MX2007009838A

MX2007009838A - Device for delivery of trpv1 agonists

Info

Publication number: MX2007009838A
Application number: MXMX/A/2007/009838A
Authority: MX
Inventors: Curtis Jamieson Gene; Muhammad Naweed; R Bley Keith
Original assignee: R Bley Keith; Curtis Jamieson Gene; Muhammad Naweed; Neurogesx Inc
Priority date: 2005-02-14
Filing date: 2007-08-14
Publication date: 2008-10-03

Abstract

Described here are drug delivery devices including an occlusive backing layer and a drug depot containing a TRJPVl agonist and a non-hydrophilic solvent. The drug depot may take various forms, such as an adhesive polymeric matrix, liquid reservoir, or microreservoir droplets. Methods of making and using the drug delivery devices are also described.

Description

DEVICE FOR THE DISTRIBUTION OF TRPVL AGONISTS FIELD OF THE INVENTION The devices and methods described herein are in the field of drug administration. More specifically, the devices and methods relate to the dermal distribution of capsaicin and other TRPV1 agonists for pain relief.

BACKGROUND OF THE INVENTION The transient receptor potential vanilloid receptor 1 (TRPV1) is a ligand entry cation channel responsive to capsaicin, selectively expressed on small, unmyelinated peripheral nerve fibers (cutaneous nociceptors) (see, Caterina and Julius, 2001, "The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway," Annu Rev Neurosci, 24: 487-517; and Montell et al., 2002, "A unified nomenclature for the superfamily of TRP cation channels," Mol Cell, 9: 229-31). When TRPV1 is activated by agonists such as capsaicin and other factors such as heat and hydrogen ions, calcium enters the cell and pain signals are initial. Capsaicin and other TRPVl agonists can be effective for the improvement of a plurality of conditions. For example, capsaicin can be used Ref. : 185469 to treat various types of pain, such as neuropathic and chronic pain (including pain associated with diabetic neuropathy, postherpetic neuralgia, human immunodeficiency virus (HIV) infection, traumatic injury, regional pain syndrome complex, trigeminal neuralgia, erythromelalgia and phantom pain), pain produced by mixed nociceptive and / or mixed neuropathic etiologies (for example, cancer, osteoarthritis, fibromyalgia, lower back pain, inflammatory hyperalgesia, vulvar vestibulitis or vulvodynia, interstitial polyps cystitis Breast, neurogenic or overactive bladder, prosthetic hyperplasia, rhinitis, surgery, trauma, rectal hypersensitivity, mouth burning syndrome, oral mucositis, herpes (or other viral infections), prosthetic hypertrophy and headaches (see, Szallasi and Blumberg , 1999, "Vanilloid (Capsaicin) Receptors and Mechanisms," Pharm Revs, 51: 159-211; Backonja et al., "A Single One Hour Application of High-Concentration Capsaicin Patches Leads to Four Weeks of Pain Relief in Postherpetic Neuralgia Patients" American Academy of Neurology, 2003 (find extract); Berger et al., 1995, J Pain Symptom Management 10: 243-8). In addition, capsaicin can be used to treat skin conditions such as dermatitis, pruritus, itching, psoriasis, warts and wrinkles, as well as conditions such as tinnitus and cancers. (especially skin cancers) (see, Bernstein et al., 1986, "Effects of Topically Applied Capsaicin on Modérate and Severe Psoriasis Vulgaris," J Am Acad Dermatol 15: 504-507; Ellis et al., 1993, "A Double -Blind Evaluation of Topical Capsaicin in Pruritic Psoriasis, "J Am Acad Dermatol 29: 438-42; Saper et al., 2002, Arch Neurol 59: 990-4; and Vass et al., 2001, Neuroscience 103: 189-201; Moller, 2000, "Similarities between severe tinnitus and chronic pain" J Am Acad Audiol 11: 115-24). Numerous drug delivery devices have sought to distribute capsaicin. For example, U.S. Patent No. 6,239,180 to Robbins discloses the use of a drug delivery device comprising capsaicin and / or a capsaicin analogue at a concentration greater than 5% by weight for the treatment of neuropathic pain. WO 2004/089361 to Müller discloses a topical patch comprising a therapeutic backup layer impermeable to the compound, a polysiloxane matrix containing capsaicin and an amphiphilic solvent, and a protective film to be removed before use. In addition, U.S. Publication No. 2005/0090557 to Muhammad et al. describes the distribution and pharmacological properties of topical liquid formulations of TRPV1 agonists. However, none of these references describes the distribution of capsaicin with the help of non-hydrophilic penetration enhancers in patch formulations. Specifically, none of these references disclose the use of an occlusive backing to increase the distribution of the insoluble compounds in water through the skin. The use of an occlusive backing layer to stop / minimize the escape of water from the skin, or in other words, to substantially prevent the loss of transepidermal water (TEWL), is known to those skilled in the art. technique. It is also known that the retention of this water results in hydration of the stratum corneum and in turn increases the permeability of the skin to penetrants such as drug molecules (see Roberts et al. (1993) Water: The Most Natural Penetartion Enhancer In: Pharmaceutical Skin Penetration Enhancement, Eds. KA Walter and J. Hadgraft, Marcel Dekker, New York, pp. 1-30). However, the use of this exhaust water and non-hydrophilic penetration enhancers to increase the thermodynamic activity of the drug reservoir has not been described. Accordingly, it would be desirable to have occlusive patches that include non-hydrophilic penetration enhancers for the distribution of capsaicin and other TRPV1 agonists for the treatment of pain and other conditions.

BRIEF DESCRIPTION OF THE INVENTION The present invention describes the devices and methods for the distribution of drugs to administer capsaicin and other TRPV1 agonists. In general, drug delivery devices include a therapeutically effective amount of an active agent for dermal distribution, which is useful for the treatment of pain. The devices are usually configured for topical application and to provide local administration of the drug to the area in need of treatment. Drug delivery devices can be formulated as any conventional patch, e.g., polymer matrix, adhesive or reservoir, and made by methods well known in the art. In all cases, however, the devices include an occlusive backrest, which substantially prevents transepidermal water loss and a non-hydrophilic penetration enhancer. The patches typically include capsaicin, but may also be formulated to prepare other TRPV1 agonists such as, but not limited to, capsaicinoids, capsaicin analogues, and capsaicin derivatives. The patches may include a TRPV1 agonist in an amount of at least about 0.04%, at least about 2%, at least about 4%, at least about 6%, at least about 8%, at least about 10%, at least about 20%, or at least about 30% by weight of the drug reservoir of the device. The particular non-hydrophilic penetration enhancer employed in the patches will also vary, depending on factors such as the type of device (e.g., the polymer matrix, the liquid reservoir, etc.), the adhesive used, and the like, but in all cases it will have a ClogP value greater than 1.0. Drug delivery devices can be used to treat various conditions. For example, these may be used to treat various types of pain such as, but not limited to, neuropathic and chronic pain (including pain associated with diabetic neuropathy, postherpetic neuralgia, HIV infection, traumatic pain, complex regional pain syndrome, neuralgia). trigeminal, erythromelalgia, and phantom pain), pain produced by mixed nociceptive and / or mixed neuropathic etiologies (eg, cancer, osteoarthritis, fibromyalgia, lower back pain, inflammatory hyperalgesia, vulvar vestibulitis or vulvodynia, interstitial cystitis due to breast polyps , neurogenic or overactive bladder, prosthetic hyperplasia, rhinitis, surgery, trauma, rectal hypersensitivity, burning in the mouth, oral mucositis, herpes (or other viral infections), prosthetic hypertrophy, headache). Drug delivery devices can also distribute an active agent to treat conditions such as dermatitis, pruritis, itching, psoriasis, warts and wrinkles, as well as conditions such as tinnitus and cancers (especially skin cancers). Methods for treating pain are also described. In some variations, the methods include the application of a drug delivery device having a TRPV1 agonist, a non-hydrophilic penetration enhancer with a ClogP value greater than 1.0, and an occlusive backing to the skin or mucous membrane of a subject , and the distribution of a therapeutically effective amount of the TRPV1 agonist to alleviate pain. The TRPV1 agonist may be distributed in periods of at least about 15 minutes, or periods greater than about 15 minutes, greater than about 30 minutes, greater than about 1 hour, greater than about 4 hours, greater than about 6 hours, greater than about 12 hours, greater than about 18 hours, or greater than about 24 hours or more.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a type of micro deposit of drug delivery device including a waterproof backing layer 1, a self-adhesive matrix comprising an active agent dispersed in the form of microdeposition droplets 2, and a protective film 3 to be removed before use. Figure 2 depicts a monolithic type of drug delivery device that includes a waterproof, backup layer 1, a monolithic matrix that acts as a reservoir of active agent, by which the active agent has been dissolved and / or dispersed in a polymer matrix forming a solid or gel-like mass 2, an adhesive layer 4, and a protective film to be removed before use 3. This may have an optional infusion rate control membrane (not shown) between 2 and 4 Figure 3 illustrates a monolithic type of drug delivery device comprising a waterproof backing layer 1, a monolithic matrix that acts as an active agent reservoir, whereby the active agent has been dissolved and / or dispersed in a polymeric matrix forming a mass similar to a gel or solid mass 2, a membrane 5 that controls the rate of diffusion, an adhesive layer 4 in the periphery, such that the membrane of control d e the speed of diffusion comes into direct contact with the surface of the skin on one side, and the monolithic matrix on the other side, and a protective film 3 to be removed before use. It should be noted that the waterproof backing layer 1 is heat sealed with the speed control membrane 5 of the diffusion, thereby creating a bag in which the monolithic matrix is enclosed. Figure 4 shows a type of liquid reservoir of the drug delivery device, comprising an impermeable backing layer 1, a liquid reservoir that acts as an active agent reservoir through which the active agent has been dissolved, complete or partially, in a penetration enhancer or a mixture thereof 2, and a diffusion rate control membrane 5, an adhesive layer 4, and a protective film 3 to be removed before use. Figure 5 depicts a type of liquid reservoir of the drug delivery device comprising an impermeable backing layer 1, a liquid reservoir that acts as an active agent reservoir, through which the active, complete or active agent has been dissolved. partially, in a penetration enhancer or a mixture thereof, a membrane 5 controlling the rate of diffusion, an adhesive layer 4 of the periphery such that the membrane controlling the velocity of diffusion comes into direct contact with the surface of the skin on one side, and the deposit of the liquid on the other side, and a protective film 3 to be removed before use 3. It should be noted again thatthe waterproof backing lid 1 is heat sealed with the membrane 5 which controls the diffusion rate, thereby creating a pouch in which the active agent containing the reservoir 2 of the liquid is enclosed. Figure 6 shows the in vitro release in deionized water of capsaicin from six microdeposit patches in 18 hours. Each patch contained a different concentration of capsaicin. The following concentrations of capsaicin (by weight of the drug deposit) were tested: 0.04%, 2%, 4%, 6%, 8%, and 10%. Figure 7 shows the in vitro release to deionized water of capsaicin from six monolithic patches in 24 hours. Each patch contained a different concentration of capsaicin. The following concentrations of capsaicin (by weight of the drug deposit) were tested: 0.04%, 2%, 4%, 6%, 8%, and 10%. Figure 8 shows a selective portion of the graph in Figure 7 to better illustrate the shape of the curves at the early time points (eg, 30 minutes, 1 hour and 3 hours).

DETAILED DESCRIPTION OF THE INVENTION The drug delivery devices described herein can be of any configuration, as long as they include an enhancer of non-hydrophilic penetration and distribute a therapeutically effective amount of an active agent for a stated condition, eg, pain or a skin condition. In general, the devices are patches that are configured to have an occlusive backing layer, a non-hydrophilic penetration enhancer, a partially or completely dissolved active agent in the non-hydrophilic penetration enhancer, such that the resulting composition forms the drug dispersed in an adhesive, or is a liquid reservoir or a monolithic matrix, etc., and a releasable release coating. As mentioned previously, the incorporation of an enhancer into the non-hydrophilic penetration within an occlusive patch is believed to improve the thermodynamic activity of the drug reservoir. Yet another advantage of using a non-hydrophilic penetration enhancer refers to the diminished appearance that its inclusion has on the hydrolysis of the active agents. The asters and amides are particularly sensitive to hydrolysis. Capsaicin and capsaicinoids are amides. Therefore, it is desirable to have anhydrous formulations of the pharmaceutical products containing capsaicin, in order to ensure longer shelf lives. Also, the hygroscopicity exhibited by the amphiphilic and hydrophilic solvents makes it difficult to ensure that the ingredients of the products Pharmaceuticals will be free of water during procurement, storage and manufacturing. For example, drying the patches to evaporate the solvents used to dilute the adhesives is often conducted at relatively low temperatures (eg, up to 40 ° C) which can not effectively remove any water vapors present in the formulations . This consideration makes hydrophilic and amphiphilic skin penetration enhancers less desirable for use in many different types of dosage forms including dermal and transdermal patches. In addition, amphiphilic and hydrophilic skin penetration enhancers such as ethanol, acetone, and DMSO are known to preferentially divide into the intracellular domains of the corneal extract. In contrast, non-hydrophilic skin penetration enhancers are more likely to interspersed within the structured lipids of the corneous extract and disrupt the packing of corneous cells without effectively permeabilizing the corneal cells (see Rolf Daniels, "Strategies for skin penetration enhancement, "Skin Care Forum, Issue 37, August 2004). Consequently, lower levels of skin damage or irritation may be associated with the use of non-hydrophilic skin penetration enhancers.

As used herein, the terms "active agent", "active agent", "drug", "therapeutic compound" are used interchangeably, and refer to capsaicin, other TRPV1 agonists, or combinations thereof. By "therapeutically effective amount" is meant an amount of drug effective to treat pain or any other indicated condition. In addition, as used herein, the term "drug reservoir" refers to that portion or layer of the drug delivery device in which the drug is incorporated, and excludes the occlusive backing layer, or release liner, and the diffusion velocity control membrane. It also excludes the adhesive when the drug is not present in the adhesive. The terms "penetration enhancer" and "solvent" are used interchangeably, and refer to any compound (liquid or solid) that increases the penetration of a molecule (eg, a drug molecule) into the skin excluding the following: butanediols, such as 1, 3 - butanediol, dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, propylene glycol, dipropylene glycol, tri- and diethylene glycol carboxylic acid esters, 6-18 polyethoxylated fatty alcohols carbon atoms, 2,2-dimethyl-4-hydroxymethyl-l, 3-dioxolan (Solketal®), and mixtures thereof. In addition, as used herein, the term "treat", "treatment", or "treatment" refers to the resolution or reduction of pain or symptoms or the underlying cause of a condition, or the prevention of a condition. Conditions for which capsaicin or other treatment with TRPVl agonist may be indicated include, but are not limited to, neuropathic pain, (including pain associated with diabetic neuropathy, postherpetic neuralgia, HIV / AIDS, traumatic injury, regional pain syndrome complex, trigeminal neuralgia, erythromelalgia and phantom pain), pain produced by nociceptive and / or mixed neuropathic etiologies (eg, cancer, osteoarthritis, fibromyalgia and lower back pain), headache, inflammatory hyperalgesia, interstitial cystitis, and conditions of the skin such as dermatitis, pruritis, itching, psoriasis and warts. In general, drug delivery devices containing capsaicin or another TRPV1 agonist can be used to treat any condition for which topical administration of capsaicin is beneficial. As used herein, the terms "topical", "topical administration" and "topically" refer to the local administration of capsaicin or other TRPV1 agonists to the skin or membrane mucous At the time of application, the release liner is first removed from the patch. The patch is then placed on the skin or on the mucosal surface to be treated, with the occlusive backing that is opposite the skin or the mucosal surface. If desired, a gentle pressure can be applied to the patch to ensure adhesion of the patch. The release liner is usually made from a drug impermeable, and is configured to be a disposable element, which serves only to protect the device prior to application. 1. FARMACO DISTRIBUTION DEVICES As mentioned above, the drug delivery devices described herein can be in any form, as long as they include an occlusive back-up, a non-hydrophilic penetration enhancer, and distribute a therapeutically effective amount. of a drug. In general, the backing can be adapted to provide varying degrees of flexibility to the device, according to the needs of the desired application. The functions of the backup layer are to provide an occlusive barrier that prevents the loss of transepidermal water, the drug and the penetration enhancer (s) not hydrophilic to the environment, and that protect the patch. The material chosen for the backing must show minimal permeability of the pharmaceutical compound and the enhancer and must not be incompatible with them or with the adhesive. Ideally, the backing material should be capable of forming a backing on which the drug-containing mixture can be emptied and to which it will securely bond during manufacture, storage and use. Examples of such materials include, but are not limited to, polyurethane, polyethylene, ethylene vinyl acetate, pigmented polyethylene plus polyester with / without aluminum and polyester vapor coating, with ethylene / vinyl acetate copolymer. The examples of trademarks CoTranMR and ScotchpakMR that are backup films. As an alternative to emptying the matrix directly onto the backing layer, the matrix can be emptied separately and subsequently adhered to the backing material. In one variation, the drug delivery device is a matrix system. Matrix systems are characterized (in the simplest case) by an occlusive backing layer impervious to the active agent (eg, the compound to be delivered to the subject), a layer containing the active ingredient, and a coating of release that is going to be removed before use. The cap that contains the active agent completely or partially dissolved and is ideally self-adhesive. The matrix systems can be composed of a number of layers and can include a control membrane. Adhesive polymers suitable for use in this type of system include, but are not limited to, polyacrylates, polysiloxanes, polyurethanes, polyisobutylenes, and combinations thereof. The matrix systems can be multiple layers in which the concentrations of the active agent differ in the different layers; such construction serves to modify the release profile of the active agent over time. The adhesive used in an adhesive matrix type distribution device can be selected from a variety of adhesives commercially available and known to those skilled in the art. For example, the common adhesives are those based on polyisobutylene, polyacrylate and polysiloxane. The adhesives can be even hydrophilic, such as high molecular weight polyethylene oxide or polyvinylpyrrolidone. The selection of the adhesive is critical to realize a functional, adhesive matrix drug delivery device. The non-hydrophilic penetration enhancers and the drug are loaded directly into the adhesive and thus the adhesive must retain its properties chemical, viscoelastic and adhesive in the presence of these additives. The adhesive properties include sufficient adhesion for good instant adhesion to the skin as well as maintenance of adhesion. It is often observed that adhesives become leathery and viscous in the presence of skin permeation enhancers, leading to cohesive failure and residual adhesive left on the skin of the patient after removal of the device. In some cases, the device loses adhesion completely and falls off. The loss of stickiness and adhesion properties dictates in general and limits the amount and type of non-hydrophilic enhancers that can be loaded into the adhesive matrix type distribution device. Some acrylate-based adhesives, such as those available from Avery and National Starch and Chemical Company, are capable of withstanding relatively high loads of non-hydrophilic, solvent-type and plasticizing type augmentants. In addition, Bio-PSAs from Dow-Corning are also compatible with hydrophilic penetration enhancers. Figure 1 shows an adhesive matrix type patch including an occlusive backing layer 1 and a layer of adhesive matrix 2 which serves as a reservoir for the active agent and a means of adhesion of the device to the skin. The adhesive matrix layer 2 containing the active agent can include the drug dispersed in the polymeric matrix adhesive 2. As used herein, the term "dispersed" or "dispersed" refers to the distribution of the drug throughout the length of the matrix. The drug can be dispersed in a dissolved and / or undissolved state. In still another variation, the drug delivery device is a monolithic matrix device, as shown in Figures 2 and 3. In a monolithic device, the different material of the adhesive serves as the drug reservoir. Hydrogel materials such as the matrix material can be used for these distribution devices. For example, polyurethane, gelatin and pectin can be used. The drug reservoir can also be formed in materials such as ethylcellulose, hydroxypropylcellulose (with consistencies ranging from a gel-like to a solid mass). Such drug reservoirs may contain relatively large volumes of non-hydrophilic penetration enhancers or mixtures thereof, necessary to effect drug delivery. In the case of a drug reservoir having a gel-like consistency, a membrane that controls the rate of diffusion can be included to interconnect with the surface of the skin and the reservoir. In the case of solid / solid deposit the use of the membrane that checks the diffusion speed is also optional. With reference now to Figures 2 and 3, the Monolithic matrix drug delivery device comprises an impermeable backing layer 1, a monolithic matrix layer 2, a membrane 5 controlling the diffusion rate, optionally and an adhesive layer 4. The backing 1, the membrane 5 and the layer adhesive 4 are selected as described above. One of the functions of the membrane that controls the diffusion rate is to provide the structural support for the adhesive layer which simplifies the manufacture of the device. The monolithic matrix layer is distinguished from the adhesive matrix of Figure 1, where the monolith serves as the drug reservoir and the skin adhesive is interconnected between the release liner and the monolith. In some cases, as shown in Figure 3, the adhesive layer 5 can be applied to the periphery of the patch so as not to come into contact with non-hydrophilic penetration enhancers. This is particularly desirable in situations where a high load and / or nature of non-hydrophilic penetration enhancers can interfere with adhesion. Monolithic matrix materials are generally those materials capable of maintaining a large volume of liquid such as non-hydrophilic penetration enhancers, used. Suitable materials are polymers such as methacrylate mixtures of hydroxyethyl (HEMA) and ethyl methacrylate (EMA), polyvinyl alcohols, polyvinyl pyrrolidine, gelatin, pectin, and other hydrophilic materials. The microporous particles can be incorporated into the polymer monolith to retain the solvent type augmentations used. The use of microporous particles in transdermal patches is described by Katz et al. in U.S. Patent No. 5,028,535, Sparks et al. in U.S. Patent No. 4,952,402, and Nuwayser et al. in U.S. Patent No. 4,927,687, all of which are incorporated by reference herein, in their entirety. The non-hydrophilic penetration enhancers and the drug can be loaded onto the microporous particles prior to incorporation into the hydrophilic polymer. The particles can then be uniformly dispersed throughout the matrix by mixing. At high particle loads, the release of the therapeutic compound and the non-hydrophilic penetration enhancer is increased due to the formation of channels in the polymer matrix. Suitable microporous particles are diatomaceous earth, silica, cellulose acetate fibers from Hoechst Celanese, and Polytrap® from Dow Corning. The monolithic layer can be prepared as follows. First, a solution of the adhesive polymer is obtained or prepared. Another solution or dispersion of the drug in Non-hydrophilic penetration enhancers are prepared and mixed until the drug is dissolved or uniformly dispersed. The viscosity of the solution or non-hydrophilic penetration enhancing dispersion / drug can then be adjusted by the addition and mixing of viscosity increasing agents. For example, ethylcellulose and hydroxypropylcellulose can be used to adjust the viscosity. The resulting solution or resulting dispersion is then added to the adhesive polymer solution and the mixture is homogenized, such that the solution / drug dispersion is distributed in the adhesive in the form of droplets. A suitable solvent, which is subsequently removed by drying, can be added to this mixture to facilitate homogenization and / or emptying. Examples of such solvents are n-heptane and ethyl acetate. The homogenized adhesive solution or dough can then be emptied into a mold or emptied alone or onto the desired backing material. The emptying is then left for the solvent to evaporate at room temperature or in a furnace at a slightly elevated temperature. A vacuum or air stream can be used to facilitate evaporation of the solvent. After evaporation of the solvent, the adhesive matrix takes the form of an adhesive polymeric film, which typically has a thickness in the range of about 30 to 200 μp ?.

In yet another variation, the drug delivery device is a reservoir system. In a reservoir system, a bag (formed by heat sealing an impermeable backing layer with a membrane that controls the rate of diffusion) contains the drug, dissolved completely or partially, in a liquid. Exemplary liquid deposition systems are shown in Figures 4 and 5. As used herein, the term "diffusion rate control membrane" generally refers to a semipermeable membrane that limits the rate of release of liquid. a drug from the distribution device. The membrane can be a microporous film or a non-porous partition membrane. The side facing the skin is also protected in this drug delivery device design by a film that has to be removed before use. Referring now to Figures 4 and 5, the reservoir drug delivery device includes from the side not facing the skin side facing the skin of the device, an impermeable backing layer 1, a reservoir 2 of drug (drug reservoir), a membrane 5 that controls the rate of diffusion and an adhesive layer 4. The backing layer 1 may be the same as that described for the adhesive matrix type distribution device, described above. The deposit can take various forms, for example, the drug can be dissolved in a non-hydrophilic penetration enhancer or mixtures thereof, gelled or ungelled. Alternatively, the non-hydrophilic drug / enhancer mixture (s) may conveniently be contained in the pores of a pad or foam material such as a polyurethane foam. One function of the reservoir is to maintain the nonhydrophilic enhancer (s) and the drug in good contact with the membrane layer. The diffusion velocity control membrane 5 in its simplest function provides a mechanical support for the adhesive layer 4. The membrane layer and the backing layer are heat sealed at their peripheral edges to form a pouch enclosing the reservoir of drug. As used herein, the term "peripheral edges" of the membrane and backing layers refers to the areas that are sealed together to define the limits of the drug reservoir. Therefore, the foreign membrane and the backing layer material may extend outwardly from the drug reservoir and the peripheral edges. The membrane and the adhesive layers must be freely permeable to the therapeutic compound and the enhancers. As such, the membrane layer must offer diffusional resistance designed to measure by the choice of membrane. In general, Membranes are controlled and the diffusion rate has a known MTVR value (moisture vapor transmission rate, described as g / cm2 / 24 hours.) Without being limiting, an exemplary MTVR value of 15 to 100 g / cm2 / 24 hours is generally adequate, MTVR values outside this range can be guaranteed depending, for example, on the physicochemical properties of the drug, its concentration in the reservoir, the thermodynamic properties of the reservoir and the dose of the drug, and the desired rate of administration An advantage of a reservoir system is that the saturation solubility of the drug can be adjusted more easily by modifying or non-hydrophilic penetration enhancers, included in the reservoir For thermodynamic reasons it is advantageous for the release of the drug in and on the skin, if it is present in the drug-containing parts of the drug delivery device, at a concentration that is lower than the saturation concentration. The absorption or uptake capacity of the drug delivery device for the amount of drug needed can be adjusted over a wide range to suit the particular needs by adjusting the amount of drug solution and degree of saturation of the solution. For example, the saturation of the drug solution may be in the range of almost saturated to super saturated, or the solution may contain an undissolved fraction of the drug. Drug solutions that fall saturated or super saturated are systems of high thermodynamic activity that increase the tendency of a drug to be released. In a further variation, the drug delivery device is a micro-reservoir system. Micro deposit systems are generally considered as a combination of deposit matrix systems. In a microdeposition system, a liquid ranging from one of very low viscosity to very high viscosity contains one or more drugs in a fully or partially dissolved state, and is dispersed as fine droplets in a solid adhesive matrix. If desired, the viscosity of the liquid component of the system can be increased by using viscosity-increasing agents such as ethylcellulose, hydroxypropylcellulose or a high molecular weight polyacrylic acid or its salt and / or derivatives such as esters. In one variation, a microdeposit drug delivery device includes an occlusive backup layer, a self-adhesive matrix comprising microdeposits of partial drug solution or completely dissolved in a non-hydrophilic penetration enhancer, and a protective film (coating of the penetration) to be removed before using the device. The drug (e.g., capsaicin) in the microdeposit system is completely or partially dissolved and the resulting solution and / or the mixture is gelled with a viscosity enhancing agent, e.g., ethylcellulose and / or hydroxypropylcellulose, such that when mixing with an adhesive or mixture of adhesives, this forms discrete globules that are distributed throughout the mass of adhesive forming a "microdeposito" of the drug. For the purposes of the devices and methods described herein, the terms "microdeposit" and "microdeposit droplets" refer to microdispersed droplets that include a drug, and a penetration enhancer or non-hydrophilic or penetration enhancer mixture. non-hydrophilic, and may optionally include a viscosity enhancer. The term "microdeposition system" is a collection of these microdeposition droplets dispersed in an adhesive mass (eg, a pressure sensitive adhesive (PSA)), with or without additional components. As used herein, the terms "adhesive" and "adhesive mass" refer to materials capable of adhering to the skin as well as to occlusive or waterproof backing films or membranes that control the rate of diffusion. The term "pressure sensitive adhesive" refers to an adhesive (e.g., polysiloxane, polyacrylate, or polyisobutylene) that adheres to the surface of the skin when pressed on it. In general, the self-adhesive matrix based on polysiloxane or polyacrylate or polyisobutylene, will be configured to include the active agent in an amount of at least about 0.001% by weight of the adhesive, at least about 0.01% by weight of: the adhesive , at least about 0.1% in weight > of the adhesive, at least about 1% by weight of the adhesive, at least about 3% by weight of the adhesive, at least about 5% by weight of the adhesive, at least about 10% by weight of the adhesive adhesive mass, at least about 15% by weight of the adhesive, at least about 20% by weight of the adhesive, or at least about 30% by weight of the adhesive. Surprisingly, it has now been found that a drug delivery device for treating chronic pain or skin conditions, which contains a high concentration of capsaicin or another TRPV1 agonist, can be improved by including a non-penetrating enhancer. hydrophilic in the device, which has a ClogP value of 1.0 or greater. The term "ClogP" refers to a water / octanol partition coefficient as calculated by the software "ClogP for Windows", version 4.0, by Biobyte Corp. (Claremont, California, United States).

Apart from the intrinsic ability of such penetration enhancers to increase the dermal and transepidermal distribution of the drugs, transepidermal water loss (TEWL) also plays a role in the function of the drug delivery devices described in this invention. TEWL refers to the loss of water from the surface of the skin and is a distinctly different mechanism than the loss of water by the sweat glands. This is a continuous process that is considered as a parameter to evaluate the integrity of the skin (for example, damaged or permeabilized skin shows greater TEWL). When drug reservoirs containing the penetration enhancer (eg, patches) trap and retain water leaving the surface of the skin due to TEWL, the thermodynamic activity of the pharmaceutical substance can be increased if the pharmaceutical substance has a low water solubility. Accordingly, this may result in increased release of the therapeutic compound (s) from the delivery device. Those skilled in the art appreciate that the use of amphiphilic and hydrophilic skin penetration enhancers is very common in such dispensing devices. However, in such known devices, water lost from the surface of the skin is trapped and becomes part of the drug reservoir, due to the miscibility of the water with the penetration enhancers of the skin, amphiphilic or hydrophilic contained in it. Consequently, such systems fail to take advantage of the water that results from TEWL penetration. Also, such hygroscopic systems are suitable for collecting vapor from atmospheric water during manufacture, leading to hydrolytic degradation of the drug during manufacture and / or shelf-life storage. In contrast, the drug delivery devices contemplated herein, utilize non-hydrophilic skin penetration enhancers, in which the drug (s) have been solubilized (fully or partially) and thus form a drug reservoir. . In such drug delivery devices when water lost from the surface of the skin is trapped by the reservoir, the skin penetration enhancers have increased thermodynamic activity due to their immiscibility with water. The result is that the release of the skin penetration enhancers from the reservoir is increased, and in this way more therapeutic compound is distributed to and perhaps through the skin.

A. TRPV1 AGONISTS TRPV1 agonists useful in the present invention include, but are not limited to, capsaicin capsaisin analogs and derivatives thereof, and other low molecular weight compounds (e.g., MW <1000) which are agonists for TRPVl. Capsaicin can be considered the prototypic TRPVl agonist. Capsaicin (also called 8-methyl-N-vanillill-trans-6-nonenamide; (6E) -N- [(4-hydroxy-3-methoxyphenyl) -methyl] -8-methylnon-6-enamide; N- [(-hydroxy-3-methoxyphenyl) methyl] -8-methyl- (6E) -6-nonenamide; N- (3-methoxy-4-hydroxybenzyl) -8-methylnon-tran-6-enamide; N- [(4-hydroxy-3-methoxyphenyl) methyl] -8-methyl-6-nonenamide) has the following chemical structure: Capsaicin analogs suitable for use in drug delivery devices include capsaicin derivatives of natural and synthetic origin and analogs ("capsaicinoids") such as, for example, those described in U.S. Patent No. 5,762,963, which is incorporated by reference herein in its entirety. In addition to capsaicin, a variety of capsaicin analogues and derivatives thereof, and other agonists of TRPVl can be administered. Vanilloids, such as capsaicinoids, are examples of useful TRPVl agonists. Exemplary vanilloids suitable for use with the devices and methods described herein include N-vanillin-alkanedienamides, N-vanillin-alkanedienyls, N-vanillin-cis-monounsaturated alquenamides, capsaicin, dihydrocapsaicin, norhydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin . The TRPV1 agonist may also be a compound lacking the vanillin functional group, such as piperidine or a dialdehyde-sesquirterpene (eg, warburganal, polyigodial, or isoveleral). In one embodiment, the TRPV1 agonist is a triprenylphenol, such as iscutigeral. Exemplary, additional TRPVl agonists are described in U.S. Patent Nos. 4,599,342; 5,962,532; 5,762,963; 5,221,692; 4,313,958; 4,532,139; 4,544,668; 4,564,633; 4,544,669; 4,493,848; 4,532,139; 4,564,633; and 4,544,668; and PCT publication WO 00/50387, which are incorporated by reference herein, in their entirety. Other useful TRPVl agonists include pharmacologically active gingeroles, piperines, shogaols, and more specifically, guaiacol, eugenol, zingerone, civamide, nonivamide, nuvanyl, olvanil, NE-19550, NE-21610, and NE-28345 (see Dray et al. ., 1990, Eur. J.

Pharmacol 181: 289-93 and Brand et al., 1990, Agents Actions 31: 329-40), resiniferatoxin, resiniferatoxin analogues and resiniferatoxin derivatives (eg, tiniatoxin). In addition, any stereoisomer or active geometric isomer of the above agonists can be used with the devices and methods described herein. Other suitable TRVP1 agonists are vanilloids which are portions that bind to the TRVP1 receptor such as mono-substituted, monophenolic amidated benzylamine with a cyclic, normal or branched aliphatic substitution. Other suitable TRVP1 agonists with the devices and methods described herein, can be easily identified using standard methodology, such as that described in U.S. Patent Publication No. US20030104085, the publication of which is incorporated by reference herein, In its whole. Useful assays for the identification of TRVP1 agonists include, without limitation, receptor binding assays; Functional evaluations of calcium influx stimulation and membrane potential in cells expressing the TRVP1 receptor, assays for the ability to induce cell death in such cells (eg, selective ablation of C-fiber neurons) and others assays known in the art. The mixtures of agonists and salts pharmaceutically 4 acceptable from any of the above can also be used. See Szallasi and Blumberg, 1999, Pharmacological Reviews 51: 159-211, U.S. Patent No. 5,879,696, and references therein. The concentration of the TRPV1 agonist in the device is between about 0% and about 90% by weight of the drug reservoir, between about 0% and about 70% by weight of the drug reservoir, between about 0% and about 50% by weight of the drug reservoir, between about 0% and about 30% by weight of the drug reservoir, between about 0% to about 20% of the drug reservoir, between about 0% and about 10% by weight of the drug reservoir, between about 0% and about 8% of the drug reservoir, between about 0% and 6% by weight of the drug reservoir, between about 0% and 5% by weight of the drug reservoir, between about 0% and 4% by weight of the reservoir of drug, between about 0% and 2% by weight of the drug reservoir, or between about 0% and about 1% by weight of the drug reservoir. In some cases, the concentration of the TRPV1 agonist in the device is 0.04% or less by weight of the drug reservoir. It will be appreciated that for a given total drug load, given, the loading percentage can be varied by varying the thickness of the adhesive matrix and / or the concentration of the drug in the penetration enhancer or the mixture thereof. Also, the amount of the drug in the adhesive matrix may exceed the desired therapeutic dose to maintain the high concentration gradient, so that the rate of drug release flow from the patch remains constant throughout its intended use. For example, in a device designed to deliver a total of 30 mg of the drug in a 24-hour period and then be replaced by a fresh device, as much as 50 to 100 mg of the drug can be included in the device. This ensures the high thermodynamic activity of the drug at the end of the 24-hour period. For similar reasons, non-hydrophilic enhancers may also be included in the distribution devices contemplated in this application.

B. PENETRATION / SOLVENT INCREASE Amphiphilic molecules are characterized by having a polar water-soluble group linked to a water-soluble hydrocarbon chain. In general, amphiphilic penetration enhancers have a polar head group and show appreciable solubility in aqueous and nonhydrophilic systems. These categories include: surfactants, short chain alcohols, charged quaternary ammonium compounds. Examples of such solvents amphiphiles are butanediols such as 1,3-butanediol, dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, propylene glycol, dipropylene glycol, tri- and diethylene glycol carboxylic acid esters, polyethoxylated fatty alcohols of polyethylene glycol. -18 carbon atoms or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (Solketal®) or mixtures of these solvents. Without intending to be compromised by any specific theory of operation, it is believed that penetration enhancers operate by a variety of mechanisms such as, for example, increased fluidity of the membranes, selective disturbance of the intercellular lipid bilayers present in the stratum. corneal, the opening of new polar pathways as indicated by the increased electrical conductivity of tissue (Eric W. Smith and Howard I. Maibach (1995) In: Percutaneous Penetration Enhancers CRC Press New York, pp. 1-20). Non-hydrophilic, exemplary penetration enhancers, which can be incorporated into the drug delivery devices described herein, include, but are not limited to, 1-menthone, isopropyl myristate, caprylic alcohol, lauryl alcohol, oleyl alcohol , isopropyl hexanoate, butyl acetate, methyl valerate, ethyl oleate, d- piperitone, d-pulegone, n-hexane, octanol, myristyl alcohol, methyl-nonenoyl alcohol, cetyl alcohol, cetearyl alcohol, stearyl alcohol, myristic acid, stearic acid and isopropyl palmitate. Other non-hydrophilic penetration enhancers can be identified using routine assays, eg in vitro skin permeation studies in rat, pig, or human skin using Franz diffusion cells (see Franz et al., "Transdermal Delivery" In: Treatise on Controlled Drug Delivery, A. Kydonieus, Ed Marcell Dekker: New York, 1992, pp 341-421). Many other methods for evaluating the boosters are known in the art, including the high throughput methods of Karande and Mitragotri, 2002, "High throughput screening of transdermal formulations" Pharm Res 19: 655-60, and Karande and Mitragotri, 2004 , "Discovery of transdermal penetration enhancers by high-throughput screening"). Non-hydrophilic penetration enhancers suitable for use in the present invention are non-hydrophilic, pharmaceutically acceptable penetration enhancers. A non-hydrophilic, pharmaceutically acceptable penetration enhancer can be applied to the skin of a human patient, without harmful effects (for example, it has low or acceptable toxicity at the levels used). The augmentators Non-hydrophilic penetration employees generally also have ClogP values of 1.0 or higher. Non-hydrophilic penetration enhancers having a ClogP value greater than or equal to 2.0, greater than or equal to 3.0, greater than or equal to 5.0, greater than or equal to 7.0, or greater than or equal to 9.0 may also be used. Such penetration enhancers include, but are not limited to, boosters of any of the following classes: long-chain fatty alcohols or other alcohols, including phenols and polyols, fatty acids (linear or branched), terpenes (e.g. , di- and sequiterpenes; hydrocarbons, alcohols, ketones); esters of fatty acid, ethers, amides, amines, hydrocarbons. The hydrophilicity of an amphiphilic penetration enhancer makes it typically incompatible with the adhesive, so that incorporation of the enhancing system only within the adhesive is difficult. The non-hydrophilic enhancer used in general is more hydrophobic in nature and is more compatible with the adhesive. In one variation, applicable to deposit and monolith devices, the non-hydrophilic penetration enhancer is located in the drug reservoir with the therapeutic compound. In yet another embodiment, the non-hydrophilic penetration enhancer is incorporated within the adhesive layer while the drug is located in the drug deposit. The placement of the non-hydrophilic penetration enhancer in the adhesive is often desirable because this places the enhancer in direct contact with the stratum corneum. In some cases, the penetration enhancer, not hydrophilic, is loaded into the adhesive, as well as into the drug reservoir. Specific examples of suitable non-hydrophilic solvents and their ClogP values are given in Table 1 below: Table 1: ClogP values and penetration enhancers eg emplares C. THE MICRODEPOSIT SYSTEM As previously mentioned, in one variation, the drug delivery device is a micro deposit system. The polysiloxanes can be used in this type of drug delivery device. The polysiloxanes can be made from solvent-free, two-component systems, or a solution in organic solvents. For the production of the drug delivery device, self-adhesive polysiloxanes dissolved in solvents are preferred. There are two fundamentally different variants of the polysiloxanes: the normal polysiloxane having free silanol groups as shown in formula 1, The silanol groups are derivatized by trimethylsilyl groups. Such amine-resistant polysiloxanes have also proven to be suitable for drug delivery devices containing the therapeutic compound, without basic therapeutic compounds and / or basic excipients. Formula 1 shows the structure of a linear polysiloxane molecule that is prepared from dimethylsiloxane by polycondensation. The three-dimensional crosslinking can be achieved by the additional use of methylsiloxane. Other polysiloxanes suitable for use with the methods and devices described herein have the methyl groups completely or partially replaced by other alkyl radicals, or alternatively phenyl radicals. The solvent or solvent mixture of the microdeposition system may also contain an additive enhancer of the viscosity. Exemplary viscosity increasing additives include, for example, a cellulose derivative (such as ethylcellulose or hydroxypropylcellulose) and a high molecular weight polyacrylic acid or its salt and / or derivatives such as esters. The proportion of microdeposit droplets in the matrix is typically less than about 40% by weight, more typically less than about 35% by weight and most typically between about 20 and about 30% by weight. A mixture of a medium adhesion polysiloxane and a high adhesion polysiloxane can also be used with the devices and methods described herein. The polysiloxanes suitable for use in the matrix are synthesized from bifunctional linear and polyfunctional branched oligomers, and the proportion of both types of oligomers determines the physical properties of the adhesives. More polyfunctional oligomers result in a more crosslinked adhesive with higher cohesion and reduced adhesion, less polyfunctional oligomers result in higher adhesion and reduced cohesion. For example, the high adhesion version used in the examples below, is sticky enough to adhere to human skin, while the medium adhesion version is not nearly as sticky, but is nevertheless useful to compensate for the softening effect of other ingredients in the device such as, for example, capsaisin and penetration enhancers in the microdeposits. A silicone oil (eg, dimethicone) can be added to increase the adhesive property of the matrix, for example, by using 0.5 to 5% by weight of the silicone oil. In one variation, the matrix contains at least about 0.05% to about 10% by weight of capsaicin or capsaicin analogue, about 10 to about 25% by weight of oleyl alcohol, about 0% to about 5% by weight of ethocellulose, about 0% to about 5% by weight of silicone oil, and about 55% to about 85% by weight of pressure sensitive, self-adhesive polysiloxane. The coating weight of the matrix is typically between about 30 and about 350 g / m2, and more typically between about 50 and about 120 g / m2. Suitable materials for the backing layer include, for example, a polyester film (eg, 10 to 60 μm thick), an ethylene-vinyl acetate copolymer, or the like. In yet another variation, a microdeposit type device includes a drug preparation liquid dispersed in an adhesive matrix in the form of small droplets ("microdeposition"). The appearance of a micro-deposit system is similar to a classical matrix system, and a micro-deposit system can only be recognized from a typical matrix system with difficulty, since small micro-deposits can only be recognized under the microscope. In the preceding and subsequent sections, therefore, the part containing the therapeutic compound of the drug delivery device is also described by "matrix". The size of the resulting droplets depends on the conditions of agitation of the shear forces applied during agitation. The size is very consistent and reproducible using the same mixing conditions. The microdeposition droplet size range can be from about 1 to about 150 μm, or from about 5 to about 50 μ ??, or from about 10 to about 30 μm. However, it is noted that contrary to conventional matrix systems, in microdeposition systems the therapeutic compound is contained mainly in the microdeposits (and only to a small degree in the adhesive). In this sense, the Microdeposit systems can be considered a mixed type of matrix drug distribution devices, and the reservoir drug distribution device, and combine the advantages of both variants of the drug delivery device. As in classical deposit systems, the saturation solubility can easily be adjusted by choosing the solvent at a suitable value for particular requirements, and as in classical matrix systems, the drug delivery device can be divided into devices of smaller drug distribution, using scissors without leakage. The microdeposito systems described herein may also include a membrane for controlling the rate of diffusion, to control the release of the therapeutic compound and the excipient. However, for short application times in which the therapeutic ingredient is rapidly released, a control membrane is usually not present. An example of a system composition suitable for use with the devices described herein is shown in Table 2 below.

Table 2: Exemplary composition of a matrix of a micro-reservoir system for the topical distribution of high dose capsaicin.

The thickness of the matrix can correspond to a coating weight of about 30 to about 350 g / m2, but different values can also be used depending on the properties of the specific formulation. A matrix thickness between about 50 and about 100 μp? It can also be adequate. Again, the backing layer for the drug delivery device should ideally be relatively impermeable or inert with respect to the drug and the selected non-hydrophilic solvent (for example oleyl alcohol). A suitable backing layer is polyester, but other materials are also suitable such as, for example, ethylene-vinyl acetate copolymers and polyamide. In practice, a polyester film of approximately 51 μp? Thickness has proven to be highly adequate. In order to improve the adhesion of the matrix to the backup layer, it is advantageous to siliconize the contact side of the backing layer to the matrix. Polyacrylate-based adhesives do not adhere to such siliconized films or adhere relatively poorly, while polysiloxane-based adhesives adhere relatively well taking into account their chemical similarity to siliconized films. Drug delivery devices also typically include a protective film, which protects the device during storage, but is removed before use. Typically, polyester films are used, because only these are surface treated, they are repellent to the polysiloxane-based adhesives. Suitable films are supplied by a number of manufacturers and are known to those of ordinary skill in the art.

II. METHODS OF DEVELOPMENT OF DEVICES A process for the production of a drug distribution device, topical, will now be described. Typically, this process comprises the complete or partial dissolution of the therapeutic compound in a non-hydrophilic solvent, adding this solution to a solution of a polysiloxane or the constituents of the matrix and dispersing with agitation, coating the resulting dispersion on a protective layer that is removed, and removing the polysiloxane solvent at elevated temperature, and laminating the backing layer on the dry layer. Suitable solvents for adhesive are, for example, petroleum ethers or alkanes such as n-hexane and n-heptane or ethyl acetate. The dispersion of the solution of the therapeutic compound can be carried out more easily if the viscosity of the solution of the therapeutic compound is increased by the addition of a suitable agent such as, for example, a cellulose derivative such as ethylcellulose or hydroxypropylcellulose. The dispersion is then coated on the removable protective film in a thickness, which after removal of the solvent from the adhesive, provides a matrix layer having the desired thickness. The dried layer is then laminated with the backing layer and thus the lamination of the finished drug delivery device can be obtained. The drug delivery devices can be punched from this laminate in the desired shape and sizes, and packaged in a suitable primary package bag. A primary package can be a laminate consisting of paper / glue / aluminum foil / Barex®, as described in U.S. Patent No. RE37,934, which is incorporated herein by reference in its entirety. Barex® is a heat-sealable polymer based in modified rubber-acrylonitrile copolymer, which is distinguished by a low absorptivity for volatile ingredients of the drug delivery devices. Because the micro-reservoir system typically does not have a diffusion rate control membrane that controls the release of the therapeutic compound, the only element that controls the release of the therapeutic compound into the deeper layers of the skin may be the skin or the outer layer of the skin, the stratum corneum. The optimization of the matrix composition can therefore be carried out by in-vitro permeation studies using human skin or by Franz diffusion cells as described in Venter et al., 2001, "A comparative study of an in situ adapted diffusion cell and an in vitro Franz diffusion cell method for transdermal absortion of doxylamine "Eur J Pharirt Sci, 13: 169-77.

EXAMPLES The following examples serve to more fully describe how to make and use the drug delivery devices described above. It is understood that these examples are provided for illustrative purposes only and should not be considered as limiting the scope of the invention.

EXAMPLE 1: PREPARATION OF A MICRODEPOSITE DEVICE CONTAINS 0.04% CAPSAICIN IN WEIGHT IN THE DEPOSIT OF FARMACO To 80 mg of capsaicin, 16.0 grams of oleyl alcohol were added and the components were mixed. 200 mg of ethylcellulose was added and mixed thoroughly and separated for two hours. 36.74 grams of Bio-PSA® 4201 and 146.98 grams of Bio-PSA® 4301 were added, and the mass of the adhesive was mixed vigorously until the gelled mixture of oleyl alcohol, capsaicin and ethylcellulose was uniformly dispersed as fine beads in the adhesive. The resulting adhesive matrix was subsequently coated on a release coating of 3MMR Scothcpak ™ 1022, and n-heptane solvent was dried by blowing hot air at a temperature between 35 to 40 ° C. The coating weight after removal of n-heptane was approximately 273.6 g / m2. The dried film was then laminated with the polyester backing layer, 3MMR ScothcpakMR 9733, and the finished drug delivery device was punched (5 cm x 5 cm). The punching drug delivery device was then sealed on a sack of a primary packaging laminate.

EXAMPLE 2: PREPARATION OF A MICRO-DEPICY DEVICE CONTAINING 2% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 4.0 grams of capsaicin, 20.0 grams of oleyl alcohol were added and the components mixed. 200 mg of ethylcellulose were then added and mixed thoroughly and separated for two hours. 175.80 grams of Bio-PSA 4301 were added, and the mass of the adhesive was mixed vigorously until the gelled mixture of oleyl alcohol, capsaicin and ethylcellulose was uniformly dispersed as fine beads in the adhesive. The resulting adhesive matrix was subsequently coated on a 3MMR Scothcpak ™ 1022 release coating, and the n-heptane solvent was dried by blowing hot air at a temperature between 35 to 40 ° C. The coating weight after removal of the n-heptane was approximately 277.9 g / m2. The dried film was then laminated with the polyester coating layer, 3MMR ScothcpakMR 9733, and the finished drug delivery device was punched (5 cm x 5 cm). The punching drug delivery devices were then sealed in a sack of a primary package laminate.

EXAMPLE 3: PREPARATION OF A MICRO-DECISION DEVICE CONTAINING 4% CAPSAICIN BY WEIGHT IN THE DRUG DEPOSIT To 8.0 grams of capsaicin, 36.0 were added grams of oleyl alcohol and the components were mixed. 2.0 mg of ethylcellulose were then added and mixed thoroughly and separated for two hours. 154.0 grams of Bio-PSA 4301 were added, and the mass of the adhesive was mixed vigorously until the gelled mixture of oleyl alcohol, capsaicin and ethylcellulose was uniformly dispersed as fine beads in the adhesive. The resulting adhesive matrix was subsequently coated on a 3MMR Scothcpak ™ 1022 release coating, and the n-heptane solvent was dried by blowing hot air at a temperature between 35 to 40 ° C. The coating weight after removal of n-heptane was approximately 218.4 g / m2. The dried film was then laminated with the polyester coating layer, 3MMR ScothcpakMR 9733, and the finished drug delivery device was punched (5 cm x 5 cm). The punching drug delivery devices were then sealed in a sack of a primary package laminate.

EXAMPLE 4: PREPARATION OF A MICRO-DEPICY DEVICE CONTAINING 6% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 12.0 grams of capsaicin, 40.0 grams of oleyl alcohol were added and the components mixed. 4.0 mg of ethyl cellulose was then added and mixed thoroughly and separated for two hours. They added 144. 0 grams of Bio-PSA 4301, and the mass of the adhesive was mixed vigorously until the gelled mixture of oleyl alcohol, capsaicin and ethylcellulose was uniformly dispersed as fine beads in the adhesive. The resulting adhesive matrix was subsequently coated on a 3MMR Scothcpak ™ 1022 release coating, and the n-heptane solvent was dried by blowing hot air at a temperature between 35 to 40 ° C. The coating weight after removal of the n-heptane was approximately 245.0 g / m2. The dried film was then laminated with the polyester coating layer, 3MMR ScothcpakMR 9733, and the finished drug delivery device was punched (5 cm x 5 cm). The punching drug delivery devices were then sealed in a sack of a primary package laminate.

EXAMPLE 5: PREPARATION OF A MICRO-DECISION DEVICE CONTAINING 8% CAPSAICIN BY WEIGHT IN THE DRUG DEPOSIT To 16.0 grams of capsaicin, 44.0 grams of oleyl alcohol were added and the components mixed. 4.0 mg of ethyl cellulose was then added and mixed thoroughly and separated for two hours. 136.0 grams of Bio-PSA8 4301 were added, and the mass of the adhesive was mixed vigorously until the gelled mixture of oleyl alcohol, capsaicin and ethylcellulose was uniformly dispersed as fine globules in the adhesive. The resulting adhesive matrix was subsequently coated on a 3MMR Scothcpak ™ 1022 release coating, and the n-heptane solvent was dried by blowing hot air at a temperature between 35 to 40 ° C. The coating weight after removal of n-heptane was approximately 352.9 g / m2. The dried film was then laminated with the polyester coating layer, 3MMR ScothcpakR 9733, and the finished drug delivery device was punched (5 cm x 5 cm). The punching drug delivery devices were then sealed in a sack of a primary package laminate.

EXAMPLE 6: PREPARATION OF A MICRO-DECISION DEVICE CONTAINING 10% CAPSAICIN BY WEIGHT IN THE DRUG DEPOSIT At 20.0 grams of capsaicin, 50.0 grams of oleyl alcohol were added and the components mixed. 4.0 mg of ethyl cellulose was then added and mixed thoroughly and separated for two hours. 126.0 grams of Bio-PSA® 4301 were added, and the mass of the adhesive was mixed vigorously until the gelled mixture of oleyl alcohol, capsaicin and ethylcellulose was uniformly dispersed as fine beads in the adhesive. The resulting adhesive matrix was subsequently coated on a 3MMR Scothcpak ™ 1022 release coating, and the n-heptane solvent was dried by blowing hot air at a temperature between 35 to 40 ° C. The coating weight after removal of the n-heptane was approximately 81.8 g / m2. The dried film was then laminated with the polyester coating layer, 3MMR ScothcpakMR 9733, and the finished drug delivery device was punched (5 cm x 5 cm). The punching drug delivery devices were then sealed in a sack of a primary package laminate.

EXAMPLE 7: PREPARATION OF A MONOLITHIC DEVICE CONTAINING 0.04% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 1.2 grams of capsaicin, 1000 mg of oleyl alcohol was added and the components mixed. 1999 mg of gelatin was added and mixed thoroughly. The polyester backing layer, 3MMR ScothcpakMR 9733 was heat sealed with 3MMR CoTranMR 9712 to make a 5 cm x 5 cm punch with an open end. The polyester backing layer was extended beyond the boundaries of the punch by approximately 1 cm on all sides. The above mixed contents were filled into the punch, and rolled to make a layer of uniform thickness that extended towards the edges of the punch. The open side was then sealed by heat. The layer of The polyester backing extended out of the punch was then coated with a thin layer of Bio-PSA * 4201 and subsequently dried by blowing hot air at a temperature between 35 to 40 ° C. The dried adhesive film was then laminated with a 6 cm x 6 cm piece of the Scothcpak ™ 1022 release liner. The finished drug delivery device was then sealed in a sack of a primary package laminate.

EXAMPLE 8: PREPARATION OF A MONOLITHIC DEVICE CONTAINING 2% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 60 grams of capsaicin, 1000 mg of oleyl alcohol was added and the components were mixed. 1940 mg of gelatin were added and mixed perfectly. The polyester backing layer, 3MMR ScothcpakMR 9733 was heat sealed with 3MMR CoTranMR 9712 to make a 5 cm x 5 cm punch with an open end. The polyester backing layer was extended beyond the boundaries of the punch by approximately 1 cm on all sides. The previous mixed contents were filled into the punch, and laminates to make a layer of uniform thickness that extended towards the edges of the punch. The open side was then sealed by heat. The polyester backing layer extended out of the punch was then coated with a thin layer of Bio-PSA 4201 and Subsequently dried by blowing hot air at a temperature between 35 to 40 ° C. The dried adhesive film was then laminated with a 6 cm x 6 cm piece of the Scothcpak ™ 1022 release liner. The finished drug delivery device was then sealed in a sack of a primary package laminate.

EXAMPLE 9: PREPARATION OF A MONOLITHIC DEVICE CONTAINING 4% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 120 grams of capsaicin, 1000 mg of oleyl alcohol was added and the components mixed. 1880 mg of gelatin were added and mixed thoroughly. The polyester backing layer, 3MMR ScothcpakMR 9733, was heat sealed with 3MMR CoTranMR 9712 to make a 5 cm x 5 cm punch with an open end. The polyester backing layer was extended beyond the boundaries of the punch by approximately 1 cm on all sides. The above mixed contents were filled into the punch, and rolled to make a layer of uniform thickness that extended towards the edges of the punch. The open side was then sealed by heat. The polyester backing layer extended out of the punch was then coated with a thin layer of Bio-PSA51 4201 and subsequently dried by blowing hot air at a temperature between 35 to 40 ° C. The dried adhesive film was then laminated with a 6 cm x 6 cm piece of the Scothcpak ™ 1022 release coating. The finished drug delivery device was then sealed in a sack of a primary package laminate.

EXAMPLE 10: PREPARATION OF A MONOLITHIC DEVICE CONTAINING 6% CAPSAICIN BY WEIGHT IN THE DRUG DEPOSIT To 180 grams of capsaicin, 1000 mg of oleyl alcohol was added and the components mixed. 1820 mg of gelatin were added and mixed perfectly. The polyester backing layer, 3MR ScothcpakMR 9733 was heat sealed with 3MMR CoTranMR 9712 to make a 5 cm x 5 cm punch with an open end. The polyester backing layer was extended beyond the boundaries of the punch by approximately 1 cm on all sides. The above mixed contents were filled into the punch, and rolled to make a layer of uniform thickness that extended towards the edges of the punch. The open side was then sealed by heat. The polyester backing layer spread out of the punch was then coated with a thin layer of Bio-PSA0 4201 and subsequently dried by blowing hot air at a temperature between 35 to 40 ° C. The dried adhesive film was then laminated with a 6 cm x 6 cm piece of the Scothcpak ™ 1022 release coating.

The distribution of finished drug was then sealed in a sack of a primary packaging laminate.

EXAMPLE 11: PREPARATION OF A MONOLITHIC DEVICE CONTAINING 8% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 240 grams of capsaicin, 1000 mg of oleyl alcohol was added and the components mixed. 1760 mg of gelatin were added and mixed thoroughly. The polyester backing layer, 3MMR ScothcpakMR 9733 was heat sealed with 3MMR CoTranMR 9712 to make a 5 cm x 5 cm punch with an open end. The polyester backing layer was extended beyond the boundaries of the punch by approximately 1 cm on all sides. The above mixed contents were filled into the punch, and rolled to make a layer of uniform thickness that extended towards the edges of the punch. The open side was then sealed by heat. The polyester backing layer spread out of the punch was then coated with a thin layer of Bio-PSA® 4201 and subsequently dried by blowing hot air at a temperature between 35 to 40 ° C. The dried adhesive film was then laminated with a 6 cm x 6 cm piece of the Scothcpak ™ 1022 release liner. The finished drug delivery device was then sealed in a sack of a primary package laminate.

EXAMPLE 12: PREPARATION OF A MONOLITHIC DEVICE THAT CONTAINS 10% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 300 grams of capsaicin, 1000 mg of oleyl alcohol was added and the components were mixed. 1700 mg of gelatin were added and mixed perfectly. The polyester backing layer, 3MMR ScothcpakMR 9733 was heat sealed with 3MMR CoTranMR 9712 to make a 5 cm x 5 cm punch with an open end. The polyester backing layer was extended beyond the boundaries of the punch by approximately 1 cm on all sides. The above mixed contents were filled into the punch, and rolled to make a layer of uniform thickness that extended towards the edges of the punch. The open side was then sealed by heat. The polyester backing layer extended out of the punch was then coated with a thin layer of Bio-PSA1"4201 and subsequently dried by blowing hot air at a temperature between 35 to 40 ° C. The dried adhesive film was then laminated with a 6 cm x 6 cm piece of the Scothcpak ™ 1022 release liner. The finished drug delivery device was then sealed in a bag of a primary package laminate.

EXAMPLE 13: PREPARATION OF A MONOLITHIC DEVICE THAT CONTAINS 4% CAPSAICIN IN WEIGHT IN THE DRUG DEPOSIT To 120 grams of capsaicin, 1000 mg of oleyl alcohol was added and the components were mixed. 1880 mg of ethyl cellulose were added and mixed thoroughly. The polyester backing layer, 3MMR ScothcpakMR 9733 was heat sealed with 3MMR CoTranMR 9712 to make a 5 cm x 5 cm punch with an open end. The polyester backing layer was extended beyond the boundaries of the punch by approximately 1 cm on all sides. The above mixed contents were filled into the punch, and rolled to make a layer of uniform thickness that extended towards the edges of the punch. The open side was then sealed by heat. The polyester backing layer extended out of the punch was then coated with a thin layer of Bio-PSA * 4201 and subsequently dried by blowing hot air at a temperature between 35 to 40 ° C. The dried adhesive film was then laminated with a 6 cm x 6 cm piece of the Scothcpak ™ 1022 release liner. The finished drug delivery device was then sealed in a sack of a primary package laminate.

EXAMPLE 14: IN VITRO DISSOLUTION TESTS Type of Device Microdepository Distribution The release coatings were removed from the patches described in Examples 1-6 and mounted on a glass plate (6 cm x 6 cm) with a double-sided adhesive tape such that one side on the tape was adhered to the plate. glass and the other side to the backing layer of the patch. Six glass plates were immersed in 200 ml of DI water containing 0.1% w / v of sodium azide such that the patches were exposed to the aqueous medium without touching the container. The container was hermetically capped and mounted on an agitator. The agitation was with smooth horizontal oscillations and did not involve rotation. The solutions were sampled (200 μm of the sample size) at 30 minutes, 1 hour, 3 hours and 18 hours and analyzed on HPLC for the capsaicin content. The results of capsaicin release are listed in Table 3.

Table 3: Capsacin Release from Microdeposition Type Patches Figure 6 shows that the amount of capsaicin released is linear with time as well as with the concentration of capsaicin in the patch. It should be noted that the low amount of capsaicin released from patch of 10% w / w relative to the patch of 8% w / w is due to the relatively thin coating on the patch of 10% w / w (compare Examples 5 and 6 above).

Monolithic Type of Distribution Device. The release liners were removed from the patches described in Examples 7-12 and mounted on a glass plate (6 cm x 6 cm) with a double-sided adhesive tape such that one side on the tape was adhered to the glass plate and the other side to the backing layer of the patch. Six glass plates were immersed in 200 ml of DI water containing 0.1% w / v of sodium azide such that the patches were exposed to the aqueous medium without touching the container. The container was hermetically capped and mounted on an agitator. The agitation was with smooth horizontal oscillations and did not involve rotation. The solutions were sampled (200 μ? Of the sample size) at 30 minutes, 1 hour, 3 hours and 24 hours and analyzed on HPLC for the capsaicin content. The results of capsaicin release are listed in Table 4.

Table 4: Release of Capsaicin from Monolithic Type Patches Again in the case of the monotypic type of the patches, Figure 7 shows that the amount of capsaicin released is linear with time, as well as the concentration of capsaicin in the patch. It should be noted that in relation to the type of microdeposit of the patches, a low amount of capsaicin released from the monolithic type of patches is due, as expected, to the presence of a membrane that controls the diffusion rate.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A drug delivery device, characterized in that it comprises: a) a drug reservoir having a therapeutically effective amount of a TRPV1 agonist; b) a non-hydrophilic penetration enhancer having a ClogP value greater than 1.0; and c) an occlusive backrest.

2. The drug delivery device according to claim 1, characterized in that the active agent is selected from the group consisting of capsaicin, capsaicinoids, capsaicin analogues, capsaicin derivatives, and combinations thereof.

3. The drug delivery device according to claim 2, characterized in that the TRPV1 agonist comprises capsaicin.

4. The drug delivery device according to claim 2, characterized in that the TRPV1 agonist comprises a capsaicinoid.

5. The drug distribution device of according to claim 2, characterized in that the TRPVl agonist comprises a capsaicin analogue.

6. The drug delivery device according to claim 2, characterized in that the TRPV1 agonist comprises a capsaicin derivative.

7. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 30% of the drug depot by weight.

8. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 20% drug deposition by weight.

9. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 10% of the drug depot by weight.

10. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 8% of the drug depot by weight.

11. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 6% of the drug depot by weight.

12. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 5% of the drug depot by weight.

13. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 4% of the drug depot by weight.

14. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 2% of the drug depot by weight.

15. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist comprises at least about 0.04% of the drug depot by weight.

The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer is selected from the group consisting of 1-menthone, isopropyl myristate, dimethyl-isosorbide, caprylic alcohol, lauryl alcohol, alcohol oleic, isopropyl butyrate, isopropyl hexanoate, butyl acetate, methyl acetate, methyl valerate, ethyl oleate, d-piperitone, d-pulogen, n-hexane, citric acid, ethanol, propanol, isopropanol, ethyl, methyl propionate, methanol, butanol, tert-butanol, octanol, myristyl alcohol, methyl-nonenoyl alcohol, cetyl alcohol, cetearyl alcohol, stearyl alcohol, myristic acid, stearic acid, isopropyl palmitate, and combinations thereof.

17. The drug delivery device according to claim 16, characterized in that the non-hydrophilic penetration enhancer comprises oleyl alcohol.

18. The drug delivery device according to claim 16, characterized in that the non-hydrophilic penetration enhancer comprises 1-menthone.

19. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer has a ClogP value greater than or equal to 2.0.

20. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer has a ClogP value greater than or equal to 3.0.

21. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer has a ClogP value greater than or equal to 5.0.

22. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer has a ClogP value greater than or equal to 7.0.

23. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer has a ClogP value greater than or equal to 9.0.

24. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer comprises at least about 35% by weight of the drug reservoir.

25. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer comprises at least about 30% by weight of the drug reservoir.

26. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer comprises at least about 25% by weight of the drug reservoir 27. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer comprises at least about 20% by weight of the drug reservoir. according to claim 1, characterized in that the non-hydrophilic penetration enhancer comprises at least about 15% by weight of the drug reservoir. 29. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer comprises at least about 10% by weight of the drug reservoir. 30. The drug delivery device according to claim 1, characterized in that the non-hydrophilic penetration enhancer comprises at least about 5% by weight of the drug reservoir. 31. The drug delivery device according to claim 1, characterized in that the TRPV1 agonist is dissolved, partially dissolved, or dispersed within the drug reservoir. 32. The drug delivery device according to claim 1, characterized in that the drug reservoir comprises a polymeric matrix. 33. The drug delivery device according to claim 32, characterized in that the polymer matrix comprises an adhesive matrix. 34. The drug delivery device according to claim 32, characterized in that the polymer matrix comprises a polymer selected from the group consisting of gelatin, polyacrylates, polyisobutylenes, polysiloxanes, polyurethanes, polyvinylpyrrolidones, and co-polymers and combinations thereof. 35. The drug delivery device according to claim 1, characterized in that the drug reservoir comprises the dissolved or partially dissolved TRPV1 agonist within micro-reservoirs. 36. The drug delivery device according to claim 1, characterized in that the drug reservoir comprises the TRPV1 agonist in a liquid reservoir. 37. The drug delivery device according to claim 1, characterized in that it also comprises a membrane that controls the diffusion rate. 38. A method for treating pain or a condition of the skin, characterized in that it comprises: a) the application of a drug delivery device to the skin or mucous membrane of a subject, wherein the drug delivery device comprises : to. a.) a TRPVl agonist; a.b.) a non-hydrophilic penetration enhancer having a ClogP value greater than 1; and a.c.) an occlusive backup, and b) the distribution of a therapeutically effective amount of the TRPVl agonist to alleviate pain or skin condition. 39. The method according to claim 38, characterized in that the TRPV1 agonist comprises capsaicin.