Medical patch containing capsaicin

Abstract

The present invention relates to a medical patch for administering capsaicin, including a capsaicin-containing active drug-containing layer structure, such as a medical patch for use in therapeutic methods, and to a process for manufacturing such a medical patch.

Description

[Technical Field]

[0001] The present invention relates to a medical patch for capsaicin administration, the medical patch comprising an active drug-containing layer containing a silicone polymer and a skin contact layer. Furthermore, the present invention relates to a treatment method and the use of the medical patch. [Background technology]

[0002] Capsaicin ((6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnona-6-enamide), the main bioactive component of chili peppers, is an alkaloid found in the Capsicumaceae family. It is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), which is well known as a vanilloid receptor. By binding to the TRPV1 receptor, the capsaicin molecule produces a sensation similar to damage caused by excessive heat or abrasion.

[0003] The burning and painful sensations associated with capsaicin are due to chemical interactions with sensory neurons expressing TRPV1. This receptor is a non-selective cation channel, and when activated during the detection and transmission of noxious stimuli, it causes transient Ca2+ ions. 2+ It enables the influx of calcium. Intracellular calcium is one of the most versatile second messengers in many intracellular signaling pathways, and when TRPV1 is activated, it allows cations to cross the cell membrane and enter the cell, so that the resulting neuronal depolarization stimulates the channel and transmits a signal to the brain. Therefore, TRPV1 plays an important role in pain signaling.

[0004] Capsaicin acts as a non-narcotic analgesic and is currently used to treat several pain syndromes, including neuropathic pain. Such pain is thought to arise from sensitization reactions in the peripheral and central nervous systems and can occur as a result of peripheral injury or systemic diseases such as HIV, herpes zoster, syphilis, autoimmune diseases, and diabetes. Furthermore, capsaicin has also been shown to have beneficial effects on pain relief in osteoarthritis due to its high ability to inhibit the release of substance P, a potent neuropeptide pain neuromodulator, from sensory nerves to the central nervous system. In addition, it has been suggested that capsaicin can kill cancer cells by inducing apoptosis in them.

[0005] Capsaicin is most commonly used as a topical analgesic and is available in many formulations, including creams, liquids, and patch preparations at various concentrations. For example, an 8% capsaicin patch skin delivery system is administered under the brand name QUTENZA® (Gruenenthal). This topical system is indicated for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the foot in adults, and has recently been approved for use in adults for the treatment of postoperative neuropathic pain (PSNP). QUTENZA® delivers prescription doses of capsaicin directly to the skin, resulting in reversible desensitization and dysfunction of the TRPV1 receptor, which can lead to sustained pain relief lasting up to three months.

[0006] However, capsaicin is a strong irritant, and the most common adverse reactions that occur during application of QUTENZA® include application-site reactions such as erythema, pain, and itching. In addition, it is known in the art that skin delivery systems can cause skin irritation depending on the adhesive layer.

[0007] Therefore, it is desirable to provide a medical patch for topical and / or transdermal delivery of capsaicin that overcomes the problem of skin irritation while possessing advantageous properties in terms of active drug release and adhesion. [Overview of the project]

[0008] The object of the present invention is to provide a medical patch for capsaicin administration that is improved compared to the patches described in the prior art.

[0009] A further object of the present invention is to provide a medical patch for capsaicin administration that reduces the problem of skin irritation.

[0010] A further object of the present invention is to provide a medical patch for capsaicin administration that provides a sufficient permeation rate to achieve a therapeutically effective dose. In particular, the object is to provide a medical patch for capsaicin administration that enables the acceleration of the onset of effects that contribute to reducing the delay time.

[0011] Another objective of the present invention is to provide a medical patch for capsaicin administration with improved adhesion. In particular, the objective is to provide a medical patch for capsaicin administration that meets the needs for easy application, taking into consideration not only comfort during application but also clean and painless removal, and for multiple applications when moving to a different location.

[0012] Another object of the present invention is to provide a medical patch for administering capsaicin that can be used in therapeutic methods.

[0013] These and other objectives are achieved by the present invention, and according to one aspect, the present invention relates to a medical patch for capsaicin administration comprising an active drug-containing layer structure, wherein such active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin and, (ii) at least one silicone polymer, A layer containing an active agent, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing polymer II (at least one silicone-based polymer in the active agent-containing layer is also called polymer I). In another embodiment, the present invention relates to a medical patch for capsaicin administration comprising an active agent-containing layer structure, wherein such active agent-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin and, (ii) at least one silicone polymer, A layer containing an active agent, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing a silicone gel adhesive.

[0014] The medical patch according to the present invention includes a skin contact layer in which capsaicin is poorly soluble, and the skin contact layer is preferably directly attached to the active drug-containing layer. Surprisingly, it has been found that while it has advantageous properties with respect to reducing skin irritation, it also improves drug delivery behavior and adhesion. In particular, since capsaicin is poorly soluble, for example, the saturation concentration in the skin contact layer is less than 0.1%, only a very small amount of capsaicin is present on the surface of the skin contact layer, and therefore the medical patch has advantageous properties with respect to undesirable skin reactions, thereby enabling safe application and / or removal. Thus, such an inventive medical patch has a skin contact layer in which the saturation concentration of capsaicin is negligible and a separate active drug-containing layer (not in contact with the skin), thus preventing the release of capsaicin before and / or after the medical patch is applied to and maintained on the patient's skin. On the other hand, it has been found that such a medical patch having a skin contact layer can still provide sufficient drug delivery and may allow for faster release of activity. Such capsaicin medical patches of the present invention are also advantageous in that they can be based on already approved and marketed capsaicin patches, simply supplementing them with an additional skin contact layer. Since drug delivery is sufficiently similar, there is a high probability of achieving bioequivalence with marketed products, which is highly desirable from a regulatory standpoint.

[0015] According to one specific embodiment, the present invention relates to a medical patch for administering capsaicin, comprising an active drug-containing layer structure, wherein such active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin in an amount of 5-10% by weight, (ii) At least one amine-compatible polysiloxane in an amount of 60-90% by weight, (iii) 10 to 25% by weight of diethylene glycol monoethyl ether, (iv) Ethyl cellulose in an amount of 0-2% by weight, (v) Silicone oil in an amount of 0-5% by weight, A layer containing an active agent, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing a silicone gel adhesive. The silicone gel adhesive is obtained by reacting (i) a gel-forming composition containing a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) a methylhydrogenpolysiloxane having a trimethylsilyl terminal group in the presence of (iii) a platinum catalyst.

[0016] In another specific embodiment, the present invention relates to a medical patch for administering capsaicin, comprising an active drug-containing layer structure, wherein such active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin in an amount of approximately 8% by weight, (ii) At least one amine-compatible polysiloxane in an amount of 60-90% by weight, (iii) 10 to 25% by weight of diethylene glycol monoethyl ether, (iv) Ethyl cellulose in an amount of 0-2% by weight, (v) Silicone oil in an amount of 0-5% by weight, A layer containing an active agent, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing a silicone gel adhesive. The silicone gel adhesive is obtained by reacting (i) a gel-forming composition containing a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) a methylhydrogenpolysiloxane having a trimethylsilyl terminal group in the presence of (iii) a platinum catalyst.

[0017] 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, particularly chronic neuropathic pain, and preferably in a method for treating peripheral neuropathic pain, postherpetic neuralgia of the hand and foot or neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain.

[0018] According to certain embodiments of the present invention, the present invention relates to the manufacture of pharmaceuticals for treating neuropathic pain, particularly chronic neuropathic pain, and preferably to the use of medical patches according to the present invention for the manufacture of pharmaceuticals for treating peripheral neuropathic pain, postherpetic neuralgia of the hand or foot or neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain.

[0019] According to certain embodiments of the present invention, the present invention relates to a method for treating neuropathic pain, particularly chronic neuropathic pain, preferably peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia of the hand or foot or diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain, the method comprising applying a medical patch according to the present invention to the patient's skin.

[0020] definition Within the scope of the present invention, the term “medical patch” refers to a skin delivery system for administering an active agent (capsaicin) to a patient, and also to the entire individual dose unit that is applied to the patient’s skin after removal of an optionally present release liner, the entire dose unit containing 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 (a removable protective layer), and thus the medical patch may further include a release liner.

[0021] In this context, the term “medical patch” is understood to mean an adhesive patch that can be a topical medical patch or a transdermal treatment system (TTS). Even though topical medical patches and TTSs are applied topically in the sense that they are attached to the patient’s skin, the terms “topical” or “topical administration” refer to the administration of capsaicin that relies on passive diffusion into the skin itself, thereby producing a local effect at the site of action. In contrast, the term “TTS” refers to a system in which capsaicin is delivered into the systemic circulation via transdermal delivery. Topical capsaicin administration may be preferable to transdermal capsaicin delivery systems in terms of systemic side effects, drug interactions, contraindications, and the development of tolerance.

[0022] In the sense of the present invention, the term "active drug-containing layer structure" refers to a capsaicin-containing structure that provides a surface area for the release of capsaicin during administration. The active drug-containing layer structure comprises a backing layer, an active drug-containing layer containing capsaicin, an optionally defined membrane, and a skin contact layer, as described herein. Thus, the active drug-containing layer structure contains a therapeutically effective amount of capsaicin. According to a particular embodiment, the active drug-containing layer structure is an active drug-containing self-adhesive layer structure.

[0023] Within the scope of this invention, the term “therapeutic effective dose” refers to the amount of capsaicin in a medical patch sufficient to provide a desired therapeutic effect, such as analgesia / relief, when administered to a patient via a medical patch. While TTS typically contains more capsaicin in the system than is actually delivered to the skin or systemic circulation, this is usually necessary to provide sufficient driving force for delivery from the TTS to the systemic circulation.

[0024] Within the scope of the present invention, terms such as “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 its free form, cocrystal, solvate, hydrate, inclusion complex, complex, and particulate form, which may be crystalline and / or amorphous, as well as any mixture of the aforementioned forms.

[0025] When capsaicin is contained in a medium such as a solvent, it may be soluble or dispersed, or partially soluble and partially dispersed.

[0026] Where it is stated that capsaicin is used in a specific form in the manufacture of a medical patch, this does not preclude interactions between this form of capsaicin and other components of the active drug-containing layer structure in the final medical patch, such as salt formation or complex formation. This means that even if capsaicin is included in a specific form, it may be present in the final medical patch in other forms. Unless otherwise indicated, the amount of capsaicin in the layer structure refers to the amount of capsaicin present in the medical patch during its manufacture and is calculated based on capsaicin itself, but other forms are not considered. The capsaicin starting material present in the medical patch during its manufacture may be in the form of particles. Capsaicin may be present in the active drug-containing layer structure, for example, in the form of particles, and / or may be dissolved.

[0027] In this context, the term “particles” refers to particulate materials in a solid that contain individual particles, the size of which is negligible compared to the material. In particular, particles are solids including plastics / 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 involves the dissolution of a portion of the starting material (e.g., capsaicin particles) depending on the solubility of the starting material (e.g., the solubility of capsaicin in the coating composition).

[0028] There are two main types of medical patches that use (passive) delivery of active drugs: matrix-type medical patches and reservoir-type medical patches. In matrix-type medical patches, the release of the active drug is mainly controlled by the matrix containing the active drug itself. In contrast, reservoir-type medical patches usually require a rate-limiting membrane to control the release of the active drug. In principle, matrix-type medical patches can also contain a rate-limiting membrane. However, matrix-type medical patches have the advantage of usually not requiring a rate-determining membrane compared to reservoir-type medical patches, and therefore dose dumping due to membrane rupture cannot occur. In summary, matrix-type medical patches are simple to manufacture and easy and convenient to use.

[0029] In this context, “matrix-type medical patch” is understood to mean a system or structure in which capsaicin is uniformly dissolved and / or dispersed within a polymer carrier, i.e., a matrix, forming a matrix layer together with the capsaicin and optionally any remaining components. In such a system, the matrix layer controls the release of capsaicin from the medical patch. Preferably, the matrix layer has sufficient cohesiveness to be self-supporting so that sealing between other layers is not required. Thus, the active agent-containing layer may be an active agent-containing matrix layer, in which the capsaicin is uniformly distributed within the polymer matrix. The active agent-containing matrix layer may consist of two active agent-containing matrix layers, which may be laminated together. The matrix-type medical patch may also take the form of an “adhesive-in-medication” type medical patch, in particular referring to a system in which capsaicin is uniformly dissolved and / or dispersed within a pressure-sensitive adhesive matrix. In this regard, the active agent-containing matrix layer may be an active agent-containing pressure-sensitive adhesive layer or an active agent-containing pressure-sensitive adhesive matrix layer. A medical patch containing capsaicin dissolved and / or dispersed within a polymer gel, such as a hydrogel, is also considered a matrix-type patch according to the present invention.

[0030] Medical patches having a liquid active agent reservoir are referred to as “reservoir-type medical patches.” In such systems, the release of the medical patch is preferably controlled by a rate-limiting membrane. In particular, the reservoir is sealed between the backing layer and the rate-limiting membrane. Thus, the active agent-containing layer may be an active agent-containing reservoir layer containing a liquid reservoir preferably containing capsaicin, and the active agent-containing reservoir layer and the skin contact layer may be separated by a rate-limiting membrane. In the active agent-containing reservoir layer, the capsaicin is preferably dissolved in a solvent such as ethanol or water or in a silicone oil.

[0031] Reservoir-type medical patches are not understood to be matrix-type in the sense of the present invention. However, microreservoir-type medical patches (two-phase systems having deposits (e.g., spheres, droplets) of an inner active drug-containing phase dispersed in an outer polymer phase) are considered to be matrix-type in the sense of the present invention, as they are considered in the art to be a mixed form of matrix-type and reservoir-type medical patches, distinct from homogeneous single-phase matrix-type and reservoir-type medical patches in the concept of drug transport and drug delivery.

[0032] Therefore, a microreservoir type medical patch refers to a microreservoir system in which a liquid capsaicin preparation is dispersed in an adhesive matrix in the form of small droplets ("microreservoirs"). The size of the resulting droplets depends on the agitation conditions and the shear force applied during agitation. Its size can be determined by optical microscopy (e.g., measurement with a Leica MZ16 including a camera such as the Leica DSC320) by taking photographs of the microreservoirs at different positions at magnifications between 10x and 400x, depending on the required detection limit. The size of the microreservoirs can be determined by using image analysis software. Microreservoir systems are disclosed in U.S. Patents 3,946,106, 4,053,580, 4,814,184 and 5,145,682, each of which is incorporated herein by reference. Specific microreservoir systems are described in International Patent Publication WO0101967, the disclosure of which is incorporated herein by reference. These microreservoir systems include a polysiloxane as a base polymer and an amphiphilic solvent for microreservoir droplets.

[0033] In the sense of the present invention, the term “active agent-containing layer” refers to a layer containing capsaicin and providing a release area. This term encompasses active agent-containing reservoir layers and active agent-containing matrix layers, particularly active agent-containing microreservoir layers. When the active agent-containing layer is an active agent-containing matrix layer, such 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 refers to the final solidified layer obtained after coating and drying a solvent-containing coating composition, such as those described herein. Alternatively, the active agent-containing matrix layer is obtained after melt coating and cooling. The active agent-containing matrix layer may also be manufactured by laminating two or more such solidified layers (e.g., a dry layer or a cooled layer) of the same composition to provide a desired area weight. According to certain embodiments, the matrix layer is a pressure-sensitive adhesive matrix layer.

[0034] In the context of this invention, the term "skin contact layer" refers to a layer within the active drug-containing layer structure that comes into direct contact with the patient's skin during administration. Other layers of the active drug-containing layer structure do not come into contact with the skin and do not necessarily have self-adhesive properties. The skin contact layer is either directly adhered to the active drug-containing layer or a membrane is placed between the active drug-containing layer and the skin contact layer. In this context, the term "membrane" is understood to mean a layer provided between the active drug-containing layer and the skin contact layer that is at least semipermeable to capsaicin. The membrane may be a microporous membrane or a non-porous partition membrane. Preferred membranes can be selected from the group consisting of polyethylene membranes, polyurethane-coated polyethylene terephthalate / polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate membranes. According to this invention, the skin contact layer exists as an adhesive layer.

[0035] The size of the skin contact layer and the active drug-containing layer, or the size of the skin contact layer, the membrane, and the active drug-containing layer, usually have the same extent and correspond to the release area. However, the area of ​​the skin contact layer, and optionally the area of ​​the membrane, may be larger than the area of ​​the active drug-containing layer. Even in such cases, the release area refers to the area of ​​the active drug-containing layer.

[0036] In the context of this invention, the term "backing layer" refers to a layer supporting the active drug-containing layer. At least one backing layer in a medical patch, and typically the backing layer of the active drug-containing layer, is substantially impermeable to the capsaicin contained within the layer, as well as any additives, during storage and administration, thus preventing loss of activity or cross-contamination in accordance with regulatory requirements. According to certain embodiments, the backing layer is also occluding, meaning it is substantially impermeable to water and water vapor. Suitable materials for the backing layer include polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate copolymer (EVA), polyester, polyurethane, and mixtures thereof. A suitable backing layer may be siliconeized to improve adhesion between the active drug-containing layer and the backing layer.

[0037] Furthermore, an adhesive overlay may be present. In this context, the term “adhesive overlay” is understood to mean a self-adhesive layer structure that does not contain capsaicin, has a larger area than the active agent-containing structure, provides an additional area for adhesion to the skin, but does not provide a capsaicin release area. This improves the overall adhesion of the medical patch. The area of ​​the adhesive overlay is added to the overall size of the medical patch, but not to the release area. The adhesive overlay may include a self-adhesive polymer or self-adhesive polymer mixture selected from the group consisting of acrylic polymers, polyisobutylene, styrene-isoprene-styrene copolymers, polysiloxanes, and mixtures thereof, which may be identical or different from any polymer or polymer mixture included in the active agent-containing self-adhesive layer structure. The adhesive overlay includes an adhesive layer and a backing layer which can provide occlusive or non-occlusive properties. According to certain embodiments, the backing layer of the adhesive overlay provides non-occlusive properties.

[0038] Within the scope of this invention, the term "area weight" means g / m² 2This refers to the dry weight of a specific layer, such as the active ingredient layer, provided in units. Due to manufacturing variations, the area weight value should have a tolerance of ±10%, preferably ±7.5%.

[0039] Unless otherwise specified, "%" means weight percentage.

[0040] In the sense 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 monomer and copolymers consisting of two or more monomers. Polymers can have any structure, such as linear polymers, star polymers, comb polymers, brush polymers, etc., and in the case of copolymers, any monomer sequence, such as alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can have molecular weights of, for example, more than 2,000 daltons, more than 5,000 daltons, or more than 10,000 daltons. Correspondingly, compounds with molecular weights of less than 2,000 daltons, less than 5,000 daltons, or less than 10,000 daltons are usually called oligomers.

[0041] Within the scope of the present invention, the term “pressure-sensitive adhesive” refers to a material that adheres particularly by finger pressure, is permanently tacky, exhibits strong holding power, and is removable from smooth surfaces without leaving any residue. This can be obtained from a solvent-containing adhesive coating composition, which is applied to a film and then the solvent (e.g., n-heptane or ethyl acetate) is evaporated. In this context, the term “solvent” is understood to mean any liquid substance that is preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene, and mixtures thereof.

[0042] In the context of this invention, the term "silicone-acrylic hybrid polymer" refers to a silicone and acrylate-based hybrid polymer in the form of a pressure-sensitive adhesive. Silicone-acrylic hybrid pressure-sensitive adhesives are described, for example, in EP2599847 and WO2016 / 130408. It has been found that the arrangement of the silicone and acrylic phases, providing a continuous silicone or acrylic outer phase and a corresponding discontinuous internal phase, differs depending on the solvent in which the silicone-acrylic hybrid PSA is supplied. When the silicone-acrylic hybrid PSA is supplied in n-heptane, the composition comprises a continuous silicone outer phase and a discontinuous acrylic internal phase. When the silicone-acrylic hybrid PSA composition is supplied in ethyl acetate, the composition comprises a continuous acrylic outer phase and a discontinuous silicone internal phase.

[0043] In the context of this invention, the term "silicone polymer" refers to a non-hybrid polymer (i.e., a polymer that does not contain hybrid species) containing a polysiloxane. Polysiloxanes can be prepared from a solvent-free two-component system or a solution in an organic solvent. There are two fundamentally different types of polysiloxanes: polysiloxanes having free silanol groups and amine-resistant polysiloxanes, which are distinguished in that the free silanol groups are derivatized with trimethylsilyl groups. The methyl groups can be completely or partially substituted with other alkyl radicals or phenyl radicals. The polysiloxanes used herein are synthesized from linear bifunctional oligomers and branched polyfunctional oligomers, the ratio of which determines the physical properties. A higher proportion of polyfunctional oligomers results in a higher degree of crosslinking, higher cohesiveness, and lower tackiness, while a lower proportion of polyfunctional oligomers results in higher tackiness and lower cohesiveness. The silicone polymer is preferably a mixture of high-viscosity and medium-viscosity, or high-viscosity and low-viscosity polysiloxanes. According to a particular embodiment, at least one silicone-based polymer is a silicone-based pressure-sensitive adhesive.

[0044] In the context of this invention, the term "silicone gel adhesive" refers to an elastic, gel-like material formed by lightly crosslinking a silicone polymer. This can be prepared from gel-forming compositions, as further described below, upon curing. In particular, silicone gel adhesives are formed upon curing of polysiloxanes containing reactive groups such as Si-H reactive groups and aliphatic unsaturated groups that react with each other in the presence of a hydrosilylation catalyst. According to certain embodiments, silicone gel adhesives are based on a polydimethylsiloxane network that can be formed by an addition reaction (hydrosilylation) between vinyl-functionalized polydimethylsiloxane groups (polymer) and a hydrogen-functionalized siloxane (crosslinking agent). Therefore, silicone gel adhesives are typically applied using a curable gel-forming (two-component) composition that solidifies upon curing.

[0045] In the sense of the present invention, the term "natural or synthetic rubber" refers to elastomers obtained by polymerizing unsaturated hydrocarbons such as isoprene (2-methyl-1,3-butadiene), or by copolymerizing such hydrocarbons with styrene, butadiene, etc. These include hydrocarbon polymers such as natural and synthetic polyisoprene, polybutylene, polyisobutylene, styrene / butadiene polymers, styrene-isoprene-styrene block copolymers, and butyl rubber; halogen-containing polymers such as polyacrylonitrile, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, and polychlorodiene; and other copolymers thereof. In certain embodiments, the natural or synthetic rubber may be styrene triblock copolymer or polyisobutylene.

[0046] In the sense of the present invention, the term “saturated concentration” refers to the concentration of the active agent corresponding to an equilibrium state in which the solvent (i.e., polymer II of the skin contact layer) cannot dissolve any further solute (i.e., capsaicin). As a result, the solid solute exists in equilibrium with the solid solution at a defined temperature (room temperature – the unmodified temperature determined in the laboratory where the experiment is conducted, typically within the range of 15–35°C, or approximately 18–25°C). The saturated concentration of the active agent can be expressed in weight percent based on the total weight of the active agent layer or the skin contact layer. The saturated concentration can be measured using, for example, the method described in Liu, P., Gargiulo, P., Wong, J., and Novartis. Pharm. Research. Vol. 14, p. 317 (1997) (referred to herein as the “sandwich method”). In this method, a multilayer laminate is prepared, comprising an upper protective layer and a lower protective layer sandwiching a donor layer and an acceptor layer separated by a partition membrane permeable to the active agent. The donor layer contains an excess of the active agent, while the acceptor layer contains substantially no active agent; therefore, the active agent diffuses from the donor layer through the partition membrane to the acceptor layer until it reaches a saturation concentration. The donor and acceptor layers are prepared from polymer II of the respective skin contact layers. The donor layer is supersaturated with the active agent, and the acceptor layer is prepared similarly to the donor layer but without the active agent. The prepared sandwich system is stored at room temperature for a period of time, for example, 7 days, to allow the active agent to diffuse from the donor layer to the acceptor layer. Subsequently, the residual active agent concentration in the donor layer is measured by HPLC (high-performance liquid chromatography) to finally obtain the saturation concentration of the active agent in polymer II of each skin contact layer.

[0047] As used herein, the solubility parameter (SP) is defined as a numerical estimate, the sum of all intermolecular forces empirically related to the degree of mutual solubility of chemical species. The simplest method for determining the solubility parameter is Hildebrand's method, which calculates the solubility parameter from molecular weight, boiling point, and density data that are commonly available for many substances. The formula is SP = (ΔE v / V) 1 / 2where V = molecular weight / density, and ΔE v = vaporization energy. For substances with too low vapor pressure to be detected, such as high molecular weight polymers, several methods using the sum of the contributions of atoms and groups to vaporization have been developed. Such methods for calculating the solubility parameter of a material are described, for example, in Small, J. Applied Chem. Vol. 3, p. 71 (1953). The solubility parameters (calculated by Small's method) of exemplary polymers useful in the practice of the present invention are shown below: polydimethylsiloxane 14.9 MPa 1 / 2 polyisobutylene 15.7 MPa 1 / 2 polyethylene / butylene 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 - 72 / 28) 17.4 MPa 1 / 2 polystyrene 18.6 MPa 1 / 2 polymethyl methacrylate 19.0 MPa 1 / 2 polymethyl acrylate 19.8 MPa 1 / 2 .

[0048] In the sense of the present invention, the term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, that is more than 10% soluble in at least ethanol, preferably water, polyvinylpyrrolidone, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2-propylene glycol, 1,4-butanediol, glycerol, triethanolamine, propionic acid, and acetic acid. Examples of commercially available polyvinylpyrrolidones include Kollidon® 12PF, Kollidon® 17PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90F, or povidone K90F, supplied by BASF. Different grades of Kollidon® are defined with respect to the K value, which reflects the average molecular weight of the polyvinylpyrrolidone grade. Kollidon® 12 PF features a K-value range of 10.2 to 13.8, corresponding to a nominal K-value of 12. Kollidon® 17 PF features a K-value range of 15.3 to 18.4, corresponding to a nominal K-value of 17. Kollidon® 25 features a K-value range of 22.5 to 27.0, corresponding to a nominal K-value of 25, and Kollidon® 30 features a K-value range of 27.0 to 32.4, corresponding to a nominal K-value of 30. Kollidon® 90F features 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® 90F. In this context, the term "K value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and the USP monograph for "Povidone". For all grades and types of polyvinylpyrrolidone, it is preferable that the amount of peroxide be within certain limiting ranges, and in particular, that the amount of peroxide be 500 ppm or less, 150 ppm or less, or 100 ppm or less.

[0049] The medical patch according to the present invention may be characterized by certain parameters measured in an in vitro skin penetration test.

[0050] The in vitro permeability test can be performed in a Franz diffusion cell using human or animal skin, preferably 500 μm thick, harvested human split-thickness skin with intact epidermis, with or without the addition of up to 40% by volume of organic solvents, such as ethanol, acetonitrile, isopropanol, dipropylene glycol, and PEG 400, so that the receptor medium contains, for example, 60% by volume of 0.9% sodium chloride, 30% by volume of dipropylene ene glycol, and 10% by volume of acetonitrile, and preferably 500 μm thick, intact human skin, and using a 0.9% sodium chloride solution (32°C, 0.1% azide saline) as the receptor medium.

[0051] Unless otherwise indicated, in vitro permeation tests are performed in a Franz diffusion cell using heated separated human epidermis and a 0.9% sodium chloride solution (at 32°C with 0.1% azide saline) as the receptor medium. The amount of capsaicin permeated into the receptor medium is measured periodically by taking sample volumes and using a partially effective HPLC method with a UV photometric detector (column: 150 mm inner diameter x 4.6 mm stainless steel column with C18 base and acid-inactivated stationary phase, particle size 3.5 μm, e.g., Zorbax SB C18 (Agilent); column temperature: 25°C; mobile phase: acetonitrile / water / TEA=20:80:0.35 (v / v / v)). The receptor medium is completely or partially replaced with fresh medium when taking sample volumes, and the measured amount of permeated capsaicin relates to the amount permeated between the last two sample collection points, and not to the total amount permeated up to that point.

[0052] Therefore, within the scope of the present invention, the parameter "transmission amount" is μg / cm³. 2The permeation rate is provided and relates to the amount of capsaicin that permeated during a sample interval over a specific time period. For example, in the in vitro permeation test described above, where the amount of capsaicin that permeated the receptor medium was measured at, for example, 0, 30, 60, 90, 120, 180, and 240 minutes, the "permeation rate" of capsaicin may be provided for, for example, the sample interval from 90 minutes to 120 minutes, corresponding to the measurement result at 120 minutes, in which case the receptor medium was completely replaced at 90 minutes. Alternatively, the permeation rate may be given as a "cumulative permeation rate," which corresponds to the cumulative amount of capsaicin that permeated at a particular time point. For example, in an in vitro permeation test as described above, where the amount of capsaicin permeated the receptor medium was measured at, for example, 0, 30, 60, 90, 120, 180, and 240 minutes, the "cumulative permeation amount" of capsaicin at 120 minutes corresponds to the sum of the permeation amounts at 0-30 minutes, 30-60 minutes, 60-90 minutes, and 90-120 minutes.

[0053] Within the scope of the present invention, the parameter "skin permeability rate" (also called "Δflux rate") with respect to a specific sample interval at a specific time interval is defined as μg / (cm³). 2 Provided in units of minutes (μg / cm³). 2 The amount of permeation at the above sample interval, measured by the in vitro permeation test as described above, is calculated by dividing the amount by the fraction of the sample interval. The amount of capsaicin that permeated the receptor medium is measured, for example, at 0, 30, 60, 90, 120, 180, and 240 minutes, and the "skin permeation rate" at time Δ105 is calculated by dividing the amount of permeation at the sample interval from 90 to 120 minutes by 30 minutes. The "cumulative skin permeation rate" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time.

[0054] Within the scope of the present invention, the above parameters, "penetration amount" and "skin penetration rate" (as well as "cumulative penetration amount" and "cumulative skin penetration rate"), refer to the average values ​​calculated from at least six in vitro penetration tests. Unless otherwise specified, the standard deviation (SD) of these average values ​​is given by the formula:

number

number

[0055] Within the scope of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory where the experiment is conducted, which is typically in the range of 15 to 35°C, or about 18 to 25°C.

[0056] In the sense of the present invention, the term “patient” refers to a person who exhibits specific symptoms or clinical signs of symptoms that suggest the need for treatment, a person who is receiving preventive or prophylactic treatment for a condition, or a person who has been diagnosed with a condition that requires treatment. Preferably, the patient suffers from neuropathic pain, or mixed pain of neuropathic pain and / or nociceptive pain, such as arthralgia or cancer pain.

[0057] In the context of this 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" is understood to mean neuropathic pain lasting for at least three months. When suffering from neuropathic pain, most patients complain of continuous or intermittent spontaneous pain, such as burning, stabbing, or pressure, which may be triggered particularly by light touch or cold. Ectopic activity in nerve endings, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus can cause spontaneous pain in a variety of situations. Neuropathic pain includes peripheral neuropathic pain, which particularly affects peripheral nerves, i.e., nerves outside the brain and spinal cord. In particular, neuropathic pain in the context of this invention relates to postoperative neuropathic pain, postherpetic neuralgia, and neuropathic pain associated with diabetic peripheral neuropathy of the hands and feet.

[0058] In this context, the term “postoperative neuropathic pain” is understood to mean chronic pain that develops after a surgical procedure and persists beyond the healing process, i.e., for at least three months after surgery. The pain may be localized to the surgical or injured site, radiate to the area innervated by the nerves located at that site, or radiate to dermatomes (after surgery or injury to deep somatic or visceral tissues). Chronic postoperative pain is a result of nerve damage and may be due to the surgery itself or other causes of pain, including infection or malignancy.

[0059] In this context, the term “postherpetic neuralgia” is also understood as postherpetic neuralgia and refers to pain that occurs when nerves are damaged by a past infection with herpes zoster, commonly known as shingles. The symptoms of postherpetic neuralgia are limited to or localized to the skin area where shingles developed, particularly the band-like area of ​​the trunk, and usually appear on one side of the body. Less common symptoms of postherpetic neuralgia include itching, numbness, or a “prickly sensation.”

[0060] In this context, the term "diabetic peripheral neuropathy," also known as "diabetic neuropathy," is understood to mean pain that occurs when nerves are damaged as a result of diabetes. Diabetic neuropathy can affect any nerve, but it is most commonly felt in the extremities, such as the hands and feet.

[0061] In the context of this invention, the term “arthralgia” refers to joint symptoms such as discomfort, pain, or distress in any of the joints of a patient’s body, including the joints of the spine, shoulders, hips, elbows, and knees. This includes, in particular, arthralgia 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 changes in the synovial membrane and joint capsule. Clinically, it is characterized by joint pain, stiffness, and functional limitations. While pain in osteoarthritis has traditionally been considered nociceptive, some patients also suffer from neuropathic pain. Specifically, arthralgia may be knee pain, elbow pain, hip pain, shoulder pain, hand or foot pain, or back (hip) pain.

[0062] In the context of this invention, the term "cancer pain" refers to nerve damage caused by cancer itself, and / or neuropathic cancer pain caused by treatments such as chemotherapy, radiation therapy, and surgery. Cancer pain caused by the tumor itself usually includes both 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. Neuropathic cancer pain is nerve-related (typically neuronal) pain characterized as burning or electrical sensations, but may also manifest as decreased sensation or actual muscle weakness.

[0063] According to the present invention, the medical patch described herein is suitable for use in therapeutic methods in which the medical patch is applied for a short period of time (application time) but provides a desired pain-relieving effect for a long period of time (effect duration). It is preferable that the medical patch releases approximately the total amount of capsaicin contained in the active agent-containing layer of the medical patch during the application time. Capsaicin is thought to be able to cause desensitization and inactivation of TRPV1 receptors during the application time, and as a result, can provide sustained pain relief that lasts throughout the effect duration.

[0064] In the sense of the present invention, the term "short time," i.e., application time, refers to a time in the range of less than 240 minutes or about 240 minutes, less than 180 minutes or about 180 minutes, less than 120 minutes or about 120 minutes, less than 90 minutes or about 90 minutes, less than 60 minutes or about 60 minutes, less than 45 minutes or about 45 minutes, less than 30 minutes or about 30 minutes, less than 15 minutes or about 15 minutes, or a time in the range of 30 to 90 minutes.

[0065] In the sense of the present invention, the term "long duration," i.e., duration of effect, refers to a period of at least or about one week, at least two weeks or about two weeks, at least about one month or about one month, at least one and a half months or about one and a half months, at least two months or about two months, at least three months or about three months, or one to three months.

[0066] The interval between two administrations, also called the dosing interval, needs to be adjusted as appropriate. In the sense of this invention, the term "dosing interval" refers to the period between two consecutive medical patch administrations, i.e., the interval between two consecutive points in time when the medical patch is applied to the patient's skin. Once applied, the medical patch remains on the patient's skin for the duration of application and is then removed. However, the dosing interval continues until a new medical patch is applied to the skin.

[0067] In the sense of the present invention, the term "coating composition" refers to a composition comprising all the components of the active agent-containing layer or the skin contact layer, which may be coated onto a backing layer or release liner to form the active agent-containing layer and the skin contact layer upon drying.

[0068] In the context of this invention, the term "dissolve" refers to the process of obtaining a solution that is transparent to the naked eye and free of any visible particles.

[0069] In the context of this invention, the term "crosslinking" refers to the process of crosslinking functional groups contained within an inactive coating composition.

[0070] In the context of this invention, unless otherwise specified, the term “about” means an amount that is ±10% of the disclosed amount. In some embodiments, the term “about” means an amount that is ±5% of the disclosed amount. In some embodiments, the term “about” means an amount that is ±2% of the disclosed amount. [Brief explanation of the drawing]

[0071] [Figure 1a] The cumulative capsaicin permeation amount of the medical patches prepared according to Example 1 and Reference Example is shown. [Figure 1b] The capsaicin skin penetration rate of medical patches prepared according to Example 1 and Reference Example is shown. [Modes for carrying out the invention]

[0072] Medical patch structure The present invention relates to a medical patch for the administration of capsaicin. The medical patch may be either a topical medical patch or a transdermal treatment system. According to a particular embodiment, the patch is a topical medical patch specifically for the topical administration of capsaicin.

[0073] The medical patch according to the present invention comprises an active drug-containing layer structure, and such active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin and, (ii) at least one silicone polymer, A layer containing an active agent, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing polymer II (at least one silicone-based polymer in the active agent-containing layer is also called polymer I). The active agent, capsaicin, is poorly 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 certain embodiments, the medical patch according to the present invention comprises an active agent-containing layer structure, and such active agent-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin and, (ii) at least one silicone polymer, A layer containing an active agent, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing a silicone gel adhesive.

[0074] In one embodiment, the active agent-containing layer structure may or may not include a membrane located between the active agent-containing layer and the skin contact layer. In such embodiments, the membrane is preferably a rate-limiting membrane. However, in the specific application of this example, i.e., when rapid release of the active compound is desired and the application time is short, a rate-limiting membrane is usually not present.

[0075] Preferably, the aforementioned layers of the medical patch according to the present invention adhere directly to each other, that is, the backing layer adheres directly to the active drug-containing layer, and this active drug-containing layer adheres directly to the skin contact layer on the other side. Alternatively, the active drug-containing layer adheres directly to the film, and the film adheres directly to the skin contact layer on the opposite side. In other words, the medical patch according to the present invention comprises the layers in the order of (1) backing layer, (2) active drug-containing layer, and (3) skin contact layer, or (1) backing layer, (2) active drug-containing layer, (3) film, and (4) skin contact layer.

[0076] The backing layer is, in particular, substantially impermeable to capsaicin. The backing layer is preferably made of a polyester film or an ethylene vinyl acetate copolymer with a thickness of 10 to 20 μm.

[0077] According to the present invention, the medical patch contains capsaicin, particularly in a therapeutically effective amount. Therefore, in certain embodiments, the medical patch contains capsaicin in amounts of 0.5 to 180 mg, 1.2 to 90 mg, or 19 to 45 mg. In some embodiments, the medical patch contains capsaicin in an amount of about 179 mg. In other embodiments, the medical patch contains capsaicin in amounts of about 60 mg, about 45 mg, about 30 mg, about 25 mg, about 10 mg, or about 1 mg.

[0078] The medical patch according to the present invention may be a matrix-type medical patch or a reservoir-type medical patch, and is preferably a matrix-type medical patch. In a particular embodiment, the medical patch according to the present invention is a matrix-type medical patch in which capsaicin is uniformly dissolved and / or dispersed in a polymer carrier, i.e., a matrix, and together with the capsaicin and optionally further additives, forms a matrix layer. Therefore, the active drug-containing layer is preferably an active drug-containing matrix layer. Therefore, in a particular embodiment of the medical patch according to the present invention, the active drug-containing layer is (i) Capsaicin and, (ii) at least one silicone polymer, This is an active drug-containing matrix layer.

[0079] In certain embodiments, the medical patch according to the present invention is a micro-reservoir type medical patch.

[0080] The active drug-containing layer structure according to the present invention is typically located on a removable protective layer (release liner) that is peeled off immediately before application to the patient's skin surface. Thus, the medical patch may further include a release liner. The medical patch thus protected is typically housed in a seam-sealed pouch. The packaging may be designed to be safe for children and / or easy to handle for the elderly.

[0081] A medical patch according to one embodiment of the present invention includes an adhesive skin contact layer containing a silicone gel adhesive, which provides improved adhesion when applied to a patient's skin and can be removed cleanly and painlessly. If necessary, for example, to move to another location, the medical patch can be peeled off and reapplied without losing its adhesive properties. Therefore, the medical patch is also suitable for problematic application sites such as hands or feet. Such application sites are particularly difficult due to their uneven surface and complexity, and the shape and size of the active drug-containing layer structure must be considered.

[0082] Therefore, in certain embodiments, the active agent-containing layer structure has a hexagonal shape, and the backing layer, the active agent-containing layer, and the skin contact layer have the same extent, providing the hexagonal shape of the active agent-containing layer structure. In a hexagon, all pairs of opposite sides are parallel. The sides of the hexagon are 1.5 to 10 cm long.

[0083] In certain embodiments, 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 certain embodiments, the hexagonal shape is a double hexagon formed from two identical convex hexagons that share two adjacent vertices and a common edge, with perforations along the common edge for easy separation.

[0084] Active drug-containing layer As outlined in more detail above, the medical patch according to the present invention includes an active drug-containing layer structure, in particular, the following active drug-containing layer. Such active drug-containing layer is (i) Capsaicin and, (ii) at least one silicone polymer, Includes.

[0085] In a preferred embodiment, the active agent-containing layer contains at least 0.30 mg / cm² per release area. 2 at least 0.50 mg / cm³ 2 , or at least 0.60 mg / cm³ 2 Capsaicin, and / or 1.0 mg / cm² per release area. 2 Less than 0.8 mg / cm³ 2 Less than 0.7 mg / cm³ 2 It contains less than 0.30 mg / cm² of capsaicin per release area. In particular, the active drug-containing layer contains 0.30 mg / cm². 2 ~1.0 mg / cm³ 2 , 0.30 mg / cm³ 2 ~8.0 mg / cm³ 2 , 0.50 mg / cm³ 2 ~8.0 mg / cm³ 2 , 0.60 mg / cm³ 2 ~0.8 mg / cm³ 2 , or 0.60 mg / cm³ 2 ~0.7 mg / cm³ 2 It contains capsaicin.

[0086] According to a particular embodiment, the active agent-containing layer contains capsaicin in an amount of 2-20% by weight, 5-15% by weight, or 5-10% by weight. In a particular embodiment, the active agent-containing layer contains capsaicin in an amount of about 8% by weight.

[0087] Furthermore, according to certain embodiments, at least one silicone polymer is present in the active agent-containing layer in an amount of 20-90% by weight or 60-90% by weight, based on the total weight of the active agent-containing layer. It should be understood that the aforementioned weight percentages refer to the total amount of at least one silicone polymer. For example, if two types of silicone polymers are present, the total amount in the active agent-containing layer is 20-90% by weight or 60-90% by weight, based on the total weight of the active agent-containing layer.

[0088] Therefore, in a particular embodiment of the medical patch according to the present invention, the active drug-containing layer is (i) Capsaicin in an amount of 5-10% by weight, especially about 8% by weight, and (ii) Contains at least one silicone-based polymer in an amount of 60 to 90% by weight.

[0089] Capsaicin is preferably uniformly dispersed within the active agent-containing layer, particularly within 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 polymer, or a layer containing capsaicin dissolved in a solvent to form a capsaicin solvent mixture dispersed in at least one silicone polymer in the form of precipitates (particularly droplets). In a particularly preferred medical patch, the active agent-containing layer contains capsaicin (active agent-containing solution) dissolved in an amphiphilic solvent as microreservoir droplets dispersed within the active agent-containing matrix layer. The proportion of microreservoir droplets in the active agent-containing matrix layer is typically less than about 40% by weight, less than about 35% by weight, or about 20% to about 30% by weight.

[0090] Suitable amphiphilic solvents include butanediols, particularly 1,3-butanediol, dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether (DGME), diethylene glycol monobutyl ether, propylene glycol, carboxylic acid esters of triethylene glycol and diethylene glycol, polyethoxylated fatty alcohols with 6 to 18 carbon atoms, or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, or mixtures thereof, or mixtures of these solvents. In certain embodiments, the amphiphilic solvent is diethylene glycol monoethyl ether, also known by the trademark name Transcutol®. Since the solubility of capsaicin in DGME is approximately 50% by weight, the medical patch is less susceptible to recrystallization of capsaicin even under unfavorable conditions such as partial loss of solvent or low temperatures. In addition, DGME acts as a permeation enhancer, and since it is released along with capsaicin, it maintains high levels of capsaicin concentration and thermodynamic activity within the microreservoir system despite its release.

[0091] Therefore, in certain embodiments of the present invention, the active agent-containing layer comprises diethylene glycol monoethyl ether, preferably in an amount of 10 to 25% by weight of diethylene glycol monoethyl ether.

[0092] Furthermore, it has been shown that dispersion of the active agent-containing solution can be more easily achieved when the viscosity of the active agent-containing solution is increased by the addition of a suitable agent, such as a cellulose derivative containing ethylcellulose or hydroxypropylcellulose.

[0093] Accordingly, in certain embodiments of the present invention, the active agent-containing layer comprises a thickening additive selected from the group consisting of cellulose derivatives, high molecular weight polyacrylic acid, and any mixture thereof. In particular, the active agent-containing layer comprises ethylcellulose, preferably in an amount of 0 to 2% by weight.

[0094] In a particular embodiment of the medical patch according to the present invention, the active drug-containing layer is (i) an amount of 5-10% by weight, especially an amount of about 8% by weight of capsaicin, (ii) At least one silicone-based polymer in an amount of 60 to 90% by weight, (iii) 10 to 25% by weight of diethylene glycol monoethyl ether, (iv) Ethyl cellulose in an amount of 0-2% by weight, Includes.

[0095] According to certain embodiments, at least one silicone-based polymer is a non-hybrid polymer comprising a polysiloxane. This is preferably a thermoplastic polymer, applied by a hot-melt or solvent-based process, and typically does not undergo further curing to solidify. Further details regarding these polymers are provided below. In certain embodiments, at least one silicone-based polymer is at least one amine-compatible polysiloxane.

[0096] In certain embodiments, the active agent-containing layer contains a silicone oil, preferably in an amount of 0 to 5% by weight, particularly 0.5 to 5% by weight. This includes, in particular, dimethicone.

[0097] Therefore, in a preferred embodiment of the medical patch according to the present invention, the active drug-containing layer is (i) an amount of 5-10% by weight, especially an amount of about 8% by weight of capsaicin, (ii) at least one amine-compatible polysiloxane in an amount of 60-90% by weight, particularly in an amount of 58-85% by weight, (iii) 10 to 25% by weight of diethylene glycol monoethyl ether, (iv) Ethyl cellulose in an amount of 0-2% by weight, (v) Silicone oil in an amount of 0-5% by weight, Includes.

[0098] Furthermore, in a preferred embodiment, the area weight of the active agent-containing layer is 30-200 g / m². 2 , or 50-120g / m 2 That is the case.

[0099] skin contact layer As outlined in more detail above, the medical patch according to the present invention comprises an active drug-containing layer structure, particularly including a skin contact layer, the skin contact layer being an adhesive layer containing polymer II. Preferably, the skin contact layer is an adhesive layer that adheres directly to the active drug-containing layer.

[0100] The medical patch according to the present invention is characterized in particular by low solubility of capsaicin in the skin contact layer, and in certain embodiments, the saturation concentration of capsaicin in the skin contact layer is preferably less than 0.1% by weight, as measured 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 relates to the amount of capsaicin present in the skin contact layer based on the total weight of the skin contact layer.

[0101] In certain embodiments, the saturation concentration of capsaicin in the skin contact layer is less than the concentration of capsaicin that would cause unintended adverse effects, such as skin irritation, with short-term contact. Such concentrations can be empirically determined by in vivo testing by observing whether or not adverse effects, such as any form of skin irritation (redness, erythema, itching, or other skin reactions), occur after applying a model adhesive layer having a defined capsaicin concentration to the skin for a short period, e.g., 5 seconds, 10 seconds, 30 seconds, or 1 minute. In particular, the highest acceptable saturation concentration that does not yet cause unintended adverse effects, such as skin irritation, can be determined by testing different model layers representing a range of capsaicin concentrations. On the other hand, whether a medical patch having a set of capsaicin and skin contact layer results in a saturation concentration that does not cause any adverse effects can be simply determined (without using a range of different concentrations) by testing a model adhesive layer saturated with capsaicin, or by applying such a medical patch to the skin as outlined above.

[0102] According to the present invention, the skin contact layer shields the capsaicin contained in the active drug-containing layer from the skin of the patient or other person applying / removing the patch before and / or after application of the medical patch. Therefore, the skin contact layer must be substantially free of capsaicin. This means that the skin contact layer is usually manufactured as a capsaicin-free layer. On the other hand, due to the concentration gradient, capsaicin can usually migrate over time from the active drug-containing layer to the skin contact layer 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 concentrations exceeding 0.1% by weight.

[0103] Therefore, in certain embodiments, the skin contact layer contains less than 0.1% by weight of capsaicin based on the total weight of the skin contact layer. In certain embodiments, the skin contact layer contains less than 0.01% by weight of capsaicin based on the total weight of the skin contact layer.

[0104] Polymer II in the skin contact layer plays a crucial role not only in adhesion but also in reducing skin irritation due to its elasticity. Furthermore, Polymer II does not adversely affect the delivery of capsaicin. In certain embodiments, the skin contact layer contains at least 95% by weight, at least 99% by weight, or about 100% by weight of Polymer II, 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 aforementioned weight percentage 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 50-100% by weight, based on the total weight of the skin contact layer.

[0105] A suitable polymer for Polymer II according to the present invention is, in particular, a polymer that can concentrate capsaicin to 0.1% by weight or less, 0.05% by weight or less, 0.02% by weight or less, or 0.01% by weight or less, i.e., a polymer in which capsaicin is substantially insoluble. Therefore, according to a particular embodiment, Polymer II may be a polymer or a mixture of polymers in which capsaicin is substantially insoluble.

[0106] Therefore, the solubility parameter of polymer II may differ from that of capsaicin, and in particular, it may be at least 5.0 MPa higher than that 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 It may be lower than that. In particular, the solubility parameter of polymer II is preferably 18.5 MPa, as calculated by Small's method. 1 / 2 Less than 18.0 MPa 1 / 2 Less than 17.5 MPa 1 / 2 Less than 17.0 MPa 1 / 2 Less than 16.0 MPa 1 / 2 Less than 15.0 MPa 1 / 2 It may be less than.

[0107] Polymer II can be selected from pressure-sensitive adhesive polymers. Therefore, in certain embodiments, Polymer II may be a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0108] In certain embodiments, polymer II may 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 rubber or synthetic rubber. In particular, polymer II may be a polymer or a mixture of polymers selected from the group consisting of silicone-based polymers and silicone gel adhesives.

[0109] In certain embodiments, polymer II may be a silicone gel adhesive.

[0110] Furthermore, Polymer II may be a polymer or mixture of polymers selected from silicone polymers, particularly polysiloxane-based polymers such as amine-compatible polysiloxanes, or Polymer II may be a polymer or mixture of polymers selected from natural rubber or synthetic rubber, particularly styrene triblock copolymers and / or polyisobutylene such as SIS block copolymers and / or polyisobutylene.

[0111] A preferred polymer II according to the present invention is commercially available under the trade name Soft skin adhesives (a two-component silicone adhesive that hardens when two components are mixed). Alternatively, a preferred polymer II according to the present invention is commercially available under the trade names BIO-PSA (a pressure-sensitive adhesive based on polysiloxane), JSR-SIS (a pressure-sensitive adhesive based on SIS block copolymer), and Oppanol™ (polyisobutylene).

[0112] Additionally, for example, additional polymers may be added to enhance the adhesion of the skin contact layer.

[0113] According to some embodiments, polymer II contained in the skin contact layer is different from polymer I (i.e., a silicone-based polymer) contained in the active agent-containing layer. According to other embodiments, polymer II contained in the skin contact layer is the same as polymer I (i.e., a silicone-based polymer) contained in the active agent-containing layer.

[0114] According to a particular embodiment, the area weight of the skin contact layer is 80-500 g / m². 2 This is possible. In a preferred embodiment, the skin contact layer is 100-350 g / m² 2 , 150~320g / m 2 , or 180-280g / m 2 It has a surface weight of . Such a relatively thick skin contact layer allows for gentle removal of the medical patch containing the self-adhesive layer structure according to the present invention, and is therefore advantageous in reducing skin irritation. On the other hand, even if the elasticity of the skin contact layer, and therefore the ease of removal, increases with its thickness, the total thickness of the self-adhesive layer structure should still allow for easy handling and a comfortable fit. Surprisingly, the release of the active substance was found to be unaffected by such a thick (non-active substance) skin contact layer, and on the contrary, the release of the active substance was found to be even improved compared to a medical patch without a skin contact layer. Silicone acrylic hybrid polymer

[0115] Silicone-acrylic hybrid polymers include polymerized hybrid species containing silicone-based and acrylate-based subspecies polymerized together. Therefore, silicone-acrylic hybrid polymers contain a silicone phase and an acrylic phase. In certain embodiments, the silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive.

[0116] Silicone-acrylic hybrid pressure-sensitive adhesives are typically supplied and used in solvents such as n-heptane or ethyl acetate. The solids content of pressure-sensitive adhesives is usually between 30% and 80%. Those skilled in the art recognize that the solids content can be altered by adding an appropriate amount of solvent.

[0117] 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 silicone-to-acrylate ratio may be approximately 50:50.

[0118] Suitable commercially available silicone-acrylic hybrid pressure-sensitive adhesives include the PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X=1 n-heptane-based / X=2 ethyl acetate-based), manufactured and supplied by Dow Corning in n-heptane or ethyl acetate. For example, the 7-6102 silicone-acrylic hybrid PSA with a 50 / 50 silicone / acrylate ratio is characterized by a solution viscosity of 2,500 cP at 25°C with approximately 50% solids content in ethyl acetate and a complex viscosity of 1.0e7 poise at 30°C with 0.1 rad / s. The 7-6302 silicone-acrylic hybrid PSA with a 50 / 50 silicone / acrylate ratio is characterized by a solution viscosity of 1,500 cP at 25°C with approximately 50% solids content in ethyl acetate and a complex viscosity of 4.0e6 poise at 30°C with 0.1 rad / s.

[0119] Depending on the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is supplied, the arrangement of the silicone and acrylic phases differs, providing a continuous silicone or acrylic outer phase and a corresponding discontinuous internal phase. When the silicone-acrylic hybrid pressure-sensitive adhesive is supplied in n-heptane, the composition includes a continuous silicone outer phase and a discontinuous acrylic internal phase. When the silicone-acrylic hybrid pressure-sensitive adhesive is supplied in ethyl acetate, the composition includes a continuous acrylic outer phase and a discontinuous silicone internal phase. After the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is supplied is evaporated, 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, if there is no substance that can induce a reversal of the phase arrangement of 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 will provide a continuous silicone outer phase and a discontinuous acrylic internal phase, while a pressure-sensitive adhesive layer prepared from a silicone-acrylic hybrid pressure-sensitive adhesive in ethyl acetate will provide a continuous acrylic outer phase and a discontinuous silicone internal phase. The phase configuration of the composition can be determined, for example, by a peel force test using a pressure-sensitive adhesive film or a layer prepared from a silicone-acrylic hybrid PSA composition bonded to a silicone-coated release liner. If the silicone-coated release liner cannot be peeled from the pressure-sensitive adhesive film (laminated to the backing film) or can barely be peeled due to blocking of the two silicone surfaces, the pressure-sensitive adhesive film contains a continuous silicone outer phase. The blocking occurs due to the adhesion of two silicone layers having similar surface energies. The silicone adhesive spreads well on the silicone-coated liner and can therefore form good adhesion to the liner. If the silicone-coated release liner peels off easily, the pressure-sensitive adhesive film contains a continuous acrylic outer phase. The acrylic adhesive spreads poorly due to its different surface energy and has low or almost no adhesion to the silicone-coated liner.

[0120] The silicone-acrylic hybrid polymer may be a silicone-acrylic hybrid pressure-sensitive adhesive obtained from a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups. It should be understood that the silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality may contain acrylate functionality only, methacrylate functionality only, or both acrylate and methacrylate functionality.

[0121] A silicone-acrylic hybrid pressure-sensitive adhesive may comprise (a) a silicone-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer, and (c) a reaction product with an initiator. That is, a silicone-acrylic hybrid pressure-sensitive adhesive is the product of a chemical reaction between these reactants ((a), (b), and (c)). In particular, a silicone-acrylic hybrid pressure-sensitive adhesive may comprise (a) a silicone-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) a (meth)acrylate monomer, and (c) a reaction product with an initiator (i.e., in the presence of an initiator). That is, a silicone-acrylic hybrid pressure-sensitive adhesive may comprise the product of a chemical reaction between these reactants ((a), (b), and (c)).

[0122] The reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer, and (c) an initiator may include a continuous silicone outer phase and a discontinuous acrylic inner phase, or the reaction products of (a), (b), and (c) may include a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0123] The silicone-acrylic hybrid polymer may contain a reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, where the acrylic polymer is covalently self-crosslinked and covalently bonded to the silicone polymer and / or silicone resin.

[0124] The silicone-acrylic hybrid polymer may include a reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, where the silicone resin is a triorganosiloxy unit R3SiO where R is an organic group. 1 / 2 , and the tetrafunctional siloxy unit SiO 4 / 2 Each SiO 4 / 2 For comparison, 0.1~0.9R3SiO 1 / 2 Contains in molar ratios per unit.

[0125] The acrylic polymer may contain 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)acrylate, dialkoxyalkylsilyl (meth)acrylate, and mixtures thereof, or contains a terminally capped alkoxysilyl functional group. The alkoxysilyl functional group may preferably be selected from the group consisting of trimethoxysilyl, dimethoxymethylsilyl, triethoxysilyl, diethoxymethylsilyl, and mixtures thereof.

[0126] Acrylic polymers can be prepared from a mixture containing polysiloxane-containing monomers, preferably a mixture containing polydimethylsiloxane mono(meth)acrylate.

[0127] A silicone-acrylic hybrid polymer can be prepared by a) reacting a silicone polymer with a silicone resin to form a resulting product, and b) reacting the resulting product from a) with an acrylic polymer containing a reactive functional group, wherein the components are reacted in an organic solvent.

[0128] A silicone-acrylic hybrid polymer can be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functional groups to form a resulting product, and b) reacting the resulting product from a) with a silicone polymer, wherein the components are reacted in an organic solvent.

[0129] A silicone-acrylic hybrid polymer can be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functional groups to form a resulting product, and b) reacting the resulting product from a) with a silicone resin, wherein the components are reacted in an organic solvent.

[0130] More suitable acrylic polymers, silicone resins, and silicone polymers that can be used to provide silicone-acrylic hybrid polymers according to the preceding paragraph by chemically reacting silicone polymers, silicone resins, and acrylic polymers are described in detail in WO2010 / 124187.

[0131] Silicone polymers Silicone polymers are non-curing polymers, typically applied by hot-melt or solvent-based processes, and preferably do not undergo further curing to solidify.

[0132] Silicone polymers are based on polysiloxanes; therefore, they are also called polysiloxane-based polymers. Silicone polymers are generally obtained by polycondensation of silanol-termined polydimethylsiloxane with silicate resins. Amine-compatible silicone polymers can be obtained by reacting the silicone polymer with trimethylsilyl (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer, thereby improving its stability in the presence of amines. As a result, the residual silanol functionality is capped at least partially, preferably mostly or completely, with trimethylsiloxy groups.

[0133] Therefore, in preferred embodiments, the silicone polymer is an amine-compatible polysiloxane, preferably obtained by polycondensing a silanol-terminated polydimethylsiloxane with a silicate resin, and then at least partially trimethylsilylation of the remaining silanol functionality.

[0134] In certain embodiments, the silicone polymer is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives, i.e., a polysiloxane-based pressure-sensitive adhesive or a mixture of polysiloxane-based pressure-sensitive adhesives.

[0135] Polysiloxane-based pressure-sensitive adhesives offer appropriate viscosity, rapid adhesion to various skin types including moist skin, good adhesion and cohesive properties, long-term adhesion to skin, high flexibility, moisture permeability, and compatibility with many active agents and film-substrates. Such pressure-sensitive adhesives are based on the resin-in-polymer concept, where the polysiloxane-based pressure-sensitive adhesive is prepared by the condensation reaction of silanol-terminated polydimethylsiloxane with a silica resin (also called a silicate resin). For amine stability, residual silanol functionalities are additionally capped with trimethylsiloxy groups. The content of silanol-terminated polydimethylsiloxane contributes to the viscous element of the viscoelastic behavior and affects the wetting and diffusion properties of the adhesive. The resin acts as a tackifier and reinforcing agent, participating in the elastic element. A proper balance between silanol-terminated polydimethylsiloxane and the resin provides appropriate adhesion.

[0136] As previously shown, the tackiness of silicone polymers can be altered by the resin-to-polymer ratio, i.e., the ratio of silanol-termined polydimethylsiloxane to silicate resin, preferably in the range of 50:50 to 70:30 or 55:45 to 65:35. Tackiness increases as the amount of polydimethylsiloxane relative to the resin increases. High-viscosity silicone polymers preferably have a resin-to-polymer ratio of 55:45, medium-viscosity silicone polymers preferably have a resin-to-polymer ratio of 60:40, and low-viscosity silicone polymers preferably have a resin-to-polymer ratio of 65:35.

[0137] According to certain embodiments, the pressure-sensitive adhesive may be obtained by polycondensation of silanol-terminated polydimethylsiloxane and silicate resin, preferably with a resin-to-polymer ratio of 50:50 to 70:30, or 55:45, 60:40, or 65:35. Therefore, in preferred embodiments, the silicone polymer is a mixture of pressure-sensitive adhesives obtained by polycondensation of silanol-terminated polydimethylsiloxane and silicate resin, with a resin-to-polymer ratio of 55:45 or 60:40.

[0138] Furthermore, according to certain embodiments, the silicone polymer is The solution viscosity at 25°C and with a solid content of approximately 60% in heptane is 450 mPa·s and / or 0.01 rad / s, and the complex viscosity at 30°C is 1 × 10⁻⁶ 8 Poise, and The solution viscosity at 25°C and with a solid content of approximately 60% in heptane is 500 mPa·s and / or 0.01 rad / s, and the complex viscosity at 30°C is 5 × 10⁻⁶. 6 Poise It is a mixture of pressure-sensitive adhesives.

[0139] Polysiloxane-based pressure-sensitive adhesives are supplied and used in solvents such as n-heptane, ethyl acetate, or other volatile silicone fluids. The solids content of polysiloxane-based pressure-sensitive adhesives in solvents is typically 60–85%, 70–80%, or 60–75%. Those skilled in the art recognize that the solids content can be altered by adding an appropriate amount of solvent.

[0140] The high-viscosity silicone polymer preferably has a complex viscosity of about 5 × 10 at 0.01 rad / s and 30°C. 6 The poise, medium viscosity silicone polymer preferably has a complex viscosity of about 5 × 10 at 30°C and a viscosity of 0.01 rad / s. 7 The poise, low-viscosity silicone polymer preferably has a complex viscosity of about 5 × 10 at 30°C and a viscosity of 0.01 rad / s. 8It is a poise polymer. The high viscosity amine-compatible silicone polymer preferably has a complex viscosity of about 5 × 10 at 30°C and a viscosity of 0.01 rad / s. 6 The poise, medium viscosity amine-compatible silicone polymer preferably has a complex viscosity of about 5 × 10 at 30°C and a viscosity of 0.01 rad / s. 8 The poise, low-viscosity amine-compatible silicone polymer preferably has a complex viscosity of about 5 × 10 at 30°C and a viscosity of 0.01 rad / s. 9 It is poise. The preferred polysiloxane-based pressure-sensitive adhesive according to the present invention is characterized by a solution viscosity at 25°C and a solids content of 60% in n-heptane, which is preferably greater than about 150 mPa·s, or between about 200 mPa·s and about 700 mPa·s, measured using a Brookfield RVT viscometer with spindle #5 at 50 RPM. These also have a viscosity of about 1 × 10 at 0.01 rad / s at 30°C. 9 Less than poise, or approximately 1 x 10 5 ~Approx. 9×10 8 It may be characterized by Poise complex viscosity.

[0141] Suitable silicone polymers are commercially available under the trade name BIO-PSA. Examples of commercially available silicone 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 in n-heptane or ethyl acetate and are typically supplied. For example, BIO-PSA 7-4201 has a solution viscosity of 450 mPa·s at 25°C and in heptane with a solid content of approximately 60%, and a viscosity of 1 × 10⁻¹⁶ at 0.01 rad / s at 30°C. 8 It is characterized by the complex viscosity of Poise. BIO-PSA7-4301 has a solution viscosity of 500 mPas at 25°C and with a solid content of approximately 60% in heptane, and a viscosity of 5 × 10⁻⁶ at 0.01 rad / s at 30°C. 6 It has a complex viscosity in Poise.

[0142] A polysiloxane-based pressure-sensitive adhesive is obtained according to the following scheme. [ka] Such polysiloxane-based pressure-sensitive adhesives are available under the trade names Liveo® BIO-PSA7-4401, BIO-PSA7-4501, or BIO-PSA7-4601, supplied in the solvent n-heptane (indicated by code "01"), or under the trade names Liveo® BIO-PSA7-4402, BIO-PSA7-4502, and BIO7-4602, supplied in the solvent ethyl acetate (indicated by code "02"). Typical solids content in the solvent ranges from 60 to 75%. Code "44" indicates low viscosity with a resin-to-polymer ratio of 65:35, code "45" indicates medium viscosity with a resin-to-polymer ratio of 60:40, and code "46" indicates high viscosity with a resin-to-polymer ratio of 55:45.

[0143] A polysiloxane-based amine-compatible pressure-sensitive adhesive is obtained according to the following scheme. [ka] Such polysiloxane-based amine-compatible pressure-sensitive adhesives are available under the trade names Liveo® BIO-PSA7-4101, BIO-PSA-7-4201, or BIO-PSA7-4301, supplied in the solvent n-heptane (indicated by code "01"), or under the trade names Liveo® BIO-PSA7-4102, BIO-PSA7-4202, and BIO7-4302, supplied in the solvent ethyl acetate (indicated by code "02"). Typical solids content in the solvent ranges from 60 to 75%. Code "41" indicates low viscosity with a resin-to-polymer ratio of 65:35, code "42" indicates medium viscosity with a resin-to-polymer ratio of 60:40, and code "43" indicates high viscosity with a resin-to-polymer ratio of 55:45.

[0144] Silicone gel adhesive Silicone gel adhesives are elastic, gel-like materials formed from lightly crosslinked silicone polymers. Therefore, in contrast to the silicone polymers used herein, silicone gel adhesives are based on curable gel-forming compositions. Silicone gel adhesives provide adhesion of medical patches to the skin while simultaneously mitigating skin irritation. Furthermore, drug delivery of the medical patch is not adversely affected, and remarkably, skin permeability is improved.

[0145] Silicone gel adhesives, also known as silicone gels, are described, for example, in WO2011 / 022199A2.

[0146] Silicone gel adhesives are generally formed from linear or branched silicones having reactive groups. Such reactive groups undergo crosslinking reactions during curing. An example of a crosslinking reaction is hydrosilylation, in which a silicone having Si-H reactive groups reacts with a silicone having aliphatic unsaturated reactive groups in the presence of a hydrosilylation catalyst. These materials are described, for example, in US5,656,279, US5,891,076, EP0322118 and US4,991,574, which are incorporated herein by reference. An alternative reaction is condensation curing, in which an alkoxy and / or hydroxy-containing siloxane is cured with a catalyst, as described in US4,831,070, which is incorporated herein by reference.

[0147] Generally, 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 between SiH groups and Si-alkenyl groups. These compositions cure at normal ambient temperatures, but curing can be accelerated by heating to high temperatures, for example, 40-140°C, or by irradiation with UV light.

[0148] Suitable alkenyl groups include, but are not limited to, vinyl, allyl, and hexenyl groups, which comprise two to about six carbon atoms. The alkenyl groups in this component may be located at terminal, pendant (non-terminal), or both terminal and pendant positions. The remaining silicon-bonded organic groups in the alkenyl-substituted polydiorganosiloxane are independently selected from the group consisting of non-aliphatic unsaturated monovalent hydrocarbon groups and monovalent halogenated hydrocarbon groups. These groups typically comprise one to about 20 carbon atoms, or one to eight carbon atoms, and are not limited to, but are methyl, ethyl, propyl, and butyl alkyl groups; phenyl aryl groups; and 3,3,3-trifluoropropyl alkyl halides. Typically, at least 50% of the organic groups in the alkenyl-substituted polydiorganosiloxane are methyl. The structure of the alkenyl-substituted polydiorganosiloxane is typically linear, but may include some branching due to the presence of trifunctional siloxane units. The viscosity of the alkenyl-substituted polydiorganosiloxane can be any desired value. For example, 0 mm 2 / s super~100,000mm 2 / s, or 50mm 2 / s~80,000mm 2 / s, or 300mm 2 / s~3,000mm 2 It can be set to / s.

[0149] Methods for preparing the alkenyl-substituted polydiorganosiloxane (i) of the present invention, such as the condensation of the corresponding halosilane or the equilibration of the cyclic polydiorganosiloxane, are well known in the art.

[0150] Alkenyl-substituted polydiorganosiloxanes can be used in gel-forming compositions in amounts of 10% to 90% by weight, 40% to 90% by weight, or 50% to 80% by weight, 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 to 1% by weight, or 0.05 to 1% by weight, based on the weight of the alkenyl-substituted polydiorganosiloxane.

[0151] Organosiloxanes containing silicon-bonded hydrogen atoms (ii) are also known in the art, for example, as described 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 non-aliphatic unsaturated monovalent hydrocarbon groups and monovalent halogenated hydrocarbon groups. These groups typically contain one to about 20 carbon atoms, or one to eight carbon atoms, and include, but are not limited to, alkyl groups such as methyl, ethyl, propyl, and butyl; aryl groups such as phenyl; and alkyl halides such as 3,3,3-trifluoropropyl. In one embodiment of the present invention, at least 50% of the organic groups in the silicon-bonded hydrogen atom-containing organosiloxane are methyl. The structure of the silicon-bonded hydrogen atom-containing organosiloxane is typically linear, but may include some branching due to the presence of trifunctional siloxane units. The viscosity of organosiloxanes containing silicon-bonded hydrogen atoms can be any desired viscosity. For example, 0 mm 2 / s super~100,000mm 2 / s, or 5mm 2 / s~500mm 2 It can be set to / s.

[0152] Methods for preparing the silicon-bonded hydrogen atom-containing organosiloxanes of the present invention by appropriate co-hydrolysis of chlorosilanes are known in the art, and all of the following references are incorporated herein by reference: US Patent No. 2,877,255 to Clark; Japanese Laid Open Patent Application (KOKAI) SHO62 (1987)-39660 to Mogi et al.; and US Patent Nos. 5,446,185 and US No. 5,493,040 to Cobb et al.

[0153] Organosiloxanes containing silicon-bonded hydrogen atoms can be used in the gel-forming composition in amounts of 1% to 30% by weight, 5% to 20% by weight, or 5% to 15% by weight, 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 0.05% to 1.44% by weight, based on the weight of the organosiloxane containing silicon-bonded hydrogen atoms.

[0154] In the gel-forming composition, it is preferable that (i) and (ii) exist such that the ratio of (H as SiH):(alkenyl as Si-alkenyl) is generally in the range of 0.1:1 to 10:1.

[0155] Hydrosilylation catalysts (iii) facilitate the addition reaction between alkenyl-substituted polydiorganosiloxanes and organosiloxanes containing silicon-bonded hydrogen. Any known hydrosilylation catalysts can be used, including platinum group metals, compounds containing platinum group metals, or microencapsulated platinum group metals or compounds containing them. These platinum group metals include platinum, rhodium, ruthenium, palladium, osmium, and iridium. Platinum and platinum compounds are preferred catalysts due to their high activity in hydrosilylation reactions. One type of platinum catalyst is a complex of chloroplatinic acid and a specific vinyl-containing organosiloxane compound, disclosed by Willig in U.S. Patent No. 3,419,593 (incorporated herein by reference). A specific catalyst of this type is the reaction product of chloroplatinic acid and 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane.

[0156] The hydrosilylation catalyst is present in an amount sufficient to cure the composition of the present invention. Typically, the catalyst concentration is sufficient to provide platinum group metals in amounts of 0.1 ppm to 500 ppm (parts per million), or 1 ppm to 100 ppm, or 1 ppm to 50 ppm, based on the weights of (i) and (ii).

[0157] From the above viewpoint, in a preferred embodiment of the present invention, the silicone gel adhesive is obtained by reacting (i) a gel-forming composition comprising a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogenpolysiloxane having a trimethylsilyl terminal group and (iii) a platinum catalyst. Here, preferably, (i) and (ii) are present such that the ratio of (H as SiH):(alkenyl as Si-alkenyl) is generally in the range of 0.1:1 to 10:1.

[0158] An optional component is a hydroxy-substituted silicone resin described in U.S. Patent Application No. 2007-0202245, which is incorporated herein by reference. This resin is typically of formula R3 3SiO 1 / 2 Groups having ("M" groups) and formula SiO 4 / 2 It contains a group having ("Q" group), where R 3 The R groups are alkyl groups having 1 to 6 carbon atoms or alkylene groups having 1 to 6 carbon atoms, typically methyl or vinyl. When alkenyl groups are present in the resin, the mol-% of R groups present as alkenyl groups is typically less than 10 mol-% or 5 mol-%. The number ratio 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% to 5% by weight or 1.0% to 5% by weight of silicon-bonded hydroxyl groups.

[0159] The resin can be used in the gel-forming composition in an amount of 2% to 45% by weight, or 5% to 40% by weight, or 10% to 35% by weight, depending on the weight of the gel-forming composition and the resin.

[0160] Therefore, in a preferred embodiment, the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive containing about 2 to about 45% by weight of at least one hydroxyl-substituted silicate resin.

[0161] According to certain embodiments, the silicone gel adhesive is a two-component silicone adhesive system that hardens when two components are mixed. Examples of such commercially available two-component silicone adhesives include Liveo® Soft Skin Adhesives (MG7-9700, MG7-9800, MG7-9850, and MG7-9900, etc.), which are provided as a kit containing components A and B. This is a platinum-catalyzed, soft, filler-free elastomeric silicone adhesive for bonding medical devices to skin with moderate adhesion and mild release. The two components A and B are preferably mixed in a 1:1 ratio.

[0162] A silicone gel adhesive layer can be manufactured by processes known in the art. For example, the gel can be pre-formed (e.g., as a sheet) on a substrate such as a liner by molding, calendering, extrusion, spraying, brushing, hand application, casting, or coating. Alternatively, the silicone gel layer can be manufactured by applying a gel-generating composition to a substrate by spraying, coating, bar coating, etc. The gel-generating composition applied to the substrate is cured, and a silicone gel adhesive is formed on the substrate.

[0163] Polymers based on natural or synthetic rubber Examples of 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, polyacrylonitrile, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, polychlorodiene, and other halogen-containing polymers, as well as other copolymers thereof. These polymers may be used in combination with tackifiers, particularly as defined below.

[0164] According to certain embodiments, the polymer may be a styrene-based 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.

[0165] In certain embodiments, the polymer may be at least one SIS block copolymer. The at least one SIS block copolymer may consist of three blocks of polystyrene, polyisoprene, and polystyrene, and in particular have a molecular weight of about 100,000 to 200,000. In certain embodiments, the SIS block copolymer may contain polystyrene and polyisoprene blocks in a ratio of about 10:90% to about 30:70%, or about 15:85%, or about 22:78%.

[0166] In other embodiments, the polymer is at least one type of polyisobutylene, and may be a combination of two different types of polyisobutylene, particularly a combination of low molecular weight polyisobutylene and high molecular weight polyisobutylene. In certain embodiments, the ratio of low molecular weight polyisobutylene to high molecular weight polyisobutylene is in the range of 75:25 to 90:10.

[0167] A suitable SIS block copolymer according to the present invention is 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.

[0168] 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) may also be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene are in the range of 100:1 to 1:100, 95:5 to 40:60, or 90:10 to 75:25. Specific examples of polyisobutylene combinations are B10 / B100 in a ratio of 85 / 15, or B12 / B100 in a ratio of 80 / 20. Oppanol® B100 has a viscosity-average molecular weight Mv of 1,110,000, a weight-average molecular weight Mw of 1,550,000, and an average molecular weight distribution Mw / Mn of 2.9. Oppanol® B10 has a viscosity-average molecular weight Mv of 40,000, a weight-average molecular weight Mw of 53,000, and an average molecular weight distribution Mw / Mn of 3.2. Oppanol® B12 has a viscosity-average molecular weight Mv of 55,000, a weight-average molecular weight Mw of 70,000, and 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.

[0169] Further additives The medical patch according to the present invention, particularly the active drug-containing layer, may further contain at least one additive or excipient. The additive or excipient is preferably selected from the group consisting of crystallization inhibitors, solubilizers, fillers, skin care substances, pH adjusters, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers, particularly from crystallization inhibitors, skin care substances, tackifiers, softeners, stabilizers, and permeation enhancers. Such additives may be present in the active drug-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 drug-containing layer.

[0170] It should be noted that in pharmaceutical formulations, formulation components are classified according to their physicochemical and physiological properties, as well as their function. This means, in particular, that a substance or compound classified in one category may not be excluded from being classified in another category of formulation components. For example, a particular polymer may be both a crystallization inhibitor and a tackifier. Some substances may, for example, be typical emollients while simultaneously acting as permeability enhancers. Those skilled in the art can, based on general knowledge, determine which category(s) of formulation components a substance or compound belongs to. Details regarding excipients and additives are provided below, but these are not to be understood as being mutually exclusive. Other substances not expressly listed herein may also be used in accordance with the present invention, and substances and / or compounds expressly listed in one category of formulation components are not excluded from use as other formulation components in the sense of the present invention.

[0171] In certain embodiments, the medical patch, particularly the active drug-containing layer, may further contain a crystallization inhibitor. Suitable examples of crystallization inhibitors include polyvinylpyrrolidone, vinyl acetate / vinylpyrrolidone copolymers, and cellulose derivatives. The crystallization inhibitor is preferably polyvinylpyrrolidone, and more preferably soluble polyvinylpyrrolidone. The crystallization inhibitor may increase the solubility of capsaicin or inhibit the crystallization of capsaicin.

[0172] In certain embodiments, the medical patch, particularly the active drug-containing layer, further comprises a stabilizer, which is preferably selected from tocopherol and its ester derivatives, and ascorbic acid and its ester derivatives. Preferred stabilizers include sodium metabisulfite, ascorbyl esters of fatty acids such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopherol acetate, and tocopherol linoleate.

[0173] In certain embodiments, the medical patch, particularly the active drug-containing layer, further comprises a emollient / plasticizer. Exemplary emollient / plasticizers include linear or branched saturated or unsaturated alcohols, triglycerides, and polyethylene glycols having 6 to 20 carbon atoms.

[0174] In certain embodiments, the medical patch, particularly the active drug-containing layer, further comprises a solubilizer. The solubilizer preferably improves the solubility of capsaicin in the active drug-containing layer. Preferred solubilizers include, for example, glycerol esters, polyglycerol esters, propylene glycol esters, and polyoxyethylene esters of medium-chain and / or long-chain fatty acids, such as glyceryl monolinoleate, medium-chain glycerides and medium-chain triglycerides, nonionic solubilizers produced by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose, and their derivatives, such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and their derivatives; and nonionic triblocks having a central hydrophobic chain of polyoxypropylene adjacent to two hydrophilic chains of polyoxyethylene known as poloxamers. Copolymers; water-soluble derivatives of vitamin E; pharmaceutical-grade or aggregated spherical isomalt; polyester glycol, polyvinyl acetate, and polyvinyl caprolactam graft copolymers, also abbreviated as PVAc-PVCap-PEG and known as Soluplus®; refined grades of naturally derived castor oil, polyethylene glycol 400, polyoxyethylene sorbitan monooleate (such as polysorbate 80), or propylene glycol; diethylene glycol monoethyl ether; glucono-delta-lactone; corn and potato starch; and any of the soluble polyvinylpyrrolidones listed below, as well as insoluble / crosslinked polyvinylpyrrolidones such as crospovidone. However, permeation enhancers mentioned below can also act as solubilizers. Furthermore, crystallization inhibitors can also act as solubilizers.

[0175] In certain embodiments, the medical patch, particularly the active drug-containing layer, may further contain a pH adjuster. Suitable pH adjusters include mild acids and bases, including amine derivatives, inorganic alkali derivatives, and polymers having basic or acidic functionality.

[0176] In certain embodiments, the medical patch, particularly the active drug-containing layer, further comprises a preservative. Suitable preservatives include parabens, formaldehyde-releasing agents, isothiazolinone, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid, and anisic acid.

[0177] In certain embodiments, the medical patch, particularly the active agent-containing layer, may further contain skincare substances. Such substances may be used to avoid or reduce skin irritation detectable by a skin reaction score. Suitable skincare substances include sterol compounds such as cholesterol, deexpanthenol, α-bisabolol, and antihistamines.

[0178] Fillers such as silica gel, titanium dioxide, and zinc oxide may be used in combination with silicone polymers to influence specific physical parameters such as cohesiveness and bonding strength in a desired manner.

[0179] If the active agent-containing layer needs to be self-adhesive, and one or more polymers that do not provide sufficient self-adhesion are selected, a tackifier is added. The tackifier can be selected from polyvinylpyrrolidone (which can maintain the adhesion of the matrix layer due to its water-absorbing ability and can therefore be considered a tackifier in a broad sense), triglycerides, polyethylene glycol, dipropylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethylpolysiloxane and polybutene, preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.

[0180] In certain embodiments, the medical patch, particularly the active drug-containing layer, may further contain a permeability enhancer. The permeability enhancer is a substance that affects the barrier properties of the stratum corneum in the sense that it increases the permeability of the active drug. Examples of permeability enhancers include polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; aliphatic ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myrislate; urea and urea derivatives (such as allantoin); polar solvents such as dimethyldecyl phosphooxide, methyl cetyl sulfoxide, dimethylourarylamine, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethyl sulfoxide, decylmethyl sulfoxide, and dimethylformamide; and high molecular weight aliphatic surfactants such as salicylic acid, amino acids, benzyl nicotinate, and lauryl sulfate. Other drugs include oleic acid, linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate, tocopherol linoleate, propyl oleate, and isopropyl palmitate. If the active drug-containing layer further contains a permeation enhancer, the permeation enhancer is preferably selected from diethylene glycol monoethyl ether (Transcutol®), diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, and dimethylpropylene urea. The medical patch according to the present invention has been found to provide sufficient permeability of capsaicin even in the absence of a permeation enhancer. Therefore, in certain embodiments of the present invention, the active drug-containing layer does not contain a permeation enhancer.

[0181] Release characteristics The medical patches according to the present invention are designed to deliver capsaicin locally to produce a local effect at the site of action, or to deliver capsaicin transdermally into the systemic circulation for a predetermined period. Topical administration of capsaicin relies on diffusion into the skin itself and does not require transdermal release into the systemic circulation; however, in vitro skin penetration experiments still provide a suitable indicator of whether effective local release is occurring.

[0182] According to a specific embodiment, for the medical patch, the cumulative permeation amount of capsaicin measured by a Franz diffusion cell using excised human skin is 0.1 - 1.0 μg / cm 2 or about 0.3 μg / cm 2 and / or the skin permeation rate of capsaicin measured by a Franz diffusion cell using excised human skin is 0.06 μg / (cm 2 h) - 0.3 μg / (cm 2 h), or 0.2 μg / (cm 2 h) - 1.2 μg / (cm 2 h), or about 0.6 μg / (cm 2 h) after 60 minutes, is provided.

[0183] In a specific embodiment of the present invention, for the medical patch according to the present invention above, the skin permeation rate of capsaicin measured by a Franz diffusion cell using excised human skin is 0 μg / (cm 2 h) - 0.9 μg / (cm 2 h) in the first 60 minutes, 0.6 μg / (cm 2 h) - 1.2 μg / (cm 2 h) from 60 minutes to 90 minutes, 0.8 μg / (cm 2 h) - 1.4 μg / (cm 2 h) from 90 minutes to 120 minutes, 0.9 μg / (cm 2 h) - 1.6 μg / (cm 2 h) from 120 minutes to 240 minutes, is provided.

[0184] In a specific embodiment, the medical patch provides therapeutically effective skin permeation of capsaicin within less than 90 minutes or within less than 60 minutes after the medical patch is applied to the skin.

[0185] Therapeutic method / Medical use The medical patch according to the present invention is suitable for use in therapeutic methods, particularly in methods for treating human patients.

[0186] In certain embodiments, the medical patch according to the present invention is for use in a treatment method in which the medical patch is applied to the patient's skin for preferably 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 for use in a treatment method having an administration interval of at least about 1.5 months, at least about 2 months, or at least about 3 months. Therefore, it is preferable that the medical patch be applied only after a drug-free period of at least 90 days following the removal of a preceding medical patch.

[0187] In preferred embodiments, the medical patch according to the present invention is used in a method for treating neuropathic pain, particularly chronic neuropathic pain, which preferably includes postherpetic neuralgia, postoperative neuralgia (e.g., post-inguinal hernia pain, post-thoracotomy pain, or post-mastectomy pain), post-traumatic neuropathy, polyneuropathy (e.g., pain associated with diabetic neuropathy), chemotherapy-induced neuropathy, tumor-related neuropathy, HIV-related neuropathy, alcohol-related neuropathy, small-diameter fiber neuropathy or complex regional pain syndrome, radiculopathy, or compression syndromes such as carpal tunnel syndrome.

[0188] The medical patch according to the present invention is more preferably used in methods for treating peripheral neuropathic pain, postherpetic neuralgia of the hand and foot or neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain.

[0189] In certain embodiments, the medical patch according to the present invention is used in a method of treating neuropathic pain associated with postherpetic neuralgia or neuropathic pain associated with diabetic peripheral neuropathy of the hand or foot in human patients, particularly adults. In certain embodiments, the medical patch according to the present invention is used in a method of treating postoperative neuropathic pain in human patients, particularly adults.

[0190] In connection with the above, the medical patch according to the present invention is preferably applied to at least one body surface of a patient, particularly a body surface selected from the back, buttocks, legs, feet, or hands. The preferred application time for the medical patch according to the present invention is less than 60 minutes or about 60 minutes for the back, buttocks, or legs, and less than 30 minutes or about 30 minutes for the feet or hands.

[0191] In certain embodiments, the present invention also relates to a method for treating neuropathic pain, particularly chronic neuropathic pain, preferably peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia of the hand or foot or diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain, comprising applying a medical patch described herein to the skin of a patient.

[0192] Manufacturing process The medical patch according to the present invention can be manufactured using a process that includes the following steps. 1.1) Coating with an active agent-containing coating composition, wherein the composition is (i) Capsaicin and, (ii) comprising at least one silicone polymer, Coating the composition onto the first foil, coating, 1.2) Drying the coated coating composition to form an active agent-containing layer, 1.3) Laminating the active drug-containing layer with the backing layer, Includes.

[0193] The silicone polymer is preferably non-curable and is therefore typically applied by a solvent-based process. Accordingly, at least one silicone polymer is preferably supplied in a solvent, and the solids content in the solvent is preferably 40 to 75% by weight. The solvent is preferably selected from alcoholic solvents, particularly methanol, ethanol, isopropanol and mixtures thereof, and non-alcoholic solvents, particularly ethyl acetate, hexane, heptane, petroleum ether, toluene and mixtures thereof, more preferably selected from non-alcoholic solvents, most preferably ethyl acetate or n-heptane.

[0194] It is preferable that capsaicin is 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 preparation is dispersed in the active agent-containing coating composition in the form of droplets (microreservoir system). The amphiphilic solvent should not be mixed with the solvent for the silicone polymer, or may be mixed only slightly.

[0195] The coated active agent-containing coating composition is solidified by drying. Drying is preferably carried out at a temperature of 20-60°C or 30-40°C.

[0196] This process further involves the following steps: 2.1) Coating with an inactive coating composition, wherein the composition is (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) At least one organosiloxane containing a silicon-bonded hydrogen atom, (iii) comprising at least one catalyst for the reaction between a SiH group and a Si-alkenyl group, Coating the composition onto the second foil, coating, 2.2) Crosslinking the inactive coating composition at a temperature of 50°C to 150°C, or irradiating it with ultraviolet light to form a skin contact layer, 2.3) Laminating the skin contact layer with the release liner, It may include.

[0197] The inactive coating composition forms a silicone gel adhesive in the skin contact layer during curing, i.e., when the reactive groups of the silicone polymer are crosslinked. Crosslinking is preferably carried out at a temperature of 40 to 140°C.

[0198] The active agent-containing layer and the skin contact layer are preferably prepared separately as described above, then the foil is removed, and the two layers are laminated together by stacking the open sides to obtain the active agent-containing layer structure. Therefore, this process further involves the following steps: 3.1) Remove the foil from the active agent-containing layer and the skin contact layer, 3.2) Obtaining an active drug-containing layer structure by stacking the open side of the active drug-containing layer on the open side of the skin contact layer, It may include. The preparation of the active agent-containing layer may be performed before or after the preparation of the skin contact layer, or the preparation of the two layers may be performed in parallel. [Examples]

[0199] Next, the present invention will be described more fully with reference to the attached examples. However, it should be understood that the following description is illustrative only and should not be considered as limiting the present invention in any sense. The numerical values ​​provided in the examples regarding the amount or area weight of components in the composition may vary slightly due to manufacturing variations.

[0200] Example 1 and Reference Example For the medical patches of Example 1 and Reference Example, the skin penetration rate and utilization rate of capsaicin were measured by in vitro experiments.

[0201] The medical patch according to Example 1 is different from the medical patch according to the reference example by an additional skin contact layer. Therefore, the two medical patches were prepared in the same manner, except that the steps of preparing and coating the inactive coating composition and laminating the obtained inactive layer with the previously prepared capsaicin-containing layer were not performed in the reference example.

[0202] Capsaicin-containing coating composition For both Example 1 and the reference example, the formulation of the capsaicin-containing coating composition is summarized in Table 1.1 below. The solid content % values refer to the amount (Amt) in weight %.

[0203] [Table 1]

[0204] Preparation of capsaicin-containing coating composition Transcutol was first thickened with ethyl cellulose under stirring (100 - 300 rpm).

[0205] The polysiloxane mixture and silicone oil were placed in a container and stirred for at least 5 minutes (100 - 300 rpm) before adding the ethyl cellulose / Transcutol solution. After further stirring for 10 minutes (100 - 300 rpm), capsaicin was added. Then, the mixture was stirred at about 250 - 300 rpm until a homogeneous mixture was obtained (for at least 60 minutes).

[0206] Coating of capsaicin-containing coating composition The obtained capsaicin-containing coating composition was coated onto a fluoropolymer-coated polyester film (Scotchpak (trademark) 1022). The solvent was removed at room temperature over about 20 - 30 minutes.

[0207] The thickness of the coating was such that the areal weight of the capsaicin-containing layer was about 80 g / m by removal of the solvent2 I chose to make it so.

[0208] Next, the resulting capsaicin-containing microreservoir layer was laminated with a backing layer (polyester film, 19 μm).

[0209] Deactivating coating composition The formulation of the inactive coating composition for Example 1 is summarized in Table 1.2 below. The solids content % value refers to the amount in weight % (Amt).

[0210] [Table 2]

[0211] Preparation of an inactive coating composition Both components were weighed separately, and component A was added to a mixing container, followed by component B. The mixture was then mixed at approximately 100 rpm for about 10 minutes until a homogeneous mixture of component A and component B was obtained.

[0212] Coating of an inactive coating composition Within a time frame of approximately 30 minutes, the obtained inactive coating composition was coated onto an adhesive foil. The coating temperature was set to 120°C. The resulting inactive layer was heated at this temperature for approximately 40 minutes.

[0213] The coating thickness, after solvent removal, is approximately 230.0 g / m² for the inactive (skin contact) layer. 2 I chose to make it so.

[0214] The resulting inactive (skin-contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 125 μm).

[0215] Layers of capsaicin-containing layer and inactive (skin contact) layer. Next, an inactive (skin-contact) layer was laminated with the capsaicin-containing layer. For this purpose, the adhesive foil used for coating and drying the layers was removed, and the open sides of the resulting active-containing layer and inactive (skin-contact) layer were laminated together, resulting in a capsaicin-containing self-adhesive layer structure comprising a backing layer, a capsaicin-containing layer, and an inactive (skin-contact) layer. Here, the capsaicin-containing layer is bonded to the backing layer, the inactive (skin-contact) layer is bonded to the capsaicin-containing layer, and this structure is closed by a release liner bonded to the inactive (skin-contact) layer.

[0216] Preparation of medical patches Individual medical patches were punched out from the capsaicin-containing self-adhesive layer structure obtained as described above. The medical patches were then sealed in pouches made of primary packaging material.

[0217] Measurement of skin permeability The permeation rate of medical patches prepared according to Example 1 and Reference Example was measured by an in vitro experiment conducted using a 10.0 ml Franz diffusion cell in accordance with the OECD guidelines (adopted April 13, 2004). Split-thickness human skin (female abdomen, date of birth 1981) harvested during cosmetic surgery was used. Heat-separated epidermis was used for all medical patches. The emission area from the medical patch was 1.171 cm². 2 The die-cut was punched out. The amount of capsaicin that permeated through Franz cell receptor medium (0.9% sodium chloride solution containing 0.1% azide saline as an antibacterial agent) was measured at a temperature of 32±1℃, and the corresponding skin permeation rate was calculated.

[0218] The results are shown in Table 1.3 and Figure 1A.

[0219] [Table 3]

[0220] The corresponding skin permeation rate (Δflux rate) was calculated based on the respective permeation amounts.

[0221] The results are shown in Table 1.4 and FIG. 1B.

[0222] [Table 4] The above results show that, surprisingly, the skin permeation rate of the capsaicin medical patch of the present invention according to Example 1 is almost the same or slightly higher / faster compared to the same (reference example-based) patch without a skin contact layer. As outlined above, this means that the patch of the present invention can simply add a skin contact layer without changing the (approved) drug release behavior of the commercial product, based on the already approved and commercially available capsaicin patch, and is therefore very advantageous.

[0223] The present invention relates particularly to the following further clauses. 1. A medical patch for capsaicin administration comprising an active agent-containing layer structure, wherein the active agent-containing layer structure comprises A) a backing layer, and B) an active agent-containing layer comprising (i) capsaicin, and (ii) at least one silicone-based polymer, and an active agent-containing layer, C) a skin contact layer, and the skin contact layer is an adhesive layer containing Polymer II. The medical patch.

[0224] 2. The medical patch according to clause 1, wherein the Polymer II is a polymer or a mixture of polymers in which the capsaicin is substantially insoluble.

[0225] 3. The medical patch according to clause 1 or 2, wherein the Polymer II is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0226] 4. The medical patch according to any one of Clauses 1 to 3, wherein Polymer II is a polymer or mixture of polymers selected from the group consisting of silicone acrylic hybrid polymers, silicone polymers, silicone gel adhesives, and polymers based on natural rubber or synthetic rubber.

[0227] 5. The medical patch according to any one of Clauses 1 to 4, wherein Polymer II is a polymer or mixture of polymers selected from the group consisting of silicone polymers and silicone gel adhesives.

[0228] 6. The medical patch according to any one of Clauses 1 to 5, wherein the polymer II is a silicone gel adhesive.

[0229] 7. The medical patch according to Clause 6, wherein the silicone gel adhesive is obtained by reacting a gel-forming composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane containing a silicon-bonded hydrogen atom, and (iii) at least one catalyst for the reaction between the SiH group and the Si-alkenyl group.

[0230] 8. The medical patch according to Clause 6 or 7, wherein the silicone gel adhesive is obtained by reacting (i) a gel-forming composition comprising a copolymer of vinylmethylsiloxane and dimethylsiloxane, (ii) a methylhydrogenpolysiloxane having a trimethylsilyl terminal group, and (iii) a platinum catalyst.

[0231] 9. The medical patch according to any one of the clauses 6 to 8, wherein the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive containing about 2 to about 45% by weight of at least one hydroxyl-substituted silicate resin.

[0232] 10. The medical patch according to any one of the clauses 1 to 9, wherein the saturated concentration of capsaicin in the skin contact layer is less than 0.1% by weight, less than 0.05% by weight, less than 0.02% by weight, or less than 0.01% by weight.

[0233] 11. The area weight of the skin contact layer is 100 to 350 g / m². 2 , 150~320g / m 2 , or 180-280g / m 2 A medical patch as described in any one of clauses 1 to 10.

[0234] 12. The medical patch according to any one of the clauses 1 to 11, wherein the skin contact layer comprises at least 95% by weight, at least 99% by weight, or about 100% by weight of the polymer II, based on the total weight of the skin contact layer.

[0235] 13. The medical patch according to any one of the clauses 1 to 12, wherein the skin contact layer contains less than 0.1% by weight or less than 0.01% by weight of the capsaicin, based on the total weight of the skin contact layer.

[0236] 14. The medical patch according to any one of the clauses 1 to 13, wherein the active agent-containing layer comprises capsaicin in an amount of 2 to 20% by weight, 5 to 15% by weight, or 5 to 10% by weight.

[0237] 15. The medical patch according to Clause 14, wherein the active agent-containing layer comprises about 8% by weight of the capsaicin.

[0238] 16. The active agent-containing layer contains at least 0.30 mg / cm³ 2 at least 0.50 mg / cm³ 2 , or at least 0.60 mg / cm³ 2 A medical patch containing capsaicin, as described in any one of clauses 1 to 15.

[0239] 17. The active agent-containing layer contains 1.0 mg / cm³ 2 Less than 0.8 mg / cm³ 2 Less than 0.7 mg / cm³ 2 A medical patch containing less than 100% capsaicin, as described in any one of clauses 1 to 16.

[0240] 18. The medical patch described in any one of the clauses 1 to 17, comprising capsaicin in an amount of 0.5 to 180 mg, 1.2 to 90 mg, or 19 to 45 mg.

[0241] 19. The medical patch described in any one of the clauses 1 to 18, comprising capsaicin in an amount of approximately 179 mg, approximately 60 mg, approximately 45 mg, approximately 30 mg, approximately 25 mg, approximately 10 mg, or approximately 1 mg.

[0242] 20. The medical patch according to any one of the clauses 1 to 19, wherein the at least one silicone 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.

[0243] 21. The medical patch according to any one of Clauses 1 to 20, wherein the silicone polymer is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0244] 22. The medical patch according to Clause 21, wherein the pressure-sensitive adhesive is obtained by polycondensation of silanol-terminated polydimethylsiloxane and silicate resin, preferably having a resin-to-polymer ratio of 50:50 to 70:30, or 55:45, 60:40, or 65:35.

[0245] 23. The medical patch according to any one of Clauses 1 to 22, wherein the silicone polymer is a mixture of pressure-sensitive adhesives obtained by polycondensation of silanol-termined polydimethylsiloxane and silicate resin, and the resin-to-polymer ratio is 55:45 or 60:40.

[0246] 24. The silicone polymer is The solution viscosity at 25°C and with a solid content of approximately 60% in heptane is 450 mPa·s and / or 0.01 rad / s, and the complex viscosity at 30°C is 1 × 10⁻⁶ 8 Poise, and The solution viscosity at 25°C and with a solid content of approximately 60% in heptane is 500 mPa·s and / or 0.01 rad / s, and the complex viscosity at 30°C is 5 × 10⁻⁶. 6 A medical patch as described in any one of Clauses 1 to 23, which is a pressure-sensitive adhesive mixture that is a poise.

[0247] 25. The medical patch according to any one of Clauses 1 to 24, wherein the silicone polymer is an amine-compatible polysiloxane, preferably obtained by polycondensing a silanol-termined polydimethylsiloxane with a silicate resin, and then at least partially trimethylsilylating the remaining silanol functionality.

[0248] 26. The medical patch according to any one of Clauses 1 to 25, wherein the active agent-containing layer comprises diethylene glycol monoethyl ether, preferably in an amount of 10 to 25% by weight of diethylene glycol monoethyl ether.

[0249] 27. The medical patch according to any one of the clauses 1 to 26, wherein the active agent-containing layer comprises a thickening additive selected from the group consisting of cellulose derivatives, high molecular weight polyacrylic acid, and any mixture thereof.

[0250] 28. The medical patch according to any one of the clauses 1 to 27, wherein the active agent-containing layer comprises ethylcellulose, preferably in an amount of 0 to 2% by weight of ethylcellulose.

[0251] 29. The medical patch according to any one of the clauses 1 to 28, wherein the active agent-containing layer comprises silicone oil, preferably in an amount of 0 to 5% by weight of silicone oil.

[0252] 30. The area weight of the active agent-containing layer is 30 to 200 g / m². 2 , or 50-120g / m 2 A medical patch as described in any one of clauses 1 to 29.

[0253] 31. The medical patch according to any one of the clauses 1 to 30, wherein the backing layer is impermeable to capsaicin.

[0254] 32. The medical patch according to any one of the clauses 1 to 31, wherein the backing layer is made of a polyester film and its thickness is preferably 10 to 20 μm.

[0255] 33. The medical patch according to any one of the clauses 1 to 31, wherein the backing layer is made of an ethylene vinyl acetate copolymer.

[0256] 34. The medical patch according to any one of the clauses 1 to 33, wherein the skin contact layer does not contain capsaicin, and / or the medical patch further comprises a release liner.

[0257] 35. The medical patch according to any one of the clauses 1 to 34, wherein the skin contact layer is directly attached to the active agent-containing layer.

[0258] 36. The medical patch according to any one of the clauses 1 to 34, wherein the active agent-containing layer structure includes a membrane located between the active agent-containing layer and the skin contact layer, and the membrane is preferably a rate-limiting membrane.

[0259] 37. The active agent-containing layer structure has a hexagonal shape. The backing layer, the active agent-containing layer, and the skin contact layer have the same extent and provide the hexagonal shape of the active agent-containing layer structure. The aforementioned hexagonal shape includes at least one hexagon, All pairs of opposite sides of the aforementioned hexagon are parallel. A medical patch according to any one of Clauses 1 to 36, wherein the sides of the hexagon have a length of 1.5 to 10 cm.

[0260] 38. The medical patch according to Clause 37, wherein the at least one hexagon is at least one convex hexagon.

[0261] 39. The medical patch according to Clause 38, wherein the hexagonal shape includes one or two convex hexagons.

[0262] 40. The medical patch according to any one of the clauses 37 to 39, wherein the hexagonal shape is a convex hexagon.

[0263] 41. The medical patch according to any one of the clauses 37 to 40, wherein the hexagonal shape is a double hexagon formed from two identical convex hexagons that share two adjacent vertices and a common edge.

[0264] 42. The medical patch as described in Clause 41, wherein the common edge is perforated to facilitate separation.

[0265] 43. The aforementioned medical patch is The cumulative permeation of capsaicin, measured using a Franz diffusion cell with human skin samples, was 0.1–1.0 μg / cm³ over a period of approximately 60 minutes. 2 Or approximately 0.3 μg / cm³ 2 Being, and / or The skin penetration rate of capsaicin, measured using a Franz diffusion cell with human skin samples, was found to be 60 minutes later. 0.06 μg / cm³ 2 h) ~0.3 μg / (cm 2 h), or 0.2 μg / (cm³) 2 h) ~ 1.2 μg / (cm 2 h), or approximately 0.6 μg / (cm³) 2 h) that, A medical patch provided as described in any one of clauses 1 to 42.

[0266] 44. The medical patch is a topical medical patch, as described in any one of the clauses 1 to 43.

[0267] 45. The medical patch is a transdermal treatment system, as described in any one of Clauses 1 to 43.

[0268] 46. ​​The medical patch showed that the skin penetration rate of capsaicin, as measured using a Franz diffusion cell with human skin collected from the skin, 0 μg / cm³ in the first 60 minutes 2 h) ~0.9 μg / (cm 2 h), 0.6 μg / cm³ in 60-90 minutes 2 h) ~ 1.2 μg / (cm 2 h), 0.8 μg / cm³ in 90-120 minutes 2 h) ~1.4 μg / (cm 2 h), 0.9 μg / cm³ at 120-240 minutes 2 h) ~1.6 μg / (cm 2 h), A medical patch as described in any one of clauses 1 to 45, which provides the following:

[0269] 47. A medical patch as described in any one of Clauses 1 to 46, used in a method for treating neuropathic pain, particularly chronic neuropathic pain, preferably in a method for treating peripheral neuropathic pain, postherpetic neuralgia of the hand and foot or neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain.

[0270] 48. Use of any one of the medical patches described in any one of Clauses 1 to 46 for the manufacture of medicines for treating neuropathic pain, particularly chronic neuropathic pain, and preferably for the manufacture of medicines for treating peripheral neuropathic pain, postherpetic neuralgia of the hand or foot or neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain.

[0271] 49. A method for treating neuropathic pain, particularly chronic neuropathic pain, preferably peripheral neuropathic pain, postherpetic neuralgia of the hand or foot, neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain, The method comprising applying a medical patch described in any one of clauses 1 to 46 to the patient's skin.

[0272] 50. A medical patch for administering capsaicin comprising an active drug-containing layer structure, wherein the active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin and, (ii) at least one silicone polymer, The active agent-containing layer includes, C) a skin contact layer; Includes, The medical patch for administering capsaicin, wherein the skin contact layer is an adhesive layer containing a silicone gel adhesive.

[0273] 51. A medical patch for administering capsaicin comprising an active drug-containing layer structure, wherein the active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin in an amount of 5-10% by weight, (ii) At least one amine-compatible polysiloxane in an amount of 60-90% by weight, (iii) 10 to 25% by weight of diethylene glycol monoethyl ether, (iv) Ethyl cellulose in an amount of 0-2% by weight, (v) Silicone oil in an amount of 0-5% by weight, The active agent-containing layer includes, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing a silicone gel adhesive. The silicone gel adhesive is obtained by reacting (i) a gel-forming composition comprising a copolymer of vinylmethylsiloxane and dimethylsiloxane, and (ii) a methylhydrogenpolysiloxane having a trimethylsilyl terminal group, in the presence of a platinum catalyst, in the medical patch for administering capsaicin.

[0274] 52. A medical patch for administering capsaicin, comprising an active drug-containing layer structure, wherein the active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin in an amount of approximately 8% by weight, (ii) At least one amine-compatible polysiloxane in an amount of 60-90% by weight, (iii) 10 to 25% by weight of diethylene glycol monoethyl ether, (iv) Ethyl cellulose in an amount of 0-2% by weight, (v) Silicone oil in an amount of 0-5% by weight, The active agent-containing layer includes, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing a silicone gel adhesive. The silicone gel adhesive is obtained by reacting (i) a gel-forming composition comprising a copolymer of vinylmethylsiloxane and dimethylsiloxane, and (ii) a methylhydrogenpolysiloxane having a trimethylsilyl terminal group, in the presence of a platinum catalyst, in the medical patch for administering capsaicin.

Claims

1. A medical patch for administering capsaicin, comprising an active drug-containing layer structure, wherein the active drug-containing layer structure is A) Backing layer, B) An active agent-containing layer, (i) Capsaicin and, (ii) at least one type of silicone polymer, The active agent-containing layer includes, C) a skin contact layer; Includes, The skin contact layer is an adhesive layer containing polymer II. The aforementioned medical patch.

2. The medical patch according to claim 1, wherein polymer II is a polymer or mixture of polymers selected from the group consisting of silicone acrylic hybrid polymers, silicone-based polymers, silicone gel adhesives, and polymers based on natural rubber or synthetic rubber, particularly 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 is obtained by reacting a gel-forming composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane containing a silicon-bonded hydrogen atom, and (iii) at least one catalyst for the reaction between the SiH group and the Si-alkenyl group.

5. The medical patch according to claim 3 or 4, wherein the silicone gel adhesive is obtained by reacting (i) a gel-forming composition comprising a copolymer of vinylmethylsiloxane and dimethylsiloxane, (ii) a methylhydrogenpolysiloxane having a trimethylsilyl terminal group, 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 about 2 to about 45% by weight 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 capsaicin in the skin contact layer is less than 0.1% by weight, less than 0.05% by weight, less than 0.02% by weight, or less than 0.01% by weight.

8. The area weight of the skin contact layer is 100 to 350 g / m². ２ , 150-320g / m ２ , or 180-280 g / m ２ The medical patch according to any one of claims 1 to 7.

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

10. The active agent-containing layer contains at least 0.30 mg / cm³ ２ at least 0.50 mg / cm³ ２ , or at least 0.60 mg / cm³ ２ It contains capsaicin, The active agent-containing layer is less than 1.0 mg / cm ２ less than, less than 0.8 mg / cm ２ less than, or less than 0.7 mg / cm ２ The medical patch according to any one of claims 1 to 9, containing capsaicin less than.

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

12. The area weight of the active agent-containing layer is 30 to 200 g / m². ２ , or 50-120 g / m ２ A medical patch according to any one of claims 1 to 11.

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

14. The medical patch according to any one of claims 1 to 12, wherein the active agent-containing layer structure includes a membrane located between the active agent-containing layer and the skin contact layer, and the membrane is preferably a rate-limiting membrane.

15. The aforementioned medical patch is The cumulative permeation of capsaicin, measured using a Franz diffusion cell with human skin samples, was 0.1–1.0 μg / cm³ over a period of approximately 60 minutes. ２ Or approximately 0.3 μg / cm³ ２ Being, and / or The skin penetration rate of capsaicin, measured using a Franz diffusion cell with human skin samples, was 0.06 μg / cm³ after 60 minutes. ２ h) ~0.3μg / (cm ２ h), or 0.2 μg / (cm ２ h) ~1.2μg / (cm ２ h), or approximately 0.6 μg / (cm³) ２ h) that A medical patch according to any one of claims 1 to 14, which provides...

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 treatment system.

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

18. Use of the medical patch according to any one of claims 1 to 16 for the manufacture of a drug for treating neuropathic pain, particularly chronic neuropathic pain, and preferably for the manufacture of a drug for treating peripheral neuropathic pain, postherpetic neuralgia of the hand or foot or neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain.

19. A method for treating neuropathic pain, particularly chronic neuropathic pain, preferably peripheral neuropathic pain, postherpetic neuralgia of the hand or foot, neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, arthralgia, or cancer pain, The method comprising applying a medical patch according to any one of claims 1 to 16 to the skin of a patient.

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