Medical patch containing capsaicin

Abstract

The present invention relates to a medical patch for the administration of capsaicin, such as a medical patch for use in methods of treatment, comprising an active agent-containing layer structure comprising capsaicin, and a method of making such a medical patch.

Description

[0001] Technical Field of the Invention

[0002] The present invention relates to a medical patch for administering capsaicin, wherein the medical patch comprises an active agent-containing layer comprising a silicone-based polymer and a skin contact layer. In addition, the present invention relates to a treatment method and use of the medical patch. Background of the Invention

[0004] Capsaicin ((6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), the primary bioactive component of chili peppers, is an alkaloid found in the capsicum family. It is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), better known as the vanilloid receptor. By binding to the TRPV1 receptor, capsaicin molecules produce a sensation similar to excessive heat or weariness.

[0005] The burning and pain sensation associated with capsaicin is caused by its chemical interaction with sensory neurons expressing TRPV1. This receptor is a non-selective cation channel that allows Ca to flow into and out of the sensory neurons when activated during the detection and transduction of noxious stimuli. 2+ Because calcium in cells is one of the most versatile second messengers in many intracellular signaling pathways, and TRPV1, when activated, allows cations to cross the cell membrane and enter the cell, the resulting depolarization of the neuron stimulates it to signal the brain. Therefore, TRPV1 plays a key role in pain signaling.

[0006] Capsaicin has the effect as non-anesthetic analgesic, and is currently used to treat several pain syndromes, such as neuropathic pain.This pain is considered to be caused by the sensitization reaction in the periphery and central nervous system, and can occur because of peripheral damage or because of systemic disease (such as HIV, herpes zoster syphilis, autoimmune disease and diabetes).In addition, capsaicin also shows the beneficial effect of osteoarthritis pain relief, and this is due to the ability of its very strong suppression P substance release, P substance is a kind of powerful neuropeptide pain neuromodulator from sensory nerve to central nervous system.In addition, capsaicin is considered to be able to kill cancer cells by making cancer cells experience apoptosis.

[0007] Capsaicin is most commonly used as a topical analgesic and is available in many formulations of creams, liquids, and patch formulations in various strengths. For example, an 8% capsaicin patch skin delivery system is administered under the brand name QUTENZA® (Grunenthal). The topical system is indicated for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN) in the feet of adults and is currently approved for the treatment of postoperative neuropathic pain (PSNP) in adults. QUTENZA® delivers prescription-strength capsaicin directly to the skin, reversibly desensitizing and defunctionalizing TRPV1 receptors and, therefore, providing sustained pain relief lasting up to three months.

[0008] However, capsaicin is a strong irritant, and the most common adverse reactions occurring during QUTENZA® application include application site reactions such as erythema, pain, and itching. In addition, it is known in the art that dermal delivery systems may cause skin irritation, depending on the adhesive layer.

[0009] It would therefore be desirable to provide a medical patch for topical and / or transdermal delivery of capsaicin that overcomes the problem of skin irritation but still possesses favorable properties with respect to active agent release and adhesiveness.

[0010] Purpose and content of the invention

[0011] It is an object of the present invention to provide a medical patch for administering capsaicin which is improved compared to the patches described in the prior art.

[0012] Another object of the present invention is to provide a medical patch for administering capsaicin, which alleviates the problem of skin irritation.

[0013] Another object of the present invention is to provide a medical patch for administering capsaicin that provides a penetration rate sufficient to achieve a therapeutically effective dose. Specifically, the object is to provide a medical patch for administering capsaicin that enables a faster onset of action associated with a reduced lag time.

[0014] Another object of the present invention is to provide a medical patch for applying capsaicin, which has improved adhesive properties. Specifically, the object is to provide a medical patch for applying capsaicin, which meets the needs of convenient application in terms of wearing comfort and clean and painless removal and for multiple applications with repositioning.

[0015] Another object of the present invention is to provide a medical patch for administering capsaicin, which can be used in a therapeutic method.

[0016] These and other objects are achieved by the present invention, which, according to one aspect, relates to a medical patch for administering capsaicin, comprising an active agent-containing layer structure, the active agent-containing layer structure comprising:

[0017] A) backing layer;

[0018] B) an active agent-containing layer, the active agent-containing layer comprising

[0019] (i) capsaicin, and

[0020] (ii) at least one silicone-based polymer;

[0021] as well as

[0022] C) skin contact layer;

[0023] wherein the skin contact layer is an adhesive layer comprising polymer II (the at least one silicone-based polymer in the active agent-containing layer is also referred to as polymer I). In another aspect, the present invention relates to a medical patch for administering capsaicin, the medical patch comprising an active agent-containing layer structure, the active agent-containing layer structure comprising:

[0024] A) backing layer;

[0025] B) an active agent-containing layer, the active agent-containing layer comprising

[0026] (i) capsaicin, and

[0027] (ii) at least one silicone-based polymer;

[0028] as well as

[0029] C) skin contact layer;

[0030] The skin contact layer is an adhesive layer comprising a silicone gel adhesive.

[0031] Surprisingly found, comprise wherein capsaicin is slightly soluble and preferably directly attached to the medical patch according to the present invention of the skin contact layer containing active agent layer and have about reducing the advantageous characteristic of skin irritation, but have improved drug delivery behavior and adhesion characteristics simultaneously.Especially, because capsaicin is slightly soluble, for example, has less than 0.1% saturation concentration in the skin contact layer, on the surface of the skin contact layer, only there is the capsaicin of not significant amount, so that the medical patch has about undesirable skin reaction advantageous characteristic, and therefore can safely apply and / or remove.Therefore, this medical patch of the present invention with skin contact layer (wherein the saturation concentration of capsaicin is negligible) and separated active agent layer (not in contact with the skin) prevents capsaicin from being applied to the medical patch on the patient's skin and remaining on the patient's skin before and / or after release.On the other hand, it has been found that this medical patch with skin contact layer still can provide sufficient drug delivery, and may even allow active agent to release faster. In addition, the capsaicin medical patches of the present invention are advantageous because they can be based on already approved and marketed capsaicin patches, supplemented only with another skin contact layer. Since drug delivery is sufficiently similar, the prospect of achieving bioequivalence with commercial products is excellent, which is highly desirable from a regulatory perspective.

[0032] According to a specific aspect, the present invention relates to a medical patch for administering capsaicin, the medical patch comprising an active agent-containing layer structure, the active agent-containing layer structure comprising:

[0033] A) backing layer;

[0034] B) an active agent-containing layer, the active agent-containing layer comprising

[0035] (i) capsaicin in an amount of 5% to 10% by weight,

[0036] (ii) at least one amine-compatible polysiloxane in an amount of 60% to 90% by weight,

[0037] (iii) diethylene glycol monoethyl ether in an amount of 10% to 25% by weight,

[0038] (iv) ethyl cellulose in an amount of 0% to 2% by weight, and

[0039] (v) silicone oil in an amount of 0% to 5% by weight;

[0040] as well as

[0041] C) skin contact layer;

[0042] wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive, and wherein the silicone gel adhesive is obtainable by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

[0043] According to another specific aspect, the present invention relates to a medical patch for administering capsaicin, the medical patch comprising an active agent-containing layer structure, the active agent-containing layer structure comprising:

[0044] A) backing layer;

[0045] B) an active agent-containing layer, the active agent-containing layer comprising

[0046] (i) capsaicin in an amount of about 8% by weight,

[0047] (ii) at least one amine-compatible polysiloxane in an amount of 60% to 90% by weight,

[0048] (iii) diethylene glycol monoethyl ether in an amount of 10% to 25% by weight,

[0049] (iv) ethyl cellulose in an amount of 0% to 2% by weight, and

[0050] (v) silicone oil in an amount of 0% to 5% by weight;

[0051] as well as

[0052] C) skin contact layer;

[0053] wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive,

[0054] and wherein the silicone gel adhesive is obtainable by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

[0055] According to certain embodiments of the present invention, the medical patch according to the present invention is used in a method for treating neuropathic pain, in particular chronic neuropathic pain, and preferably in a method for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands and feet, postoperative neuropathic pain, joint pain or cancer pain.

[0056] According to certain embodiments of the present invention, the present invention relates to the use of a medical patch according to the present invention for the manufacture of a medicament for the treatment of neuropathic pain, in particular chronic neuropathic pain, and preferably for the manufacture of a medicament for the treatment of peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands or feet, postoperative neuropathic pain, joint pain or cancer pain.

[0057] According to certain embodiments of the present invention, the present invention relates to a method for treating neuropathic pain, in particular chronic neuropathic pain and preferably peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands or feet, postoperative neuropathic pain, joint pain or cancer pain, which method comprises applying a medical patch according to the present invention to the skin of a patient.

[0058] definition

[0059] Within the meaning of the present invention, the term "medical patch" refers to a skin delivery system for administering an active agent (capsaicin) to a patient, and refers to the entire individual dosing unit that is applied to the patient's skin after removing the optional release liner and contains a therapeutically effective amount of capsaicin in an active agent-containing layer structure. The active agent-containing layer structure may be located on a release liner (detachable protective layer), and thus, the medical patch may also include a release liner.

[0060] In this context, the term "medical patch" is understood to mean an adhesive patch, which can be a topical medical patch or a transdermal therapeutic system (TTS). Although topical medical patches and TTS are applied topically in the sense that they adhere to the patient's skin, the terms "topical" or "topical application" refer to the administration of capsaicin that relies on passive diffusion into the skin itself, which creates a local effect at the point of action. In contrast, the term "TTS" refers to a system that administers capsaicin to the systemic circulation via transdermal delivery. Topical capsaicin administration may be superior to capsaicin transdermal delivery systems in terms of systemic side effects, drug interactions, contraindications, and the development of tolerance.

[0061] Within the meaning of the present invention, the term "active agent-containing layer structure" refers to a capsaicin-containing structure that provides an area for capsaicin release during application. The active agent-containing layer structure comprises a backing layer, an active agent-containing layer comprising capsaicin, optionally a film, and a skin contact layer as described herein. Thus, the active agent-containing layer structure comprises a therapeutically effective amount of capsaicin. According to a specific embodiment, the active agent-containing layer structure is an active agent-containing self-adhesive layer structure.

[0062] Within the meaning of the present invention, the term "therapeutically effective amount" means the amount of capsaicin in the medical patch that is sufficient to provide the desired therapeutic effect, such as pain relief / relief, if administered to a patient via the medical patch. A TTS typically contains more capsaicin in the system than is actually available to the skin and systemic circulation, which is generally necessary to provide sufficient driving force for delivery from the TTS to the systemic circulation.

[0063] Within the meaning of the present invention, the terms "active agent" and "capsaicin" refer to capsaicin in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include, but are not limited to, capsaicin in free form, co-crystals, solvates, hydrates, inclusion compounds, complexes, and the like, as well as capsaicin in the form of particles that may be micronized, crystalline, and / or amorphous, and any mixtures thereof.

[0064] When contained in a medium such as a solvent, the capsaicinoids may be dissolved or dispersed or partially dissolved and partially dispersed.

[0065] When mentioning that capsaicin is used to make a medical patch in a specific form, this does not exclude the interaction between the capsaicin of this form and other components of the active agent layer structure in the final medical patch, such as salt formation or complexation. This means that even if capsaicin is included in a specific form, it may also be present in the final medical patch in another form. Unless otherwise noted, the amount of the capsaicin in the layer structure specifically relates to the amount of the capsaicin included in the medical patch during the manufacture of the medical patch, and is calculated based on the capsaicin itself rather than other forms. In the manufacture of the medical patch process, the capsaicin starting material included in the medical patch can be in the form of particles. Capsaicin can, for example, be present in the active agent layer structure in the form of particles and / or dissolution.

[0066] In this context, the term "particles" refers to solid particulate material comprising individual particles whose size is negligible compared to the material. Specifically, particles are solids, including plastic / deformable solids, including amorphous and crystalline materials. The term "dispersion" refers to a step or combination of steps in which the starting material (e.g., capsaicin) is not completely dissolved. Dispersion in the sense of the present invention includes the dissolution of a portion of the starting material (e.g., capsaicin particles), which depends on the solubility of the starting material (e.g., the solubility of capsaicin in the coating composition).

[0067] There are two main types of medical patches for use (passive) active agents to be sent, i.e. matrix type medical patches and reservoir type medical patches. In the matrix type medical patch, the release of active agent is mainly controlled by the matrix itself comprising the active agent. In contrast, the reservoir type medical patch usually requires a rate-controlled membrane for controlling the release of the active agent. In principle, the matrix type medical patch also can contain a rate-controlled membrane. However, the matrix type medical patch is favourable because, compared with the reservoir type medical patch, usually does not need rate to determine the membrane, and does not cause dosage dumping due to membrane rupture. In summary, the matrix type medical patch is not too complicated to make, and is easy and convenient to use.

[0068] In this context, "matrix type medical patch" is understood to mean a system or structure in which capsaicin is uniformly dissolved and / or dispersed in a polymer carrier (i.e., matrix), and the polymer carrier forms a matrix layer with capsaicin and optional remaining ingredients. In such a system, the matrix layer controls the release of capsaicin from the medical patch. Preferably, the matrix layer has sufficient cohesiveness to self-support so that no sealing is required between the other layers. Therefore, the active agent-containing layer can be an active agent-containing matrix layer, in which capsaicin is uniformly distributed in the polymer matrix. The active agent-containing matrix layer can include two active agent-containing matrix layers, which can be laminated together. The matrix type medical patch can particularly be in the form of a "drug in adhesive" type medical patch, and the drug-containing medical patch in the adhesive refers to a system in which capsaicin is uniformly dissolved and / or dispersed in a pressure-sensitive adhesive matrix. For this reason, the active agent-containing matrix layer can also be an active agent-containing pressure-sensitive adhesive layer or an active agent-containing pressure-sensitive adhesive matrix layer. According to the present invention, a medical patch comprising capsaicin dissolved and / or dispersed in a polymer gel (e.g., a hydrogel) is also considered to be a matrix type.

[0069] The term "reservoir-type medical patch" refers to a medical patch having a liquid active agent reservoir. In such a system, the release of capsaicin is preferably controlled by a rate-controlling membrane. Specifically, the reservoir is sealed between the backing layer and the rate-controlling membrane. Therefore, the active agent-containing layer can be an active agent-containing reservoir layer, which preferably comprises a liquid reservoir containing capsaicin, and wherein the active agent-containing reservoir layer and the skin contact layer can be separated by a rate-controlling membrane. In the active agent-containing reservoir layer, capsaicin is preferably dissolved in a solvent such as ethanol or water or in silicone oil.

[0070] Within the meaning of the present invention, reservoir-type medical patches should not be understood as matrix-type. However, microreservoir-type medical patches (two-phase systems with deposits (e.g., spheres, droplets) of an inner active agent-containing phase dispersed in an outer polymer phase) are considered to be matrix-type within the meaning of the present invention, and the microreservoir-type medical patches are considered in the art to be a hybrid form of matrix-type medical patches and reservoir-type medical patches, which is different from homogeneous single-phase matrix-type medical patches and reservoir-type medical patches in the concepts of drug transport and drug delivery.

[0071] Therefore, micro-reservoir type medical patch refers to a micro-reservoir system, in which the liquid capsaicin preparation is dispersed in an adhesive matrix in the form of small droplets ("micro-reservoirs"). The size of the resulting droplets depends on the shear force applied during stirring conditions and stirring. It can be determined by optical microscopy (e.g., by including a Leica MZ16 of a camera, such as a Leica DSC320) by taking a photo of the micro-reservoir at different positions according to the required detection limit with an enhancement factor between 10 and 400 times. By using imaging analysis software, the size of the micro-reservoir can be determined. Micro-reservoir systems are disclosed in U.S. Patent Nos. 3,946,106, 4,053,580, 4,814,184 and 5,145,682, each of which is incorporated herein by reference. Specific micro-reservoir systems are described in International Patent Publication WO0101967, the disclosure of which is incorporated herein by reference. These micro-reservoir systems contain polysiloxanes as base polymers and amphiphilic solvents for micro-reservoir droplets.

[0072] Within the meaning of the present invention, the term "active agent-containing layer" refers to a layer containing capsaicin and providing a release area. The term encompasses active agent-containing reservoir layers and active agent-containing matrix layers, and in particular active agent-containing microreservoir layers. If the active agent-containing layer is an active agent-containing matrix layer, the layer is present in a matrix-type medical patch. As used herein, the active agent-containing layer is preferably an active agent-containing matrix layer, and it refers to a final solidified layer, such as the final solidified layer obtained after coating and drying a solvent-containing coating composition as described herein. Alternatively, the active agent-containing matrix layer is obtained after melt coating and cooling. The active agent-containing matrix layer can also be manufactured by laminating two or more such solidified layers of the same composition (e.g., dried or cooled layers) to provide the required area weight. According to a specific embodiment, the matrix layer is a pressure-sensitive adhesive matrix layer.

[0073] Within the meaning of the present invention, the term "skin-contact layer" refers to the layer included in the active agent-containing layer structure that is in direct contact with the patient's skin during application. The other layers of the active agent-containing layer structure do not contact the skin and do not necessarily have self-adhesive properties. The skin-contact layer is directly attached to the active agent-containing layer, or a membrane is located between the active agent-containing layer and the skin-contact layer. In this context, the term "membrane" is understood to mean a layer provided between the active agent-containing layer and the skin-contact layer and is at least semi-permeable to capsaicin. The membrane can be a microporous membrane or a non-porous barrier membrane. Preferred membranes can be selected from the group consisting of: polyethylene films, polyurethane-coated polyethylene terephthalate / polyethylene films, polyurethane films and ethylene vinyl acetate films. According to the present invention, the skin-contact layer is present as an adhesive layer.

[0074] The dimensions of the skin-contact layer and the active agent-containing layer, or the dimensions of the skin-contact layer, the membrane, and the active agent-containing layer, are generally coextensive and correspond to the release area. However, the area of ​​the skin-contact layer and, optionally, the membrane, can also be larger than the area of ​​the active agent-containing layer. In this case, the release area still refers to the area of ​​the active agent-containing layer.

[0075] In the meaning of the present invention, term " backing layer " refers to the layer that supports the active agent layer.At least one backing layer in the medical patch and the backing layer containing active agent layer usually are substantially impermeable to capsaicin contained in the layer and optionally any additive during storage and application, and therefore prevent active agent loss or prevent cross contamination according to regulatory requirements.According to specific embodiments, the backing layer is also obstructive, which means that it is substantially impermeable to water and water vapor.The material that is suitable for backing layer includes polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate copolymer (EVA), polyester, polyurethane and their mixture.Suitable backing layer can be siliconized, to improve the adhesion of containing active agent layer and backing layer.

[0076] In addition, an adhesive covering layer may be present. In this context, the term "adhesive covering layer" is understood to mean a self-adhesive layer structure that does not contain capsaicin and is larger in area than the active agent-containing structure, and provides an additional area for adhesion to the skin, but does not provide an area for releasing capsaicin. Thus, it enhances the overall adhesion properties of the medical patch. The area of ​​the adhesive covering layer increases the overall size of the medical patch, but does not increase the release area. The adhesive covering layer may comprise a self-adhesive polymer or a self-adhesive polymer mixture selected from the group consisting of acrylic acid polymers, polyisobutylene, styrene-isoprene-styrene copolymers, polysiloxanes, and mixtures thereof, which may be identical or different to any polymer or polymer mixture included in the active agent-containing self-adhesive layer structure. The adhesive covering layer comprises a backing layer and an adhesive layer that may provide blocking or non-blocking properties. According to a specific embodiment, the backing layer of the adhesive covering layer provides non-blocking properties.

[0077] Within the meaning of the present invention, the term "areal weight" refers to the dry weight of a specific layer (e.g., the active agent-containing layer) expressed in g / m 2 Due to manufacturing variability, the tolerance for area weight values ​​is ±10%, preferably ±7.5%.

[0078] If not indicated otherwise, "%" means wt.% (weight %).

[0079] Within the meaning of the present invention, the term "polymer" (e.g. polymer I or II) refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. The polymer can have any architecture, such as linear polymers, star polymers, comb polymers, brush polymers, and in the case of copolymers any monomer arrangement, such as alternating, statistical, block copolymers or grafted polymers. The minimum molecular weight varies depending on the polymer type and is known to the skilled person. The polymer can, for example, have a molecular weight higher than 2000, higher than 5000 or higher than 10,000 daltons. Accordingly, compounds with a molecular weight lower than 2000, lower than 5000 or lower than 10,000 daltons are generally referred to as oligomers.

[0080] Within the meaning of the present invention, the term "pressure-sensitive adhesive" refers to a material that adheres, in particular, with finger pressure, is permanently tacky, exerts a strong holding force, and should be removable from smooth surfaces without leaving residue. It can be obtained by coating a solvent-containing adhesive coating composition on a film and evaporating the solvent (e.g., n-heptane or ethyl acetate). In this context, the term "solvent" is understood to mean any liquid substance, preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene, and mixtures thereof.

[0081] Within the meaning of the present invention, the term "silicone-acrylic hybrid polymer" refers to a hybrid polymer based on silicone and acrylate in the form of a pressure-sensitive adhesive. Silicone-acrylic hybrid pressure-sensitive adhesives are described, for example, in EP 2 599 847 and WO 2016 / 130408. It has been found that the arrangement of the silicone and acrylic phases, which provide a continuous silicone or acrylic outer phase and a corresponding discontinuous inner phase, differs depending on the solvent in which the silicone-acrylic hybrid PSA is provided. If the silicone-acrylic hybrid PSA is provided in n-heptane, the composition contains a continuous silicone outer phase and a discontinuous acrylic inner phase. If the silicone-acrylic hybrid PSA composition is provided in ethyl acetate, the composition contains a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0082] Within the meaning of the present invention, the term "silicone-based polymer" refers to a non-hybrid polymer (i.e., a polymer that does not include hybrid substances) comprising polysiloxanes. Polysiloxanes can be made from solvent-free two-component systems or solutions in organic solvents. They exist in two fundamentally different variants: polysiloxanes with free silanol groups and amine-resistant polysiloxanes, the difference being that the free silanol groups are derived from trimethylsilyl groups. The methyl groups can be completely or partially replaced by other alkyl groups or alternatively phenyl groups. As used herein, polysiloxanes are synthesized from linear bifunctional and branched chain multifunctional oligomers, the ratio of which determines their physical properties. More multifunctional oligomers produce adhesives with a higher degree of crosslinking, which have higher cohesion and reduced viscosity, while fewer multifunctional oligomers produce higher viscosity and reduced cohesion. Silicone-based polymers are preferably mixtures of high-viscosity and medium-viscosity or high-viscosity and low-viscosity polysiloxanes. According to a specific embodiment, at least one silicone-based polymer is a silicone-based pressure-sensitive adhesive.

[0083] Within the meaning of the present invention, the term "silicone gel adhesive" refers to an elastic, colloid-like material formed by lightly crosslinked silicone polymers. It can be prepared from a composition that produces a gel, as further described below, after curing. Specifically, silicone gel adhesives are formed after curing of polysiloxanes containing reactive groups (such as Si-H reactive groups and aliphatic unsaturated groups), which react with each other in the presence of a hydrosilylation catalyst. According to a specific embodiment, silicone gel adhesives are based on a polydimethylsiloxane network that can be formed in an addition reaction (hydrosilylation) between vinyl-functional polydimethylsiloxane groups (polymer) and hydrogen-functional siloxanes (crosslinking agents). Therefore, silicone gel adhesives are typically applied using a curable gel-producing (2-component) composition that solidifies after curing.

[0084] Within the meaning of the present invention, the term "natural or synthetic rubber" refers to an elastomer that can be obtained by polymerizing unsaturated hydrocarbons such as isoprene (2-methyl-1,3-butadiene) or by copolymerizing such hydrocarbons with styrene, butadiene, etc. It includes natural and synthetic polyisoprenes, polybutylenes and polyisobutylenes, styrene / butadiene polymers, styrene-isoprene-styrene block copolymers, hydrocarbon polymers such as butyl rubber, halogen-containing polymers such as polypropylene-nitrile, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride and polychlorodiene, and other copolymers thereof. In certain embodiments, the natural or synthetic rubber may be a styrene triblock copolymer or polyisobutylene.

[0085] Within the meaning of the present invention, the term "saturation concentration" refers to the concentration of the active agent corresponding to the equilibrium state in which the solvent (i.e., polymer II of the skin contact layer) cannot further dissolve the solute (i.e., capsaicin) and, therefore, at a defined temperature (room temperature, the unaltered temperature found in the laboratory room where the experiments were conducted, and typically within the range of 15 to 35° C. or about 18 to 25° C.), the solid solute exists in equilibrium with the solid solution. The saturation concentration of the active agent can be expressed as % by weight based on the total weight of the active agent layer or the skin contact layer, respectively. The saturation concentration can be determined, for example, using the method described by Liu, P., Gargiulo, P., Wong, J., and Novartis. Pharm. Research. Vol. 14, p. 317 (1997) (herein referred to as the "sandwich method"), wherein a multilayer laminate is prepared comprising an upper protective layer and a lower protective layer sandwiched between a donor layer and a receptor layer, the donor layer and the receptor layer being separated by a barrier membrane permeable to the active agent. Because the donor layer contains an excess of active agent and the receptor layer is essentially free of active agent, the active agent diffuses from the donor layer through the isolation membrane into the receptor layer until a saturation concentration is achieved. The donor and receptor layers are made from the corresponding polymer II of the skin contact layer. The donor layer is supersaturated with the active agent, while the receptor layer is prepared similarly to the donor layer, but does not contain the active agent. The prepared sandwich system is stored at room temperature for a certain period of time, for example, 7 days, to allow the active agent to diffuse from the donor layer into the receptor layer. The remaining active agent concentration in the donor layer is then determined by HPLC (high performance liquid chromatography) to ultimately determine the saturation concentration of the active agent in the corresponding polymer II of the skin contact layer.

[0086] As used herein, the solubility parameter (SP) is defined as the sum of all intermolecular attractions which, as a numerical estimate, are empirically related to the degree of mutual solubility of chemical substances. The most convenient method for determining the solubility parameter is the Hildebrand method, which calculates the solubility parameter from molecular weight, boiling point, and density data, which are commonly available for many materials: SP = (ΔE v / V) 1 / 2 , where V = molecular weight / density, and ΔE v = evaporation energy. For materials whose vapor pressure is too low to be detected, such as high molecular weight polymers, several methods have been developed that use the sum of the contributions of atoms and groups to evaporation. This method of calculating the solubility parameter of a material has been described, for example, by Small, J. Applied Chem. Vol. 3, p. 71 (1953). Some solubility parameters (calculated by Small's method) for exemplary polymers that can be used in the practice of the present invention are as follows: polydimethylsiloxane 14.9 MPa 1 / 2, polyisobutylene 15.7 MPa 1 / 2 , polyethylene / butene 16.2 MPa 1 / 2 , polyisoprene 16.6 MPa 1 / 2 , polyethylene 16.6 MPa 1 / 2 , polybutadiene 16.6 MPa 1 / 2 , polybutadiene-co-styrene (75 / 25 to 72 / 28) 17.4 MPa 1 / 2 , polystyrene 18.6MPa 1 / 2 , polymethyl methacrylate 19.0 MPa 1 / 2 , polymethyl acrylate 19.8 MPa 1 / 2 .

[0087] Within the meaning of the present invention, the term "soluble polyvinyl pyrrolidone" refers to polyvinyl pyrrolidone, also known as povidone, which is soluble in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, polyethylene glycol 400, 1,2 propylene glycol, 1,4 butylene glycol, glycerol, triethanolamine, propionic acid and acetic acid in an amount greater than 10%. Examples of commercially available polyvinyl pyrrolidone include Kollidon® 12PF, Kollidon® 17PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F, or povidone K90F, supplied by BASF. The different grades of Kollidon® are determined by the K value, which reflects the average molecular weight of the polyvinyl pyrrolidone grade. Kollidon® 12 PF is characterized by a K value range of 10.2 to 13.8, corresponding to a nominal K value of 12. Kollidon® 17 PF is characterized by a K value range of 15.3 to 18.4, corresponding to a nominal K value of 17. Kollidon® 25 is characterized by a K value range of 22.5 to 27.0, corresponding to a nominal K value of 25, and Kollidon® 30 is characterized by a K value range of 27.0 to 32.4, corresponding to a nominal K value of 30. Kollidon® 90 F is characterized by a K value range of 81.0 to 97.2, corresponding to a nominal K value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30, and Kollidon® 90 F. In this context, the term "K value" refers to the value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph. Eur.) and the USP "Polyvidone" monograph. For all grades and types of polyvinylpyrrolidone, the amount of peroxide is preferably within certain limits, in particular, the amount of peroxide is equal to or less than 500 ppm, equal to or less than 150 ppm or equal to or less than 100 ppm.

[0088] The medical patch according to the present invention can be characterized by certain parameters as measured in an in vitro skin penetration test.

[0089] In vitro permeation tests can be performed using human or animal skin, and preferably using dermabrasion-thick human skin with a thickness of 500 μm and an intact epidermis, and using a 0.9% sodium chloride solution as the receptor medium (32° C., 0.1% saline azide) with or without the addition of up to 40% by volume of an organic solvent, such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG400, so that the receptor medium can, for example, contain 60% by volume of 0.9% sodium chloride, 30% by volume of dipropylene glycol and 10% by volume of acetonitrile.

[0090] Unless otherwise specified, in vitro permeation tests were performed in Franz diffusion cells using heat-dissociated human epidermis and using 0.9% sodium chloride solution as the receptor medium (32°C, 0.1% saline azide). The amount of capsaicin that permeated into the receptor medium was determined periodically using a partially validated HPLC method (column: stainless steel column 150 mm x 4.6 mm inner diameter, using C18 base and acid-inactivated stationary phase, 3.5 μm particle size, such as Zorbax SB C18 (Agilent); column temperature: 25°C; mobile phase: acetonitrile / water / TEA = 20:80:0.35 (v / v / v), using a UV photometric detector by taking a sample volume. When taking a sample volume, the receptor medium was completely or partially replaced by fresh medium, and the amount of capsaicin that was measured was related to the amount of permeation between the last two sampling points, rather than the total amount permeated so far.

[0091] Therefore, within the meaning of the present invention, the parameter "permeability" is expressed in μg / cm 2Provided and relates to the amount of capsaicin that has permeated within a sample interval at a certain elapsed time. For example, in an in vitro permeation test as described above, where the amount of capsaicin that has permeated into the receptor medium has been measured, for example, at 0, 30, 60, 90, 120, 180, and 240 minutes, a "permeation amount" of capsaicin can be given for a sample interval from, for example, the 90th minute to the 120th minute, corresponding to the measurement at the 120th minute, wherein the receptor medium was completely replaced at the 90th minute. The permeation amount can also be given as a "cumulative permeation amount," corresponding to the cumulative amount of capsaicin that has permeated at a certain point in time. For example, in an in vitro permeation test as described above, in which the amount of capsaicin permeated into the receptor medium has been measured, for example, at 0, 30, 60, 90, 120, 180 and 240 minutes, the "cumulative permeation amount" of capsaicin at 120 minutes corresponds to the sum of the amounts permeated from 0 to 30 minutes, from 30 to 60 minutes, from 60 to 90 minutes and from 90 to 120 minutes.

[0092] Within the meaning of the present invention, the parameter "skin permeation rate" (also called "delta flow rate") for a certain sample interval over a certain elapsed time is expressed in µg / (cm 2 *min) and is provided by the amount of permeation (in µg / cm2) of the sample compartment measured by the in vitro permeation test as described above. 2 The "skin permeation rate" is calculated by dividing the amount of permeation (in minutes) by the number of minutes of the sample interval. For example, in an in vitro permeation test as described above, where the amount of capsaicin permeated into the receptor medium has been measured at, for example, 0, 30, 60, 90, 120, 180, and 240 minutes, the "skin permeation rate" at delta time point 105 is calculated as the amount of permeation for the sample interval from minute 90 to minute 120 divided by 30 minutes. The "cumulative skin permeation rate" can be calculated from the corresponding cumulative permeation by dividing the cumulative permeation by the elapsed time.

[0093] Within the meaning of the present invention, the above parameters "permeation amount" and "skin permeation rate" (as well as "cumulative permeation amount" and "cumulative skin permeation rate") refer to the average values ​​calculated from at least 6 in vitro permeation tests. Unless otherwise indicated, the standard deviation (SD) of these average values ​​refers to the corrected sample standard deviation calculated using the following formula:

[0094]

[0095] where n is the sample size, is the observed value, and is the mean of the observations.

[0096] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in a laboratory room where the experiments are performed, and is typically within the range of 15 to 35°C or about 18 to 25°C.

[0097] Within the meaning of the present invention, the term "patient" refers to a subject who has clinically manifested one or more specific symptoms indicating a need for treatment, is undergoing prophylactic or preventative treatment for a condition, or has been diagnosed as having a condition to be treated. Preferably, the patient suffers from neuropathic pain or mixed neuropathic and / or nociceptive pain, such as joint pain or cancer pain.

[0098] Within the meaning of the present invention, the term "neuropathic pain" refers to pain caused by a lesion or disease of the somatosensory nervous system. In this context, the term "chronic neuropathic pain" should be understood to mean neuropathic pain that lasts for at least three months. When suffering from neuropathic pain, most patients complain of persistent or intermittent spontaneous pain such as burning, tingling, squeezing properties, which may be accompanied by induced pain, especially for light touch and cold. For example, ectopic activity in nerve terminal neuromas, compressed nerves or nerve roots, dorsal root ganglia and thalamus may form the basis of spontaneous pain in different diseases. Neuropathic pain includes peripheral neuropathic pain that particularly affects peripheral nerves, and peripheral nerves mean nerves located outside the brain and spinal cord. In particular, neuropathic pain within the meaning of the present invention relates to postoperative neuropathic pain and neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy of the hands or feet.

[0099] In this context, the term "postoperative neuropathic pain" should be understood to mean chronic pain that develops after a surgical procedure and persists beyond the healing process (i.e., at least three months after surgery). The pain is localized to the surgical or injured area, projects to areas of nerve innervation located in this area, or involves the dermatome (after surgery / injury to deep somatic or visceral tissue). Chronic postoperative pain is a result of nerve damage and can be attributed to the surgery itself or other causes of pain, including infection, malignancy, etc.

[0100] In this context, the term "postherpetic neuralgia" (also known as postherpetic neuralgia) should be understood to mean pain that occurs if a nerve is damaged due to a previous herpes zoster infection (commonly known as shingles). Symptoms of postherpetic neuralgia are often confined or localized to the area of ​​skin where the shingles rash first broke out in a band around the trunk, usually on one side of the body. Less common symptoms of postherpetic neuralgia include itching, numbness, or a "pins and needles" sensation.

[0101] In this context, the term "diabetic peripheral neuropathy" (also called "diabetic neuropathy") should be understood to mean the pain that occurs if nerves are damaged due to diabetes. Although diabetic neuropathy can affect any nerve, it is most common in the extremities, such as the hands or feet.

[0102] Within the meaning of the present invention, the term "joint pain" refers to joint disorders, such as discomfort, pain or soreness in any joint of the patient's body, including the spine, shoulders, hips, elbows and knees. This especially includes joint pain caused by arthritis, such as osteoarthritis. In this context, the term "osteoarthritis" is understood to mean a degenerative disease characterized by cartilage erosion, bone hypertrophy, subchondral sclerosis, and synovial and cystic changes. Its clinical characteristics are joint pain, stiffness, and limited function. Although the pain of osteoarthritis is traditionally considered to be noxious, some patients also have neuropathic pain. Joint pain can specifically be knee pain, elbow pain, hip pain, shoulder pain, hand or foot pain, or (lower) back pain.

[0103] Within the meaning of the present invention, the term "cancer pain" refers to neuropathic cancer pain caused by nerve damage attributable to the cancer itself and / or treatments including chemotherapy, radiotherapy, and surgery. Cancer pain caused by the tumor itself usually involves nociceptive and neuropathic components, and mixed pain is more common than neuropathic cancer pain caused by cancer treatment. Most cancer pain caused by chemotherapy is purely neuropathic in nature. Neuropathic cancer pain is nerve-related (usually neuron-related) pain that is characterized by a burning or electric shock sensation; however, it sometimes manifests as decreased sensation or actual muscle weakness.

[0104] According to the present invention, the medical patch as described herein is suitable for use in a method of treatment in which the medical patch is applied for a short period of time (application time) but provides the desired pain relief effect for an extended period of time (duration of action). During the application time, the medical patch preferably releases substantially all of the capsaicin contained in the active agent-containing layer of the medical patch. Capsaicin is believed to be able to desensitize and defunctionalize TRPV1 receptors during the application time, allowing it to provide sustained pain relief that lasts during the duration of action.

[0105] Within the meaning of the present invention, the term "short time" (i.e., application time) relates to a time of less than or about 240 minutes, less than or about 180 minutes, less than or about 120 minutes, less than or about 90 minutes, less than or about 60 minutes, less than or about 45 minutes, less than or about 30 minutes, less than or about 15 minutes, or between 30 and 90 minutes.

[0106] Within the meaning of the present invention, the term "extended period of time" (i.e., duration of action) relates to a period of at least or about 1 week, at least or about 2 weeks, at least or about 1 month, at least or about 1.5 months, at least or about 2 months, at least or about 3 months, or between 1 and 3 months.

[0107] The interval (also referred to as dosing interval) between the two dosage forms is used and needs to be adjusted accordingly. Within the meaning of the present invention, the term "dosing interval" refers to the time between two consecutive medical patch applications, that is, the interval between two consecutive time points at which the medical patch is applied to the patient's skin. After application, the medical patch is only maintained on the patient's skin during the application time and is subsequently removed. However, the dosing interval continues until a new medical patch is applied to the skin.

[0108] Within the meaning of the present invention, the term "coating composition" refers to a composition comprising all components of the active agent-containing layer or the skin contact layer, respectively, which composition can be coated onto a backing layer or a release liner to form the active agent-containing layer and the skin contact layer after drying.

[0109] Within the meaning of the present invention, the term "dissolution" refers to the process of obtaining a solution that is clear and does not contain any particles visible to the naked eye.

[0110] Within the meaning of the present invention, the term "crosslinking" refers to the process of crosslinking the functional groups contained in the coating composition without active agent.

[0111] Within the meaning of the present invention and unless otherwise indicated, the term "about" refers to an amount of ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount of ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount of ±2% of the disclosed amount. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] Figure 1a The cumulative permeation amount of capsaicin of the medical patches prepared according to Example 1 and Reference Example is shown.

[0113] Figure 1b The capsaicin skin permeation rates of the medical patches prepared according to Example 1 and Reference Example are shown. DETAILED DESCRIPTION

[0114] Medical patch structure

[0115] The present invention relates to a medical patch for administering capsaicin. The medical patch can be a topical medical patch or a transdermal therapeutic system. According to certain embodiments, the patch is a topical medical patch, particularly for topical administration of capsaicin.

[0116] The medical patch according to the present invention comprises an active agent-containing layer structure, wherein the active agent-containing layer structure comprises:

[0117] A) backing layer;

[0118] B) an active agent-containing layer, the active agent-containing layer comprising

[0119] (i) capsaicin, and

[0120] (ii) at least one silicone-based polymer;

[0121] as well as

[0122] C) skin contact layer;

[0123] The skin contact layer is an adhesive layer comprising polymer II (the at least one silicone-based polymer in the active agent-containing layer is also referred to as polymer I). The active agent capsaicin is slightly soluble in the skin contact layer. For example, the saturation concentration of capsaicin in the skin contact layer may be less than 0.1% by weight. In a specific embodiment, the medical patch according to the present invention comprises an active agent-containing layer structure comprising:

[0124] A) backing layer;

[0125] B) an active agent-containing layer, the active agent-containing layer comprising

[0126] (i) capsaicin, and

[0127] (ii) at least one silicone-based polymer;

[0128] as well as

[0129] C) skin contact layer;

[0130] The skin contact layer is an adhesive layer comprising a silicone gel adhesive.

[0131] In one embodiment, the active agent-containing layer structure may or may not include a membrane between the active agent-containing layer and the skin contact layer. In such embodiments, the membrane is preferably a rate-controlling membrane. However, for certain applications, such as in the present case, where a short application time is required and rapid release of the active compound is desired, a rate-controlling membrane is typically not present.

[0132] Preferably, the above-mentioned layers of the medical patch according to the present invention are directly attached to each other, i.e. the backing layer is directly attached to the active agent-containing layer, which is directly attached to the skin contact layer on the other side. Alternatively, the active agent-containing layer is directly attached to the membrane, which is directly attached to the skin contact layer on the other side. In other words, the medical patch according to the present invention comprises its layers in the following order: (1) backing layer, (2) active agent-containing layer, and (3) skin contact layer, or (1) backing layer, (2) active agent-containing layer, (3) membrane, and (4) skin contact layer.

[0133] In particular, the backing layer is substantially impermeable to capsaicin. It may consist of a polyester film (preferably with a thickness of 10-20 μm) or an ethylene-vinyl acetate copolymer.

[0134] According to the present invention, the medical patch comprises a particularly therapeutically effective amount of capsaicin. Thus, in certain embodiments, the medical patch comprises capsaicin in an amount of 0.5 to 180 mg, 1.2 to 90 mg, or 19 to 45 mg. In some embodiments, the medical patch comprises capsaicin in an amount of about 179 mg. In other embodiments, the medical patch comprises capsaicin in an amount of about 60 mg, about 45 mg, about 30 mg, about 25 mg, about 10 mg, or about 1 mg.

[0135] The medical patch according to the present invention can be a matrix type medical patch or a reservoir type medical patch, and is preferably a matrix type medical patch. In a specific embodiment, the medical patch according to the present invention is a matrix type medical patch, wherein capsaicin is uniformly dissolved and / or dispersed in a polymer carrier (i.e., a matrix), and the polymer carrier forms a matrix layer together with capsaicin and optionally other additives. Therefore, the active agent-containing layer is preferably an active agent-containing matrix layer. Therefore, in certain embodiments of the medical patch according to the present invention, the active agent-containing layer is an active agent-containing matrix layer, and the active agent-containing matrix layer comprises

[0136] (i) capsaicin, and

[0137] (ii) at least one silicone-based polymer.

[0138] In a specific embodiment, the medical patch according to the present invention is a microreservoir-type medical patch.

[0139] The active agent layer structure according to the present invention is usually located on a separable protective layer (release liner) and is removed from the separable protective layer before being applied to the patient's skin surface. Therefore, the medical patch may also include a release liner. The medical patch protected in this way is usually stored in a seam-sealed pouch. Packaging can be child-proof and / or suitable for the elderly.

[0140] The medical patch according to one embodiment of the present invention comprising an adhesive skin contact layer comprising a silicone gel adhesive provides improved wearability and clean and painless removal when applied to the patient's skin. If necessary, for example, in the case of repositioning, the medical patch can be removed and applied again without losing adhesion. Therefore, the medical patch is even suitable for problematic application sites, such as hands or feet. Due to surface unevenness and complexity, this type of application site is particularly challenging and needs to be considered according to the shape and size of the active agent layer structure.

[0141] Thus, in a particular embodiment, the active agent-containing layer structure has a hexagonal shape, wherein the backing layer, the active agent-containing layer and the skin contact layer extend together and provide the hexagonal shape of the active agent-containing layer structure, and the hexagonal shape comprises at least one hexagon, wherein

[0142] Each pair of opposite sides of the hexagon is parallel, and

[0143] The sides of the hexagon have a length of 1.5 to 10 cm.

[0144] In certain embodiments, the at least one hexagon may be at least one convex hexagon, and the hexagonal shape may preferably include one or two convex hexagons. In particular, the hexagonal shape is a convex hexagon. In a specific embodiment, the hexagonal shape is a double hexagon formed by two identical convex hexagons, which share two adjacent vertices and a common edge, wherein the common edge is preferably perforated to facilitate tearing.

[0145] Active agent layer

[0146] As outlined in more detail above, the medical patch according to the present invention comprises an active agent-containing layer structure, which in particular comprises an active agent-containing layer comprising

[0147] (i) capsaicin, and

[0148] (ii) at least one silicone-based polymer.

[0149] In a preferred embodiment, the active agent-containing layer contains at least 0.30 mg, at least 0.50 mg, or at least 0.60 mg of capsaicin per square centimeter of release area, and / or less than 1.0 mg, less than 0.8 mg, or less than 0.7 mg of capsaicin per square centimeter of release area. In particular, the active agent-containing layer contains 0.30 mg to 1.0 mg, 0.30 mg to 8.0 mg, 0.50 mg to 8.0 mg, 0.60 mg to 0.8 mg, or 0.60 mg to 0.7 mg of capsaicin per square centimeter of release area.

[0150] According to certain embodiments, the active agent-containing layer comprises capsaicin in an amount of 2% to 20%, 5% to 15%, or 5% to 10% by weight. In a specific embodiment, the active agent-containing layer comprises capsaicin in an amount of about 8% by weight.

[0151] In addition, according to certain embodiments, the at least one silicone-based polymer is present in the active agent-containing layer in an amount of 20% to 90% by weight or 60% to 90% by weight, based on the total weight of the active agent-containing layer. It should be understood that the above-mentioned wt% amounts refer to the total amount of the at least one silicone-based polymer. For example, if two silicone-based polymers are present, the total amount in the active agent-containing layer is 20% to 90% by weight or 60% to 90% by weight, based on the total weight of the active agent-containing layer.

[0152] Therefore, in certain embodiments of the medical patch according to the present invention, the active agent-containing layer comprises

[0153] (i) capsaicin in an amount of 5% to 10% by weight, in particular in an amount of about 8% by weight, and

[0154] (ii) at least one silicone-based polymer in an amount of 60% to 90% by weight.

[0155] Capsaicin is preferably uniformly distributed in the active agent-containing layer, particularly in the active agent-containing matrix layer. As used herein, the active agent-containing matrix layer is a layer containing capsaicin dissolved or dispersed in at least one silicone-based polymer or containing capsaicin dissolved in a solvent to form a capsaicin-solvent mixture, which is dispersed in at least one silicone-based polymer in the form of a sediment (particularly droplets). In particularly preferred medical patches, the active agent-containing layer comprises capsaicin dissolved in an amphiphilic solvent (containing active agent solution) in the form of microreservoir droplets distributed in the active agent-containing matrix layer. The ratio of microreservoir droplets in the active agent-containing matrix layer is typically less than about 40% by weight or less than about 35% by weight or between about 20% by weight and about 30% by weight.

[0156] Suitable amphiphilic solvents include butanediol, in particular 1,3-butanediol, dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether (DGME), diethylene glycol monobutyl ether, propylene glycol, triethylene glycol and diethylene glycol formate, polyethoxylated fatty alcohols having 6 to 18 carbon atoms or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane or any mixtures thereof or mixtures of these solvents. In a particular embodiment, the amphiphilic solvent is diethylene glycol monoethyl ether, also known by the trade name Transcutol ® As is known. Since the solubility of capsaicin in DGME is about 50% by weight, even under unfavorable conditions (such as partial loss of solvent or low temperature), medical patches are not suitable for recrystallization of capsaicin. In addition, DGME acts as a penetration enhancer that is released together with capsaicin, and therefore makes the concentration and thermodynamic activity of capsaicin in the micro-reservoir system remain at a high level despite its release.

[0157] Therefore, in certain embodiments of the present invention, the active agent-containing layer comprises diethylene glycol monoethyl ether, and preferably comprises diethylene glycol monoethyl ether in an amount of 10% to 25% by weight.

[0158] Furthermore, it has been demonstrated that dispersion of the active agent-containing solution can be achieved more easily if the viscosity of the active agent-containing solution is increased by adding suitable agents, such as cellulose derivatives, including ethylcellulose or hydroxypropylcellulose.

[0159] Therefore, in certain embodiments of the present invention, the active agent-containing layer comprises a viscosity-increasing additive selected from the group consisting of cellulose derivatives and high molecular weight polyacrylic acid and any mixtures thereof. In particular, the active agent-containing layer comprises ethyl cellulose, and preferably comprises ethyl cellulose in an amount of 0% to 2% by weight.

[0160] In certain embodiments of the medical patch according to the present invention, the active agent-containing layer comprises

[0161] (i) capsaicin in an amount of 5% to 10% by weight, in particular in an amount of about 8% by weight,

[0162] (ii) at least one silicone-based polymer in an amount of 60% to 90% by weight,

[0163] (iii) diethylene glycol monoethyl ether in an amount of 10% to 25% by weight, and

[0164] (iv) ethyl cellulose in an amount of 0% to 2% by weight.

[0165] According to certain embodiments, the at least one silicone-based polymer is a non-hybrid polymer comprising a polysiloxane. It is preferably a thermoplastic polymer that is applied by a hot melt or solvent-based method and typically solidifies without further curing. Additional details about these polymers are provided below. In a specific embodiment, the at least one silicone-based polymer is at least one amine-compatible polysiloxane.

[0166] In certain embodiments, the active agent-containing layer comprises silicone oil, and preferably comprises silicone oil in an amount of 0% to 5% by weight, in particular 0.5% to 5% by weight. This particularly includes dimethicone.

[0167] Therefore, in a preferred embodiment of the medical patch according to the present invention, the active agent-containing layer comprises

[0168] (i) capsaicin in an amount of 5% to 10% by weight, in particular in an amount of about 8% by weight,

[0169] (ii) at least one amine-compatible polysiloxane in an amount of 60% to 90% by weight, in particular 58% to 85% by weight,

[0170] (iii) diethylene glycol monoethyl ether in an amount of 10% to 25% by weight,

[0171] (iv) ethyl cellulose in an amount of 0% to 2% by weight, and

[0172] (v) silicone oil in an amount of 0% to 5% by weight.

[0173] Furthermore, in a preferred embodiment, the area weight of the active agent-containing layer is in the range of 30 to 200 g / m 2 or 50 to 120 g / m 2 within the range.

[0174] Skin contact layer

[0175] As outlined in more detail above, the medical patch according to the invention comprises an active agent-containing layer structure comprising, inter alia, a skin contact layer, wherein the skin contact layer is an adhesive layer comprising polymer II. The skin contact layer is preferably directly attached to the active agent-containing layer.

[0176] The medical patch according to the present invention is particularly characterized by the low solubility of capsaicin in the skin-contact layer. In certain embodiments, the saturation concentration of capsaicin in the skin-contact layer is preferably less than 0.1% by weight, as determined by the "sandwich method." In certain embodiments, the saturation concentration of capsaicin in the skin-contact layer is less than 0.05% by weight, less than 0.02% by weight, or less than 0.01% by weight. Preferably, the saturation concentration of capsaicin in the skin-contact layer is about 0% by weight. The saturation concentration refers to the amount of capsaicin present in the skin-contact layer based on the total weight of the skin-contact layer.

[0177] In certain embodiments, the saturation concentration of capsaicin in the skin contact layer is less than the capsaicin concentration that causes any unexpected harmful effect (such as skin irritation after short-term contact).Such concentration can be empirically tested in vivo by observing whether harmful effects occur or not after applying a model adhesive layer with a limited capsaicin concentration on the skin for a short time (such as 5 seconds, 10 seconds, 30 seconds or 1 minute), such as any form of skin irritation (redness, erythema, itching or other skin reactions).In particular, the different model layers representing a series of capsaicin concentrations can be tested to determine the highest acceptable saturation concentration that has not yet caused any unexpected harmful effect (such as skin irritation reaction).On the other hand, whether the medical patch with a certain group of capsaicin and skin contact layer produces a saturation concentration that does not cause any harmful effect can be simply by testing a model adhesive layer saturated with capsaicin or the medical patch, i.e., by being applied to the skin as outlined above and determining (without a series of different concentrations).

[0178] According to the present invention, before and / or after application of the medical patch, the skin contact layer shields the capsaicin contained in the active agent layer from the skin of the patient or other application / removal personnel. Therefore, the skin contact layer needs to be substantially free of capsaicin. This means that the skin contact layer is usually made into a layer that does not contain capsaicin. However, due to the concentration gradient, capsaicin can usually migrate from the active agent layer to the skin contact layer over time until equilibrium is reached. However, this migration is limited by the saturation concentration of capsaicin in the skin contact layer. In certain embodiments, the skin contact layer does not allow capsaicin to be present at a concentration greater than 0.1% by weight.

[0179] Thus, in certain embodiments, the skin contact layer comprises capsaicin in an amount less than 0.1 wt % based on the total weight of the skin contact layer. In specific embodiments, the skin contact layer comprises capsaicin in an amount less than 0.01 wt % based on the total weight of the skin contact layer.

[0180] The polymer II in the skin contact layer determines the adhesive properties and, in particular, reduces skin irritation due to its elasticity. In addition, polymer II does not negatively affect the delivery of capsaicin. In certain embodiments, the skin contact layer comprises polymer II in an amount of at least 95% by weight, at least 99% by weight, or about 100% by weight, based on the total weight of the skin contact layer. In particular, the skin contact layer may consist essentially of polymer II. It should be understood that the above-mentioned % by weight amounts refer to the total amount of polymer II. For example, if polymer II is a mixture of polymers, the total amount in the skin contact layer is 50% to 100% by weight, based on the total weight of the skin contact layer.

[0181] In particular, polymers suitable as polymer II according to the present invention are polymers that allow the concentration of capsaicin to no more than 0.1% by weight, no more than 0.05% by weight, no more than 0.02% by weight, or no more than 0.01% by weight, i.e., polymers in which capsaicin is substantially insoluble. Thus, according to certain embodiments, polymer II may be a polymer or a mixture of polymers in which capsaicin is substantially insoluble.

[0182] Thus, the solubility parameter of polymer II may be different from the solubility parameter of the active agent, and in particular may be at least 5.0 MPa lower than the solubility parameter of capsaicin. 1 / 2 , at least 6.0 MPa 1 / 2 , at least 8.0 MPa 1 / 2 or at least 10.0 MPa 1 / 2 In particular, the solubility parameter of polymer II may preferably be less than 18.5 MPa as calculated by the method of Small. 1 / 2 , less than 18.0MPa 1 / 2 , less than 17.5 MPa 1 / 2 , less than 17.0 MPa 1 / 2 , less than 16.0 MPa 1 / 2 or less than 15.0 MPa 1 / 2 .

[0183] Polymer II may be selected from pressure sensitive adhesive polymers. Thus, in certain embodiments, polymer II may be a pressure sensitive adhesive or a mixture of pressure sensitive adhesives.

[0184] In certain embodiments, polymer II can be a polymer or a mixture of polymers selected from the group consisting of silicone acrylic hybrid polymers, silicone-based polymers, silicone gel adhesives, and polymers based on natural or synthetic rubbers. In particular, polymer II can be a polymer or a mixture of polymers selected from the group consisting of silicone-based polymers and silicone gel adhesives.

[0185] In certain embodiments, polymer II may be a silicone gel adhesive.

[0186] Furthermore, polymer II may be a polymer or a mixture of polymers chosen from silicone-based polymers, in particular polysiloxane-based polymers, such as amine-compatible polysiloxanes, or polymer II may be a polymer or a mixture of polymers chosen from natural or synthetic rubbers, in particular styrene triblock copolymers and / or polyisobutylenes, such as SIS block copolymers and / or polyisobutylenes.

[0187] Suitable polymers II according to the invention are commercially available, for example, under the trade name Softskin Adhesives (two-part silicone adhesives that cure after mixing the two components). Alternatively, suitable polymers II according to the invention are commercially available, for example, under the trade names BIO-PSA (pressure-sensitive adhesives based on polysiloxanes), JSR-SIS (pressure-sensitive adhesives based on SIS block copolymers), and Oppanol™ (polyisobutylene).

[0188] Other polymers may also be added to enhance the adhesion of the skin contact layer.

[0189] According to some embodiments, the polymer II contained in the skin contact layer is different from the polymer I (i.e., a silicone-based polymer) contained in the active agent-containing layer. According to other embodiments, the polymer II contained in the skin contact layer is the same as the polymer I (i.e., a silicone-based polymer) contained in the active agent-containing layer.

[0190] According to certain embodiments, the area weight of the skin contact layer may be between 80 and 500 g / m 2 In a preferred embodiment, the skin contact layer may have a thickness of 100 to 350 g / m 2 , 150 to 320 g / m 2 or 180 to 280 g / m 2 The area weight of the self-adhesive layer is relatively thick. This relatively thick skin contact layer enables gentle removal of the medical patch containing the self-adhesive layer structure according to the present invention and is therefore conducive to reducing skin irritation. On the other hand, even if the elasticity and therefore the ease of removability of the skin contact layer increase with increasing thickness, the total thickness of the self-adhesive layer structure should still allow for simple handling and wearing comfort. Surprisingly, it was found that, when compared with a medical patch without a skin contact layer, the release of the active agent was not affected by this thick (inactive) skin contact layer, but on the contrary was even improved.

[0191] Silicone acrylic hybrid polymer

[0192] The silicone acrylic hybrid polymer comprises a polymeric hybrid material comprising a silicone-based sub-material and an acrylate-based sub-material that have been polymerized together. Thus, the silicone acrylic hybrid polymer comprises a silicone phase and an acrylic phase. In certain embodiments, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.

[0193] Silicone acrylic hybrid pressure sensitive adhesives are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of the pressure sensitive adhesive is typically between 30% and 80%. Skilled persons will appreciate that the solids content can be varied by adding an appropriate amount of solvent.

[0194] The weight ratio of silicone to acrylate in the silicone acrylic hybrid pressure sensitive adhesive may be 5:95 to 95:5, or 20:80 to 80:20, or 40:60 to 60:40, or the ratio of silicone to acrylate may be about 50:50.

[0195] Commercially available suitable silicone acrylic hybrid pressure-sensitive adhesives include the PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X = 1 n-heptane / X = 2 ethyl acetate) manufactured by Dow Corning and supplied in n-heptane or ethyl acetate. For example, the 7-6102 silicone acrylic hybrid PSA having a 50 / 50 silicone / acrylate ratio is characterized by a solution viscosity of 2,500 cP in ethyl acetate at 25°C and approximately 50% solids content, and a complex viscosity of 1.0e7 poise at 0.1 rad / s at 30°C. The 7-6302 silicone acrylic hybrid PSA having a 50 / 50 silicone / acrylate ratio has a solution viscosity of 1,500 cP in ethyl acetate at 25°C and approximately 50% solids content, and a complex viscosity of 4.0e6 poise at 0.1 rad / s at 30°C.

[0196] Depending on the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is provided, the arrangement of the silicone and acrylic phases, which provide a continuous silicone or acrylic outer phase and a corresponding discontinuous inner phase, differs. If the silicone-acrylic hybrid pressure-sensitive adhesive is provided in n-heptane, the composition contains a continuous silicone outer phase and a discontinuous acrylic inner phase. If the silicone-acrylic hybrid pressure-sensitive adhesive is provided in ethyl acetate, the composition contains a continuous acrylic outer phase and a discontinuous silicone inner phase. After evaporation of the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is provided, the phase arrangement of the resulting pressure-sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of any substance that could cause a reversal of the phase arrangement in the silicone-acrylic hybrid pressure-sensitive adhesive composition, a pressure-sensitive adhesive layer prepared from a silicone-acrylic hybrid pressure-sensitive adhesive in n-heptane provides a continuous silicone outer phase and a discontinuous acrylic inner phase, while a pressure-sensitive adhesive layer prepared from a silicone-acrylic hybrid pressure-sensitive adhesive in ethyl acetate provides a continuous acrylic outer phase and a discontinuous silicone inner phase. Can, for example, determine the phase arrangement of composition with the pressure-sensitive adhesive film or layer prepared by silicone acrylic hybrid PSA composition in the peel force test, and described pressure-sensitive adhesive film or layer is attached to siliconized release liner.If siliconized release liner can not or can hardly be removed from pressure-sensitive adhesive film (laminated to backing film) because of the obstruction of two silicone surfaces, then pressure-sensitive adhesive film contains continuous silicone outer phase.Obstruction is caused by adhering two silicone layers, and these two silicone layers comprise similar surface energy.Silicone adhesive shows good spreading property on siliconized liner, and therefore can produce good adhesion to liner.If siliconized release liner can be easily removed, then pressure-sensitive adhesive film contains continuous acrylic outer phase.Acrylic adhesive does not have good spreading property because of different surface energies, and therefore has low adhesion or almost no adhesion to siliconized liner.

[0197] The silicone acrylic hybrid polymer may be a silicone acrylic hybrid pressure sensitive adhesive that may be obtained from a silicone-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups. It should be understood that the silicone-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups may include only acrylate functional groups, only methacrylate functional groups, or both acrylate and methacrylate functional groups.

[0198] The silicone acrylic hybrid pressure-sensitive adhesive may comprise the reaction product of (a) a silicone-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator. In other words, the silicone acrylic hybrid pressure-sensitive adhesive is the product of a chemical reaction between these reactants ((a), (b), and (c)). In particular, the silicone acrylic hybrid pressure-sensitive adhesive may comprise the reaction product of (a) a silicone-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) a (meth)acrylate monomer, and (c) an initiator (i.e., in the presence of an initiator). In other words, the silicone acrylic hybrid pressure-sensitive adhesive may comprise the product of a chemical reaction between these reactants ((a), (b), and (c)).

[0199] The reaction product of (a) a silicone-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous silicone outer phase and a discontinuous acrylic inner phase, or the reaction product of (a), (b), and (c) may contain a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0200] The silicone acrylic hybrid polymer may comprise the reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bonded to the silicone polymer and / or the silicone resin.

[0201] The silicone acrylic hybrid polymer may comprise the reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, wherein the silicone resin contains triorganosiloxy units R3SiO 1 / 2 (where R is an organic group) and a tetrafunctional siloxy unit SiO 4 / 2 , the molar ratio of each SiO 4 / 2 0.1 to 0.9 R3SiO units 1 / 2 unit.

[0202] The acrylic polymer may comprise at least an alkoxysilyl functional monomer, a polysiloxane-containing monomer, a halosilyl functional monomer, or an alkoxyhalosilyl functional monomer. In certain embodiments, the acrylic polymer is prepared from an alkoxysilyl functional monomer selected from the group consisting of trialkoxysilyl (meth)acrylates, dialkoxyalkylsilyl (meth)acrylates, and mixtures thereof, or comprises a capped alkoxysilyl functional group. The alkoxysilyl functional group may preferably be selected from the group consisting of trimethoxysilyl, dimethoxymethylsilyl, triethoxysilyl, diethoxymethylsilyl, and mixtures thereof.

[0203] The acrylic polymers may also be prepared from mixtures comprising silicone-containing monomers, preferably from mixtures comprising polydimethylsiloxane mono(meth)acrylate.

[0204] Silicone acrylic hybrid polymers can be prepared by a) reacting a silicone polymer with a silicone resin to form the resultant product, and b) reacting the resultant product of a) with an acrylic polymer containing reactive functional groups, wherein the components are reacted in an organic solvent.

[0205] Silicone acrylic hybrid polymers can be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functional groups to form a resultant product, and b) reacting the resultant product of a) with a silicone polymer, wherein the components are reacted in an organic solvent.

[0206] Silicone acrylic hybrid polymers can be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functional groups to form a resultant product, and b) reacting the resultant product of a) with a silicone resin, wherein the components are reacted in an organic solvent.

[0207] Other suitable acrylic polymers, silicone resins and silicone polymers that can be used to chemically react together silicone polymers, silicone resins and acrylic polymers to provide the silicone acrylic hybrid polymers according to the preceding paragraphs are detailed in WO 2010 / 124187.

[0208] Silicone-based polymers

[0209] Silicone-based polymers are non-curing polymers that are typically applied by hot melt or solvent-based methods and preferably set without undergoing further curing.

[0210] Silicone-based polymers are based on polysiloxanes. Therefore, they may also be referred to as polysiloxane-based polymers. Silicone-based polymers are typically obtained by the polycondensation of silanol-terminated polydimethylsiloxanes with silicate resins. Amine-compatible silicone-based polymers can be obtained by reacting silicone-based polymers with trimethylsilyl groups (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer and thereby provide enhanced stability in the presence of amines. Therefore, the residual silanol functional groups are at least partially, preferably mostly or completely, terminated with trimethylsiloxy groups.

[0211] Thus, in a preferred embodiment, the silicone-based polymer is an amine-compatible polysiloxane and is preferably obtainable by polycondensation of a silanol-terminated polydimethylsiloxane with a silicate resin followed by at least partial trimethylsilylation of the residual silanol functionality.

[0212] In certain embodiments, the silicone-based polymer is a pressure sensitive adhesive or a mixture of pressure sensitive adhesives, ie, a polysiloxane-based pressure sensitive adhesive or a mixture of polysiloxane-based pressure sensitive adhesives.

[0213] Pressure-sensitive adhesives based on polysiloxanes provide suitable tack and quick bonding, suitable adhesion and cohesiveness to various skin types (including wet skin), lasting adhesion to skin, high flexibility, moisture permeability and compatibility with many active agents and film substrates. This type of pressure-sensitive adhesive is based on the concept of polymer-coated resins, wherein the pressure-sensitive adhesive based on polysiloxanes is prepared by the condensation reaction of silanol-terminated polydimethylsiloxane and silicon dioxide resin (also referred to as silicate resin). For obtaining amine stability, residual silanol functional groups are capped with trimethylsiloxy in addition. The silanol-terminated polydimethylsiloxane content is helpful to the viscous component with viscoelasticity, and affects the wettability and spreadability of adhesive. Resin serves as tackifier and reinforcing agent, and participates in elastic component. The appropriate balance between silanol-terminated polydimethylsiloxane and the resin provides appropriate bonding properties.

[0214] As previously mentioned, the viscosity of silicone-based polymers can be adjusted by the resin-to-polymer ratio, i.e., the ratio of silanol-terminated polydimethylsiloxane to silicate resin, which is preferably in the range of 50:50 to 70:30 or 55:45 to 65:35. Viscosity increases with increasing amounts of polydimethylsiloxane relative to the resin. High-viscosity silicone-based polymers preferably have a resin-to-polymer ratio of 55:45, medium-viscosity silicone-based polymers preferably have a resin-to-polymer ratio of 60:40, and low-viscosity silicone-based polymers preferably have a resin-to-polymer ratio of 65:35.

[0215] According to certain embodiments, the pressure-sensitive adhesive is obtainable by the polycondensation of a silanol-terminated polydimethylsiloxane with a silicate resin, preferably at a resin to polymer ratio of 50:50 to 70:30 or 55:45, 60:40 or 65:35. Thus, in a preferred embodiment, the silicone-based polymer is a mixture of pressure-sensitive adhesives obtainable by the polycondensation of a silanol-terminated polydimethylsiloxane with a silicate resin, at a resin to polymer ratio of 55:45 or 60:40.

[0216] Additionally, according to certain embodiments, the silicone-based polymer is a mixture of pressure-sensitive adhesives wherein

[0217] The solution viscosity in heptane at 25°C and about 60% solids content is 450 mPa s and / or the complex viscosity at 0.01 rad / s at 30°C is 1×10 8 Park, and

[0218] The solution viscosity in heptane at 25°C and about 60% solids content is 500 mPa s and / or the complex viscosity at 0.01 rad / s at 30°C is 5×10 6 moor.

[0219] Silicone-based pressure-sensitive adhesives are supplied and used in solvents such as n-heptane, ethyl acetate, or other volatile silicone oils. The solids content of silicone-based pressure-sensitive adhesives in solvent is typically between 60% and 85%, between 70% and 80%, or between 60% and 75%. Those skilled in the art will appreciate that the solids content can be varied by adding an appropriate amount of solvent.

[0220] The high viscosity silicone-based polymer preferably has a viscosity of about 5 x 10 6 The complex viscosity of the medium viscosity silicone-based polymer is preferably about 5 x 10 poise at 0.01 rad / s and 30°C. 7 The low viscosity silicone-based polymer preferably has a complex viscosity of about 5 x 10 poise at 0.01 rad / s and 30°C. 8 The high viscosity amine-compatible silicone-based polymer preferably has a composite viscosity of about 5 x 10 poise at 0.01 rad / s and 30°C. 6 The medium viscous amine-compatible silicone-based polymer preferably has a complex viscosity of about 5 x 10 poise at 0.01 rad / s and 30°C. 8 The low viscosity amine-compatible silicone-based polymer preferably has a complex viscosity of about 5 x 10 poise at 0.01 rad / s and 30°C. 9 Preferred polysiloxane-based pressure-sensitive adhesives according to the present invention are characterized by a solution viscosity in n-heptane at 25° C. and 60% solids content of greater than about 150 mPa s or from about 200 mPa s to about 700 mPa s, preferably as measured at 50 rpm using a Brookfield RVT viscometer equipped with a No. 5 spindle. These pressure-sensitive adhesives may also be characterized by a complex viscosity at 0.01 rad / s of less than about 1 x 10 9 Poise is about 1x 10 5 About 9 x 10 8 moor.

[0221] Suitable silicone-based polymers are commercially available under the trade name BIO-PSA. Examples of commercially available silicone-based PSA compositions include the standard Liveo™ BIO-PSA series (7-4400, 7-4500, and 7-4600 series) and the amine-compatible (end-capped) Liveo™ BIO-PSA series (7-4100, 7-4200, and 7-4300 series), which are manufactured and typically supplied in n-heptane or ethyl acetate. For example, BIO-PSA 7-4201 is characterized by a solution viscosity of 450 mPa s in heptane at 25° C. and about 60% solids content, and a complex viscosity of 1×10 s at 0.01 rad / s at 30° C. 8 The solution viscosity of BIO-PSA 7-4301 in heptane at 25°C and about 60% solids content is 500 mPa s, and the complex viscosity at 0.01 rad / s at 30°C is 5×10 6 moor.

[0222] Pressure-sensitive adhesives based on polysiloxanes are available according to the following scheme:

[0223]

[0224] The pressure-sensitive adhesive of this type based on polysiloxane can be obtained by trade name Liveo BIO-PSA 7-4401, BIO-PSA-7-4501 or BIO-PSA 7-4601, and described pressure-sensitive adhesive provides (by coding " 01 " indication) in solvent normal heptane, or with trade name Liveo BIO-PSA 7-4402, BIO-PSA 7-4502 and BIO 7-4602 obtain, and described pressure-sensitive adhesive provides (by coding " 02 " indication) in solvent ethyl acetate.Typical solids content in the solvent is within the scope of 60% to 75%.The resin and polymer ratio of coding " 44 " indication 65:35 produces low tack, the resin and polymer ratio of coding " 45 " indication 60:40 produces medium tack, and the resin and polymer ratio of coding " 46 " indication 55:45 produces high tack.

[0225] Amine-compatible pressure-sensitive adhesives based on polysiloxanes can be obtained according to the following scheme:

[0226]

[0227] The pressure-sensitive adhesive of this type based on polysiloxane can be obtained by trade name Liveo BIO-PSA 7-4101, BIO-PSA-7-4201 or BIO-PSA 7-4301, and described pressure-sensitive adhesive provides (by coding " 01 " indication) in solvent normal heptane, or with trade name Liveo BIO-PSA 7-4102, BIO-PSA 7-4202 and BIO 7-4302 obtain, and described pressure-sensitive adhesive provides (by coding " 02 " indication) in solvent ethyl acetate.Typical solids content in the solvent is within the scope of 60% to 75%.Coding " 41 " indicates the resin and polymer ratio of 65:35, produces low viscosity, coding " 42 " indicates the resin and polymer ratio of 60:40, produces medium viscosity, and coding " 43 " indicates the resin and polymer ratio of 55:45, produces high viscosity.

[0228] Silicone gel adhesive

[0229] Silicone gel adhesives are elastic, colloid-like materials formed from lightly cross-linked silicone polymers. Therefore, in contrast to silicone-based polymers as used herein, silicone gel adhesives are based on compositions that produce curable gels. Silicone gel adhesives provide the adhesion of medical patches to the skin while simultaneously alleviating skin irritation. Furthermore, drug delivery through the medical patch is not negatively impacted, and surprisingly, skin permeability is even improved.

[0230] Silicone gel adhesives are also called silicone gels and are described, for example, in WO 2011 / 022199 A2.

[0231] Silicone gel adhesives are usually formed by straight or branched chain silicones having reactive groups thereon. Such reactive groups undergo cross-linking reactions during curing. Examples of cross-linking reactions include hydrosilylation reactions, in which silicones having Si-H reactive groups react with silicones having aliphatic unsaturated reactive groups in the presence of a hydrosilylation catalyst. These materials are described in, for example, US 5,656,279, US 5,891,076, EP 0 322 118 and US 4,991,574, which are incorporated herein by reference. Alternative reactions are condensation cures, in which siloxanes containing alkoxy and / or hydroxyl groups solidify in the presence of a catalyst as described in US 4,831,070, which are incorporated herein by reference.

[0232] Typically, silicone gel adhesives are obtained by reacting a gel-forming composition comprising: (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane containing silicon-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of SiH groups with Si-alkenyl groups. These compositions cure at normal ambient temperatures, but curing can be accelerated by heating to elevated temperatures (e.g., from 40 to 140° C.) or by applying UV light.

[0233] Suitable alkenyl groups contain 2 to about 6 carbon atoms and are exemplified by, but not limited to, vinyl, allyl, and hexenyl. The alkenyl groups in this component may be located at terminal, side chain (non-terminal), or both terminal and side chain positions. The remaining silicon-bonded organic groups in the alkenyl-substituted polydiorganosiloxane are independently selected from the group consisting of monovalent hydrocarbon groups and monovalent halogenated hydrocarbon groups that are free of aliphatic unsaturation. These groups typically contain 1 to about 20 carbon atoms, or 1 to 8 carbon atoms, and are exemplified by, but not limited to, alkyl groups such as methyl, ethyl, propyl, and butyl; aryl groups such as phenyl; and halogenated alkyl groups such as 3,3,3-trifluoropropyl. Typically, at least 50% of the organic groups in the alkenyl-substituted polydiorganosiloxane are methyl groups. The structure of the alkenyl-substituted polydiorganosiloxane is typically linear, however, it may contain some branches due to the presence of trifunctional siloxane units. The viscosity of the alkenyl-substituted polydiorganosiloxane may be any desired viscosity. For example, it may be >0 mm 2 / s to 100,000 mm 2 / s, or 50 mm 2 / s to 80,000 mm 2 / s, or 300 mm 2 / s - 3,000 mm 2 / s.

[0234] Methods for preparing the alkenyl-substituted polydiorganosiloxanes (i) of the present invention, such as condensation of the corresponding halosilanes or equilibration of cyclic polydiorganosiloxanes, are well known in the art.

[0235] The alkenyl-substituted polydiorganosiloxane can be used in the gel-forming composition in an amount of 10 wt.% to 90 wt.%, or 40 wt.% to 90 wt.%, or 50 wt.% to 80 wt.%, based on the weight of the composition. The amount of alkenyl groups present in the alkenyl-substituted polydiorganosiloxane is typically in the range of 0.05 wt.% to 1 wt.%, or 0.05 wt.% to 1 wt.%, based on the weight of the alkenyl-substituted polydiorganosiloxane.

[0236] Organosiloxanes containing silicon-bonded hydrogen atoms (ii) are also known in the art, as described, for example, in U.S. Patent No. 3,983,298. The hydrogen atoms in this component may be located at terminal, pendant (non-terminal) or both terminal and pendant positions. The remaining silicon-bonded organic groups in this component are independently selected from the group consisting of monovalent hydrocarbon groups and monovalent halogenated hydrocarbon groups that are free of aliphatic unsaturation. These groups typically contain 1 carbon to about 20 carbon atoms or 1 carbon to 8 carbon atoms and are exemplified by, but not limited to, alkyl groups such as methyl, ethyl, propyl, and butyl; aryl groups such as phenyl; and halogenated alkyl groups such as 3,3,3-trifluoropropyl. In one embodiment of the present invention, at least 50% of the organic groups in the organosiloxane containing silicon-bonded hydrogen atoms are methyl groups. However, the structure of the organosiloxane containing silicon-bonded hydrogen atoms is generally linear; it may contain some branching due to the presence of trifunctional siloxane units. The viscosity of the organosiloxane containing silicon-bonded hydrogen atoms can be any desired viscosity. For example, it can be >0 mm 2 / s to 100,000 mm 2 / s, or 5 mm 2 / s to 500 mm 2 / s.

[0237] Methods for preparing the organosiloxanes of the present invention containing silicon-bonded hydrogen atoms by co-hydrolysis of appropriate chlorosilanes are known in the art; U.S. Patent No. 2,877,255 to Clark; Japanese Published Patent Application (KOKAI) SHO 62 (1987)-39660 to Mogi et al.; and U.S. Patent No. 5,446,185 and U.S. Patent No. 5,493,040 to Cobb et al., all of which are incorporated herein by reference.

[0238] The organosiloxane containing silicon-bonded hydrogen atoms can be used in the gel-forming composition in an amount of 1 wt.% to 30 wt.%, or 5 wt.% to 20 wt.%, or 5 wt.% to 15 wt.%, based on the weight of the composition. In one embodiment, the amount of hydrogen groups present in the organosiloxane containing silicon-bonded hydrogen atoms is between 0.05 wt.% and 1.44 wt.%, based on the weight of the organosiloxane containing silicon-bonded hydrogen atoms.

[0239] In the composition that produces the gel, (i) and (ii) are preferably present such that the ratio of (H as SiH):(alkenyl as Si-alkenyl) is typically in the range of 0.1:1 to 10:1.

[0240] The hydrosilylation catalyst (iii) promotes the addition reaction of alkenyl-substituted polydiorganosiloxanes with organosiloxanes containing silicon-bonded hydrogen. The hydrosilylation catalyst can be any well-known hydrosilylation catalyst comprising a platinum group metal, a compound containing a platinum group metal, or a microencapsulated platinum group metal or a compound containing them. These platinum group metals include platinum, rhodium, ruthenium, palladium, osmium, and iridium. Platinum and platinum compounds are preferred catalysts based on their high activity levels in the hydrosilylation reaction. One type of platinum catalyst is a complex of chloroplatinic acid and certain vinyl-containing organosiloxane compounds disclosed by Willig in U.S. Patent No. 3,419,593, which is incorporated herein by reference. A specific catalyst of this type is the reaction product of chloroplatinic acid and 1,3-divinyl-1,1,3,3-tetramethyldisiloxane.

[0241] The hydrosilylation catalyst is present in an amount sufficient to cure the composition of the present invention. Typically, the concentration of the catalyst is sufficient to provide 0.1 ppm to 500 ppm (parts per million), or 1 ppm to 100 ppm, or 1 ppm to 50 ppm of platinum group metal, based on the weight of (i) and (ii).

[0242] In view of the above, in a preferred embodiment of the present invention, a silicone gel adhesive can be obtained by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst, wherein (i) and (ii) are preferably present so that the ratio of (H as SiH):(alkenyl as Si-alkenyl) is generally in the range of 0.1:1 to 10:1.

[0243] An optional ingredient is a hydroxy substituted silicone resin as described in U.S. Patent Application No. 2007-0202245, which is incorporated herein by reference. The resin typically comprises a hydroxy substituted silicone resin having the formula R 3 3SiO 1 / 2 A group ("M" group) and a group having the formula SiO 4 / 2 A group ("Q" group) wherein R 3 The R group is an alkyl group having 1 to 6 carbon atoms or an alkylene group having 1 to 6 carbon atoms, typically methyl or vinyl. If alkenyl groups are present in the resin, the mol% of R groups present as alkenyl groups is typically < 10 mol% or 5 mol%. The ratio of the number of M groups to Q groups is typically in the range of 0.6:1 to 4:1 or 0.6:1 to 1.0:1. Silicone resins typically contain 0.1 wt% to 5 wt% or 1.0 wt% to 5 wt% silicon-bonded hydroxyl groups.

[0244] The resin can be used in the gel-generating composition in an amount of 2 wt.% to 45 wt.%, or 5 wt.% to 40 wt.%, or 10 wt.% to 35 wt.%, based on the weight of the gel-generating composition and the resin.

[0245] Thus, in a preferred embodiment, the silicone gel adhesive is a silicate resin reinforced silicone gel adhesive comprising from about 2% to about 45% by weight of at least one hydroxy-substituted silicate resin.

[0246] In some embodiments, silicone gel adhesive is a 2-component silicone adhesive system that solidifies after mixing two components. The example of this type of two-part silicone adhesive commercially available comprises the Liveo™ soft skin adhesive (for example MG 7-9700, MG 7-9800, MG 7-9850 and MG 7-9900) that provides in the form of a test kit comprising components A and B. It is a soft, non-filled elastic silicone adhesive catalyzed by a platinum catalyst, and the soft, non-filled elastic silicone adhesive catalyzed by the platinum catalyst is used for medical devices to be adhered to skin with medium adhesion and can be gently removed. Two components A and B are preferably mixed in a ratio of 1:1.

[0247] The silicone gel adhesive layer can be prepared by methods known in the art. For example, the gel can be preformed (e.g., preformed into a sheet) by molding, squeezing, extruding, spraying, brushing, manually applying, casting, or coating on a substrate (such as a liner). Alternatively, the silicone gel layer can be prepared by applying a gel-forming composition to a substrate by spraying, coating, rod coating, etc. After application to the substrate, the gel-forming composition is cured to produce a silicone gel adhesive on the substrate.

[0248] Polymers based on natural or synthetic rubber

[0249] Polymers based on natural or synthetic rubber include hydrocarbon polymers such as (natural and synthetic) polyisoprene, polybutylene and polyisobutylene, styrene / butadiene polymers, styrene-isoprene-styrene block copolymers, butyl rubber, halogen-containing polymers such as polyacrylonitrile, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride and polychlorodiene, and other copolymers thereof. The polymers can be used in combination with an adhesive as defined below.

[0250] According to certain embodiments, the polymer can be a styrene triblock copolymer selected from the group consisting of: styrene-ethylene-styrene (SES) block copolymer, styrene-butadiene-styrene (SBS) block copolymer, styrene-isoprene-styrene (SIS) block copolymer, styrene-ethylene / butylene-styrene (S-EB-S) block copolymer, styrene-ethylene / butylene / propylene-styrene (s-EBS-S) block copolymer, styrene-isoprene / butadiene-styrene (S-IB-S) block copolymer, and mixtures thereof.

[0251] In certain embodiments, the polymer may be at least one SIS block copolymer. The at least one SIS block copolymer may be composed of three blocks of polystyrene, polyisoprene, and polystyrene, and may particularly have a molecular weight of about 100,000 to 200,000. In certain embodiments, the SIS block copolymer may comprise polystyrene blocks and polyisoprene blocks in a ratio of about 10:90 (%) to about 30:70 (%), or in a ratio of about 15:85 (%) or about 22:78 (%).

[0252] In other embodiments, the polymer is at least one polyisobutylene and can be a combination of two different types of polyisobutylenes, particularly a combination of a low molecular weight polyisobutylene and a high molecular weight polyisobutylene. In a particular embodiment, the ratio of the low molecular weight polyisobutylene to the high molecular weight polyisobutylene is in the range of 75:25 to 90:10.

[0253] Suitable SIS block copolymers according to the invention are commercially available, for example, under the trade name JSR-SIS.Specific SIS block copolymer based pressure sensitive adhesives are available under the trade names JSR-SIS5229 and JSR-SIS5002.

[0254] Suitable polyisobutylenes according to the present invention are commercially available, for example, under the trade name Oppanol®. Combinations of high molecular weight polyisobutylenes (B100, B80) and low molecular weight polyisobutylenes (B10, B11, B12, B13) can be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene range from 100:1 to 1:100, from 95:5 to 40:60, or from 90:10 to 75:25. Specific examples of polyisobutylene combinations are a B10 / B100 ratio of 85 / 15 or a B12 / B100 ratio of 80 / 20. Oppanol® B100 has a viscosity-average molecular weight Mv of 1,110,000 and a weight-average molecular weight Mw of 1,550,000, with an average molecular weight distribution Mw / Mn of 2.9. Oppanol® B10 has a viscosity average molecular weight Mv of 40,000 and a weight average molecular weight Mw of 53,000, with an average molecular weight distribution Mw / Mn of 3.2. Oppanol® B12 has a viscosity average molecular weight Mv of 55,000 and a weight average molecular weight Mw of 70,000, with an average molecular weight distribution Mw / Mn of 3.2. Suitable polyisobutylene adhesives are also commercially available, for example, under the trade name Duro-Tak™ 87-6908.

[0255] Other additives

[0256] The medical patch according to the present invention and in particular the active agent-containing layer may further comprise at least one additive or excipient. The additive or excipient is preferably selected from the group consisting of a crystallization inhibitor, a solubilizer, a filler, a skin care substance, a pH regulator, a preservative, an adhesive, a softener, a stabilizer and a penetration enhancer, in particular selected from a crystallization inhibitor, a skin care substance, an adhesive, a softener, a stabilizer and a penetration enhancer. Such additives may be present in the active agent-containing layer in an amount of 0.001% to 15% by weight, for example 1% to 10% by weight or 0.01% to 5% by weight, based on the total weight of the active agent-containing layer.

[0257] It should be noted that in pharmaceutical preparations, formulation components are classified according to their physicochemical and physiological properties and according to their function. Specifically, this means that the substance or compound belonging to a category is not excluded from belonging to the formulation components of another category. For example, a certain polymer can be a crystallization inhibitor, but also an adhesive. Some substances can, for example, be typical softeners, but serve as penetration enhancers at the same time. Skilled personnel can determine which or which categories of formulation components a certain substance or compound belongs to based on their common sense. Hereinafter, details about excipients and additives are provided, but these details should not be construed as exclusive. Other substances not clearly listed in this specification also can be used according to the present invention, and the substances and / or compounds clearly listed in a class of formulation components are not excluded from being used as another formulation component in the sense of the present invention.

[0258] In certain embodiments, the medical patch, particularly containing the active agent layer, may also include a crystallization inhibitor. Suitable examples of crystallization inhibitors include polyvinyl pyrrolidone, vinyl acetate / vinyl pyrrolidone copolymers and cellulose derivatives. Crystallization inhibitors are preferably polyvinyl pyrrolidone, more preferably soluble polyvinyl pyrrolidone. Crystallization inhibitors can increase the solubility of capsaicin or suppress the crystallization of capsaicin.

[0259] In certain embodiments, the medical patch, particularly the active agent-containing layer, further comprises a stabilizer, wherein the stabilizer is preferably selected from tocopherol and its ester derivatives and ascorbic acid and its ester derivatives. Preferred stabilizers include sodium metabisulfite, ascorbic acid esters of fatty acids (such as ascorbyl palmitate), ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate, and tocopheryl linoleate.

[0260] In certain embodiments, the medical patch, particularly the active agent-containing layer, further comprises a softener / plasticizer. Exemplary softeners / plasticizers include linear or branched saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, and polyethylene glycol.

[0261] In certain embodiments, the medical patch, particularly the active agent layer, further comprises a solubilizing agent. The solubilizing agent preferably improves the solubility of the capsaicin in the active agent layer. Preferred solubilizing agents include, for example, glycerides, polyglycerol esters, propylene glycol esters, and polyoxyethylene esters of medium and / or long chain fatty acids, such as monolinolein, medium chain glycerides, and medium chain triglycerides; nonionic solubilizing agents prepared by reacting castor oil with ethylene oxide, and any mixture thereof, which may also contain fatty acids or fatty alcohols, cellulose and methylcellulose, and derivatives thereof, such as hydroxypropyl cellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof, nonionic triblock copolymers (called poloxamers) having a central polyoxypropylene hydrophobic chain with two polyoxyethylene hydrophilic chains attached to the side, and polyoxyethylene esters. er)), water-soluble derivatives of vitamin E, pharmaceutical grade or condensed spherical isomalt, polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam-based graft copolymers (also abbreviated as PVAc-PVCap-PEG and called Soluplus®), purified grade natural source castor oil, polyethylene glycol 400, polyoxyethylene sorbitan monooleate (such as polysorbate 80) or propylene glycol, diethylene glycol monoethyl ether, glucono-δ-lactone, corn and potato starch and any soluble polyvinyl pyrrolidone mentioned below, as well as insoluble / cross-linked polyvinyl pyrrolidone, such as cross-linked polyvinyl pyrrolidone. However, the penetration enhancers mentioned below may also serve as solubilizers. In addition, crystallization inhibitors may also serve as solubilizers.

[0262] In certain embodiments, the medical patch, particularly the active agent-containing layer, may further comprise a pH adjuster. Suitable pH adjusters include weak acids and weak bases, including amine derivatives, inorganic base derivatives, and polymers with basic or acidic functional groups.

[0263] In certain embodiments, the medical patch, particularly the active agent-containing layer, further comprises a preservative. Suitable preservatives include parabens, formaldehyde releasers, isothiazolinones, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid, and anisic acid.

[0264] In certain embodiments, the medical patch, particularly the active agent-containing layer, may further comprise a skin-protecting substance. Such substances can be used to prevent or reduce skin irritation, as detected by a skin reaction score. Suitable skin-protecting substances include sterol compounds (such as cholesterol), dexpanthenol, α-bisabolol, and antihistamines.

[0265] Fillers such as silica gel, titanium dioxide, and zinc oxide can be used in combination with silicone-based polymers in order to influence certain physical parameters, such as cohesion and bond strength, in a desired manner.

[0266] In the case where the active agent-containing layer needs to have self-adhesive properties and one or more polymers that do not provide sufficient self-adhesive properties are selected, an adhesive is added. The adhesive can be selected from polyvinyl pyrrolidone (polyvinyl pyrrolidone can maintain the adhesion of the matrix layer due to its water absorption capacity and can therefore be considered as an adhesive in a broad sense), triglycerides, polyethylene glycol, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutylenes, preferably polyvinyl pyrrolidone, and more preferably soluble polyvinyl pyrrolidone.

[0267] In certain embodiments, the medical patch may further include a penetration enhancer. A penetration enhancer is a substance that affects the barrier properties of the stratum corneum in the sense of increasing the permeability of capsaicin. Some examples of penetration enhancers are polyhydroxy alcohols, such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils, such as olive oil, squalene, and lanolin; fatty ethers, such as cetyl ether and oleyl ether; fatty acid esters, such as isopropyl myristate; urea and urea derivatives, such as allantoin; polar solvents, such as dimethyldecyl phosphine oxide, methyl hexadecyl sulfoxide, dimethylaurylamine, dodecyl pyrrolidone, isosorbide, dimethylacetonide, dimethyl sulfoxide, decyl methyl sulfoxide, and dimethylformamide, salicylic acid, amino acids, benzyl nicotinate, and higher molecular weight aliphatic surfactants, such as lauryl sulfate. Other agents include oleic and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate and isopropyl palmitate. If the active agent-containing layer also includes a penetration enhancer, the penetration enhancer is preferably selected from diethylene glycol monoethyl ether (Transcutol®), diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate and dimethylpropylene urea. It has been found that even in the absence of a penetration enhancer, the medical patch according to the present invention also provides sufficient capsaicin permeability. Therefore, in certain embodiments of the present invention, the active agent-containing layer does not include a penetration enhancer.

[0268] Release Features

[0269] The medical patch according to the present invention is designed to be used for topical administration of capsaicin to produce a local effect at the point of action, or for transdermal administration of capsaicin to the systemic circulation over a predetermined period of time. Although topical administration of capsaicin relies on diffusion into the skin itself and does not require transdermal release into the systemic circulation, in vitro skin permeation experiments still provide a good indication of whether there is effective surface release.

[0270] According to certain embodiments, the medical patch provides 0.1 to 1.0 μg / cm2 of EDTA over a period of about 60 minutes as measured on human skin excised using a dermatome in a Franz diffusion cell. 2or about 0.3 µg / cm 2 Cumulative permeation of capsaicin of 0.06 µg / (cm2) after 60 minutes as measured in human skin excised with a dermatome in a Franz diffusion cell. 2 h) to 0.3 µg / (cm 2 h) or 0.2 µg / (cm 2 h) to 1.2 µg / (cm 2 h) or about 0.6 µg / (cm 2 h) Capsaicin skin penetration rate.

[0271] In a particular embodiment of the present invention, the medical patch according to the present invention as described above provides the following capsaicin skin permeation rate as measured using dermatome-sectioned human skin in a Franz diffusion cell:

[0272] 0 µg / (cm2) in the first 60 minutes 2 h) to 0.9 µg / (cm 2 h),

[0273] From the 60th to the 90th minute, 0.6 µg / (cm 2 h) to 1.2 µg / (cm 2 h),

[0274] From 90 to 120 minutes, 0.8 µg / (cm 2 h) to 1.4 µg / (cm 2 h),

[0275] From 120 to 240 minutes, 0.9 µg / (cm 2 h) to 1.6 µg / (cm 2 h).

[0276] In certain embodiments, the medical patch provides therapeutically effective skin penetration of capsaicin in less than 90 minutes or less than 60 minutes after application of the medical patch to the skin.

[0277] Treatment methods / medical uses

[0278] The medical patch according to the invention is suitable for use in methods of treatment, and in particular in methods of treatment of human patients.

[0279] In certain embodiments, the medical patch according to the present invention is used in a method of treatment, wherein the medical patch is preferably applied to the patient's skin for less than 90 minutes, less than 60 minutes, or less than 30 minutes. In certain embodiments, the medical patch according to the present invention is used in a method of treatment with a dosing interval of at least or about 1.5 months, at least or about 2 months, or at least or about 3 months. Therefore, the medical patch is preferably applied only after discontinuing use for at least 90 days after removing the previous medical patch.

[0280] In a preferred embodiment, the medical patch according to the present invention is used in a method for treating neuropathic pain, in particular chronic neuropathic pain, preferably including postherpetic neuralgia, postoperative neuralgia (such as post-herniotomy pain, post-thoracotomy pain or post-mastectomy pain), post-traumatic neuropathy, polyneuropathy (such as painful diabetic neuropathy, chemotherapy-induced neuropathy, tumor-induced neuropathy, HIV-related neuropathy, alcohol-related neuropathy, small fiber neuropathy) or complex regional pain syndrome, radiculopathy or pressure syndrome (such as carpal tunnel syndrome).

[0281] The medical patch according to the present invention is further preferably used in a method for treating peripheral neuropathic pain, neuropathic pain of the hands and feet associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, joint pain or cancer pain.

[0282] In certain embodiments, the medical patch according to the present invention is used in a method for treating neuropathic pain associated with postherpetic neuralgia or neuropathic pain associated with diabetic peripheral neuropathy in the hands or feet of a human patient, particularly an adult. In certain embodiments, the medical patch according to the present invention is used in a method for treating postoperative neuropathic pain in a human patient, particularly an adult.

[0283] In conjunction with the above, the medical patch according to the present invention is preferably applied to at least one body surface of the patient, particularly selected from the back, buttocks, legs, feet or hands. The preferred application time of the medical patch according to the present invention is less than or about 60 minutes on the back, buttocks or legs, and less than or about 30 minutes on the feet or hands.

[0284] According to a particular aspect, the present invention also relates to a method for treating neuropathic pain, in particular chronic neuropathic pain and preferably peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) in the hands or feet, postoperative neuropathic pain, joint pain or cancer pain, which method comprises applying to the skin of a patient a medical patch as described herein.

[0285] Manufacturing method

[0286] The medical patch according to the present invention can be manufactured using a method comprising the following steps:

[0287] 1.1) Applying an active agent-containing coating composition on a first foil, wherein the active agent-containing coating composition comprises

[0288] (i) capsaicin, and

[0289] (ii) at least one silicone-based polymer;

[0290] 1.2) drying the applied coating composition to form an active agent-containing layer;

[0291] 1.3) Laminating the active agent-containing layer to the backing layer.

[0292] The silicone-based polymer is preferably non-curing and is therefore typically applied by a solvent-based method. Therefore, the at least one silicone-based polymer is preferably provided in a solvent, wherein the solids content of the solvent is preferably 40% to 75% by weight. The solvent is preferably selected from alcoholic solvents, in particular methanol, ethanol, isopropanol, and mixtures thereof; and non-alcoholic solvents, in particular ethyl acetate, hexane, heptane, petroleum ether, toluene, and mixtures thereof, and is more preferably selected from non-alcoholic solvents, and most preferably ethyl acetate or n-heptane.

[0293] Capsaicin is preferably uniformly dissolved or dispersed in the active agent-containing coating composition. According to certain embodiments, capsaicin is provided in an amphiphilic solvent, such as diethylene glycol monoethyl ether, 1,3-butanediol, dipropylene glycol, or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, and the capsaicin formulation is dispersed in the active agent-containing coating composition in the form of small droplets (micro-reservoir system). The amphiphilic solvent is immiscible with the solvent used for the silicone-based polymer or is miscible with it only to a small extent.

[0294] The applied active agent-containing coating composition is solidified by drying. Drying is preferably performed at a temperature of 20 to 60°C or 30 to 40°C.

[0295] The method may further comprise the following steps:

[0296] 2.1) Applying a coating composition containing no active agent on the second foil, wherein the coating composition containing no active agent comprises

[0297] (i) at least one alkenyl-substituted polydiorganosiloxane,

[0298] (ii) at least one organosiloxane containing silicon-bonded hydrogen atoms, and

[0299] (iii) at least one catalyst for the reaction of SiH groups with Si-alkenyl groups;

[0300] 2.2) crosslinking the active agent-free coating composition at a temperature of 50° C. to 150° C. or by applying UV light to form a skin contact layer;

[0301] 2.3) Laminate the skin contact layer with the release liner.

[0302] After curing (ie crosslinking of the reactive groups of the silicone polymer), the active agent-free coating composition forms a silicone gel adhesive of the skin contact layer. Crosslinking is preferably carried out at a temperature of 40°C to 140°C.

[0303] The active agent-containing layer and the skin contact layer are preferably prepared separately as indicated above and then laminated together by removing the foil and then laminating the open sides of the two layers together to give the active agent-containing layer structure. Thus, the method may further comprise the following steps:

[0304] 3.1) removing the foil from the active agent-containing layer and the skin contact layer; and

[0305] 3.2) The open side of the active agent-containing layer is laminated to the open side of the skin contact layer to obtain the active agent-containing layer structure.

[0306] The preparation of the active agent-containing layer can be carried out before or after the preparation of the skin contact layer, or the preparation of both layers can be carried out in parallel.

[0307] Example

[0308] The present invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should not be construed as limiting the present invention in any way. The numerical values ​​provided in the examples regarding the amounts or areal weights of the ingredients in the compositions may vary slightly due to manufacturing variability.

[0309] Example 1 and Reference Example

[0310] The capsaicin skin penetration rate and utilization rate of the medical patches of Example 1 and Reference Example were determined by in vitro experiments.

[0311] The medical patch according to Example 1 differs from the medical patch according to Reference Example in that it has another skin contact layer. Therefore, two medical patches were prepared in the same manner, except that the steps of preparing and applying the active agent-free coating composition and laminating the resulting active agent-free layer with the previously prepared capsaicin-containing layer were omitted in Reference Example.

[0312] Capsaicin-containing coating composition

[0313] The formulations of the capsaicin-containing coating compositions in Example 1 and Reference Examples are summarized in Table 1.1 below. The solids % values ​​refer to the amount in % by weight (Amt).

[0314] Table 1.1

[0315]

[0316] Preparation of capsaicin-containing coating composition

[0317] Transcutol was initially thickened in the presence of ethylcellulose under stirring (100-300 rpm).

[0318] The polysiloxane mixture and silicone oil were placed in a container and stirred (100-300 rpm) for at least 5 minutes before adding the ethylcellulose / Transcutol solution. After stirring for an additional 10 minutes (100-300 rpm), capsaicin was added. The mixture was then stirred at approximately 250-300 rpm until a homogeneous mixture was obtained (at least 60 minutes).

[0319] Application of capsaicin-containing coating composition

[0320] The resulting capsaicin-containing coating composition was coated on a fluoropolymer-coated polyester film (Scotchpak™ 1022). The solvent was removed at room temperature for approximately 20-30 minutes.

[0321] The coating thickness is chosen so that removal of the solvent yields approximately 80 g / m 2 Area weight of the capsaicin-containing layer.

[0322] The resulting capsaicin-containing microreservoir layer was then laminated with a backing layer (polyester film, 19 μm).

[0323] Active agent-free coating composition

[0324] In Example 1, formulations without active agent coating compositions are summarized in Table 1.2 below. The % solids values ​​refer to amounts in % by weight (Amt).

[0325] Table 1.2

[0326]

[0327] Preparation of coating compositions without active agents

[0328] The two components were weighed separately, and then component A and component B were added to the mixing container in sequence. The mixture was then mixed at about 100 rpm for about 10 minutes until a homogeneous mixture of component A and component B was obtained.

[0329] Application of coating compositions without active agents

[0330] The resulting active agent-free coating composition was applied to the foil of the adhesive assembly within a timeframe of approximately 30 minutes. The coating temperature was set at 120° C. The resulting active agent-free layer was heated at this temperature for approximately 40 minutes.

[0331] The coating thickness was chosen so that removal of the solvent yielded approximately 230 g / m 2 The layer thickness of the active agent-free (skin contact) layer is 1.5 Å.

[0332] The resulting active agent-free (skin contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 125 μm).

[0333] Lamination of a capsaicin-containing layer with a non-active agent (skin contact) layer

[0334] The active agent-free (skin contact) layer is then laminated to the capsaicin-containing layer. For this purpose, the foil of the adhesive device used for coating and drying the layers is removed, and the resulting open sides of the active agent-containing layer and the active agent-free (skin contact) layer are laminated together to produce a capsaicin-containing self-adhesive layer structure comprising a backing layer, a capsaicin-containing layer, and an active agent-free (skin contact) layer, wherein the capsaicin-containing layer is attached to the backing layer and the active agent-free (skin contact) layer is attached to the capsaicin-containing layer, and wherein the structure is closed by a release liner, which is attached to the active agent-free (skin contact) layer.

[0335] Preparation of medical patches

[0336] Individual medical patches were punched out from the capsaicin-containing self-adhesive layer structure obtained as described above, and then sealed into a primary packaging material bag.

[0337] Measurement of skin penetration

[0338] According to the OECD guideline (adopted on April 13, 2004), the permeation capacity of the medical patches prepared according to Example 1 and Reference Example was determined by using a 10.0 ml Franz diffusion cell in vitro. Split thickness human skin (female abdomen, date of birth 1981) from cosmetic surgery was used. All medical patches used thermally separated epidermis. Punching out a release area of ​​1.171 cm from the medical patch was performed. 2 The amount of capsaicin permeation was measured in a receptor medium (0.9% sodium chloride solution with 0.1% saline azide as antibacterial agent) of a Franz cell at a temperature of 32 ± 1°C and the corresponding skin permeation rate was calculated.

[0339] The results are shown in Table 1.3 and Figure 1A.

[0340] Table 1.3

[0341]

[0342] *: Standard deviation is calculated based on the n-method.

[0343] The corresponding skin permeation rate (Δ flux) was calculated based on the corresponding permeation amount.

[0344] The results are shown in Table 1.4 and Figure 1B.

[0345] Table 1.4

[0346]

[0347] *: Standard deviation is calculated based on the n-method.

[0348] The above results show that the skin permeation rate of the capsaicin medical patch of the present invention according to Example 1 is surprisingly almost the same, or even slightly higher / faster, when compared to the same patch without a skin contact layer (according to the reference example). As outlined above, this means that the patch of the present invention can be based on an approved and marketed capsaicin patch, with the patch of the present invention merely supplemented with another skin contact layer, which may not change the (approved) drug release behavior of the commercial product, which is very advantageous.

[0349] The present invention particularly relates to the following other items:

[0350] 1. A medical patch for administering capsaicin, comprising an active agent-containing layer structure, wherein the active agent-containing layer structure comprises:

[0351] A) backing layer;

[0352] B) an active agent-containing layer, the active agent-containing layer comprising

[0353] (i) capsaicin, and

[0354] (ii) at least one silicone-based polymer;

[0355] as well as

[0356] C) skin contact layer;

[0357] The skin contact layer is an adhesive layer comprising polymer II.

[0358] 2. The medical patch according to item 1, wherein

[0359] The polymer II is a polymer or a mixture of polymers in which the capsaicin is substantially insoluble.

[0360] 3. The medical patch according to item 1 or 2, wherein

[0361] The polymer II is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0362] 4. The medical patch according to any one of items 1 to 3, wherein

[0363] The polymer II is a polymer or a mixture of polymers selected from the group consisting of silicone acrylic hybrid polymers, silicone based polymers, silicone gel adhesives and natural or synthetic rubber based polymers.

[0364] 5. The medical patch according to any one of items 1 to 4, wherein

[0365] The polymer II is a polymer or a mixture of polymers selected from the group consisting of silicone-based polymers and silicone gel adhesives.

[0366] 6. The medical patch according to any one of items 1 to 5, wherein

[0367] The polymer II is a silicone gel adhesive.

[0368] 7. The medical patch according to item 6, wherein

[0369] The silicone gel adhesive can be obtained by reacting a gel-forming composition comprising: (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane containing silicon-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of SiH groups with Si-alkenyl groups.

[0370] 8. The medical patch according to item 6 or 7, wherein

[0371] The silicone gel adhesive can be obtained by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

[0372] 9. The medical patch according to any one of items 6 to 8, wherein

[0373] The silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive containing from about 2 wt % to about 45 wt % of at least one hydroxyl-substituted silicate resin.

[0374] 10. The medical patch according to any one of items 1 to 9, wherein

[0375] The saturation concentration of the capsaicin in the skin contact layer is less than 0.1 wt%, less than 0.05 wt%, less than 0.02 wt%, or less than 0.01 wt%.

[0376] 11. The medical patch according to any one of items 1 to 10, wherein

[0377] The area weight of the skin contact layer is 100 to 350 g / m 2 , 150 to 320 g / m 2 or 180 to 280 g / m 2 within the range.

[0378] 12. The medical patch according to any one of items 1 to 11, wherein

[0379] The skin contact layer comprises the polymer II in an amount of at least 95 wt%, at least 99 wt%, or about 100 wt%, based on the total weight of the skin contact layer.

[0380] 13. The medical patch according to any one of items 1 to 12, wherein

[0381] The skin contact layer comprises the capsaicin in an amount of less than 0.1 wt % or less than 0.01 wt % based on the total weight of the skin contact layer.

[0382] 14. The medical patch according to any one of items 1 to 13, wherein

[0383] The active agent-containing layer comprises the capsaicin in an amount of 2 wt % to 20 wt %, 5 wt % to 15 wt %, or 5 wt % to 10 wt %.

[0384] 15. The medical patch according to item 14, wherein

[0385] The active agent-containing layer comprises capsaicin in an amount of about 8% by weight.

[0386] 16. The medical patch according to any one of items 1 to 15, wherein

[0387] The active agent-containing layer contains at least 0.30 mg / cm 2 , at least 0.50mg / cm 2 or at least 0.60 mg / cm 2 Capsaicin.

[0388] 17. The medical patch according to any one of items 1 to 16, wherein

[0389] The active agent-containing layer contains less than 1.0 mg / cm 2 , less than 0.8 mg / cm 2 or less than 0.7 mg / cm 2 Capsaicin.

[0390] 18. The medical patch according to any one of items 1 to 17, wherein

[0391] The medical patch contains the capsaicin in an amount of 0.5 to 180 mg, 1.2 to 90 mg, or 19 to 45 mg.

[0392] 19. The medical patch according to any one of items 1 to 18, wherein

[0393] The medical patch comprises the capsaicin in an amount of about 179 mg, about 60 mg, about 45 mg, about 30 mg, about 25 mg, about 10 mg, or about 1 mg.

[0394] 20. The medical patch according to any one of items 1 to 19, wherein

[0395] The at least one silicone-based polymer is present in the active agent-containing layer in an amount of 20 wt% to 90 wt% or 60 wt% to 90 wt% based on the total weight of the active agent-containing layer.

[0396] 21. The medical patch according to any one of items 1 to 20, wherein

[0397] The silicone-based polymer is a pressure sensitive adhesive or a mixture of pressure sensitive adhesives.

[0398] 22. The medical patch according to item 21, wherein

[0399] The pressure sensitive adhesive may be obtained by polycondensation of a silanol terminated polydimethylsiloxane with a silicate resin, preferably with a resin to polymer ratio of 50:50 to 70:30 or 55:45, 60:40 or 65:35.

[0400] 23. The medical patch according to any one of items 1 to 22, wherein

[0401] The silicone-based polymer is a mixture of pressure-sensitive adhesives obtainable by polycondensation of silanol-terminated polydimethylsiloxane and silicate resin, with the ratio of resin to polymer being 55:45 or 60:40.

[0402] 24. The medical patch according to any one of items 1 to 23, wherein

[0403] The silicone-based polymer is a mixture of pressure-sensitive adhesives, wherein

[0404] The solution viscosity in heptane at 25°C and about 60% solids content is 450 mPa s and / or the complex viscosity at 0.01 rad / s at 30°C is 1×10 8 Park, and

[0405] The solution viscosity in heptane at 25°C and about 60% solids content is 500 mPa s and / or the complex viscosity at 0.01 rad / s at 30°C is 5×10 6 moor.

[0406] 25. The medical patch according to any one of items 1 to 24, wherein

[0407] The silicone-based polymer is an amine-compatible polysiloxane and is preferably obtainable by polycondensation of a silanol-terminated polydimethylsiloxane with a silicate resin followed by at least partial trimethylsilylation of the residual silanol functionality.

[0408] 26. The medical patch according to any one of items 1 to 25, wherein

[0409] The active agent-containing layer includes diethylene glycol monoethyl ether, and preferably includes diethylene glycol monoethyl ether in an amount of 10% to 25% by weight.

[0410] 27. The medical patch according to any one of items 1 to 26, wherein

[0411] The active agent-containing layer comprises a viscosity-increasing additive selected from the group consisting of cellulose derivatives and high molecular weight polyacrylic acid and any mixtures thereof.

[0412] 28. The medical patch according to any one of items 1 to 27, wherein

[0413] The active agent-containing layer comprises ethylcellulose, and preferably comprises ethylcellulose in an amount of 0% to 2% by weight.

[0414] 29. The medical patch according to any one of items 1 to 28, wherein

[0415] The active agent-containing layer contains silicone oil, and preferably contains the silicone oil in an amount of 0% to 5% by weight.

[0416] 30. The medical patch according to any one of items 1 to 29, wherein

[0417] The area weight of the active agent-containing layer is 30 to 200 g / m 2or 50 to 120 g / m 2 within the range.

[0418] 31. The medical patch according to any one of items 1 to 30, wherein

[0419] The backing layer is impermeable to capsaicin.

[0420] 32. The medical patch according to any one of items 1 to 31, wherein

[0421] The backing layer consists of a polyester film, preferably with a thickness of 10-20 μm.

[0422] 33. The medical patch according to any one of items 1 to 31, wherein

[0423] The backing layer is composed of ethylene-vinyl acetate copolymer.

[0424] 34. The medical patch according to any one of items 1 to 33, wherein

[0425] The skin contact layer does not contain capsaicin, and / or the medical patch further comprises a release liner.

[0426] 35. The medical patch according to any one of items 1 to 34, wherein

[0427] The skin contact layer is directly attached to the active agent-containing layer.

[0428] 36. The medical patch according to any one of items 1 to 34, wherein

[0429] The active agent-containing layer structure comprises a membrane positioned between the active agent-containing layer and the skin contacting layer, wherein the membrane is preferably a rate-controlling membrane.

[0430] 37. The medical patch according to any one of items 1 to 36, wherein

[0431] The active agent-containing layer structure has a hexagonal shape, wherein

[0432] The backing layer, the active agent-containing layer and the skin contact layer extend together and provide the hexagonal shape of the active agent-containing layer structure, and

[0433] The hexagonal shape comprises at least one hexagon, wherein

[0434] Each pair of opposite sides of the hexagon is parallel, and

[0435] The sides of the hexagon have a length of 1.5 to 10 cm.

[0436] 38. The medical patch according to item 37, wherein

[0437] The at least one hexagon is at least one convex hexagon.

[0438] 39. The medical patch according to item 38, wherein

[0439] The hexagonal shape includes one or two convex hexagons.

[0440] 40. The medical patch according to any one of items 37 to 39, wherein

[0441] The hexagonal shape is a convex hexagon.

[0442] 41. The medical patch according to any one of items 37 to 40, wherein

[0443] The hexagonal shape is a double hexagon formed by two identical convex hexagons that share two adjacent vertices and their common sides.

[0444] 42. The medical patch according to item 41, wherein

[0445] The common edge is perforated to facilitate tearing.

[0446] 43. The medical patch according to any one of items 1 to 42, wherein

[0447] The medical patch provides

[0448] 0.1 to 1.0 µg / cm2 as measured on human skin excised using a dermatome in a Franz diffusion cell over a period of approximately 60 minutes 2 or about 0.3 µg / cm 2 Cumulative capsaicin penetration, and / or

[0449] 0.06 µg / (cm2) after 60 minutes as measured in human skin excised using a dermatome in a Franz diffusion cell 2 h) to 0.3 µg / (cm 2 h) or 0.2 µg / (cm 2 h) to 1.2 µg / (cm 2 h) or about 0.6 µg / (cm 2 h) Capsaicin skin penetration rate.

[0450] 44. The medical patch of any one of items 1 to 43, wherein the medical patch is a topical medical patch.

[0451] 45. The medical patch according to any one of items 1 to 43, wherein the medical patch is a transdermal therapeutic system.

[0452] 46. ​​The medical patch according to any one of items 1 to 45, wherein

[0453] The medical patch provided the following capsaicin skin permeation rates as measured using dermatome-excised human skin in a Franz diffusion cell:

[0454] 0 µg / (cm2) in the first 60 minutes 2 h) to 0.9 µg / (cm 2 h),

[0455] From the 60th to the 90th minute, 0.6 µg / (cm 2 h) to 1.2 µg / (cm 2 h),

[0456] From 90 to 120 minutes, 0.8 µg / (cm 2 h) to 1.4 µg / (cm 2 h),

[0457] From 120 to 240 minutes, 0.9 µg / (cm 2 h) to 1.6 µg / (cm 2 h).

[0458] 47. The medical patch according to any one of items 1 to 46,

[0459] The medical patch is used in a method for treating neuropathic pain, particularly chronic neuropathic pain, and preferably in a method for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) in the hands and feet, postoperative neuropathic pain, joint pain, or cancer pain.

[0460] 48. Use of the medical patch according to any one of items 1 to 46,

[0461] The medical patch is used for manufacturing a medicament for treating neuropathic pain, particularly chronic neuropathic pain, and preferably for manufacturing a medicament for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) in the hands or feet, postoperative neuropathic pain, joint pain, or cancer pain.

[0462] 49. A method of treating neuropathic pain, in particular chronic neuropathic pain, and preferably peripheral neuropathic pain, neuropathic pain of the hands or feet associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, joint pain or cancer pain,

[0463] The method comprises applying the medical patch according to any one of items 1 to 46 to the skin of a patient.

[0464] 50. A medical patch for administering capsaicin, the medical patch comprising an active agent-containing layer structure, the active agent-containing layer structure comprising:

[0465] A) backing layer;

[0466] B) an active agent-containing layer, the active agent-containing layer comprising

[0467] (i) capsaicin, and

[0468] (ii) at least one silicone-based polymer;

[0469] as well as

[0470] C) skin contact layer;

[0471] The skin contact layer is an adhesive layer comprising a silicone gel adhesive.

[0472] 51. A medical patch for administering capsaicin, the medical patch comprising an active agent-containing layer structure, the active agent-containing layer structure comprising:

[0473] A) backing layer;

[0474] B) an active agent-containing layer, the active agent-containing layer comprising

[0475] (i) capsaicin in an amount of 5% to 10% by weight,

[0476] (ii) at least one amine-compatible polysiloxane in an amount of 60% to 90% by weight,

[0477] (iii) diethylene glycol monoethyl ether in an amount of 10% to 25% by weight,

[0478] (iv) ethyl cellulose in an amount of 0% to 2% by weight, and

[0479] (v) silicone oil in an amount of 0% to 5% by weight;

[0480] as well as

[0481] C) skin contact layer;

[0482] wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive,

[0483] And wherein the silicone gel adhesive is obtainable by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

[0484] 52. A medical patch for administering capsaicin, the medical patch comprising an active agent-containing layer structure, the active agent-containing layer structure comprising:

[0485] A) backing layer;

[0486] B) an active agent-containing layer, the active agent-containing layer comprising

[0487] (i) capsaicin in an amount of about 8% by weight,

[0488] (ii) at least one amine-compatible polysiloxane in an amount of 60% to 90% by weight,

[0489] (iii) diethylene glycol monoethyl ether in an amount of 10% to 25% by weight,

[0490] (iv) ethyl cellulose in an amount of 0% to 2% by weight, and

[0491] (v) silicone oil in an amount of 0% to 5% by weight;

[0492] as well as

[0493] C) skin contact layer;

[0494] wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive,

[0495] And wherein the silicone gel adhesive is obtainable by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

Claims

1. A medical patch for administering capsaicin, comprising an active agent-containing layer structure, wherein the active agent-containing layer structure comprises: A) backing layer; B) an active agent-containing layer, the active agent-containing layer comprising (i) capsaicin, and (ii) at least one silicone-based polymer; as well as C) skin contact layer; The skin contact layer is an adhesive layer comprising polymer II.

2. The medical patch according to claim 1, wherein The polymer II is a polymer or a mixture of polymers selected from the group consisting of silicone acrylic hybrid polymers, silicone based polymers, silicone gel adhesives and polymers based on natural or synthetic rubber, in particular selected from the group consisting of silicone based polymers and silicone gel adhesives.

3. The medical patch according to claim 1 or 2, wherein The polymer II is a silicone gel adhesive.

4. The medical patch according to claim 3, wherein The silicone gel adhesive can be obtained by reacting a gel-forming composition comprising: (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane containing silicon-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of SiH groups with Si-alkenyl groups.

5. The medical patch according to claim 3 or 4, wherein The silicone gel adhesive can be obtained by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

6. The medical patch according to any one of claims 3 to 5, wherein The silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive containing from about 2 wt % to about 45 wt % of at least one hydroxyl-substituted silicate resin.

7. The medical patch according to any one of claims 1 to 6, wherein The saturation concentration of the capsaicin in the skin contact layer is less than 0.1 wt%, less than 0.05 wt%, less than 0.02 wt%, or less than 0.01 wt%.

8. The medical patch according to any one of claims 1 to 7, wherein The area weight of the skin contact layer is 100 to 350 g / m 2 , 150 to 320 g / m 2 or 180 to 280 g / m 2 within the range.

9. The medical patch according to any one of claims 1 to 8, wherein The active agent-containing layer comprises the capsaicin in an amount of 2 wt % to 20 wt %, 5 wt % to 15 wt %, or 5 wt % to 10 wt %, or about 8 wt %.

10. The medical patch according to any one of claims 1 to 9, wherein The active agent-containing layer contains at least 0.30 mg / cm 2 , at least 0.50 mg / cm 2 or at least 0.60 mg / cm 2 Capsaicin, and / or The active agent-containing layer contains less than 1.0 mg / cm 2 , less than 0.8 mg / cm 2 or less than 0.7 mg / cm 2 Capsaicin.

11. The medical patch according to any one of claims 1 to 10, wherein The medical patch contains the capsaicin in an amount of 0.5 to 180 mg, 1.2 to 90 mg, or 19 to 45 mg.

12. The medical patch according to any one of claims 1 to 11, wherein The area weight of the active agent-containing layer is 30 to 200 g / m 2 or 50 to 120 g / m 2 within the range.

13. The medical patch according to any one of claims 1 to 12, wherein The skin contact layer is directly attached to the active agent-containing layer.

14. The medical patch according to any one of claims 1 to 12, wherein The active agent-containing layer structure comprises a membrane positioned between the active agent-containing layer and the skin contacting layer, wherein the membrane is preferably a rate-controlling membrane.

15. The medical patch according to any one of claims 1 to 14, wherein The medical patch provides 0.1 to 1.0 µg / cm2 as measured on human skin excised using a dermatome in a Franz diffusion cell over a period of approximately 60 minutes 2 or about 0.3 µg / cm 2 Cumulative capsaicin penetration, and / or 0.06 µg / (cm2) after 60 minutes as measured in human skin excised using a dermatome in a Franz diffusion cell 2 h) to 0.3µg / (cm 2 h) or 0.2 µg / (cm 2 h) to 1.2 µg / (cm 2 h) or about 0.6 µg / (cm 2 h) Capsaicin skin penetration rate.

16. The medical patch according to any one of claims 1 to 15, wherein the medical patch is a topical medical patch or a transdermal therapeutic system.

17. The medical patch according to any one of claims 1 to 16, The medical patch is used in a method for treating neuropathic pain, particularly chronic neuropathic pain, and preferably in a method for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) in the hands and feet, postoperative neuropathic pain, joint pain, or cancer pain.

18. Use of the medical patch according to any one of claims 1 to 16, The medical patch is used for manufacturing a medicament for treating neuropathic pain, particularly chronic neuropathic pain, and preferably for manufacturing a medicament for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) in the hands or feet, postoperative neuropathic pain, joint pain, or cancer pain.

19. A method of treating neuropathic pain, in particular chronic neuropathic pain, and preferably peripheral neuropathic pain, neuropathic pain of the hands or feet associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, joint pain or cancer pain, The method comprises applying the medical patch according to any one of claims 1 to 16 to the skin of a patient.

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