers are utilized for insoluble drug substances. High molecular weight grade hydrophilic carriers are utilized for soluble drug substances. Preferably, a blend of low and high molecular weight hydrophilic carriers are selected such that any desired molecular weight can be accomplished by adjusting the ratio of the blend.
In another embodiment of the present invention, the hydrophilic carrier is a blend of hydroxypropyl methylcelluloses having different molecular weights and/or viscosities.
Preferably, the ratio of the blend of hydroxypropyl methylcelluloses can vary from 1:99 to 99:1 with respect to low and higher molecular weight of hydroxypropyl methylcelluloses.
Preferably, the hydrophilic carrier in said core is present in a concentration of about 5 to 99% W/W of the weight of the core.
In an embodiment of the present invention, the hydrodynamic diffusion enhancer is a substance which has the inherent capability of drawing water towards it, thereby increasing the rate at which water diffuses through a membrane, then absorbs this water, and swells and increases its volume and creates an internal hydrodynamic pressure.
Preferably, the hydrodynamic diffusion enhancer is selected from the group consisting of gellan gum, starches, clays, celluloses, cellulose derivatives, alginates, crospovidone (Polyplasdone(copyright) and Polyplasdone(copyright) XL (ISP, Wayne, N.J.)), croscarmellose sodium (Ac-Di-Sol(copyright), FMC Corp., Philadelphia, Pa.), sodium starch glycolate (Explotab(copyright), Penwest, Patterson, N.Y.) and combinations thereof. Any excipient which has the inherent capability of drawing water towards it, thereby increasing the rate at which water diffuses through a membrane, then absorbs this water, and swells and increases its volume and creates an internal hydrodynamic pressure would be capable of functioning as a hydrodynamic diffusion enhancer and thus would be a suitable hydrodynamic diffusion enhancer for the pharmaceutical compositions of the present invention.
Preferably, the hydrodynamic diffusion enhancer in said core is present in a concentration of about 5 to 60% W/W of the weight of the core.
In an embodiment of the present invention, the binders are substances which can be used to granulate powders that may not otherwise have adequate flowability characteristics required for the tabletting process.
Preferably, the fillers and binders are each selected from the group consisting of polyethylene glycols, microcrystalline cellulose, lactose, starches, starch derivatives, mannitol, sorbitol, dextrose, sucrose, maltodextrin, celluloses, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or other sugars, polysaccharides and gums, etc. and combinations thereof. Any conventional binder would also be suitable as a binder in the pharmaceutical compositions of the present invention.
Preferably, the fillers in said core are present in a concentration of about 2 to 40% W/W of the weight of the core.
Preferably, the binders in said core are present in a concentration of bout 1 to 10% W/W of the weight of the core.
In an embodiment of the present invention, the lubricants and flow promoters are selected from the group consisting of stearic acid, talc, waxes, stearic acid salts, stearic acid derivatives, sodium stearyl fumarate, corn starch, silica derivatives and combinations thereof.
Preferably, the lubricants in said core are present in a concentration of about 0.25 to 4% W/W of the weight of the core.
In an embodiment of the present invention, the optional seal coating membrane, which is also typically known as a film coat, functions to seal all surface pores and to provide a uniform surface for the next coating step.
Preferably, the optional seal coating membrane is present in a concentration of about 0-5% W/W of the core.
The optional seal coating membrane is obtained by preferably spray coating seal coating dispersions onto the surface of uncoated cores using appropriate coating equipment. Usually these dispersions contain low viscosity hydrophilic polymers such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, and plasticizers such as polyethylene glycol 400. These dispersions are commercially available as Opadry(copyright) Clear and Opadry(copyright) both from Colorcon, West Point, Pa. Similar seal coating dispersions are also available from other suppliers. The seal coating membrane is applied to the surface of an uncoated core to smooth out the surface of the core.
In an embodiment of the present invention, the functional coating membrane is applied on top of the core or on top of the optional seal coating membrane.
Preferably, the functional coating membrane is an aqueous polymeric dispersion comprising dispersed plasticizers, film extenders and diffusion enhancers.
Preferably, the functional coating membrane comprises ethylcellulose as an aqueous dispersion, preferably with appropriate coating ingredients dispersed therein.
Preferably, the ratio of the polymer to film extender in the aqueous polymeric dispersion of the functional coating membrane is from about 0.25-0.75 to 0.99-0.01.
Functional coating membranes are obtained by preferably spraying functional coating dispersions onto the surface of the seal coated cores. However, these functional coating dispersions can also be coated straight onto the surface of the uncoated cores. These functional coating dispersions preferably contain a hydrophobic polymer such as ethyl cellulose, a plasticizer, a film extender/diffusion enhancer, and other excipients such as detackifiers or opacifiers, etc. The hydrophobic polymer is mixed with a film extender/diffusion enhancer to give the hydrophobic polymer some degree of hydrophilicity. The plasticizer is added to reduce the glass transition temperature (Tg) of the polymer so that it can be coalesced at a lower temperature (such as 60xc2x0 C.). The plasticizer also makes the functional coating membrane flexible so that it can stretch to some degree without breaking. Examples of such commercially available aqueous polymeric dispersions suitable for use in the present invention are Surelease(copyright) (Colorcon, West Point, Pa.) and Aquacoat(copyright) (FMC Corp, Philadelphia, Pa.). The plasticizers and film extender/diffusion enhancers are dispersed into the commercially available functional coating dispersions such as Aquacoat(copyright) or Surelease(copyright) and then sprayed onto the surface of the uncoated or seal coated cores. Other functional coating dispersions preferably contain acrylic methacrylic copolymers. Examples of such functional coating dispersions commercially available are Eudragit(copyright) (Rohm Pharma GmbH, Weiterstadt, Germany). Aqueous polymeric dispersions containing acrylic methacrylic copolymers, cellulose acetate and other cellulose derivative polymers can be formulated in to aqueous polymers and used for the same purpose. Similar functional coating dispersions can be prepared with other hydrophilic or lyophilize polymers which would be suitable for this purpose.
Preferably, the functional coating membrane is present in a concentration of about 1-25% W/W of the weight of the core.
In an embodiment of the present invention, the optional top coating membrane allows the functional coating membrane to be coalesced.
Preferably, the optional top coating membrane is an aqueous coating dispersion, and preferably the aqueous coating dispersion is present in a concentration of about 0-5% W/W of the core.
Preferably, the aqueous coating dispersion of the optional top coating membrane further comprises dispersed colours.
The aqueous dispersion of the optional top coating membrane may contain any desirable color to color the tablets.
The optional top coating membrane is obtained by preferably spraying top coating dispersions onto the surface of the functional coating membrane. These top coating dispersions are commercially available as Opadry(copyright) white or Opadry(copyright) red, etc., named after the colorant present in the dispersion. Other equivalent brands of functional coating dispersions commercially available in the market are also suitable.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and
(ii) a functional coating membrane surrounding said core.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a functional coating membrane surrounding said core; and
(iii) a top coating membrane surrounding said functional coating membrane.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core; and
(iii) a functional coating membrane surrounding said seal coating membrane.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane, and
(iv) a top coating membrane surrounding said functional coating membrane.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and
(ii) a functional coating membrane surrounding said core;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a functional coating membrane surrounding said core; and
(iii) a top coating membrane surrounding said functional coating membrane;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core; and
(iii) a functional coating membrane surrounding said seal coating membrane;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane, and
(iv) a top coating membrane surrounding said functional coating membrane;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants; and
(ii) a functional coating membrane surrounding said core wherein the method comprises:
(iii) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(iv) granulating the blend with a binder to obtain a wet mass;
(v) drying the wet mass at 60xc2x0 C. for 3 hours;
(vi) lubricating the granules with a lubricant;
(vii) compressing the lubricated granules to form a core;
(viii) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the core;
(ix) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants;
(ii) a functional coating membrane surrounding said seal coating membrane; and
(iii) a top coating membrane surrounding said functional coating membrane, wherein the method comprises:
(iv) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(v) granulating the blend with a binder to obtain a wet mass;
(vi) drying the wet mass at 60xc2x0 C. for 3 hours;
(vii) lubricating the granules with a lubricant;
(viii) compressing the lubricated granules to form a core;
(ix) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the core;
(x) applying a top coating membrane with aqueous coating dispersions to the surface of the functional coating membrane; and
(xi) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane; wherein the method comprises:
(iv) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(v) granulating the blend with a binder to obtain a wet mass;
(vi) drying the wet mass at 60xc2x0 C. for 3 hours;
(vii) lubricating the granules with a lubricant;
(viii) compressing the lubricated granules to form a core;
(ix) applying a seal coating membrane to the surface of the core to smooth out the surface;
(x) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the seal coating membrane;
(xi) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane; and
(iv) a top coating membrane surrounding said functional coating membrane, wherein the method comprises:
(v) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(vi) granulating the blend with a binder to obtain a wet mass;
(vii) drying the wet mass at 60xc2x0 C. for 3 hours;
(viii) lubricating the granules with a lubricant;
(ix) compressing the lubricated granules to form a core;
(x) applying a seal coating membrane to the surface of the core to smooth out the surface;
(xi) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the seal coating membrane;
(xii) applying a top coating membrane with aqueous coating dispersions to the surface of the functional coating membrane; and
(xiii) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for controlling the duration of the time delay before which the active ingredient is released from the pharmaceutical composition and the duration of release of the active ingredient(s) after such time delay.
The present invention provides pharmaceutical compositions that contain many ingredients which perform many functions. It is the combination of some or all of these ingredients in the pharmaceutical compositions of the present invention that release the desired active ingredient from the pharmaceutical composition with the desired release profile.
The mechanism of release of the controlled onset sustained release pharmaceutical compositions of the present invention described above is as follows:
1) As the dosage form comes into contact with the gastrointestinal fluids, the optional top coating membrane, when present, hydrates and erodes, thus exposing the functional coating membrane to the environment of the gastrointestinal tract. With time, the gastrointestinal fluids hydrate the film extender/diffusion enhancer in the functional coating membrane and create channels which penetrate the functional coating membrane of the dosage form, thus exposing the optional seal coating membrane to the gastrointestinal fluids. The amount of functional coating membrane applied to the core and the ratio of the polymer to film extender/diffusion enhancer in the functional coating membrane may be adjusted to control the rate at which the gastrointestinal fluids penetrate the functional coating membrane. The optional seal coating membrane, when present, hydrates and erodes, thus exposing the core to the gastrointestinal fluids.
2) The hydrodynamic diffusion enhancer in the core promotes the entry of the gastrointestinal fluids into the core by working as a sponge inside the core. When the required amount of gastrointestinal fluid enters the core, the hydrodynamic diffusion enhancer hydrates and begins to swell. The hydrophilic carrier also hydrates and swells during this time and contributes to the hydrodynamic swelling force provided by the hydrodynamic diffusion enhancer. The ratio of the amount of hydrophilic carrier to hydrodynamic diffusion enhancer can be adjusted to control the extent and degree of swelling by the core. The active ingredient also comes into contact with the gastrointestinal fluids and starts to dissolve. While the hydrodynamic diffusion enhancer and the hydrophilic carrier are swelling inside the core, the functional coating membrane surrounding the core prevents release of the active ingredient, resulting in a time delay in the onset of release of the active ingredient from the dosage form. The predetermined time delay can be varied from between about 30 minutes to 6 hours.
3) Upon further swelling, the core stretches and expands the functional coating membrane surrounding the core and helps the active ingredient to permeate through the functional coating membrane and pass out of the dosage form. The rate at which the active ingredient can diffuse out of the dosage form is controlled by the composition of the core and the composition and amount of the functional coating membrane applied to the core. The amount of hydrodynamic diffusion enhancer in the core may be adjusted such that the hydrodynamic swelling force generated by this material and the time required to generate this force are adequate to stretch and expand the functional coating membrane by the end of the required time delay in order to facilitate the release of the active ingredient from the dosage form.
4) Depending upon the composition of the core and the amount of the functional coating membrane applied to the core, the swelling core may generate adequate hydrodynamic swelling force to eventually rupture the functional coating membrane. If and when the functional coating membrane ruptures, it ruptures around the edges of the dosage form. Rupturing in this way may leave the functional coating membrane on the upper and the bottom surfaces of the dosage form intact for an extended period of time. The remaining intact functional coating membrane together with the fully hydrated core control the release of the active ingredient from the dosage form in a substantially zero order fashion for the desired period of time. The release of the active ingredient from the dosage form after the programmed time delay can be varied from a substantially zero order rate of release to a substantially first order rate of release. The sustained release of the active ingredient from the dosage form can be adjusted from between about 6 to 24 hours post the initial programmed time delay.
The pharmaceutical compositions of the present invention have several advantages. The present invention enables persons skilled in the art to manufacture controlled onset and sustained release pharmaceutical compositions using mostly aqueous dispersions and using conventional equipment which are used by most pharmaceutical companies. Thus, the pharmaceutical compositions disclosed in the present invention are essential to deliver active ingredients to humans or animals in an environmentally friendly form, with all of the desired functionality of controlled onset and sustained release, with no risk of adverse side effects from residual solvents.
The controlled onset feature of the present pharmaceutical compositions provide for: a) release of the active ingredient at specific locations along the gastrointestinal tract, or b) colonic release of the active ingredient or c) protection of the stomach from any damage the active ingredient may cause or d) facilitation of high levels of the active ingredient in the blood during any desired time period during the day or night such as, early morning hours to provide maximum protection against heart attacks, or e) the treatment of diseases that occur only in certain portions of the gastrointestinal tract such as ulcerative colitis in the colon, etc.
The sustained release feature of the present pharmaceutical compositions are extremely useful in providing uniform blood levels of active ingredients to obtain a more consistent pharmacological response, reduce peak to trough ratios and thereby reduce the incidence and/or severity of side effects, improve patient compliance, reduce the cost of overall treatment, etc.
Thus, combining both the features of controlled onset and sustained release into a single pharmaceutical composition along with using environmentally friendly manufacturing processes that do not use ozone depleting solvents and/or carcinogenic solvents to produce such a pharmaceutical composition and using conventional manufacturing equipment, the pharmaceutical compositions of the present invention are a significant advancement over the current state of art technology (prior art).

Controlled onset and sustained release dosage forms and the preparation thereof

Abstract: (i) a core comprising:

Abstract: (a) an active ingredient;

Abstract: (b) a hydrophilic carrier;


A heat exchanger includes a plurality of flat tubes, a header collecting tube connected to the flat tubes, and fins joined to the flat tubes. The header collecting tube includes a first partition member partitioning an internal space into upper and lower internal spaces, a second partition member partitioning the upper internal space into first and second spaces, an inflow port formed at a bottom part of the first space, an upper communicating passage, a lower communicating passage. A third partition member partitions the lower internal space into an ascension space and an inflow space. A lower communicating port allows refrigerant to pass from the inflow space to the ascension space. The lower communicating port and the refrigerant passages of the flat tubes that are connected to the lower internal space are arranged so as not to overlap each other as viewed along the longitudinal direction of the flat tubes.

Heat exchangers having a plurality of flat tubes, fins which are joined to the plurality of flat tubes, and header collecting tubes which are coupled respectively to the plurality of flat tubes at a first end side and another end side thereof, for bringing about heat exchange between a refrigerant flowing through the interior the flat tubes and air flowing to the outside of the flat tubes, are known in the prior art.
For example, the heat exchanger disclosed in Japanese Laid-open Patent No. H02-219966 is configured such that a plurality of outflow tubes extending in a horizontal direction are connected at either end to header collecting tubes that respectively extend in a vertical direction.
The heat exchanger disclosed in Japanese Laid-open Patent No. H02-219966 is directed to the problem that, in the interior of the header collecting tubes that extend in the vertical direction, liquid phase refrigerant of high specific gravity collects towards the bottom while gas phase refrigerant of low specific gravity collects towards the top, thereby giving rise to eccentric flow; in order to solve this problem, the feature of forming a throttle inside the header collecting tubes is proposed.
Passing the refrigerant through the throttle formed in this manner facilitates mixing of the gas phase refrigerant and the liquid phase refrigerant, while at the same time improves the flow velocity, making it easy for the refrigerant to reach the top within the header collecting tubes, thereby suppressing eccentric flow of the refrigerant.

Heat exchanger and air conditioning apparatus