An imbalance compensation system includes a receiver, a first path and a second path electrically coupled to the receiver, and a 90 degree hybrid coupler electrically connected to the second path, wherein the first path is configured to convey an in-phase (I) signal and the second path is configured to convey a quadrature phase (Q) signal. A processor is configured to perform Finite Impulse Response (FIR) filtering upon the I signal and the Q signal, wherein the processor is configured with an inverse matrix of coefficients corresponding to a frequency-dependent phase imbalance and a frequency-dependent amplitude imbalance between the I signal and the Q signal. The processor is configured to perform FIR filtering to attenuate an image signal down to a system noise floor when the processor simultaneously receives signals in a primary Nyquist region and a conjugate Nyquist region.

Hardware necessary to facilitate electronic signal intelligence gathering activity often includes a digital wideband receiver to detect multiple signals of unknown characteristics with a reasonable instantaneous dynamic range. In an effort to double the available bandwidth of a given system, other technology disciplines have implemented an in-phase/quadrature phase (I/Q) technique to extend the available sampling range beyond the primary Nyquist zone. Through this method, incoming signals are processed both in their native format, as well as in a 90° phase shifted format. By converting an input signal into both real and complex data, the available signal set may be extended to the conjugate Nyquist zone (from negative half of the sampling frequency to DC), thus doubling the bandwidth.
While the extended bandwidth realized by the I/Q technique is beneficial, operational problems have thus far prevented implementation in electronic signal intelligence gathering hardware. Unfortunately, variations in manufacturing tolerances in the quadrature phase shift hardware result in unavoidable imbalance in the I/Q channels. This produces an image signal, or alias signal (image and alias may be used interchangeably herein), in Fast Fourier Transform (FFT) analysis. As a consequence, the instantaneous dynamic range deteriorates.
Many of the techniques used to mitigate the effects of I/Q imbalance have been explored in signal processing disciplines wherein received signals are of a known frequency having well defined waveforms. The operational bandwidth is often narrow. As a result, many prior art techniques assume that the imbalance is frequency independent (since they are operating in a narrow band environment). However, electronic signal intelligence applications often include unknown frequencies or waveforms, and prior art imbalance compensation techniques are ineffective when imbalance correction is assumed to be frequency independent.
Further, prior art techniques that address frequency dependent mismatch issues, are incapable of applying mismatch correction when signals are simultaneously received in both Nyquist zones. In electronic signal intelligence scenarios, correction techniques must be capable of supporting simultaneous reception of signals in both Nyquist regions.
Therefore, there exists a need in the art for methods and apparatus to compensate for I/Q imbalances in wideband signal processing applications.

Methods and apparatus for wideband imbalance compensation

The United States of America as represented by the Secretary of the Air Force


The invention relates to a roll press including at least three rolls forming several press nips for the treatment of a web of material. One press roll comprises a very flexible roll shell which is rotatable around a fixed support and is mounted on the support by at least one support element which has a concave support surface for defining a wide press nip with a cylindrical backing roll. The backing roll forms an additional press nip with at least one not sag-controlled roll. To obtain as uniform as possible a press nip between the backing roll and at least one additional roll which is without sag control, the circumference of the roll shell of the backing roll decreases axially towards its ends, i.e., that roll may be crowned. In addition, the backing roll may have its own roll shell support elements which are either in the press plane or are inclined slightly out of the press plane and/or the hydraulic pressure fluid supplied to the press roll and to the backing roll is adapted to supply a greater pressing force by the press roll. Optionally, a fourth press roll may form a nip with the additional roll. A felt passes through each nip.

The present invention relates to a roll press including at least three rolls which form several press nips such as may be used, for instance, for dewatering or smoothing a fiber web, like a paper web. The invention particularly concerns profiling of the rolls and application of the roll shell supports for optimizing application of pressure in the nips.
The roll press with which the invention is used typically includes a shoe press type roll having a stationary support, a flexible roll shell which rotates around the support and a concave shoe or shoes along the support. The shoe press roll cooperates with a backing roll to define a press nip between the flexible roll shell and the backing roll at the concave shoe. The backing roll may sag between its end supports due to its weight and to the pressure applied to it by the press roll.
A third roll may cooperate with the backing roll to counter the sag. If the backing roll cooperates with a third roll which is not sag controlled, as shown in WO 93/12289, which corresponds to U.S. Pat. No. 5,404,811, difficulties can occur, due to roll sag, in the formation of a uniform press nip which is to be as straight as possible.
Although it is possible to provide the backing roll or the third roll with support elements in the press plane for controlling the sag of the shells of those rolls, this requires considerable expense. Furthermore, considerable thermal problems can be produced in the customary hydraulic support elements if the backing roll and/or the third roll are heated so as to improve the web dewatering or smoothing.


Techniques are provided for establishing and managing a distributed credential store. An identity service aggregates identity information from one or more identity stores and maintains the information as a remote credential store. Initially, the remote credential store, or portions thereof, is transmitted to a principal service as an initial configuration of a local credential store. A principal interacts with the principal service for defining or modifying a policy that identifies portions of the remote credential store which are to be synchronized with the local credential store. In some embodiments, the principal interacts with the principal service for defining a local policy that identifies portions of the local credential store which are not synchronized with the remote credential store. The interactions between the credential stores are trusted and secured.

As individuals continue using the Internet for connecting to a myriad of services and resources, a variety of confidential information and identity information about those individuals needs to be managed, synchronized, and securely distributed. In many instances, this information is concurrently and manually managed in environments local to the individuals, in local enterprise environments associated with the individuals, and in environments that are local to the services and resources.
Having the identity and confidential information housed and managed in a variety of environments presents a number of challenging problems. For example, individuals are not always properly authenticated into their enterprise environment, which means that access to some information may not be available to individuals who use different computing devices from time to time and who are not properly logged into their appropriate enterprise environments from time to time.
Additionally, management of the identity and confidential information usually occurs in multiple environments. That is, an individual maintains some information, the enterprise maintains other information, and the services or resources maintain still other information. In some cases, the same information is separately managed in duplicate. This creates synchronization problems for the individuals and for network administrators.
Furthermore, the information, as it is being managed and manually maintained or utilized, becomes unduly exposed during network transmissions. This means that each time portions of the information are transmitted for purposes of authentication or for purposes of synchronization it can become compromised and intercepted. This results in a variety of security issues which must be established for network interactions that involve the transfer of the information.
Typically, security measures will entail establishing trust relationships utilizing public-private key pairs with encryption and the like. The encryption is used in secure communications for minimizing exposure to confidential information and identity information. However, mobile individuals may not have static key pairs with services and may often use a laptop to connect from a variety of Internet Service Providers (ISPs), such that the individuals do not have static Internet Protocol (IP) addresses which can uniquely and securely establish the needed trusted relationships between the individuals and other services or resources. Consequently, individuals are often limited in their use of or prohibited in their use of certain confidential and identity information in many contexts when adequate security measures are enforced in conventional manners.
Thus, even the most elaborate conventional techniques that attempt to automate and synchronize an individual's confidential information and identity information still falls short of providing a consistent level of sustainable service, because in many cases the user is unable to effectively access some of his/her needed information.
Thus, there is a need for establishing and managing a distributed credential store, where that credential store can be securely accessed, better managed, and consumed in order to provide an improved level of consistent service.

Techniques for establishing and managing a distributed credential store


A method and apparatus for dynamically predicting the outcome and the tar address of a multiple-target branch instruction, where the multiple-target branch instruction contains at least two potential target addresses, not including the fall through address. In addition, this method and apparatus can also be used to predict multiple single-target branches simultaneously. The apparatus stores information indicating the outcome of previous executions and predictions of the multiple-target branch instruction in a branch prediction table. In addition, multiple target addresses (at least two) are associated with the multiple-target branch instruction. Using the information indicating the outcome of the previous execution of the multiple-target branch instruction, the apparatus predicts the outcome of a next execution of the multiple-target branch instruction, and predicts which, if any, of the target addresses associated with the multiple-target branch instruction, will be taken.

Microprocessors often employ the use of pipelining to enhance performance. Within a pipelined microprocessor, the functional units necessary for executing different stages of an instruction are operated simultaneously on multiple instructions to achieve a degree of parallelism leading to performance increases over non-pipelined microprocessors. As an example, an instruction fetch unit, an instruction decode unit and an instruction execution unit may operate simultaneously. During one clock cycle, the instruction execution unit executes a first instruction while the instruction decode and execute unit decodes a second instruction and the fetch unit fetches a third instruction. During a next clock cycle, the execution unit executes the newly decoded instruction while the instruction decode and execute unit decodes the newly fetched instruction and the fetch unit fetches yet another instruction. In this manner, neither the fetch unit nor the decode and execute unit need to wait for the instruction execution unit to execute the last instruction before processing new instructions. In state-of-the-art microprocessors, the steps necessary to fetch and execute an instruction are sub-divided into a larger number of stages to achieve a deeper degree of pipelining.
A pipelined CPU operates most efficiently when the instructions are executed in the sequence in which the instructions appear in memory. Unfortunately, this is typically not the case. Rather, computer programs typically include a large number of branch instructions, which, upon execution, may cause instructions to be executed in a sequence other than as set forth in memory. More specifically, when a branch instruction is encountered in the program flow, execution continues either with the next sequential instruction from memory or execution jumps to an instruction specified at a "branch target" address. Typically the branch specified by the instruction is said to be "Taken" if execution jumps and "Not Taken" if execution continues with the next sequential instruction from memory.
Branch instructions are either unconditional, meaning the branch is taken every time the instruction is executed, or conditional, meaning the branch is taken or not depending upon a condition. Instructions to be executed following a conditional branch are not known with certainty until the condition upon which the branch depends is resolved. However, rather than wait until the condition is resolved, state-of-the-art microprocessors may perform a branch prediction, whereby the microprocessor tries to determine whether the branch will be Taken or Not Taken, and if Taken, to predict or otherwise determine the target address for the branch. If the branch instruction is predicted to be Taken, the microprocessor fetches and speculatively executes the instruction found at the predicted branch target address. The instructions executed following the branch prediction are "speculative" because the microprocessor does not yet know whether the prediction will be correct or not. Accordingly, any operations performed by the speculative instructions cannot be fully completed. For example, if a memory write operation is performed speculatively, the write operation cannot be forwarded to external memory until all previous branch conditions are resolved, otherwise the instruction may improperly alter the contents of the memory based on a mispredicted branch. If the branch prediction is ultimately determined to be correct, the speculatively executed instructions are retired or otherwise committed to a permanent architectural state. In the case of a memory write, the write operation is normally forwarded to external memory. If the branch prediction is ultimately found to be incorrect, then any speculatively executed instructions following the mispredicted branch are typically flushed from the system. For the memory write example, the write is not forwarded to external memory, but instead is discarded.
As can be appreciated, when a branch prediction is correct, a considerable improvement in processor performance is gained. If the branch prediction is incorrect, the microprocessor is no worse off than had it initially waited until resolution of the branch condition.
A wide variety of techniques have been developed for performing branch prediction. Typically, various tables are provided for storing a history of previous branch executions or branch predictions along with indications of whether the branch predictions were proven to be correct or not. Predictions are made for newly encountered branches by evaluating the history of prior branch executions or prior branch predictions. In some microprocessors, the logic for performing branch predictions is quite complex and time consuming. It is, however, desirable to perform the branch prediction as quickly as possible. Ideally, a branch prediction is performed using the same number of clock cycles as it takes to fetch an instruction, thereby ensuring that the instruction cache need not be stalled while waiting for instruction pointers corresponding to predicted branches.
Advanced compiler techniques now used, reorder the instructions of a program to move non-branch instructions forward in the execution so instructions can be executed without instruction flow changes. This reordering results in multiple branch instructions being scheduled together at the bottom of an instruction scheduling block. Prior art branch prediction systems require each branch instruction to be separately predicted and fetched, which requires multiple clock cycles. Therefore, to improve performance, it is desirable for the system to be able to predict the outcome of multiple branch instructions simultaneously, instead of sequentially.

Dynamic branch prediction for branch instructions with multiple targets

Institute for the Development of Emerging Architectures, L.L.P.


A system, method, and computer program product for allowing a user to fix errors in a user input is described. An original user input providing a destination address or a point of interest is received by an in-vehicle computing system. Upon receiving a user input indicating an error in interpreting the original user input, the user is presented with a new query requesting the user to enter a portion of or a category associated with the original input. Once the updated user input providing a portion of the original input is received, the user input is identified and executed based on the original user input entry and the updated user input.

In-vehicle systems capable of providing navigation instructions, playing a song, making a phone call, etc, have become commonplace in vehicles. In-vehicle systems can comprise interface buttons, joysticks, touch interface display monitors, microphones and speakers to allow users to interact with the in-vehicle system. Users typically use a microphone to input speech or voice commands, wherein the in-vehicle system interprets the user's speech command and executes one or more actions responsive to the user's command. However, in-vehicle systems can often make mistakes in recognizing users' speech commands.
In-vehicle systems typically allow a user to re-input a speech command when the in-vehicle system does not recognize an input or when a user indicates that the in-vehicle system misrecognized the user's command. However, such a method of fixing mistakes in recognizing a user's input is ineffective. For example, a user can re-input the same speech command in order to fix a previously misrecognized command and the in-vehicle system can make the same mistake in misrecognizing the users' input. A user can thus be required to re-input a speech command several times without fixing the mistake in the in-vehicle system's recognition of the speech command. Such a method of re-inputting speech commands without yielding correct results can frustrate a user and lead to a poor user experience.
In addition, the American Axle and Manufacturing Guidelines (AAM GL), provides that a single glance time on display screen of an in-vehicle system should not exceed two seconds and the time to complete a task on an in-vehicle system should not exceed twenty seconds of total glance time. A user seeking to fix mistakes in an in-vehicle system's recognition a voice command by re-inputting the speech command typically has to perform a series of steps. For example, a user seeking to re-input a misrecognized address must press a 'back' or a 'home' button one or more times to reach a state name input interface, a city name, street number or street name input interface menus and re-input location information in each interface menu. Such a method of fixing mistakes thus typically requires more than two seconds of glance time and more than twenty seconds to complete the input task.

System and method of fixing mistakes by going back in an electronic device


A semiconductor force sensor capable of preventing a diaphragm part (37) from being broken and accurately measuring a force applied thereto in a direction orthogonal to the diaphragm part (37), wherein a force transmitting means for applying a measured force to the diaphragm part (37) of a semiconductor force sensor element (31) is formed of a sphere (33) having a rigidity, and a through hole (63) passing through an opposed wall part (55) toward the diaphragm (37) is formed in the opposed wall parts (55) at a position opposed to the center part of the diaphragm part (37) so that a part of the sphere (33) can face the outside of the opposed wall part (55) and stores a part of the remaining part of the sphere (33) to allow the sphere (33) to be moved only in a direction orthogonal to the diaphragm part (37) and rotated on the center part of the diaphragm part (37).

Japanese Patent Application Laid-Open Publication No. 118935/1993 discloses a semiconductor force sensor including a semiconductor force sensor element having a diaphragm section and a sphere for transmitting a force to the diaphragm section. The semiconductor force sensor warps the diaphragm section by the force applied to the sphere and converts a change in this force to an electric signal, thereby measuring the force applied to the sphere or turning on or off a switch. In the semiconductor force sensor, a recess section, in which the sphere is placed, is formed in the central portion of the semiconductor force sensor element, and a through hole, into which the sphere to fitted, is formed in the opposed wall section of an receiving case facing the recess section so that part of the sphere faces outside. With this structure, positioning of the sphere is achieved by the through hole in the opposed wall section with the sphere being secured in the semiconductor force sensor element.
In such a semiconductor force sensor, however, when a force in a direction other than a direction orthogonal to the diaphragm section is transmitted to the diaphragm section through the sphere, an undue force is applied to the diaphragm section, so that the diaphragm section might be broken. Further, a force applied to the direction orthogonal to the diaphragm section could not be measured accurately.
Japanese Utility Model Application No. 38779/1987 (Japanese Utility Model Application Laid-Open publication No. 146734/1988) relating to a microfilm discloses a pressure-sensitive sensor including a sensor element constituted by a thin plate fixed to a receiving case and a composite piezoelectric sheet having electrodes, and a sphere for transmitting a force to the thin plate. The pressure-sensitive sensor applies the force on the sphere to the composite piezoelectric sheet through the thin plate, converts a change in this force to an electric signal, and measures a pressure applied to the sphere. In this pressure-sensitive sensor, a through hole into which the sphere is fitted is formed in the opposed wall section of the receiving case facing the thin plate so that part of the sphere faces outside. With this structure, positioning of the sphere is achieved by the through hole in the opposed wall section with the sphere being in contact with the thin plate.
However, the sensor element in this pressure-sensitive sensor is energized against the sphere through the thin plate by a spring. Thus, the sphere is strongly abutted onto the edge of the through hole in the receiving case. For this reason, when a force in a direction other than the direction orthogonal to the thin plate is transmitted to the thin plate through the sphere, most of the force (force including even the force in the direction other than the direction orthogonal to the thin plate) is measured. Then, there was a problem that the force applied to the direction orthogonal to the thin plate could not be accurately measured.
An object of the present invention is to provide a semiconductor force sensor that can prevent an undue force from being applied to a diaphragm section therein, and thus can prevent the diaphragm section being broken.
Another object of the present invention is to provide a semiconductor force sensor that can accurately measure a force applied to a direction orthogonal to the diaphragm section.


An audio system is provided that employs time-frequency analysis and/or synthesis techniques for processing audio obtained from a microphone array. These time-frequency analysis/synthesis techniques can be more robust, provide better spatial resolution, and have less computational complexity than existing adaptive filter implementations. The time-frequency techniques can be implemented for dual microphone arrays or for microphone arrays having more than two microphones. Many different time-frequency techniques may be used in the audio system. As one example, the Gabor transform may be used to analyze time and frequency components of audio signals obtained from the microphone array.

Personal computers and other computing devices usually play sounds with adequate sound quality but do a poor job at recording audio. With today's processing power, storage capacities, broadband connections, and speech recognition engines of the computing world, there is an opportunity for computing devices to use sounds to deliver more value to users. Computer systems can provide better live communication, voice recording, and user interfaces than phones.
However, most computing devices continue to use the traditional recording paradigm of a single microphone. A single microphone, however, does not accurately record audio because the microphone tends to pick up too much ambient noise and adds too much electronic noise. Generally speaking, single microphone based noise reduction algorithms are only effective for stationary environment noise suppression. They are not suitable for non-stationary noise reduction, such as background talking in a busy street, subway station, or cocktail party. Thus, users who desire better recording quality commonly resort to expensive tethered headsets.


The present invention comprises non occlusive compositions for transdermal delivery of nicotine, and more particularly pharmaceutically acceptable salts thereof, and methods of making same. The composition may, for example, be a gel suitable for transdermal or transmucosal applications. The compositions of the present invention typically comprise a mixture of water and alcohol, and a solvent system having a mono alkyl ether of diethylene glycol and a glycol present in specified ratios and in specific amounts, wherein the pH of the gel is usually between a pH of 5.5 and 7. The compositions may include further components, for example, the hydroalcoholic vehicle may further comprise additional penetration enhancer(s), buffering agent(s), antioxidant(s), stabilizer(s) and/or gelling agent(s). The invention also relates to a method for the sustained delivery of nicotine pharmaceutically acceptable salts to treat a variety of conditions and disorders.

Transdermal delivery, i.e. the ability to deliver pharmaceuticals agents into and through skin surfaces, provides many advantages over oral or parenteral delivery techniques. In particular, transdermal delivery provides a safe, convenient and non invasive alternative to traditional administration systems that can provide a straightforward dosage regimen, relatively slow release of the drug into a patient's system, and control over blood concentrations of the drug. In contrast to oral administration, transdermal delivery typically does not produce the plasmatic peaks and valleys created by oral delivery and G.I. tract absorption. Second, transdermal delivery causes no gastrointestinal irritation, does not present restrictions around the time that the drug should be administered or whether or not the patient may eat afterwards. In particular, once-a-day transdermal delivery offers ease of use and is convenient, without the requirement to remember to take a drug at a specific time. Third, transdermal delivery improves patient compliance for patients who cannot swallow medication, for drugs with unpleasant taste and/or undergoing significant metabolism in the liver; the resulting increased bio-availability, which means that smaller doses may be used for the same drug, is responsible for minimized side effects. In contrast to parenteral administration, transdermal delivery typically does not cause pain and/or anxiety associated with needles, and does not present the risk of introducing infection to treated individuals, the risk of contamination or infection of health care workers caused by accidental needle-sticks and the risk of disposal of used needles.
The advantage of transdermal delivery is particularly enhanced in case of hydrophilic drugs, because of the molecular nature of the G.I. tract. As a lipid membrane, the G.I. tract possesses hydrophobic properties, thus the more hydrophilic a drug is, and the more likely it is to be absorbed poorly through the G.I. tract. A well known example of this problem is sodium alendronate, a bisphosphonate, which needs to be administered in very large doses because only a very small fraction of the drug (about 0.6) % is absorbed indeed when administered orally (please refer to FOSAMAX® Tablets and Oral Solutions Prescribing Information, issued by Merck & Co., Inc., the entire content is incorporated herein for information).
However, despite its clear advantages, transdermal delivery also poses inherent challenges, in part because of the nature of skin. Skin is essentially a thick membrane that protects the body by acting as a barrier. Consequently, passive delivery through intact skin necessarily entails the transport of molecules through a number of structurally different tissues, including the stratum corneum, the viable epidermis, the papillary dermis and the capillary walls in order for the drug to gain entry into the blood or lymph system. Each tissue features a different resistance to penetration, but the stratum corneum is the strongest barrier to the absorption of transdermal and topical drugs. The tightly packed cells of the stratum corneum are filled with keratin. The keratinization and density of the cells may be responsible for skin's impermeability to certain drugs. Transdermal delivery systems must therefore be able to overcome the various resistances presented by each type of tissue.
In recent years, advances in transdermal delivery include the formulation of skin penetration enhancing agents, also known as permeation enhancers. Permeation enhancers are often lipophilic chemicals that readily move into the stratum corneum and enhance the movement of drugs through the skin. Energy-assisted skin permeation techniques also have emerged to improve transdermal delivery, including heat, ultrasound, iontophoresis, and electroporation. But even with these methodologies, only a limited number of drugs can be administered transdermally without problems such as sensitization or irritation occurring.
Transdermal delivery is different from topical delivery. Drugs administered transdermally are absorbed through skin or mucous membranes and provide effects beyond the application site. In contrast, purpose of a topical drug, e.g., antibiotic ointment, anti-acne cream, hair-growing lotion, anti-itching spray, is to administer medication at the site of intended action. Topical medications typically should be designed not to permit significant drug passage into the patient's blood and/or tissues. Topical formulations are often used to treat infections or inflammations. They also are used as cleansing agents, astringents, absorbents, keratolytics, and emollients. The vehicle of a topical treatment, i.e. the non-active component(s) that carries the active ingredient(s), may interact with the active ingredient(s), changing the drug's effectiveness. The vehicle may also cause skin irritation or allergic reactions in some patients. Thus, the vehicle must be selected with extreme care. Topical formulations may be prepared as pastes, gels, creams, ointments, lotions, solutions, or aerosols. Occlusion with household plastic wrap, bandages, plasters, or plastic tape, is often used in conjunction with topical treatments to improve the drug's absorption and its effectiveness. Typically non-occlusive dosage forms are applied to the skin or mucosa and are left uncovered and open in the atmosphere. Because the non-occlusive dosage form is left uncovered, unwanted transfer of the pharmaceutical formulation to the clothing of the user or even to other individuals in close proximity to the user is unavoidable. Other drawbacks of the non-occlusive dosage form include evaporation of the formulation, removal of the formulation from the skin or mucosa, for example, by bathing or by other activities, and the non absorption of the formulation through the skin, which is discussed below.
The inefficiencies of drug permeation across or through the skin or mucosa barriers are known. It is also known that the permeation of a drug in a non-occlusive transdermal or transmucosal dosage form can be as little as 1% and usually is no more than 15%. Thus, a vast majority of the active drug remains unabsorbed on the skin or mucosa surface. Because the vast majority of the drug remains on the skin and does not penetrate the skin or mucosa surfaces, the bioavailability of the particular drug is not optimal, and also a high risk of contamination of other individuals in close proximity to the user is presented by the unwanted transfer of the pharmaceutical formulation in the non-occlusive dosage form.
Problems associated with the unwanted transfer of a particular pharmaceutical formulation to others are well documented. For example, Delanoe et al. reported the androgenization of female partners of volunteers applying a testosterone gel preparation during contraceptive studies (Delanoe, D., Fougeyrollas, B., Meyer, L. & Thonneau, P. (1984): "Androgenisation of female partners of men on medroxyprogesterone acetate/percutaneous testosterone contraception", Lancet 1, 276-277). Similarly, Yu et al. reported virilization of a two-year-old boy after incidental and unintentional dermal exposure to a testosterone cream applied to his father's arm and back (Yu, Y. M., Punyasavatsu, N., Elder, D. & D'Ercole, A. J. (1999): "Sexual development in a two-year old boy induced by topical exposure to testosterone", Pediatrics, 104, 23).
Moreover, the patient information brochure for ANDROGEL® (1% testosterone gel from Unimed Pharmaceuticals Inc.) emphasizes the potential for transfer of testosterone to other people and/or clothing and the brochure includes safety measures to be taken by the individual using the non-occlusive dosage form.
One way to overcome or minimize this contamination issue is to physically protect the transdermal dosage form by covering skin with the applied pharmaceutical formulation means of a patch device, a fixed reservoir, an application chamber, a tape, a bandage, a sticking plaster, or the like, which remain on the skin at the site of application of the formulation for a prolonged length of time. This is usually accomplished with occlusive dosage forms.
Occlusive dosage forms present some advantages over non-occlusive dosage forms such as assisting the rate of penetration of drugs across the skin by maintaining the thermodynamic activity of the drug close to its maximum (the thermodynamic activity of a drug in a dermal formulation is proportional to the concentration of the drug and the selection of the vehicle, and according to the laws of thermodynamics, the maximum activity of a drug is related to that of the pure drug crystal). However occlusive dosage forms also exhibit several major drawbacks. For example, occlusive dosage forms present a high potential of local skin irritation caused by the prolonged contact on the skin of the drug, volatiles, vehicle excipients, and the adhesive used to attach the occlusive device, e.g., the patch, to the skin. In addition, the occlusive nature of certain occlusive dosage forms, such as the patch device, also restrict the natural ability of the skin to "breathe," and thereby increases the risk of irritation.
In addition to the aforementioned drawbacks of occlusive dosage forms, significant serious hazards have been documented regarding the high drug loading that is specific to patches. For example, several cases of abuses with remaining fentanyl in fentanyl patches have been reported. See, Marquardt K. A., Tharratt R. S., "Inhalation abuse of fentanyl patch", J Toxicol Clin. Toxicol. 1994; 32(1):75-8; Marquardt K. A., Tharratt R. S., Musallam N. A., "Fentanyl remaining in a transdermal system following three days of continuous use.", Ann Pharmacother. 1995 October; 29(10):969-71; Flannagan L M, Butts J D, Anderson W H., "Fentanyl patches left on dead bodies—potential source of drug for abusers.", J Forensic Sci. 1996 March; 41(2):320-1. Severe incidental intoxication cases have also been documented. See Hardwick Jr., W, King, W., Palmisano, P., "Respiratory Depression in a Child Unintentionally Exposed to Transdermal Fentanyl Patch", Southern Medical Journal, September 1997.
Patch products typically contain patient information, which clearly indicate the risks discussed above. For instance, OXYTROL™ (an oxybutynin patch commercialized by WATSON Pharmaceuticals, Inc. USA) contains patient information that indicates the following warning: "Since the patch will still contain some oxybutynin, throw it away so that it can not be accidentally worn or swallowed by another person, especially a child." The high level of active drug residues is thus a critical drawback of patches. Such accidents could not occur with the use of gel formulations.
Although attempts have been made to overcome drawbacks associated with both occlusive and non-occlusive drug forms, such attempts have been futile. For example, as noted above, one drawback of non-occlusive dosage forms is evaporation of the formulation, which is left open in the atmosphere. The formulation of non-occlusive supersaturated systems could have achieved an ideal merge but transdermal formulations, which rely on supersaturation technologies, present a major drawback of formulation instability, both prior to and during application to the skin due to solvent evaporation. See Davis A F and Hadgraft J—Supersaturated solutions as topical drug delivery systems, Pharmaceutical Skin Penetration Enhancement, Marcel Dekker Inc, New York (1993) 243-267 ISBN 0 8247 9017 0, which is incorporated herein by reference.
Notably, extraordinary physicochemical changes occur with the evaporation of the solvent system, which result in modifications of the concentration of the active agent, which may even lead to drug precipitation, thereby altering the diffusional driving force of the formulation. See Ma et al, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22 (1995). Consequently, the percutaneous absorption of the active agent may be quite different from that when the solvent was present.
In addition, controlling drug crystallization is of particular interest for non-occlusive transdermal systems. Campbell et al. resorted to a method of heating a crystalline hydrate to a temperature above the melting point in order to prevent the crystallization of the formulation. See, U.S. Pat. No. 4,832,953. Ma et al found that PVP added to the matrix acts as an effective crystallization inhibitor for norethindrone acetate transdermal delivery systems. See, Int. J. of Pharm. 142 (1996) pp. 115-119). DE-A-4210711 affirms that cholesterol and SiO2 are crystallization inhibitors for 17-.beta.-estradiol transdermal delivery system. WO 95/18603 describes soluble PVP as crystal inhibitor for patch devices and affirms that soluble PVP increases the solubility of a drug without negatively affecting the adhesion or the rate of drug delivery from the pressure-sensitive adhesive composition.
Additionally, the inhibition of crystallization in transdermal devices was reported by Biali et al. See, U.S. Pat. No. 6,465,005 in which it is described that the use of a steroid (estradiol for instance) as an additive in a process of manufacture or storage of a transdermal device acts as a crystallization inhibitor during storage of the device.
Further, transdermal delivery from semi-solid formulations faces opposite requirements. The drug delivery system should enable absorption of an extensive amount of active drug through the skin within the shortest period of time in order to prevent contamination of individuals, transfer to clothing or accidental removing. The drug delivery system should also provide sustained release of the active drug over 24 hours ideally, so that only once-daily application is required. This drug delivery system should also prevent drug crystallization at the application surface area.
Drug delivery systems having such properties may be achieved by combining various solvents. A volatile solvent may be defined as a solvent that changes readily from solid or liquid to a vapor, that evaporates readily at normal temperatures and pressures. Here below is presented data for some usual solvents, where volatility is reflected by the molar enthalpy of vaporization ΔvapH, defined as the enthalpy change in the conversion of one mole of liquid to gas at constant temperature. Values are given, when available, both at the normal boiling point tb, referred to a pressure of 101.325 kPa (760 mmHg), and at 25° C. (From "Handbook of Chemistry and Physics, David R. Lide, 79th edition (1998-1999)—Enthalpy of vaporization (6-100 to 6-115). Stanislaus et al. (U.S. Pat. No. 4,704,406 on Oct. 9, 2001) defined as volatile solvent a solvent whose vapor pressure is above 35 mm Mg when the skin temperature is 32° C., and as non-volatile solvent a solvent whose vapor pressure is below 10 mm Mg at 32° C. skin temperature. Examples of non-volatile solvents include, but are not limited to, propylene glycol, glycerin, liquid polyethylene glycols, or polyoxyalkylene glycols. Examples of volatile solvents include, but are not limited to, ethanol, propanol, or isopropanol.
TABLE 1Enthalpy of vaporization of certain solventstbΔvapH (tb)ΔvapH (25° C.)Ethanol78.338.642.3Propan-2-ol (isopropanol)82.339.945.4Propanol97.241.447.5Butan-2-ol99.540.849.7Butan-1-ol117.743.352.4Ethylene glycol mono methyl ether124.137.545.2Ethylene glycol mono ethyl ether135.039.248.2Ethylene glycol mono propyl ether149.841.452.11,2-Propylene glycol187.652.4Not availableDiethylene glycol mono methyl ether193.046.6Not availableDiethylene glycol mono ethyl ether196.047.5Not available1,3-Propylene glycol214.457.9Not availableGlycerin290.061.0Not available
Numerous authors have investigated evaporation and transdermal penetration from solvent systems. For Example, Spencer et al. (Thomas S. Spencer, "Effect of volatile penetrants on in vitro skin permeability", AAPS workshop held in Washington D.C. on Oct. 31-Nov. 1, 1986) established that the relationship between volatility and penetration is not absolute and depends on many parameters such as for instance hydration of the tissue or the solubility of the penetrant in the tissue. Stinchcomb et al. reported that the initial uptake of a chemical (hydrocortisone, flurbiprofen) from a volatile solvent system (acetone) is more rapid than that from a non-volatile solvent system (aqueous solution). With an aqueous solution, close to the saturation solubility of the chemical, the driving force for uptake remains more or less constant throughout the exposure period. Conversely, for a volatile vehicle which begins evaporating from the moment of application, the surface concentration of the chemical increases with time up to the point at which the solvent has disappeared; one is now left with a solid film of the chemical from which continued uptake into the stratum corneum may be very slow and dissolution-limited.
Risk assessment following dermal exposure to volatile vehicles should pay particular attention, therefore, to the duration of contact between the evaporating solvent and the skin (Audra L. Stinchcomb, Fabrice Pirot, Gilles D. Touraille, Annette L. Bunge, and Richard H. Guy, "Chemical uptake into human stratum corneum in vivo from volatile and non-volatile solvents", Pharmaceutical Research, Vol. 16, No 8, 1999). Kondo et al. studied bioavailability of percutaneous nifedipine in rats from binary (acetone and propylene glycol PG or isopropyl myristate IPM) or ternary (acetone-PG-IPM) solvent systems, compared with the results from simple PG or IPM solvent systems saturated with the drug. (Kondo et al. S, Yamanaka C, Sugimoto I., "Enhancement of transdermal delivery by superfluous thermodynamic potential. III. Percutaneous absorption of nifedipine in rats", J Pharmaco Biodyn. 1987 December; 10(12):743-9).
U.S. Pat. No. 6,299,900 to Reed et al. discloses a non-occlusive, percutaneous, or transdermal drug delivery system—having active agent, safe and approved sunscreen as penetration enhancer, and optional volatile liquid. The invention describes a transdermal drug delivery system, which comprises at least one physiologically active agent or prodrug thereof and at least one penetration enhancer of low toxicity being a safe skin-tolerant ester sunscreen. The composition comprises an effective amount of at least one physiologically active agent, at least one non-volatile dermal penetration enhancer; and at least one volatile liquid.
U.S. Pat. No. 5,891,462 to Carrara discloses a pharmaceutical formulation in the form of a gel suitable for the transdermal administration of an active agent of the class of estrogens or of progestin class or of a mixture thereof, comprising lauryl alcohol, diethylene glycol mono ethyl ether and propylene glycol as permeation enhancers.
Mura et al. describe the combination of diethylene glycol mono ethyl ether and propylene glycol as a transdermal permeation enhancer composition for clonazepam (Mura P., Faucci M. T., Bramanti G., Corti P., "Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations", Eur. J. Pharm. Sci., 2000 February; 9(4): 365-72)
Williams et al. reports the effects of diethylene glycol mono ethyl ether (TRANSCUTOL™) in binary co-solvent systems with water on the permeation of a model lipophilic drug across human epidermal and silastic membranes (A. C. Williams, N. A. Megrab and B. W. Barry, "Permeation of oestradiol through human epidermal and silastic membranes from saturated TRANSCUTOL®/water systems", in Prediction of Percutaneous Penetration, Vol. 4B, 1996). Many references may also illustrate the effect of TRANSCUTOL™ as an intracutaneous drug depot builder well known to one skilled in the art.
U.S. Pat. No. 5,658,587 to Santus et al. discloses transdermal therapeutic systems for the delivery of alpha adrenoceptor blocking agents using a solvent enhancer system comprising diethylene glycol mono ethyl ether and propylene glycol.
U.S. Pat. No. 5,662,890 to Punto et al. discloses alcohol-free cosmetic compositions for artificially tanning the skin containing a combination of diethylene glycol monoethyl ether and dimethyl isosorbide as permeation enhancer.
U.S. Pat. No. 5,932,243 to Fricker et al. discloses a pharmaceutical emulsion or microemulsion preconcentrate for oral administration of macrolide containing a hydrophilic carrier medium consisting of diethylene glycol mono ethyl ether, glycofurol, 1,2-propylene glycol, or mixtures thereof.
U.S. Pat. Nos. 6,267,985 and 6,383,471 to Chen et al. disclose pharmaceutical compositions and methods for improved solubilization of triglycerides and improved delivery of therapeutic agents containing diethylene glycol mono ethyl ether and propylene glycol as solubilizers of ionizable hydrophobic therapeutic agents.
U.S. Pat. No. 6,426,078 to Bauer et al. discloses an oil-in water microemulsion containing diethylene glycol mono ethyl ether or propylene glycol as co-emulsifier of lipophilic vitamins.
Many research experiments have been carried out on diethylene glycol mono ethyl ether (marketed under the trademark TRANSCUTOL™ by Gattefosse) as an intracutaneous drug depot builder. For example, Ritschel, W. A., Panchagnula, R., Stemmer, K., Ashraf, M., "Development of an intracutaneous depot for drugs. Binding, drug accumulation and retention studies, and mechanism depot for drugs", Skin Pharmacol, 1991; 4: 235-245; Panchagnula, R. and Ritschel, W. A., "Development and evaluation of an intracutaneous depot formulation of corticosteroids using TRANSCUTOL® as a cosolvent, in vitro, ex vivo and in-vivo rat studies", J. Pharm. Pharmacology. 1991; 43: 609-614; Yazdanian, M. and Chen, E., "The effect of diethylene glycol mono ethyl ether as a vehicle for topical delivery of ivermectin", Veternary Research Com. 1995; 19: 309-319; Pavliv, L., Freebern, K., Wilke, T., Chiang, C-C., Shetty, B., Tyle, P., "Topical formulation development of a novel thymidylate synthase inhibitor for the treatment of psoriasis", Int. J. Pharm., 1994; 105: 227-233; Ritschel, W. A., Hussain, A. S., "In vitro skin permeation of griseofulvin in rat and human skin from an ointment dosage form", Arzneimeittelforsch/Drug Res. 1988; 38: 1630-1632; Touitou, E., Levi-Schaffer, F., Shaco-Ezra, N., Ben-Yossef, R. and Fabin, B., "Enhanced permeation of theophylline through the skin and its effect on fibroblast proliferation", Int. J. Pharm., 1991; 70: 159-166; Watkinson, A. C., Hadgraft, J. and Bye, A., "Enhanced permeation of prostaglandin E2 through human skin in vitro", Int. j. Pharm., 1991; 74: 229-236; Rojas, J., Falson, F., Courraze, G., Francis, A., and Puisieux, F., "Optimization of binary and ternary solvent systems in the percutaneous absorption of morphine base", STP Pharma Sciences, 1991; 1: 71-75; Ritschel, W. A., Barkhaus, J K., "Use of absorption promoters to increase systemic absorption of coumarin from transdermal drug delivery systems", Arzneimeittelforsch/Drug Res. 1988; 38: 1774-1777.
Thus there remains a need to provide a pharmaceutically acceptable transdermal or transmucosal pharmaceutical formulation or drug delivery system that exhibits the advantages of both occlusive systems (high thermodynamic activity) and non-occlusive systems (low irritation and sensitization potential, and excellent skin tolerance) while overcoming the disadvantages of these systems. The novel transdermal or transmucosal pharmaceutical formulation of the present invention satisfies this need.
The present invention is directed to the transdermal administration of a nicotine compound and pharmaceutically acceptable salts thereof. The preferred nicotine compound is nicotine, a well know, highly characterized alkaloid that can be isolated from the dried leaves of Nicotiana tabacum. A variety of patents have disclosed nicotine-containing compositions, such as chewing gums, nicotine-impregnated dermal patches, nicotine inhalers and the like: see, e.g., U.S. Pat. Nos., 7,029,692, 6,995,265, 6,828,336, 6,676,959, 6,596,740, 6,479,076, the entire content of which are incorporated herein as reference. Nicotine, the primary alkaloid in tobacco products binds stereo-selectively to nicotinic-cholinergic receptors on autonomic ganglia, the adrenal medulla, neuromuscular junctions and in the brain. Nicotine exerts two effects, a stimulant effect exerted at the locus ceruleus and a reward effect in the limbic system. Intravenous administration of nicotine causes release of acetylcholine, norepinephrine, dopamine, serotonine, vasopressin, beta-endorphin and ACTH. Nicotine is a highly addictive substance. Nicotine also induces peripheral vasoconstriction, tachycardia and elevated blood pressure. Nicotine inhalers and patches are used to treat smoking withdrawal syndrome. Nicotine is classified as a stimulant of autonomic ganglia. Nicotine, or 1-methyl-2-(3-pyridyl)pyrrolidone, is an oily colourless or pale yellow liquid with a pyridine odour, a molecular weight of about 162, an octanol:water partition coefficient (log P) of about 1.2, a dissociation constant (pKa) of about 3.1, a solubility in water of about and a melting point of approximately −79° C. Nicotine is miscible with water below 60° C. (See monograph of nicotin in Clarke's Analysis of Drugs and Poisons, ©Pharmaceutical Press 2005, the entire content of which is herein incorporated as reference). Nicotine is readily absorbed from the gastro-intestinal tract, the buccal mucosa, the respiratory tract, and intact skin, and widely distributed throughout the tissues. Nicotine undergoes extensive first-pass metabolism when administered orally, thus reducing the bioavailability. Oral bioavailability of nicotine is about 30%.
Nicotine numerous commercial uses include utilities such as a fumigant, an insecticide and the like. It is therapeutically valuable in the treatment of the smoking withdrawal syndrome. Nicotine has also been found therapeutically valuable in the treatment of other conditions involving release of dopamine such as attention deficit hyperactive disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome, schizophrenia, Alzheimer's disease, Parkinson's disease, anxiety and depression (see, e.g., U.S. Pat. Nos. 6,911,475; 6,479,076; 6,034,079, 5,278,176); in the therapeutic angiogenesis and vasculogenesis (see, e.g., U.S. Pat. No. 6,417,205); in the treatment of inflammatory bowel disease (see, e.g., U.S. Pat. No. 6,166,044).
Several drug products containing nicotine are currently marketed (as of July 2006) in the US: see U.S. Food and Drug Administration, Center for Drug Evaluation and Research website, from where the excerpt table herein after is extracted:
DRUG NAMEACTIVE INGREDIENTDOSAGE FORMCOMPANYCOMMITNICOTINETROCHE/LOZENGE;GLAXOSMITHKLINEPOLACRILEXORALCONSHABITROLNICOTINEFILM, EXTENDEDNOVARTISRELEASE;TRANSDERMALNICODERM CQNICOTINEFILM, EXTENDEDSANOFI AVENTIS USRELEASE;TRANSDERMALNICORETTENICOTINEGUM, CHEWING;GLAXOSMITHKLINEPOLACRILEXBUCCALNICORETTENICOTINEGUM, CHEWING;GLAXOSMITHKLINE(MINT)POLACRILEXBUCCALNICOTINENICOTINEFILM, EXTENDEDSANORELEASE;TRANSDERMALNICOTINENICOTINEGUM, CHEWING;PERRIGOPOLACRILEXPOLACRILEXBUCCALNICOTROLNICOTINESPRAY, METERED;PHARMACIA ANDNASALUPJOHNFILM, EXTENDEDRELEASE;TRANSDERMALINHALANT; ORALPROSTEPNICOTINEFILM, EXTENDEDAVEVARELEASE;TRANSDERMAL
However, the herein above drug products, and more particularly transdermal patches, are not free of drawbacks.
Inherently to the occlusive nature of the transdermal patches, nicotine transdermal systems are often reported to cause skin irritation. See, for instance, Greenland et al. in "A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch", Drug Saf. 1998 April; 18(4):297-308: the meta-analysis represented a synthesis of data from 41 groups of nicotine patch recipients totaling 5501 patients, and 33 groups of placebo recipients totaling 3752 patients. The incidences of several minor adverse effects were clearly elevated among the nicotine-patch groups, especially localized skin irritation. See also Smith et al., in "Smoking cessation: a clinical study of the transdermal nicotine patch", J Am Osteopath Assoc. 1995 November; 95(11):655-6, 661-2. See also Frederikson et al., in "High dose transdermal nicotine therapy for heavy smokers: safety, tolerability and measurement of nicotine and cotinine levels", Psychopharmacology (Berl). 1995 December; 122(3):215-22. See also Sudan in "Nicotine skin patch treatment and adverse reactions: skin irritation, skin sensitization, and nicotine as a hapten", J Clin Psychopharmacol. 1995 April; 15(2):145-6. See also Andersen et al. in "Chemical and pharmacologic skin irritation in man: a reflectance spectroscopic study", Contact Dermatitis. 1991 November; 25(5):283-9. See also Gupta et al., in "Bioavailability and absorption kinetics of nicotine following application of a transdermal system", Br J Clin Pharmacol. 1993 September; 36(3):221-7.
Skin irritation caused by nicotine transdermal patches is caused by the intrinsic skin-irritant properties of the drug itself, but also by the occlusive nature of the patch (which prevents the skin from normally "breathing"), and also by the adhesives used to maintain the skin attached to the skin. Indeed, patients are often asked to change regularly the change of application of the patch in order to prevent/minimize such unpleasant local skin reactions
Besides drawbacks commonly associated with transdermal patches, nicotine transdermal patches do also present inherent drawbacks. For instance, Klemsdal et al. ("Physical exercise increases plasma concentrations of nicotine during treatment with a nicotine patch.", in Br J Clin Pharmacol. 1995 June; 39(6):677-9) have demonstrated that because of the occlusion, mean plasma nicotine concentration increased from 9.8 to 11.0 ng ml-1 (P=0.015) during physical exercise, and fell non-significantly from 10.5 to 10.2 ng ml-1 during rest. The increase in plasma nicotine concentration during exercise may be related to an exercise-induced increase in blood flow in the patch area. It is believed that such variations of nicotine mean plasma concentration following physical exercise is minimized and/or prevented if applying non-occlusive nicotine dosage forms.
Prather et al. in "Nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) in women and obese men compared with normal-sized men", J Clin Pharmacol. 1993 July; 33(7):644-9, reported that nicotine Cmax and AUC values were significantly lower in obese compared with normal-sized men, and that nicotine AUC was strongly correlated to body weight and body mass index. It is believed that transdermal semi-solid dosage forms, such as transdermal gels, would minimize such variations of nicotine bioavailability since they offer a greater dosing flexibility by simply increasing or decreasing the dose of gel to be rubbed on the skin.
Woolf et al. reported that 18 children had bitten, chewed, or swallowed part of a transdermal nicotine patch. All four commercial brands of transdermal nicotine patch were represented; no brand was associated with more symptoms or an increased severity of illness. It is also highlighted that pediatric exposures to patches containing other medications, such as clonidine, have been previously reported in the past (see electronic article "Childhood Poisoning Involving Transdermal Nicotine Patches", Pediatrics Vol. 99 No. 5 May 1997, p. e4). Indeed, patient information leaflets of transdermal patches very often emphasize the disposal guidelines of patches, which should be folded in half and thrown away out of the reach of children.
U.S. Pat. No. 4,597,961 describes an occlusive pad comprising a reservoir for liquid nicotine base to be affixed to the skin in a variety of places.
U.S. Pat. No. 5,230,896 describes a transdermal delivery system for nicotine which comprises a nicotine base, an acrylate polymer adhesive, a stabilizer and a polyester film backing.
U.S. Pat. No. 5,603,947 describes a skin or buccal patch for providing nicotine replacement therapy which comprises a matrix type laminated composite in which the matrix is composed of a mixture of nicotine in a polymer.
U.S. Pat. No. 5,633,008 describes a method of administering nicotine transdermally in which a nicotine patch, capable of administering nicotine for at least 16 hours at rates that are efficacious in smoking cessation therapy, is applied in the morning upon waking and removed prior to sleep.
U.S. Pat. No. 5,783,207 describes a nicotine-containing dosage-form comprising an attached holder member which may be used to manipulate the dosage form within the mouth of the patient.
U.S. Pat. No. 5,935,604 describes a nasal drug delivery composition comprising a complex of an ion-exchange material with nicotine or a pharmacologically-acceptable salt or derivative thereof.
U.S. Pat. No. 6,165,497 describes subsaturated rate-controlled transdermal nicotine therapeutic delivery systems which utilize an in-line adhesive to maintain the systems on the skin.
U.S. Pat. No. 6,479,076 describes compositions containing nicotine and an uncrosslinked, water-insoluble vinylpyrrolidone copolymer to be applied on the skin of patients.
U.S. Pat. No. 6,596,740 describes nicotine nasal spray compositions.
U.S. Pat. No. 6,676,959 describes nicotine-containing oral solid pharmaceutical compositions essentially comprising apolar, polar and surface-active components and giving a rapid transmucosal absorption.
U.S. Pat. No. 6,828,336 describes nicotine-containing, controlled release composition in powder form for oral administration from which nicotine release rate is not less than 70% over a 10 minute period.
U.S. Pat. No. 7,029,692 describes transdermal nicotine patches containing monoterpene ketones as odour-improving substances.
No admission is made that any reference, including any patent or patent document, cited in this specification constitutes prior art. In particular, it will be understood that, unless otherwise stated, reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in United States of America or in any other country. The discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinency of any of the documents cited herein.
In view of the aforementioned, there remains a need to provide a pharmaceutically acceptable transdermal or transmucosal pharmaceutical formulation or drug delivery system containing nicotine or pharmaceutically acceptable salts thereof that exhibits the advantages of both occlusive systems (high thermodynamic activity) and non-occlusive systems (low irritation and sensitization potential, and excellent skin tolerance) while overcoming the disadvantages of these systems. The novel transdermal or transmucosal pharmaceutical formulation of the present invention satisfies this need.
The formulations of the present invention as described herein below provide a number of advantages for the transdermal delivery of nicotine and its derivatives. These include, but are not limited to, continuous, steady-state delivery, which can provide sustained blood levels of the agent(s).

This patent is subject to a terminal disclaimer.

Pharmaceutical compositions of nicotine and methods of use thereof


Aspects of the disclosure relate generally to using a primary and secondary authentication to provide a user with access to protected information or features. To do so, a computing device may generate depth data based on a plurality of images of a user. The computing device may then compare the generated depth data to pre-stored depth data that was generated based on a pre-stored plurality of images. If authentication is successful, the user may be granted access to features of the computing device. If authentication is unsuccessful, then a secondary authentication may be performed. The secondary authentication may compare facial features of a captured image of the user to facial features of a pre-stored image of the user. If authentication is successful, then the primary authentication may be performed again. This second time, the user may be granted access if authentication is successful, or denied access if authentication is unsuccessful.

Security systems for computing devices may authenticate a user before providing access to information or features associated with a computing device. For example, some systems implement username and passwords or PIN numbers as a means for authentication. Other systems employ biometrics as a security function through the use of fingerprint verification or facial recognition. However, in some examples, these systems may be bypassed using an image to spoof the authentication.


Mechanical overloads in a reciprocating gas compressor can cause irreparable damage to compressor components if the source of the overloads is not repaired. A method of detecting mechanical overloads includes forming a mechanical fuse that is configured to strain under overload conditions, and observing a condition of the mechanical fuse. The condition of the mechanical fuse is indicative of whether the compressor experienced a mechanical overload. By simply observing the mechanical fuse, overload conditions can be checked during routine inspections and maintenance checks.

The invention relates to gas compressor maintenance and reliability and, more particularly, to a method for prevention/detection of mechanical overload in a reciprocating gas compressor.
An overload condition in a gas compressor can cause damage to compressor components that may affect operation and efficiency of the compressor. Repeated overload occurrences can compound damage to the compressor components, often beyond repair.
Currently, there is no ability beyond observing normal operation of the compressor to determine whether the compressor experienced an overload event. For example, excessive vibration during operation of the compressor provides evidence of a problem, which may have been caused by an overload condition after which the compressor can be shut down and inspected. At this point, however, equipment damage may be beyond repair.
It would thus be desirable to enable detection of an overload condition during routine maintenance and inspection of the compressor so that the problem or defect in the compressor components can be corrected before further damage is caused due to persistent overload events.

Method for prevention/detection of mechanical overload in a reciprocating gas compressor


A steering system for a machine having at least one steerable traction device is disclosed. The steering system may have a steering actuator operatively connected to the at least one steerable traction device, and a travel speed sensor configured to generate a signal indicative of a travel speed of the machine. The steering mechanism may also have an operator input device having a deadzone. The deadzone may vary in response to the signal. The steering system may also have a controller in communication with the steering actuator, the operator input device, and the travel speed sensor. The controller may be configured to affect operation of the steering actuator in response to operation of the operator input device only when the operation of the operator input device deviates from the deadzone.

Mobile machines, including wheel loaders, haul trucks, motor graders, and other types of heavy equipment, are used for a variety of tasks. In order to accomplish these tasks, the machines typically include hydraulic and/or electric actuators that cause the machine to steer. For example, a machine may include an articulated joint and one or more associated hydraulic cylinders connected between the joint and a frame of the machine. In response to an operator input to a control system, the hydraulic cylinders expand and retract to cause a forward end of the machine to pivot about the articulated joint relative to a back end of the machine, thereby steering the machine. In another example, the machine may include one or more wheels that pivot at a vertical joint between the wheel and the frame. One or more hydraulic cylinders may be connected between the wheel and the frame of the machine to expand and retract in response to the operator input to a control system, thereby causing the wheel to pivot about the joint and steer the machine.
The steering of the machine may be controlled through a number of different strategies. One strategy includes controlling a steering position of the machine based on a positional input of the operator. In other words, as the operator turns a steering wheel or tilts a joystick lever a particular angle away from a neutral position, the articulated joint or wheel is pivoted an amount corresponding to the particular angle. Another strategy includes controlling a steering speed of the machine based on a speed input of the operator. That is, as the operator manipulates the steering wheel or joystick lever, a speed of the manipulation may be determined and the pivot speed of the articulation joint or wheel correspondingly controlled.
Regardless of which strategy is utilized to effect steering of the machine, it may be beneficial to modify the steering gain (i.e., the ratio of steering output actuation to steering input) and/or the steering deadzone (i.e., the minimum displacement amount away from the neutral position or the minimum input speed of the steering wheel or joystick required before steering of the machine is effected) in response to a travel speed of the machine. For example, when moving at low speeds, the operator may want the gain to be high and the deadzone small for responsive steering. In contrast, when moving a higher speeds, the operator may desired the gain to be smaller and the deadzone larger to prevent unintentional steering and minimize over corrections.
Examples of a positional input steering system and a velocity input steering system utilizing variable gain is disclosed in U.S. Patent Publication No. 2005/0139412 (the '412 publication) by Vigholm published on Jun. 30, 2005. The '412 publication describes a wheel loader having an articulation point and being steered by adjustment of an angle between two drive axles relative to the articulation point. A steering wheel and a steering lever are provided in parallel for steering control of the wheel loader. When either the steering wheel or steering lever are moved from a neutral position, the position of the steering wheel and lever are sensed. Based on the sensed position, the angle between the drive axles is correspondingly adjusted.
The magnitude of the angle between the drive axles described in the '412 publication and the speed at which the angle is adjusted depend on a travel speed of the wheel loader. That is, when the wheel loader is traveling relatively slow, upon moving either the steering wheel or lever to a particular position, the corresponding adjustment angle is greater and is achieved more slowly than when the wheel loader is traveling faster. In this manner, a large gentle-feeling steering deflection is provided to the operator at slow speeds, while a quick, yet controllable deflection is provided to the operator at high speeds.
The '412 publication also describes that the speed at which the adjustment angle is achieved can be affected by the steering speed input of the operator. In other words, if an operator turns the steering wheel quickly to a predetermined position, the corresponding adjustment angle will be achieved quicker than if the operator turns the steering wheel slowly.
Although the wheel loader steering system of the '412 publication may describe two alternate steering strategies (i.e., position input-position controlled and velocity input-velocity controlled), it may be limited. In particular, the system of the '412 publication does not allow the two alternate strategies to be selectively implemented within the same machine or with the same steering input device (i.e., the steering wheel or lever). There may be situations when an operator desires the velocity input of the steering wheel or lever to effect the adjustment angle such as when traveling at high speeds, and other situations when the operator desires the velocity input to have no affect such as when traveling at low speeds. In addition, when both the steering wheel and lever are provided on the same machine, an operator may desire the steering wheel input velocity to affect the adjustment angle of the wheel loader, but the steering lever velocity to have no affect on the adjustment angle. The wheel loader steering system of the '412 publication does not provide the operator with these capabilities. In addition, the '412 publication does not describe a deadzone, or a travel speed of the wheel loader affecting the deadzone.
The disclosed steering system is directed to overcoming one or more of the problems set forth above.

Steering system having multiple strategies and variable deadzone


The invention is a method and apparatus for the detection of terahertz radiation. In one embodiment, frequency modulated spectroscopy is performed on a swept source of coherent far infrared electromagnetic radiation that is focused on a target. A beam of radiation passes through a cell in which the target is housed, losing energy as certain frequencies are absorbed by contaminants in the target. A detector is positioned to determine how much energy is lost by the radiation (e.g., which frequencies fail to transmit through the cell), thereby indicating the presence of contaminants in the target.

There is an increasing demand for systems for military, private or individual use that are capable of detecting and analyzing chemical and biological contaminants, such as explosives (e.g., TNT or DNT). One method of detecting such contaminants uses rotational microwave spectroscopy. The rotational and vibrational modes of molecules (e.g., contaminant molecules) have energies that naturally correspond to energies of photons in a spectrum of radiation. A source generates radiation that interacts with contaminant molecules present in a "target" to be analyzed, so that specific frequencies of emitted radiation are absorbed by the molecules. A detector is positioned to identify the frequencies that fail to transmit through the target, and the failure of a particular frequency to transmit can indicate the presence of a specific absorbing contaminant.
The far infrared (or terahertz) spectrum of radiation is particularly well-suited for use in systems such as that described above, because the spectrum corresponds to the vibrational and rotational modes of many chemicals, including explosives, and contains a great deal of signature information. Unfortunately, work in the terahertz spectrum is made extremely difficult and inconvenient by a lack of coherent sources of radiation that can operate continuously and tune over a wide range of the terahertz wavelength spectrum.
Therefore, there is a need in the art for a terahertz system that can be used to detect the presence of chemical and biological contaminants.

Method and apparatus for the detection of terahertz radiation absorption


A sensing cable is provided which includes exposed and/or unexposed optical fibers or wires disposed through the length of the sensing cable. The sensing cable includes a slotted core which is a one-piece integral member having a plurality of channels formed on a perimeter of the slotted core and which extend along a length of the slotted core. The sensing cable includes at least one exposed component which is disposed in a first channel of the plurality of channels and which extends along a length of the first channel. The sensing cable includes at least one unexposed component which is encased by a protective member, and the unexposed component and the protective member are disposed in a second channel of the plurality of channels. The unexposed component and the protective member extend along a length of the second channel.

1. Field
The present invention generally relates to sensing cables, and more particularly, to sensing cables which detect external pressure and strain.
2. Description of the Related Art
In recent years optical fibers have been used for sensing the distribution of temperature in oil and gas downhole and logging cables. Temperature sensing using distributed temperature sensing with optical fiber is a well mown technology. Generally in this system, a cable containing an optical fiber encased in a stainless steel tube (SST) is used. In this cable structure, the optical fiber is protected by the SST from external pressures and strain. Using optical fibers for measuring external pressure and strain is desired by the oil and gas industry for both downhole and logging applications. Brillouin Optical Time Domain Reflectometry (BOTDR) analyzing systems for sensing temperature and pressure distribution at the same time is under development. However, detecting external pressure and strain are both extremely difficult due to inaccuracies and dependability of the cable structure and/or fiber.
This disclosure illustrates new cable designs that address these concerns, but the invention is not limited to these specific applications, nor is the invention required to address any of these concerns.


A common command interface (CCI) provides an interface abstraction allowing network device applications to maintain one set of code for each command regardless of which command interface (e.g., web, CLI, NMS, etc.) initiates the command. That is, the command code in each application may be shared across multiple command interfaces. The interface abstraction allows new applications including additional commands to be added to a network device and existing applications to be dynamically upgraded to include new and/or modified commands without having to modify the CCI. Thus, the network device may provide the increased flexibility of having multiple command interfaces while minimizing the complexity required to maintain commands across those interfaces. In addition, a community command interface may be used to connect the common command interfaces of multiple network devices.

Initially, telecommunications and data communications equipment (hereinafter referred to as network devices) were administered/controlled through a Command Line Interface (CLI) that provided the user (i.e., administrator) with a textual interface through which the administrator could type in commands. CLI connections are typically made either directly with the device through a console or remotely through a telnet connection. With the growth of the Internet, web interfaces were also created to allow administrators to remotely control network devices through web pages. In general, web interfaces provide easier access with a more visually rich format through Hypertext Markup Language (HTML). For example, commands may be grouped and displayed according to particular categories and hyperlinks may be used to allow the administrator to jump between different web pages.
To accommodate the preferences of a large number of users and because both interfaces have advantages, often, both a CLI interface and a web interface are provided to a network device. Additional interfaces may also be provided. This flexibility, however, can be costly to maintain because although many of the commands provided on the interfaces are the same, the applications corresponding to the commands must include separate code for each interface. Thus, within, for example, an Asynchronous Transfer Mode (ATM) application, a command such as "Show ATM Stats" is essentially multiple commands: a different one for each interface. While some functions may be shared, for the most part the code for each command/interface is separate. Thus, if a command needs to be changed or upgraded, each set of code must be modified. Similarly, to add a single, new command, the application writer must develop a set of code for each interface.
In addition, applications running on the network device must maintain an Application Programming Interface (API) for each external interface and must be knowledgeable about the source of each received command so that responses will be provided in the appropriate format, for example, HTML for a web interface or ASCII for a CLI. If an interface is modified or the interaction between the interface and the command within the application changes, the application will likely need to be changed. For certain software architectures, this may require a new release of the software running the network device, and the network device may need to be brought down while the software is re-installed. Thus, providing different types of interfaces increases flexibility but also increases the complexity of maintaining consistent commands across each interface and the complexity of responding to commands.