Systems and processes for animating an avatar are provided. An example process of animating an avatar includes at an electronic device having one or more processors and memory, receiving text, determining an emotional state, and generating, using a neural network, a speech data set representing the received text and a set of parameters representing one or more movements of an avatar based on the received text and the determined emotional state.

Avatars are used to represent the users of electronic devices. The avatars can represent the appearance of a user or can represent an idealized or completely fictional representation of the user. Avatars can then be associated with a user so that the appearance of the avatar to others triggers an association or link with the user. Avatars can be created and edited for such use, including use in multimedia communications.
In some circumstances, an avatar may be created based on a representation of the user received by an electronic device. However, such creation may be limited to considering only particular representations or inputs, such as video input including the user. Additionally, creating these avatars may require specific types of video inputs or video inputs that include very specific features. Thus, the creation of avatars in this manner may only function when specific circumstances are met, resulting in an incomplete avatar, an avatar that does not accurately represent the user, or no avatar being created. Further, in some instances an animated avatar may be desired when these types of inputs are not available, such as when a user may only supply a textual input. Additionally, current avatars may not adequately provide a desired emotion because the range of motions considered and used to animate the avatar do not include motions used by humans to convey certain emotions.


Integrated photoluminescence (PL)-based chemical and biological sensors are provided comprising a photodetector (PD), a long-pass filter, an excitation source, and a sensing element, all based on thin films or structures. In one embodiment the light source is an organic light emitting device (OLED) and the sensing element is based on thin films or solutions in microfluidic channels or wells. The PD and optical filters are based on thin film amorphous or nanocrystalline silicon and related materials. In another embodiment, sensor components are fabricated on transparent substrates, which are attached back-to-back to generate a compact, integrated structure.

Detection and quantification of analytes are of prime interest in medical, biochemical, analytical chemical, occupational safety, microelectronic, environmental, military, and forensic applications. Electrochemical sensors can be used for these applications. However, electrochemical sensors consume analytes, have long response times, are limited with regard to in vivo use, and are susceptible to poisoning by various contaminants. Optical sensing and probing are alternatives to electrochemical sensors. Various studies on optical methods of analyte detection have been reported in which a dye is immobilized in an analyte-permeable layer. In particular, these studies include sensors whose photoluminescence ("PL") is affected by the analyte. Such affects may include a change in the PL intensity, spectrum, decay time, or polarization.
Commercially available optical sensors typically employ inorganic single crystal III-V compound light-emitting diodes ("LEDs") as the light source. However, the need to incorporate optical components to convey light to the sensor and to collect the PL for readout increases complexity, size, and costs. Thus, single crystal III-V compound inorganic LEDs do not permit simple fabrication of integrated multisensor arrays.
In general, PL-based (bio)chemical sensors include a luminescent sensing element (the PL of which probes the analyte or agent), a light source that excites the PL of that element, a photodetector (PD), a power supply, and the electronics for signal processing. Light sources such as lasers or inorganic LEDs either may be difficult to integrate with the other components due to size, geometrical, or operational constraints, or they involve intricate integration procedures. In addition, they often generate heat, which can damage the sensing element or analyte.
Luminescent chemical and biological sensors detect changes in the PL intensity (IPL) or lifetime (τPL) of the sensing element caused by the analyte. In spite of potential widespread applications, the PD and light sources necessary to excite their PL typically have not been fully integrated with the sensing element. Consequently, the unintegrated devices are relatively bulky, costly, require trained operators, and are limited in their applications. As an example, the current commercial oxygen sensors for remote or local sensing, e.g., Ocean Optics FOXY sensor (see, e.g., www.oceanoptics.com), PreSense, and FCI Environmental Inc. employ GaN LEDs as the light source. The need to incorporate additional components such as optical fibers and their couplers to guide the light back and forth increases the size, cost, and complexity of the unit.
U.S. Pat. No. 6,331,438, the disclosure of which is incorporated by reference herein in its entirety, refers to an exemplary organic light-emitting device ("OLED") excitation source and sensing element for analyte detection. What is needed is further integration of the PD and filters to provide very compact, robust, inexpensive, and autonomous sensors for real world applications, including multianalyte monitoring.

Integrated thin-film sensors and methods

Iowa State University Research Foundation, Inc.


A rail system and transfer vehicle for a storage retrieval system. The rails are fabricated to include a vehicle support surface that supports a transfer vehicle, a load support surface that supports the skid, tote, vessel, or pallet to be stored, a spacing surface that defines the distance between the load support surface and the vehicle support surface. Attached to the load support surface is an alignment surface that extends upwardly at an angle between 40 and 80 from the horizontal. When a misaligned pallet is lowered, it first contacts the alignment surface and as it continues to be lowered, interaction between the alignment surface and the misaligned pallet causes the pallet to move into alignment with the rail system before coming to rest on the load support surface. The rail system can be used in conjunction with a high weight capacity transfer vehicle. Load lift is provided by a plurality of interconnected screw jacks. The screw jacks can be raised, lowered, and precisely controlled by an inverter duty AC gear motor connected to the jacks by a sprocket/chain system.

1. Field of the Invention
The present invention relates to transfer vehicles and support systems used to transfer pallets, totes, skids and the like within a defined storage retrieval system. More particularly, the present invention relates to a system that allows precision movement, placement and replacement of both light and heavy loads in a storage retrieval system.
2. Description of the Related Art
Automated storage retrieval systems are used to retrieve and place loaded and unloaded pallets, totes, skids and the like within a predesigned storage layout. Use of such automated storage retrieval systems reduces materials handling costs by reducing personnel costs and storage floor area while simultaneously increasing flexibility within the system.
For example, in the bakery industry dough is allowed to ferment for specified times in troughs. Stackers and unstackers are used to store and retrieve the troughs in multilevel systems that decrease the floor area needed to handle a given capacity line. Such a system may include a shuttle vehicle and an on board transfer vehicle to provide random access to troughs. The storage retrieval system may be part of a larger system that transports, greases, weighs, degasses and dumps the troughs.
Other types of industrial processes may also require batch processing. For example, a container or pallet may be loaded with a substance requiring low temperature aging for a certain time. Loading the containers or pallets may take place at a loading station. The containers are then transported to a storage area. After a given time in the storage area, the containers are retrieved, transported to an unloading station and the container unloaded. The container may then be transported to a container storage area. Such functions can be highly automated with the assistance of automated storage and retrieval systems.
In order to conserve floor space, it is desirable to store loads in multilevel systems or in grids in which nearly 100% of available floor space can be utilized. If stored in grids, two load carrying devices are commonly used. A transfer vehicle is commonly used to move loads within storage lanes. To move loads between storage lanes, the transfer vehicle, supporting the load, is moved onto a shuttle vehicle that moves in a direction perpendicular to the transfer vehicle. By utilizing two load carrying devices, any location on the grid can be accessed. Such a grid allows high utilization of floor space.
In a grid system having a multitude of pallets supporting loads, pallets are constantly being moved in order to access pallets that are blocked by other pallets. The constant retrieving, moving, and replacement of pallets can be easily monitored by automated systems that keep track of each discrete pallet's location within the grid. A more difficult problem arises from cumulative placement errors that occur because of the constant pallet movement. Cumulative placement errors eventually can cause a pallet to be placed in a position that could cause a subsequent processing failure because of pallet misplacement. For example, if a tote lid must be removed, the tote must be placed within certain location parameters. If not within those parameters, the lid removal system would unable to grasp or remove the lid.
Another difficulty with such grid systems is that the transfer vehicles have relatively low load carrying capacity. Payloads are now limited to about two tons because of the load raising and lowering ability of the transfer vehicles. Many load raising and lowering systems are cam operated but as load requirements increase, cams become larger thus necessitating larger transfer vehicles which increases grid spacing and overall system cost. As increased loads require larger cams, gearboxes and motors must also increase in power and size because of the minimal mechanical advantage in cam drives. Complex hydraulic systems are more difficult and costly to control, are likely to develop leak problems and are more costly to maintain. It is most desirable to have simple systems that require little maintenance.
What is needed is a system that allows precision automated placement, movement and storage of loads. It is also desirable to have larger weight handling capacity in the transfer vehicle than is currently available. Such systems would allow higher load carrying capacity within the grid system and provide unlimited movement and placement of loads within the system without causing improper placement failures in subsequent processing operations.
Shea, U.S. Pat. No. 1,402,257, shows a freight handling apparatus used to raise and lower freight loads. A plurality of threaded rods were connected by a series of sprockets and chains
Although the prior art apparatus solved their specific problems of handling freight, the inventors were not required to address the problem of precision placement or automated load raising and lowering.

Precision placement storage and retrieval system


A radar level gauge system for determining the filling level of a filling material in a tank is disclosed. The system comprises an antenna device for emitting measuring signals towards the surface of the filling material and a receiver device for receiving echo signals from the tank. Further, the system comprises processing circuitry for determining the filling level of the tank based on said echo signal, wherein said processing circuitry is adapted to amplify the received echo signals in dependence of the distance from which the echo signals originates, in such a way that an echo signal from a lower filling level is more amplified than an echo signal from a higher filling level. The processing circuitry is adjustable to optimize the amplification of the echo signal based on the height of the tank.

Radar level gauges are in wide use for making non-contact measurements of the level of products such as process fluids, granular compounds and other materials. These devices utilize antennas to transmit electromagnetic waves toward the material being monitored and to receive electromagnetic echoes which are reflected at the surface of the material being monitored. However, in a practical situation more than one radar echo usually can be seen and the dynamic range for the variation of all possible echoes is quite large.
However, a problem experienced in this type of level gauges is that the signal strength from a surface echo reduces as a function of measured distance. Typically, the signal strength reduces by 50% if the distance is doubled. As a consequence, the dynamic range in the receiver part is not optimally used. One method known in the art to compensate for this loss of signal strength is to amplify the received signal with a magnitude which is increased as a function of distance, so called IF-gain. Further, many radar level gauge systems have to work under low current and voltages and should preferably use low cost components. Thus, many of the classical methods for increased dynamic range may not be employable.
In order to solve the above-related problem, it has been proposed to increase the signal strength of the received signals in dependence of the distance from which the echoes originates. For example, U.S. Pat. No. 6,031,421 discloses a pulsed system for radar level gauging using sensitivity time control (STC), where the amplification in the receiver is controlled to provide a exponential gain with increased distance. U.S. Pat. No. 6,107,957 discloses a FMWC (frequency modulated continuous wave) radar level gauge using a similar amplification gain-control in order to provide an amplification inversely proportional to the distance from which the echoes originate.
However, a problem with these known systems is that they are relatively insensitive and static, and unable to adapt to the specific conditions related to the tank in which they are to be used, Specifically, the known systems are conventionally dimensioned for a maximal measuring distance, e.g. 30 meters. However, in practical use the tanks are of varying height, whereby non-optimal amplification is provided.
Still further, most known systems have problems related to the noise level, due to the increased noise level generated by the amplification. This is particularly disadvantageous in measuring systems subjected to high noise levels.
It is therefore a need for a more effective amplification control for use in level gauging.

Automatic sensitivity control for radar level gauges

Abstract: A corresponding processing circuitry and method of operation is also disclosed.


A seatbelt retractor reduces the temporary weight during seatbelt withdrawal to increase an occupant's comfort. When a seatbelt is not being worn by an occupant (off), projections of an internal gear are placed in a circumferential center between adjacent projections by the spring force of springs. When a spool rotates in the belt withdrawing direction, the internal gear also rotates in the belt withdrawing direction. This arrangement disables a reduction mechanism's power transmission to cut off the direct connection between the spool and electric motor connected to a sun gear to reduce the temporary weight during withdrawal of the seatbelt. When the internal gear rotates at a predetermined angle, the projections come into contact with the projections to thereby stop the rotation of the internal gear. This enables the power transmission of the reduction mechanism, whereby the spool and electric motor are brought into direct connection via the reduction mechanism.

The present invention relates to a seatbelt retractor and a seatbelt system having the same installed in vehicles such as cars, in which the retractor retracts and withdraws the seatbelts by the rotation of a spool with the driving force of a motor and is used for restraining occupants with seatbelts to protect occupants.
Seatbelt systems installed in vehicles such as cars restrain occupants with seatbelts in an emergency in which high deceleration is applied to vehicles, such as a vehicle crash, to prevent the inertial movement of the occupants from seats, thereby protecting the occupants. The seatbelt systems have a seatbelt retractor that retracts and withdraws a seatbelt with a spool and stops the withdrawal of the seatbelt in an emergency.
PCT Japanese Translation Patent Publication No. 2003-507252 ("JP Pub. No. '252") discloses a seatbelt retractor that retracts and withdraws a seatbelt with an electric motor, which is incorporated by reference herein in its entirety. In the seatbelt retractor disclosed in JP Pub. No. '252, an electric motor is disposed in series coaxially with a belt reel (hereinafter, also referred to as a spool) on one axial side of the belt reel, in which the rotation of the electric motor is transmitted to the belt reel while being reduced in speed by a reduction mechanism including a planetary reduction gear mechanism. As the belt reel is rotated by the rotation of the electric motor in a belt retracting direction or a belt withdrawing direction, the seatbelt is retracted by or withdrawn from the belt reel.


In an implantable medical device having an electrical lead coupled to tissue of a user and a circuit for measuring the impedance of the lead, a method and apparatus for responding to impedance variations in the lead which includes measuring the impedance of the lead while monitoring physiologic parameters of the user, detecting the presence or absence of electromagnetic interference, and if the impedance of the lead is out-of-range, determining whether the electromagnetic interference exceeds a predetermined value, and if the electromagnetic interference exceeds a predetermined value, administering a therapy to the tissue of the user.

Implantable medical devices (IMDs) have many functions including the delivery of therapies to cardiac patients, neuro-stimulators, muscular stimulators, and others. For purposes of this application reference will be made only to implantable cardiac devices, it being understood that the principles herein may have applicability to other implantable medical devices as well.
An implantable cardiac device (ICD) may be a device commonly referred to as a pacemaker, which is used to stimulate the heart into a contraction if the sinus node of the heart is not properly timing, or pacing, the contractions of the heart. Modern cardiac devices also perform many other functions beyond that of pacing. For example, some cardiac devices may also perform therapies such as defibrillation and cardioversion as well as providing several different pacing therapies, depending upon the needs of the user and the physiologic condition of the user's heart. For convenience, all types of implantable cardiac devices will be referred to herein as ICDs, it being understood that the term, unless otherwise indicated, is inclusive of an implantable device capable of administering any of a number of therapies to the heart of the user.
In typical use, an ICD is implanted in a convenient location usually under the skin of the user and in the vicinity of the one or more major arteries or veins. One or more electrical leads connected to the pacemaker are inserted into or on the heart of the user, usually through a convenient vein or artery. The ends of the leads are placed in contact with the walls or surface of one or more chambers of the heart, depending upon the particular therapies deemed appropriate for the user.
One or more of the leads is adapted to carry a current from the pacemaker to the heart tissue to stimulate the heart in one of several ways, again depending upon the particular therapy being delivered. The leads are simultaneously used for sensing the physiologic signals provided by the heart to determine when to deliver a therapeutic pulse to the heart, and the nature of the pulse, e.g., a pacing pulse or a defibrillation shock.
The sensing of the physiologic signal from the heart requires a very sensitive sensing method since the signals sensed are of quite low amplitude. The presence of external, or non-physiologic, electromagnetic interference (EMI), if the field is large enough, can compromise the cardiac sensing function such that the pacemaker may fail to deliver a needed therapy or may deliver an unwanted therapy. Some types of non-physiologic EMI, such as continuous wave at high frequencies, can easily be distinguished from physiologic signals and can thus be ignored or rejected by the pacemaker circuitry. Other forms of non-physiologic EMI, however, are not easily distinguishable from physiologic signals and therefore can block or override the desired physiologic signals.
Many state-of-the-art ICDs are capable of performing either bipolar or unipolar sensing and pacing in either chamber of the heart. Unipolar pacing requires an elongated lead having only one insulated conductor therein and only one generally distal electrode disposed thereon. In most unipolar configurations the protective canister of the ICD is conductive and functions as an electrode in pacing or sensing. For bipolar pacing and/or sensing a lead having two mutually insulated conductors disposed thereon is required. Typically, one electrode is disposed at the distal end of the lead and is referred to as the "tip" electrode, while the second electrode is spaced somewhat back from the distal end of the lead and is referred to as the "ring" electrode. The current path for bipolar pacing extends from the pulse generator in the ICD, along a first of the two lead conductors to the tip electrode, through the cardiac tissue to the ring electrode and back to the ICD along the second of the two conductors.
Most modern ICDs may be programmed to pace and sense in either the bipolar or unipolar mode. This gives the implanting physician considerable flexibility in configuring an ICD system to suit the particular needs of a given patient or user. Additionally, if one of the two leads in a bipolar ICD were to fail for some reason, (e.g., breakage of a conductor due to metal fatigue, an open outer coil, an ineffective ring set screw connection, poor connections, tissue degradation at the electrode site, oxidation, etc.) it would be necessary to reprogram the ICD into unipolar pacing and sensing mode in order for the ICD to continue to perform properly.
In order to detect the failure of a lead in a bipolar ICD unit the impedance of the leads is monitored continuously and, in the event an impedance is detected that is outside a specified range, the ICD is automatically switched to unipolar pacing and sensing until the problem can be rectified. The switch can take several tens of seconds, however, because the impedance measurement must be confirmed by a series of readings before the switch is made. During this time, no pulses are provided, which results in less than optimal therapy. The delay is necessary because a high impedance reading may be caused by electromagnetic interference (EMI). In such cases an out-of-range impedance may be detected when no lead failure has occurred.
Accordingly, it is desirable provide a mechanism and method such that therapy can continue in the event of an out-of-range impedance measurement
Other desirable features and characteristics of the present invention will become apparent from the subsequent detailed description of the invention and the appended claims, taken in conjunction with the accompanying drawings and this background of the invention.

Impedance measurement in implanted device


Estimated value ratings for electronic messages such as email may be generated by scraping the content of the email and comparing the scraped content to characteristics of a prospective recipient. The recipient may also provide an actual value rating which may be compared to the estimated value rating. The recipient may also provide a desired value rating which may be compared with the estimated value rating. More effective electronic message marketing may thereby be provided for both senders and recipients.

Online buying and selling of products and services over computer networks, such as the Internet, have continued to proliferate with widespread Internet usage. In order to facilitate the sale of products and services, online sellers of products and services often design marketing campaigns wherein a given campaign message, such as an email, text message and/or instant message, is sent to a given set of recipients.
With the proliferation of email marketing, an industry of Email Service Providers (ESPs) has emerged. An ESP is an entity that provides email marketing or bulk email services. An ESP may provide tracking information showing the status of email sent to each member of an address list. ESPs also often provide the ability to segment an address list into interest groups or categories, allowing a sender to send targeted information to recipients who they believe will value the email. ESPs typically upload subscriber lists from senders for distributing email messages. The lists may be enhanced with custom fields in order to hold additional information for each subscriber for filtering and targeted messaging purposes. A sending engine also may be provided to allow senders to distribute their messages to the subscribers via the ESP.


A retention housing having a housing body is provided, the retention housing configured to be mounted to a substrate. At least one, such as a plurality of cables can be electrically connected to a respective surface of the substrate to which the retention housing is mounted. When the retention housing is mounted to the respective surface of the substrate, at least a portion of the at least one cable can be compressed between a ground element supported by the respective surface of the substrate and a corresponding upper wall of the housing body, such that the at least one cable is placed into electrical communication with a ground plane defined by the substrate.

Cable assemblies can be used to electrically connect one electrical component to another electrical component. For instance, high speed signal cables can be electrically connected to a substrate to construct a plug type electrical connector configured to be mated to a complementary receptacle connector. In connecting high speed signal cables to a substrate, insulating layers of the cable may be removed thereby exposing signal conducts. These exposed signal conductors may result in electromagnetic interference, such as cross talk. Mitigating such electromagnetic interference is desirable.


An apparatus controls a main display and a sub-display. The apparatus includes a section which displays, on the sub-display, clock information indicating of time, a section which acquires changed time information, when the time information has been changed, and a section which changes a present value of the time of the clock information displayed on the sub-display, based on the acquired changed time information.

1. Field of the Invention
The present invention relates to an information-processing apparatus, and a clock information display control method for use in the information-processing apparatus.
2. Description of the Related Art
In general, in an information-processing apparatus such as a personal computer, an operating system manages various system information items. As one of such system information items, system time information such as "time and date" is known. The management of system time information by the operating system facilitates time management of various data items, represented by the management of the date and time of file creation.
Specifically, the operating system manages system time information and the time zone of the computer, thereby displaying, for example, the present time in the form of a clock on the desk top screen of the computer, and managing the date and time of file creation using the system time information. A user can change the date and time of the system time information managed by the operating system, when necessary. Further, when the user has designated a time zone, the operating system automatically sets and manages the data and time corresponding to the designated zone.
However, the present time displayed as a clock on the display screen by the operating system cannot be seen before the operating system has booted up. Further, in a laptop type or notebook type personal computer, the display screen cannot be seen even after the system has booted up, if the display is closed, and accordingly the clock on the display screen cannot be seen.

Information-processing apparatus and clock information display control method for use in the apparatus


A method for joining records from database tables is proposed. Join attributes are ordered into a sequence S0, and a scope C is initialized to empty. Tables including a join attribute A that is first in S0 are identified. A new sequence S′ omits A from S0. Iteration through each identified table proceeds in join attribute A order. The iteration utilizes a tree index structure for each identified table where the index key includes all join attributes in the identified table in S0 order. For each matched value v of the join attribute located during the iterating, a new scope Cv is created by appending “A=v” to the scope C. If S′ is empty, a tuple corresponding to the scope Cv is output. Otherwise, S0 is set to S′ and for each scope Cv, C is set to Cv and the steps beginning with the identifying step are recursively invoked.

The present invention relates generally to database operations, and, more specifically, to join operations on relational database tables.
Database management systems make it possible for users to store and update large collections of information, while also supporting queries over that information. Combining data from several tables is a fundamental operation used by relational database management systems when performing database queries. In a join operation, one or more conditions specify how rows in each participating table should be related in order to generate a query result. Though the output of a join operation may be further processed to generate a query result, the cost of the join operation(s) is typically dominant in terms of both time and space. Several algorithms have been proposed for implementing joins including sort-merge join, nested-loop join, index-nested-loop join, and hash join. These algorithms are typically used to join two tables at a time, with more complex join queries broken down into a sequence of pairwise joins.


A steering knuckle to be used with the steering assembly of a vehicle such as a farming tractor is disclosed. The steering knuckle comprises preconfigured attachment areas where attachment element(s) or bracket(s) can be releasably yet rigidly secured. The attachment areas may be further reinforced with additional knuckle material (e.g. metal, metallic alloy). The steering knuckle therefore provides predetermined and preconfigured attachment location(s) where a wheel-replacing track system can be secured, thereby allowing the track system to be mounted to the vehicle while avoiding attachment at inconvenient or weak locations.

Soil compaction and floatation have always been important issues for farmers operating tractors and other farming vehicles in their fields. It has thus been found advantageous to replace two or even all four wheels of a farming tractor with track systems which use endless traction bands instead of wheels for propulsion.
Using track systems instead of wheels brings several advantages when operated on soft terrains. The larger surface area of the traction bands improves the floatation and reduces soil compaction. The configuration of the track systems also generally improves the overall traction of the tractor.
However, tractors are still typically sold with wheels and are typically configured to be operated with wheels. Hence, when an operator wants to replace the wheels of its tractor with track systems, the track systems must be properly fitted to the model of tractor of the operator. However, as track systems are typically aftermarket products, track system manufacturers must generally manufacture attachment brackets made specifically for each model of tractors, or more generally, for each model of vehicles, to which the track systems can be installed. However, having to manufacture specific attachment brackets for each model of tractors can be quite expensive.
Furthermore, tractors are typically not configured to be equipped with track systems. Hence, mounting track systems to a tractor generally necessitates the attachment of the track systems to the tractor at locations which, in some case, were not initially designed to support and sustain the additional load and strain imparted by the track systems during use.
This is true of track systems installed as replacement of steerable wheels, typically the front wheels, since the track systems need to remain steerable. Hence, the installation generally involves the attachment of the track systems to or near the steering knuckles (e.g. to the wheel hubs, to the bolts holding the kingpin, etc.).
However, as the steering knuckles of a tractor are generally not made nor configured to support track systems, these installations may, in some cases, cause premature wearing of steering components of the tractor or even premature failure of those components. These installations can also cause premature wearing of components of the track systems (i.e. the traction band, road wheels, idler wheels, etc.) due, for instance, to misalignment between the track systems and the vehicle.
Hence, despite the advantages of using track systems on farming tractors and other vehicles, there are still some shortcomings that need to be addressed.


Modulation of neural signaling of a branch of the GSN supplying the adrenal gland can regulate the secretion of signaling molecules from the adrenal medulla. In particular, epinephrine, norepinephrine and enkephalin release can be independently regulated.

The adrenal medulla is a primary output of the sympathetic nervous system. It is composed of a highly vascularized cluster of neuroendocrine adrenal chromaffin cells. Upon stimulation through the sympathetic splanchnic nerve, the adrenal chromaffin cells release multiple signaling molecules into the systemic circulation. Examples of the signaling molecules are the regulatory hormones including the catecholamines (e.g. epinephrine (Epi) and norepinephrine (NE)) as well as a host of neuro- and vasoactive peptide transmitters (e.g. enkephalin) (Habib et al., 2001). Together these signaling molecules regulate multiple processes that prepare the body for defense or escape under the acute sympatho-adrenal stress response.
Under homeostatic physiological conditions, the sympathetic nervous system fires at a baseline rate, setting the basal sympathetic tone and working in concert with the parasympathetic nervous system to place the organism into a 'rest and digest' status of energy storage. Under these conditions, adrenal chromaffin cells release modest amounts of catecholamine into the circulation to help regulate physiological functions including shunting of blood to viscera, increasing enteric activity and maintaining basal heart rate.
Emotional or psychological stress, injury or environmental insult initiates the sympathetic 'fight or flight' stress response, leading to a surge in serum catecholamine levels. Thus, perception or even anticipation of danger or harm (anxiety), trauma, pain, hypovolemia from hemorrhage or fluid loss, hypotension, anoxia, extremes of temperature, hypoglycemia, and severe exercise can cause rapid secretion of catecholamines. Under these conditions, NE is released from postganglionic sympathetic nerves throughout the periphery as well as from the adrenal medulla, while Epi is exclusively released from the adrenal medulla (Marley & Prout, 1965; Goldstein et al., 1983; Carmichael & Winkler, 1985; Habib et al., 2001). Specific physiological responses to acute stress, and their signaling molecules from the adrenal medulla, include generalized analgesia (enkephalin), increased cardiac output, blood pressure and blood flow to skeletal muscle (catecholamines, atrial natriuretic factor, neuropeptide Y), elevated blood glucose (epinephrine, pancreastatin) and, under extreme injury or shock, an anti-clotting activity (tissue-type plasminogen activator).
The mechanism for the stressor-dependent segregated release of signaling molecules secreted from the adrenal medulla is not understood. Independent regulation of the secretion of signaling molecules from the adrenal gland, especially those from the adrenal medulla, would be useful in therapeutics. It is therefore an object of the invention to modulate adrenal medullary secretion, such as regulating the independent secretion of NE, Epi and enkephalin.
The invention also aims to modulate adrenal medulla output in a way that has minimal impact on basal body function.
The invention also aims to assist in treating conditions associated with impaired control of adrenal medullary secretion, such as impaired catecholamine and/or enkephalin control.
The invention also aims to treat a subject who suffers from, or is at risk of, pathological stress, e.g. by suppressing the catecholamine surge.


MOS Transistors and bipolar junction transistors are connected to input pads and output pads for implementing electrostatic discharge protection. By conducting a power clamp circuit and applying a substrate-trigger technology, electrostatic discharge protection is further enhanced. For instance, positive ESD stress protection can be enhanced between signal pads (input pads and output pads) and VSS by using NMOS transistors and field oxide devices. Negative ESD stress protection can be enhanced between signal pads and VDD by using PMOS transistors.

1. Field of the Invention
The present invention relates to an integrated circuit, and more particularly, to an integrated circuit with an electrostatic discharge protection circuit.
2. Description of the Prior Art
Generally, electrostatic discharge (ESD) stress testing for integrated circuits (ICs) include pin-to-pin testing modes, such as a positive-to-VSS (PS) mode, a negative-to-VSS (NS) mode, a positive-to-VDD (PD) mode and a negative-to-VDD (ND) mode, and a testing mode between power pins, such as a VDD-to-VSS (DS) mode. Take the PS mode for example. A positive ESD stress is applied to an input pin to be tested so as to discharge a VSS pin connected to ground while a VDD pin and other pins are floating.
For complementary metal-oxide semiconductor (CMOS) integrated circuits, components for ESD protection circuits can be diffusion or poly-resistors, diodes with p-n junction, MOS transistors, field-oxide devices, bipolar junction transistors, or SCR devices with p-n-p-n structure. However, these components have different properties and thereby have different ESD protection capabilities.
Please refer to FIG. 1, which is an input ESD protection circuit in an integrated circuit 1 based on the prior art. The IC 1 comprises an input pad (I/P) 16, an input resistor R1, an internal circuit 13, a power clamp circuit 14, and an input ESD protection circuit. The input ESD protection circuit comprises two parasitical resistances R2, R3, an N-type metal oxide semiconductor (MOS) transistor 22 and a PMOS transistor 24, so that ESD protection is formed between the input pad 16 and VDD and between the input pad 16 and VSS. The power clamp circuit 14 is an ESD protection between VDD and VSS.
The input ESD protection circuit of FIG. 1 utilizes a gate-grounded NMOS transistor and a gate-grounded PMOS transistor, generating a protection circuit for two-way protection. It can provide a good performance for ESD protection, but triggering voltages for transistors are significantly high.
Pleaser refer to FIG. 2, which is an input ESD protection circuit in an integrated circuit 2 based on the prior art. The input ESD protection circuit of the IC 2 comprises two diodes 26, 28 so as to form ESD protection between the input pad 16 and VDD and between the input pad 16 and VSS.
For example, since a forward-biased diode has a working voltage (about 0.8 to 1.2 volts) far smaller than that (about −13 to −15 volts) of a reverse-biased diode, heat generated by the forward-biased diode is accordingly far smaller than that of the reverse-biased diode if ESD currents flowing through these two diodes are equal. The forward-biased diode has an ESD protection capability far superior to that of the reverse-biased diode if their sizes are equal. A diode that an ESD protection circuit comprises is usually forward-biased. Therefore, it only provides a one-way ESD protection circuit with lower ESD protection capability than that of FIG. 1.
Please refer to FIG. 3, which is an input ESD protection circuit in an integrated circuit 3 based on the prior art. The input ESD protection circuit of the IC 3 comprises two NMOS transistors 32, 34, and a parasitical substrate resistance Rsub to form the ESD protection circuit.
In FIG. 3, the prior art adopts a substrate-triggered technology to improve the performance of ESD protection. As shown in FIG. 3, the transistor 34 is made to be in the breakdown situation to trigger a body terminal of the transistor 32 to be turned on, so that the ESD current can be bypassed through the transistor 32. However, the drawback is that the triggering voltage of the transistor 34 in the breakdown situation is high.
Please refer to FIG. 4, which is an input ESD protection circuit in an integrated circuit 4 based on the prior art. The input ESD protection circuit of the IC 4 comprises two NMOS transistors 44, 42, a resistor 46, a capacitor 48, and a parasitical substrate resistance Rsub to form the ESD protection circuit.
In FIG. 4, the prior art utilizes the resistor 46 and the capacitor 48 to charge and discharge. As shown in FIG. 4, the transistor 44 is turned on earlier so as to bypass the ESD current. Since the charge/discharge time depends on values of the resistor 46 and the capacitor 48, high loading at the input pad 16 results and performance for high-speed data access is reduced.

Integrated circuit with an electrostatic discharge protection circuit


Disclosed is an imaging member comprising a conductive substrate, a photogenerating layer comprising a photogenerating material in contact with the substrate, and a charge transport layer in contact with the photogenerating layer, the charge transport layer comprising a charge transport material, a polymer containing carboxylic acid groups or groups capable of forming carboxylic acid groups, and a hydroquinone antioxidant, wherein the photogenerating layer is situated between the charge transport layer and the conductive substrate.

Disclosed herein are improved photosensitive imaging members. More specifically, disclosed herein are imaging members exhibiting improved electrical and photodischarge properties and improved lateral charge migration resistance. One embodiment is directed to an imaging member comprising a conductive substrate, a photogenerating layer comprising a photogenerating material in contact with the substrate, and a charge transport layer in contact with the photogenerating layer, said charge transport layer comprising a charge transport material, a polymer containing carboxylic acid groups or groups capable of forming carboxylic acid groups, and a hydroquinone antioxidant, wherein the photogenerating layer is situated between the charge transport layer and the conductive substrate.
The formation and development of images on the surface of photoconductive materials by electrostatic means is well known, and is commonly referred to, variously, as electrophotography, xerography, electrophotographic imaging, electrostatographic imaging, and the like. The basic electrophotographic imaging process, as taught by C. F. Carlson in U.S. Pat. No. 2,297,691, entails placing a uniform electrostatic charge on a photoconductive imaging member (also commonly referred to as a photoreceptor), which can be in the form of a plate, drum, belt, or any other desired form, exposing the imaging member to a light and shadow image to dissipate the charge on the areas of the imaging member exposed to the light, and developing the resulting electrostatic latent image by depositing on the image a finely divided electroscopic material known as toner. In the Charge Area Development (CAD) scheme, the toner will normally be attracted to those areas of the imaging member which retain a charge, thereby forming a toner image corresponding to the electrostatic latent image. In the Discharge Area Development (DAD) scheme, the toner will normally be attracted to those areas of the imaging member which are uncharged, thereby forming a toner image corresponding to a negative of the electrostatic latent image. The developed image can then be transferred to a substrate such as paper. The transferred image can subsequently be permanently affixed to the substrate by heat, pressure, a combination of heat and pressure, or other suitable fixing means such as solvent or overcoating treatment.
Photoreceptor materials comprising inorganic or organic materials wherein the charge generating and charge transport functions are performed by discrete contiguous layers are known. Additionally, layered photoreceptor members are disclosed in the prior art, including photoreceptors having an overcoat layer of an electrically insulating polymeric material. Other layered photoresponsive devices have been disclosed, including those comprising separate photogenerating layers and charge transport layers as described in U.S. Pat. No. 4,265,990, the disclosure of which is totally incorporated herein by reference. Photoresponsive materials containing a hole injecting layer overcoated with a hole transport layer, followed by an overcoating of a photogenerating layer, and a top coating of an insulating organic resin, are disclosed in U.S. Pat. No. 4,251,612, the disclosure of which is totally incorporated herein by reference. Examples of photogenerating layers disclosed in these patents include trigonal selenium and phthalocyanines, while examples of transport layers include certain aryl diamines as illustrated therein.
In addition, U.S. Pat. No. 3,041,167 discloses an overcoated imaging member containing a conductive substrate, a photoconductive layer, and an overcoating layer of an electrically insulating polymeric material. This member can be employed in electrophotographic imaging processes by initially charging the member with an electrostatic charge of a first polarity, followed by exposing it to form an electrostatic latent image that can subsequently be developed to form a visible image.
Additional conventional photoreceptors and their materials are disclosed in, for example, U.S. Pat. Nos. 5,489,496, 4,579,801, 4,518,669, 4,775,605, 5,656,407, 5,641,599, 5,344,734, 5,721,080, 5,017,449, 6,200,716, 6,180,309, and 6,207,334, the disclosures of each of which are totally incorporated herein by reference.
U.S. Pat. No. 7,267,917 (Tong et al.), the disclosure of which is totally incorporated herein by reference, discloses a charge transport layer composition for a photoreceptor including at least a binder, at least one arylamine charge transport material, e.g., N,N′-diphenyl-N,N′-bis(3-methylphenyl)-(1,1′-biphenyl)-4,4′-diamine, and at least one polymer containing carboxylic acid groups or groups capable of forming carboxylic acid groups. The charge transport layer forms a layer of photoreceptor, which also includes an optional anti-curl layer, a substrate, an optional hole blocking layer, an optional adhesive layer, a charge generating layer, and optionally one or more overcoat or protective layers.
While known materials and devices are suitable for their intended purposes, a need remains for improved photosensitive imaging members. For example, it is desirable to increase the surface discharge speed of the photoreceptor to allow for higher speed printing applications. It is also desirable to minimize any Lateral Charge Migration (LCM) and to minimize changes in the electrical characteristics of the photoreceptor during prolonged electrical cycling. Lateral charge migration is the movement of charges on or near the surface of an almost insulating photoconductor surface, and has the effect of smoothing out the spatial variations in the surface charge density profile of the latent image. It can be caused by a number of different substances or events, such as ionic contaminants from the environment, naturally occurring charging device effluents, and the like, which cause the charges to move. LCM can occur locally or over the entire photoconductor surface. As a result, some of the fine features present in the input image may not be present in the final print. Increasing the print speed without changing the print engine architecture reduces the time from the exposure stage to the development stage, which reduces the time available for the photoreceptor's surface to discharge. If the charges are still in transit, a higher surface voltage on the photoreceptor remains during development, which consequently has a negative impact on print quality. To solve this problem, high discharge rate charge transport molecules have been tested in the hopes of enabling increased print speeds. N,N,N′N′-Tetra(4-methylphenyl)-(1,1′-biphenyl)-4,4′-diamine is one example of a high discharge rate charge transport molecule. High discharge rate charge transport molecules, however, also tend to exhibit undesirably high lateral charge migration, and attempts at reducing the LCM tend to entail some decrease of discharge rate to improve LCM. It would be highly desirable to reduce LCM while either leaving discharge rate unchanged or improving discharge rate.
As used herein, "discharge rate" refers to the voltage drop over time and is based upon a discharge over a discharge interval at a given light intensity, wherein discharge is defined as the voltage drop or difference between the initial surface voltage before light exposure and the surface voltage after light exposure at the end of the discharge interval. Discharge interval is defined as the time period from the light exposure stage to the development stage (which is essentially the time available for the photoreceptor surface to discharge from an initial voltage to a development voltage) and light intensity is defined as the intensity of light used to generate discharge in the photoreceptor. The exposure light intensity influences the amount of discharge, and increasing or decreasing light intensity will respectively increase or decrease the voltage drop over a given discharge interval.

This patent is subject to a terminal disclaimer.


A multiple piece turbine airfoil having an outer shell with an airfoil tip that is attached to a root with an internal structural spar is disclosed. The root may be formed from first and second sections that include an internal cavity configured to receive and secure the one or more components forming the generally elongated airfoil. The internal structural spar may be attached to an airfoil tip and place the generally elongated airfoil in compression. The configuration enables each component to be formed from different materials to reduce the cost of the materials and to optimize the choice of material for each component.

Typically, gas turbine engines include a compressor for compressing air, a combustor for mixing the compressed air with fuel and igniting the mixture, and a turbine blade assembly for producing power. Combustors often operate at high temperatures that may exceed 2,500 degrees Fahrenheit. Typical turbine combustor configurations expose turbine vane and blade assemblies, to these high temperatures. As a result, turbine airfoils, such as turbine vanes and blades must be made of materials capable of withstanding such high temperatures. In addition, turbine airfoils often contain internal cooling systems for prolonging the life of the airfoils and reducing the likelihood of failure as a result of excessive temperatures.
Typically, turbine airfoils, such as turbine blades are formed from an elongated portion having one end configured to be coupled to an inner rotor assembly. The airfoil is ordinarily composed of a leading edge, a trailing edge, a suction side, and a pressure side. The inner aspects of most turbine airfoils typically contain an intricate maze of cooling circuits forming a cooling system. The cooling circuits in the airfoils receive air from the compressor of the turbine engine and pass the air through the root of the blade that is attached to the rotor assembly. The cooling circuits often include multiple flow paths that are designed to remove heat from the turbine airfoil. At least some of the air passing through these cooling circuits is exhausted through orifices in the leading edge, trailing edge, suction side, and pressure side of the airfoil. While much attention has been paid to cooling technologies, hot spots still occur in the airfoils. In turn, the conventional monolithic airfoils are configured to accommodate the highest heat loads on the airfoil. Typical materials capable of handling the high heat loads of the exhaust gases are often expensive and present manufacturing challenges.

Multiple piece turbine engine airfoil with a structural spar


A method is provided for delaying the onset of ejaculation in an individual. The method involves systemic and on demand administration to an individual of a pharmaceutical formulation containing an amount of an active agent selected from the group consisting of clomipramine and pharmacologically acceptable acid addition salts thereof. Drug delivery may be accomplished via any route designed to provide systemic levels of the active agent effective to delay the onset of ejaculation. Pharmaceutical formulations and dosage forms are provided as well.

This invention relates generally to methods and pharmaceutical compositions for treating sexual dysfunction; more particularly, the invention relates to treatment of premature ejaculation, preferably by on demand administration of clomipramine or a pharmacologically acceptable acid addition salt thereof.
Premature ejaculation is a debilitating sexual dysfunction. This dysfunction can lead to an inability to enter or sustain relationships and can cause psychological damage to sufferers. Premature ejaculation can also impair reproductive success.
Previous methods of treating premature ejaculation included psychological therapies, topical anesthetics and the use of devices (U.S. Pat. Nos. 5,535,758, 5,063,915, 5,327,910, and 5,468,212). All of these methods have significant drawbacks. Psychological therapies benefit only a subset of patients and require specialized therapists who may not be available to all patients, particularly in remote areas. Furthermore, psychological therapies cannot alleviate premature ejaculation resulting from non-psychological causes. Anesthetic agents decrease sensitivity of tissues, thereby diminishing sexual pleasure. Also, topical anesthetics can be transferred to sexual partners and thereby decrease their sensitivity and pleasure as well. With regard to devices, these can be awkward, inconvenient and embarrassing to use. Devices are highly conspicuous, and reveal the very condition which the suffering partner may prefer to conceal. Additionally, devices can cause irritation to one or both partners.
Methods for treating premature ejaculation by systemic administration of several different pharmacologically active compounds have been described (U.S. Pat. Nos. 4,507,323, 4,940,731, 5,151,448, 5,276,042 and 5,707,999; PCT Publication No. WO 95/13072). However, these drugs may not be effective for all patients, and the side effects of these drugs can halt treatment or impair patient compliance. Disease states or adverse interactions with other drugs may contraindicate the use of these compounds or require lower dosages that may not be effective to delay the onset of ejaculation. In addition, many drugs must be administered chronically or at times that are inconvenient.
Oral administration of the antidepressant fluoxetine has been claimed to treat premature ejaculation. However, the administration of fluoxetine has many undesired aspects. U.S. Pat. No. 5,151,448 describes administration of fluoxetine on a daily basis which, according to many clinicians, presents a compliance issue as patients often miss or forget to take their dose. In addition, patients with hepatic or renal impairments may not be able to use fluoxetine due to its metabolism in the liver and excretion via the kidney. Systemic events during oral fluoxetine treatment involving the lungs, kidneys or liver have occurred, and death has occurred from overdoses. In addition, side effects of oral fluoxetine administration include hair loss, nausea, vomiting, dyspepsia, diarrhea, anorexia, anxiety, nervousness, insomnia, drowsiness, fatigue, headache, tremor, dizziness, convulsions, sweating, pruritis and skin rashes. Fluoxetine interacts with a range of drugs, often by impairing their metabolism by the liver.
U.S. Pat. No. 4,940,731 describes the oral or parenteral administration of sertraline on a daily basis for treating premature ejaculation. It has been recognized that sertraline shares many of the same problems as fluoxetine; see Martindale, The Extra Pharmacopoeia, 31st edition, at p. 333 (London: The Royal Pharmaceutical Society, 1996). Sertraline is metabolized in the liver, and is excreted in the urine and feces. Thus, patients with cirrhosis must take lower doses, and caution must be exercised when administering sertraline to patients with renal impairment. Individuals taking monoamine oxidase inhibitors cannot take sertraline due to the risk of toxicity, leading to memory changes, confusion, irritability, chills, pyrexia and muscle rigidity. Side effects resulting from oral sertraline administration include nausea, diarrhea, dyspepsia, insomnia, somnolence, sweating, dry mouth, tremor and mania. Rare instances of coma, convulsions, fecal incontinence and gynecomastia have occurred in patients undergoing sertraline therapy.
U.S. Pat. No. 5,276,042 describes daily administration of paroxetine for the treatment of premature ejaculation. Paroxetine is predominantly excreted in the urine, and decreased doses are recommended in patients with hepatic and renal impairments. Like sertraline, paroxetine cannot be given to patients undergoing treatment with a monoamine oxidase inhibitor. Side effects from oral administration of paroxetine include hyponatremia, asthenia, sweating, nausea, decreased appetite, oropharynx disorder, somnolence, dizziness, insomnia, tremor, anxiety, impaired micturition, weakness and paresthesia.
Administration of the xcex11-adrenergic blockers has been described to treat psychogenic premature ejaculation. U.S. Pat. No. 5,707,999 describes daily administration of alfuzosine or terazosine. A common side effect of these drugs is postural hypotension. In addition, daily administration increases the possibility of patients suffering from a drugxc3x97s undesirable side effects as a result of continuous exposure to the agent.
Oral administration of clomipramine to treat men suffering from premature ejaculation has been described in Strassberg et al. (1999) J. Sex Marital Ther. 25(2):89-101. The reference describes xe2x80x9cas neededxe2x80x9d oral administration xe2x80x9cas little as four hours prior to sexual activity.xe2x80x9d Such a dosing regimen, however, still fails to provide for a flexible and convenient method for treating premature ejaculation.
Thus there is a need for methods and dosage forms for treating premature ejaculation that requires no specialized psychological therapy, can be used conveniently and without embarrassment, and avoids the disadvantages associated with prior therapeutic methods and dosage forms.
Accordingly, it is a primary object of the invention to address the above-described need in the art by providing a novel method for delaying the onset of ejaculation by systemically administering on demand a pharmaceutical formulation containing an amount of an active agent selected from the group consisting of clomipramine and pharmacologically acceptable acid addition salts thereof effective to delay the onset of ejaculation by the individual during sexual activity.
It is another object of the invention to provide such a method wherein the pharmaceutical formulation is administered less than four hours prior to engaging in sexual activity.
It is a further object of the invention to provide such a method wherein the individual suffers from premature ejaculation.
It is yet a further object of the invention to provide such a method wherein the pharmaceutical formulation is administered orally.
It is another object of the invention to provide such a method wherein the pharmaceutical formulation is administered buccally.
It is a further object of the invention to provide such a method wherein the pharmaceutical formulation is administered transmucosally.
It is still a further object of the invention to provide such a method wherein the pharmaceutical formulation is administered nasally.
It is another object of the invention to provide a dosage form for delaying the onset of ejaculation in a male individual, comprising a rapid-release formulation for systemic absorption containing an amount of an active agent selected from the group consisting of clomipramine and pharmacologically acceptable acid addition salts thereof effective to delay the onset of ejaculation by the individual during sexual activity.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In a first aspect of the invention, a method is provided for delaying the onset of ejaculation, the method comprising systemically administering to the individual on demand a pharmaceutical formulation containing an active agent selected from the group consisting of clomipramine and pharmacologically acceptable acid addition salts thereof. Drug delivery may be accomplished through any route that will provide appreciable systemic levels of clomipramine effective to delay the onset of ejaculation. Thus, drug delivery may be effected by, but not limited to, oral, parenteral, buccal or pulmonary administration.
In a further aspect of the invention, a pharmaceutical dosage form is provided for delaying the onset of ejaculation in a male individual. The dosage form comprises a rapid-release formulation for the systemic absorption of an active agent selected from the group consisting of clomipramine and its pharmacologically acceptable salts. Once absorbed in the individual""s circulatory system, the active agent exerts its pharmacologic activity. The amount of active agent administered is an amount effective to delay the onset of ejaculation by the individual during sexual activity. In addition to an effective amount of the active agent, the formulation also comprises a pharmacologically acceptable carrier or vehicle. Optionally, additional components may be incorporated into the formulation as well, e.g., excipients, surfactants, preservatives (e.g., antioxidants), stabilizers, chelating agents, taste-masking agents, and the like, as will be appreciated by those skilled in the art of pharmaceutical formulation preparation and drug delivery. The pharmaceutical dosage form may be any dosage form suitable for systemic absorption and may be, but is not limited to, rapidly disintegrating tablets, effervescent tablets, sublingual tablets, buccal dosage forms, sublingual sprays, gum formulations or inhalers.
Overview and Definitions
Before describing the present invention in detail, it is to be understood that this invention is not limited to specific dosage forms, carriers, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
It must be noted that, as used in this specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to xe2x80x9can additional active agentxe2x80x9d includes a single additional active agent or mixtures of two or more additional active agents, and the like.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
The terms xe2x80x9cactive agent,xe2x80x9d xe2x80x9cdrugxe2x80x9d and xe2x80x9cpharmacologically active agentxe2x80x9d are used interchangeably herein to refer to a chemical material or compound which, when administered to an organism (human or animal) induces a desired pharmacologic effect. Included are derivatives and analogs of those compounds or classes of compounds specifically mentioned which also induce the desired pharmacologic effect. In the context of the present invention, the terms generally refer to clomipramine and its pharmacologically acceptable acid addition salts unless the context clearly indicates otherwise.
By xe2x80x9cpharmacologically acceptablexe2x80x9d is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. Similarly, a xe2x80x9cpharmacologically acceptablexe2x80x9d salt of a compound as provided herein is a salt that is not biologically or otherwise undesirable.
By the term xe2x80x9csystemically administeredxe2x80x9d applicants intend all non-local modes of administration that result in appreciable drug levels in an individual""s circulatory system. Thus, a xe2x80x9csystemically administeredxe2x80x9d drug must achieve sufficient levels in an individual""s circulatory system before the drug is available to exert its intended pharmacological and therapeutic activity.
xe2x80x9cOn demandxe2x80x9d as in xe2x80x9con demandxe2x80x9d administration is meant herein to refer to administration of an active agent immediately prior to sexual activity. Thus, xe2x80x9con demandxe2x80x9d administration requires administration of the active agent less than four hours prior to sexual activity. As will be appreciated by those skilled in the art, xe2x80x9con demandxe2x80x9d administration must take into account the time necessary for the drug to be absorbed into the individual""s circulatory system.
xe2x80x9cRapid releasexe2x80x9d and xe2x80x9cimmediate releasexe2x80x9d dosage forms immediately release drug upon contact with aqueous fluid or tissue.
xe2x80x9cSexual activityxe2x80x9d as used herein refers to all sexual activity that may result in ejaculation by a individual. Thus, xe2x80x9csexual activityxe2x80x9d includes, but is not limited to, coitus.
xe2x80x9cCarriersxe2x80x9d or xe2x80x9cvehiclesxe2x80x9d as used herein refer to carrier materials suitable for drug administration. Carriers and vehicles useful herein include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner.
By an xe2x80x9ceffectivexe2x80x9d amount of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the age and general condition of the individual, mode of administration, and the like. Thus, it is not always possible to specify an exact xe2x80x9ceffective amount.xe2x80x9d However, an appropriate xe2x80x9ceffectivexe2x80x9d amount in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.
xe2x80x9cRapidly disintegratingxe2x80x9d as in a xe2x80x9crapidly disintegrating tabletxe2x80x9d as used herein refers to a tablet that dissolves or disperses in manner that allows for the absorption of the active agent such that xe2x80x9con demandxe2x80x9d administration of the active agent is possible. Thus, many rapidly disintegrating tablets often, but not necessarily, include a disintegrant in the tablet formulation or are otherwise specially designed to quickly disintegrate upon administration.
The Active Agent
The invention, as noted above, involves the administration of clomipramine or a pharmacologically acceptable acid addition salt thereof to an individual in order to delay the onset of ejaculation.
3-Chloro-10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine
The active agent may be administered in any form that will delay the onset of ejaculation when administered to an individual. For example, the active agent may be administered as chemically synthesized in the laboratory (e.g., using the methods described in U.S. Pat. No. 3,467,650), or as obtained commercially, e.g., from the Sigma(copyright) Chemical Company (St. Louis, Mo., product number C 7291).
The clomipramine and any additional active agents present may be administered in the form of a pharmacologically acceptable salt, analog or combination thereof. Salts of the active agent may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base (typically wherein the neutral form of the drug has a neutral amino group) using conventional means, involving reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base. Preparation of basic salts of acid moieties which may be present (e.g., carboxylic acid groups) are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, trimethylamine, or the like.
Analogs and other derivatives of the active agent may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference to the pertinent literature.
Preferably, the methods and dosage forms described herein use an acid addition salt form of clomipramine. Furthermore, clomipramine hydrochloride is a particularly preferred acid addition salt.
Rapid-Release Formulations
The rapid-release formulations may be in any form suitable to provide rapid and systemic absorption of the active agent. Although the time necessary for systemic absorption will depend on the particular dosage form used, it is preferred that the formulation and dosage form provide systemically effective levels of and the desired biological response to the active agent less than 4.0, preferably less than 3.5, more preferably less than 3.0, still more preferably less than 2.5, yet more preferably less than 2.0, and yet still more preferably less than 1.5 hours following administration. It is particularly preferred that the formulation and dosage form provide systemically effective levels of the drug and the desired biological response less than 1.0 hour following administration with less than 0.5 hours being most preferred.
Depending on the intended mode of administration, the rapid-release formulations may be in the form of solid, semi-solid, liquid or aerosol dosage forms such as, for example, tablets, including buccal tablets and rapidly disintegrating tablets such as effervescent tablets, sublingual tablets and xe2x80x9copen matrix networkxe2x80x9d tablets, capsules, powders, gums, liquids, suspensions, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include an effective amount of the active agent in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc. The amount of active agent administered will, of course, be dependent on the subject being treated, the subject""s weight, the manner of administration and the judgment of the prescribing physician.
For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington, cited supra.
For oral administration, the composition will generally take the form of a tablet or capsule, or may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
One type of tablet that provides rapid release is a buccal tablet. Preferred buccal tablets will typically comprise a therapeutically effective amount of the active agent and a bioerodible (hydrolyzable) polymeric carrier that may also serve to adhere the dosage form to the buccal mucosa. The buccal dosage unit is fabricated so as to release at least a portion of the active agent immediately. In addition, the buccal dosage unit may be designed so as to erode gradually over a predetermined time period, wherein drug delivery is provided essentially throughout. Buccal drug delivery, as will be appreciated by those skilled in the art, avoids some of the disadvantages encountered with oral modes of administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. The xe2x80x9ceffective amountxe2x80x9d of clomipramine or salt thereof in the dosage unit will of course depend, inter alia, on the intended dosage, which, in turn, is dependent on the particular individual undergoing treatment, the specific indication, and the like. The dosage unit will generally contain from approximately 1.0 wt. % to about 60 wt. % active agent, preferably on the order of 1 wt. % to about 30 wt. % active agent. With regard to the bioerodible (hydrolyzable) polymeric carrier, it will be appreciated that virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the active agent to be administered and any other components that may be present in the buccal dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and copolymers, e.g., those known as xe2x80x9ccarbomersxe2x80x9d (Carbopol(copyright), which may be obtained from B.F. Goodrich, is one such polymer). Other suitable polymers include, but are not limited to: hydrolyzed polyvinylalcohol; polyethylene oxides (e.g., Sentry Polyox(copyright) water soluble resins, available from Union Carbide); polyacrylates (e.g., Gantrez(copyright), which may be obtained from GAF); vinyl polymers and copolymers; polyvinylpyrrolidone; dextran; guar gum; pectins; starches; and cellulosic polymers such as hydroxypropyl methylcellulose, (e.g., Methocel(copyright), which may be obtained from the Dow Chemical Company), hydroxypropyl cellulose (e.g., Klucel(copyright), which may also be obtained from Dow), hydroxypropyl cellulose ethers (see, e.g., U.S. Pat. No. 4,704,285 to Alderman), hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, and the like.
Other components may also be incorporated into the buccal dosage forms described herein. The additional components include, but are not limited to, disintegrants, diluents, binders, lubricants, flavorings, colorants, preservatives, and the like. Examples of disintegrants that may be used include, but are not limited to, cross-linked polyvinylpyrrolidones, such as crospovidone (e.g., Polyplasdone(copyright) XL, which may be obtained from GAF), cross-linked carboxylic methylcelluloses, such as croscarmelose (e.g., Ac-di-sol(copyright), which may be obtained from FMC), alginic acid, and sodium carboxymethyl starches (e.g., Explotab(copyright), which may be obtained from Edward Medell Co., Inc.), methylcellulose, agar bentonite and alginic acid. Suitable diluents are those that are generally useful in pharmaceutical formulations prepared using compression techniques, e.g., dicalcium phosphate dihydrate (e.g., Di-Tab(copyright), which may be obtained from Stauffer), sugars that have been processed by cocrystallization with dextrin (e.g., co-crystallized sucrose and dextrin such as Di-Pak(copyright), which may be obtained from Amstar), lactose, calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and the like. Binders, if used, are those that enhance adhesion. Examples of such binders include, but are not limited to, starch, gelatin and sugars such as sucrose, dextrose, molasses, and lactose. Particularly preferred lubricants are stearates and stearic acid, and an optimal lubricant is magnesium stearate.
Preferred sublingual dosage forms include sublingual tablets, creams, ointments and pastes with sublingual tablets being particularly preferred. The tablet, cream, ointment or paste for sublingual delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional nontoxic carriers suitable for sublingual drug administration. The sublingual dosage forms of the present invention can be manufactured using conventional processes. The sublingual dosage unit is fabricated to disintegrate rapidly. The time period for complete disintegration of the dosage unit is typically in the range of from about 10 seconds to about 30 minutes, and optimally is less than 5 minutes.
With regard to sublingual tablets, these tablets are generally small in size and intended to be dissolved under the tongue for absorption through the oral mucosa for systemic circulation. Sublingual tablets generally comprise a formulation containing drug and a pharmaceutically acceptable sugar, e.g., lactose, galactose, sucrose, mannose, glucose, ribose, xylose and combinations thereof, as a carrier. The formulation is then compressed into tablets using conventional techniques well-known in the art.
Other components may also be incorporated into the sublingual dosage forms described herein. The additional components include, but are not limited to binders, disintegrators, wetting agents, lubricants, and the like. Examples of binders that may be used include water, ethanol, polyvinylpyrrolidone, starch solution gelatin solution, and the like. Suitable disintegrators include dry starch, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic monoglyceride, lactose, and the like. Wetting agents, if used, include glycerin, starches, and the like. Particularly preferred lubricants are stearates and polyethylene glycol. Additional components that may be incorporated into sublingual dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington, cited supra.
In addition to sublingual tablets, other rapidly disintegrating tablets are preferred. Examples of such tablets are well-known in the art. Another preferred rapidly disintegrating tablet includes effervescent tablets. Effervescent tablets are described in Remington, supra, and examples may be found in the literature, and in, for example, U.S. Pat. No. 5,211,957 to Hagemann et al. Generally, effervescent tablets contain the active agent in combination with additives such as sodium bicarbonate and an organic acid. e.g., tartaric acid or citric acid. In the presence of water, these additives react to liberate carbon dioxide thereby facilitating the disintegration of the tablet. Once the tablet is substantially disintegrated, an individual swallows the resultant solution thereby providing systemic adsorption of the active agent.
Another version of a rapidly disintegrating tablet includes xe2x80x9copen matrix networkxe2x80x9d tablets. These tablets can disintegrate within seconds, i.e., within five to ten seconds, after being placed on the tongue of an individual. The contents of the tablet can then be swallowed with or without water. An example of such a tablet is found in U.S. Pat. No. 4,371,516 to Gregory et al. As described therein, the carrier provides a low density network, e.g., about 10 to about 200 mg/cm3, of water-soluble or water-dispersible material. The tablet is produced by subliming a solution containing both the drug and carrier that is subsequently directed to a mold having tablet-shaped depressions. The carrier may be any suitable material, but is preferably gelatin, with partially hydrolyzed gelatin most preferred. Other examples of rapidly disintegrating tablets that can be adapted to contain clomipramine are well-known in the art. See, for example, U.S. Pat. No. 5,776,492 to Betzing et al.
The active agent may be administered via a sublingual spray or inhaled. Sublingual sprays and inhalers are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
In addition, the active agent may be administered via a chewing gum formulation. Gum formulations containing a pharmacologically active agent and techniques for preparing such formulations are well-known in the art. For example, a gum base (available commercially from, for example, Cafosa, Inc., Calabria, Spain) is rolled in a suitable roller at about 10 to 85xc2x0 C. for about three minutes. Thereafter, all components except for the active agent, e.g., plasticizers, sugars, sweeteners, fillers, polymers and waxes, are added sequentially and rolled until a homogenous material is obtained. Then, active agent is added and rolled until the entire material is homogenous. Once homogenous, the material is removed from the roll, cooled to room temperature and processed into the desired gum shape, e.g., cubes or sticks.
The active agent may also be administered intranasally, for example in a solution, using drops or a spray. Nasal solutions are generally prepared so that they are isotonic and slightly buffered to have a pH of about 5.5 to 6.5. The solutions includes a suitable liquid carrier, e.g., a saline solution, and may also include antimicrobial preservatives, drug stabilizers, and other additives known to those of ordinary skill in the art of pharmaceutical formulation. Intranasal administration may also involve use of a dry powder spray, although administration of a solution is preferred.
The pharmaceutical formulation may include an additional active agent. Examples of additional active agents include, but are not limited to:
antidepressants including amesergide, amineptine, amitriptyline, amoxapine, benactyzine, brofaromine, bupropion, butriptyline, cianopramine, citalopram, clorgyline, clovoxamine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, etoperidone, femoxetine, fezolamine, fluoxetine, fluvoxamine, ifoxetine, imipramine, iprindole, iso-carboxazid, levoprotiline, lofepramine, maprotiline, medifoxamine, melitracen, metapramine, methylphenidate, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nialamide, nomifensine, nortriptyline, opipramol, oxaflozane, oxaprotiline, oxitriptan, paroxetine, phenelzine, pirlindole, propizepine, protriptyline, quinupramine, rolipram, selegiline, sertraline, setiptiline, sibutramine, teniloxazine, tianeptine, tofenacin, toloxatone, tranylcypromine, trazodone, trimipramine, tryptophan, venlafaxine, viloxazine, viqualine and zimeldine;
serotonin agonists including 2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone, lysergic acid diethylamide, ergot alkaloids, 8-hydroxy-(2-N,N-dipropylamino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride and mezacopride;
serotonin antagonists including ondansetron, granisetron, metoclopramide, tropisetron, dolasetron, trimethobenzamide, methysergide, risperidone, ketanserin, ritanserin, clozapine, amitryptiline, R(+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol, azatadine, cyproheptadine, fenclonine, dexfenfluramine, fenfluramine, chlor-promazine and mianserin;
adrenergic agonists including methoxamine, methpentermine, metaraminol, mitodrine, clonidine, apraclonidine, guanfacine, guanabenz, methyldopa, amphetamine, methamphetamine, epi-nephrine, norepinephrine, ethylnorepinephrine, phenylephrine, ephedrine, pseudo-ephedrine, methylphenidate, pemoline, naphazoline, tetrahydrozoline, oxymetazoline, xylometazoline, phenylpropanolamine, phenylethylamine, dopamine, dobutamine, colterol, isoproterenol, isotharine, metaproterenol, terbutaline, metaraminol, tyramine, hydroxy-amphetamine, ritodrine, prenalterol, albuterol, isoetharine, pirbuterol, bitolterol, fenoterol, formoterol, procaterol, salmeterol, mephenterine and propylhexedrine;
adrenergic antagonists including phenoxybenzamine, phentolamine, tolazoline, prazosin, terazosin, doxazosin, trimazosin, yohimbine, ergot alkaloids, labetalol, ketanserin, urapidil, alfuzosin, bunazosin, tamsulosin, chlorpromazine, haloperidol, phenothiazines, butyrophenones, pro-pranolol, nadolol, timolol, pindolol, metoprolol, atenolol, esmolol, acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, carvedilol, medroxalol, naftopidil, bucindolol, levobunolol, metipranolol, bisoprolol, nebivolol, betaxolol, carteolol, celiprolol, sotalol, propafenone and indoramin;
adrenergic neurone blockers including bethanidine, debrisoquine, guabenxan, guanadrel, guanazodine, guanethidine, guanoclor and guanoxan;
benzodiazepines including alprazolam, brotizolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazapam, oxazepam, prazepam, quazepam, temazepam and triazolam.
Particularly preferred additional active agents include benzodiazepines such as those listed above and selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, fluvoxamine, paroxetine and sertraline.
Some agents, as may be seen, are encompassed by more than one of the above categories, e.g., serotonin antagonists and antidepressants, or serotonin agonists and antagonists.
In addition to the active agent, the formulation, particularly when present in a gum or oral, buccal or sublingual tablet, will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, taste-masking agents, and the like. Binders are used to impart cohesive qualities to the formulation; suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose, and the like), and Veegum(copyright). As will be appreciated by those skilled in the art, binders, if present, must not delay disintegration of the formulation to such an extent that xe2x80x9con demandxe2x80x9d administration is ineffective. Diluents are typically necessary to increase bulk so that a dosage form of practical size is ultimately provided. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Lubricants are used to facilitate manufacture of the dosage form; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, and stearic acid. Stearates, if present, preferably represent at no more than approximately 2 wt. % of the formulation. Disintegrants are used to facilitate disintegration of the dosage form, and are generally starches, clays, celluloses, algins, gums or crosslinked polymers; sodium starch glycolate is particularly preferred. Fillers include, for example, insoluble materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, and the like, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, sorbitol, and the like. Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions. Surfactants include anionic, cationic, amphoteric and nonionic surface active agents, with anionic surfactants preferred. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions, associated with cations such as sodium, potassium, and ammonium ions. Particularly preferred surfactants include long alkyl chain sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylhexyl)sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Taste-masking agents, i.e., flavorants, are used to disguise a bitter or undesirable taste of a component and/or impart a pleasant flavor to a pharmaceutical preparation. Particularly preferred taste-masking agents include sugars (e.g., glucose, sucrose, fructose and sorbitol), anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin.
Utility and Modes of Administration
The invention provides for formulations and methods that are effective in delaying the onset of ejaculation. The present formulations are administered on demand, i.e., less than four hours prior to engaging in sexual activity. On demand administration also includes administration at almost any time within the four hour window immediately prior to engaging in sexual activity. Thus, for some dosage forms, e.g., the sublingual spray, on demand administration may take place even 10 minutes prior to engaging in sexual activity. Such flexibility in administration is desirable since the individual may administer the formulation at any convenient time within the four hour window leading up to sexual activity. In addition, because they are all systemically acting, the formulations may be discreetly administered without need for a device, thereby avoiding potential embarrassment.
Typically, although not necessarily, the individual seeking to delay the onset of ejaculation suffers from premature ejaculation. In accordance with the invention, administration of clomipramine results in systemic levels of the drug sufficient to delay the onset of ejaculation. It is preferred that the pharmaceutical formulation is administered orally, buccally or transmucosally. As will be appreciated by those skilled in the art, tablets, including effervescent tablets and xe2x80x9copen matrix networkxe2x80x9d tablets, are administered orally. These formulations are absorbed in the gastrointestinal tract, although some absorption will take place in the oral mucosa. Buccal tablets are placed in the xe2x80x9ccheek pouchxe2x80x9d wherein absorption of clomipramine primarily takes place transmucosally, primarily in the buccal mucosa. Sublingual sprays and sublingual tablets are administered under the tongue providing for rapid absorption of clomipramine transmucosally, primarily in the vascularized region under the tongue. Inhaled formulations are administered orally (tracheally) for absorption through pulmonary tissues. Gum formulations containing the active agent are chewed, thereby releasing the active agent. Once released from the gum formulation, the active agent forms a solution in the oral cavity for absorption through the oral mucosa and gastrointestinal tract when the solution is swallowed by the individual. As will be appreciated by those skilled in the art, each of these modes of administration are not xe2x80x9clocalxe2x80x9d in nature and will result in systemic levels of the active agent.
As stated above, the amount of active agent administered, and the dosing regimen used, will, of course, be dependent on, inter alia, the age and general condition of the individual being treated, the degree to which the onset of ejaculation is to be delayed, and the judgment of the prescribing physician. The dose is administered on demand. That is, administration will occur less than 4.0, preferably less than 3.5, more preferably less than 3.0, still more preferably less than 2.5, yet more preferably less than 2.0, yet still more preferably less than 1.5 hours prior to engaging in sexual activity. It is particularly preferred that administration occurs less than 1.0 hour before engaging in sexual activity with less than 0.5 hours being most preferred. As is appreciated by those skilled in the art, the methods and dosage forms of the invention relate to systemic administration. In order to achieve systemically effective levels of the drug, a typical on demand dose of the active agent is generally in the range of from about 1 mg to about 300 mg, preferably of from about 20 mg to about 200 mg with a dose in the range of from about 25 mg to about 100 mg being most preferred. Thus, unit dose forms preferably contain the active agent in these ranges as well, i.e., from about 1 mg to about 300 mg, more preferably from about 20 mg to about 200 mg with about 25 mg to about 100 mg of active agent in each unit dose form. The dosing regimen can be modulated in order to achieve satisfactory control of the onset of ejaculation.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples that follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entireties.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmaceutical formulation and the like, which are within the skill of the art. Such techniques are fully explained in the literature. In the following examples, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.) but some experimental error and deviation should be accounted for. Unless otherwise indicated, temperature is in degrees C and pressure is at or near atmospheric pressure at sea level. All reagents were obtained commercially unless otherwise indicated.

On demand administration of clomipramine and salts thereof to treat premature ejaculation


The invention relates to a retaining device for the purpose of mechanically and electrically connecting a mobile user device, in particular a mobile radio telephone or a PDA, to a vehicle.

DE 298 14 956 U1 describes a mobile telephone holder for a vehicle which comprises a base part and a telephone retaining part which matches the shape of the mobile radio telephone and serves the purpose of accommodating the mobile telephone. The base part is provided for the purpose of permanently fixing the mobile telephone holder in the vehicle. In this case, it has three hook elements by means of which the base part can be connected to the telephone retaining part. The base part is in this case simply a retaining plate which merely serves the purpose of mechanically fixing the telephone retaining part. The telephone retaining part is provided with a connection cable which connects the telephone retaining part to a handsfree device.

Retaining device for mobile user devices