Hexagonal self-adhesive layer structure

Abstract

The present invention relates to a self-adhesive layer structure for use in a medical patch having a hexagonal shape comprising at least one hexagon, a medical patch and a medical patch sheet comprising such a self-adhesive layer structure(s), as well as such a medical patch for use in a treatment method, and a manufacturing process for such a medical patch.

Description

[Technical Field]

[0001] The present invention relates to a self-adhesive layer structure for use in a medical patch having a hexagonal shape containing at least one hexagon. The present invention also relates to a medical patch comprising the self-adhesive layer structure, and a medical patch sheet comprising two or more of the self-adhesive layer structures. [Background technology]

[0002] Medical patches are adhesive patches that are placed on a patient's skin to deliver specific amounts of medication through the skin.

[0003] For thousands of years, drugs have been applied topically to the skin to treat local conditions. Recently, transdermal delivery techniques have been developed to treat various conditions beyond the local application site. While local delivery of compounds and / or drugs involves minimal penetration into the skin layers, thereby avoiding systemic effects, transdermal drugs refer to pharmaceutical compounds that are applied to the skin but pass through the outermost layer of the skin (skin barrier) to enter the bloodstream and / or to benefit more distant tissues or organs.

[0004] Therefore, the body site to which a medical patch is applied may vary depending on the therapeutic class of the drug contained therein. The site to which a systemically effective transdermal medical patch is applied typically includes a large, flat surface, such as the patient's upper arm, chest, or back. In contrast, a topical medical patch must be applied to the site of the symptom to be treated, such as the patient's hand or foot. Such application sites are particularly challenging due to their uneven surface and complexity, and the shape and size of the medical patch must be taken into consideration.

[0005] However, medical patches, especially topical medical patches, are generally only available as large patches that must be trimmed based on the application site and / or are rarely able to be applied without wrinkles to completely and seamlessly cover the application site. This requires a great deal of time and requires the applicator to have high adhesive skills. Wrinkles are undesirable because they not only affect the comfort and aesthetics of the application site, but also reduce the contact area, which can reduce the availability of active ingredients and the adhesiveness of the patch. Furthermore, trimming or cutting a patch carries the risk of contamination, as the active agent-containing adhesive layer may come into contact with the cutting tool and / or the hands of the person handling the patch.

[0006] For example, the 8% capsaicin patch skin delivery system marketed under the trade name QUTENZA® (Gruenenthal) is recommended to be cut to fit the size and shape of the treatment area. Originally, QUTENZA® covers a rectangular area measuring 14 cm x 20 cm. This topical system is indicated for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) in adults and neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet, and has recently been approved for use in adults for the treatment of postoperative neuropathic pain (PSNP). Therefore, it is often applied to the hands and fingers or lower legs and feet, and therefore must be trimmed to fit small, uneven surfaces.

[0007] It is therefore desirable to provide a self-adhesive layer structure for a medical patch that provides easy coverage of the skin area to be treated, especially over uneven surfaces that are difficult to apply. Summary of the Invention

[0008] It is an object of the present invention to provide a self-adhesive layer structure for a medical patch that is improved compared to patches described in the prior art.

[0009] It is a further object of the present invention to provide a self-adhesive layer structure for a medical patch that provides easy and time-efficient handling.

[0010] It is a further object of the present invention to provide a self-adhesive layer structure for a medical patch that allows for easy coverage of the application site. In particular, this object is to provide a self-adhesive layer structure for a medical patch that allows for easy coverage of an uneven application site without the need to cut the medical patch before application. In particular, this object is to provide a self-adhesive layer structure for a medical patch that is improved in that it facilitates seamless and complete coverage of the application site.

[0011] It is a further object of the present invention to provide a self-adhesive layer structure for a medical patch that reduces wrinkles during application, and in particular, to provide a self-adhesive layer structure for a medical patch that provides complete adhesion even to complex skin areas.

[0012] It is a further object of the present invention to provide a self-adhesive layer structure for a medical patch that is easy to wrap around a finger or toe.

[0013] It is also an object of the present invention to provide a self-adhesive layer structure for a medical patch that allows for coverage of a larger skin area without leaving gaps.

[0014] These and other objects are achieved by the present invention, which, according to one aspect, relates to a self-adhesive layer structure for use in a medical patch, the self-adhesive layer structure having a hexagonal shape, A) a backing layer; B) an active layer comprising polymer I and an active agent; the backing layer and the active layer are coextensive, providing a hexagonal shape for the self-adhesive layer structure; the hexagonal shape includes at least one hexagon; All pairs of opposite sides of the hexagon are parallel, The sides of the hexagon have a length of 0.2 to 10 cm.

[0015] It has surprisingly been found that the self-adhesive layer structure according to the invention, having a hexagonal shape with at least one hexagon having a length of 0.2 to 10 cm, has advantageous properties in that it improves coverage of small and / or uneven application areas on the human body. In particular, it has been found that the hexagonal shape makes it possible to simplify application and reduce wrinkles, without the need to cut the medical patch before application. The medical patch is therefore also suitable for problematic application areas, such as the hands or feet.

[0016] According to a particular embodiment of the present invention, the present invention relates to a medical patch, the medical patch comprising: a self-adhesive layer structure as described herein; a release liner; The release liner may be coextensive with the self-adhesive layer structure or may extend beyond the boundaries of the self-adhesive layer structure in all directions.

[0017] According to a particular embodiment of the present invention, the present invention relates to a medical patch sheet, the medical patch sheet comprising: two or more self-adhesive layer structures as described herein; a release liner; The release liner may be coextensive with the self-adhesive layer structure or may extend in all directions beyond the boundary formed by the self-adhesive layer structure.

[0018] definition Within the meaning of the present invention, the term "medical patch" refers to a transdermal delivery system through which an active agent is administered to a patient, comprising an effective amount of an active agent in a self-adhesive layer structure located on a removable protective layer (release liner). In this context, the term "medical patch" is understood to mean an adhesive patch that can be a topical medical patch or a transdermal therapeutic system (TTS). Even though topical medical patches and TTS 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 the active agent 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 an active agent is administered to the systemic circulation via transdermal delivery.

[0019] Within the meaning of the present invention, the term "self-adhesive layer structure" refers to an active agent-containing structure that provides a release area for the active agent during administration. Because it is "self-adhesive", it usually provides adhesion to the skin so that no additional support is required for fixing to the skin. The self-adhesive layer structure, as described herein, optionally includes a skin contact layer in addition to a backing layer and an active layer. Thus, the self-adhesive layer structure contains an effective amount of the active agent.

[0020] As used herein, the term "active agent" refers to a substance of interest that is delivered by the self-adhesive layer structure and provides a beneficial or desired effect on a subject's bodily symptoms, either systemically or locally, at the delivery site. Active agents, in particular, include biologically or pharmacologically active compounds, which may also be referred to as actives, drug substances, drugs, active ingredients, active pharmaceutical ingredients (APIs), etc. In this context, the term "effective amount" or "therapeutically effective amount" refers to the amount of active agent in the self-adhesive layer structure sufficient to provide a desired (therapeutic) effect, such as pain relief / relief, when administered to a patient by a medical patch. TTSs typically contain more active agent in the system than is actually delivered to the skin or systemic circulation; this is typically necessary to provide sufficient driving force for delivery from the TTS to the systemic circulation.

[0021] Within the meaning of the present invention, terms such as "active," "active agent," and the like refer to an active agent in a pharmaceutically acceptable chemical and morphological form and physical state. These forms include, but are not limited to, the active agent in free base / free acid form, protonated or partially protonated form, deprotonated or partially deprotonated form, salts, co-crystals, acid / base addition salts formed by addition of inorganic or organic acids / bases, such as hydrochlorides or tartrates, solvates, hydrates, clathrates, complexes, and the like. Also included are active agents in the form of particles, which may be micronized, crystalline, and / or amorphous, and mixtures of any of the foregoing forms.

[0022] The active agent contained in a vehicle such as a solvent may be dissolved or dispersed, or may be partially dissolved and partially dispersed.

[0023] When it is stated that an active agent is used in a specific form in the manufacture of a medical patch, this does not exclude interactions, such as salt formation or complex formation, between this form of the active agent and other components of the self-adhesive layer structure in the final medical patch. This means that even if the active agent is included in its free base / acid form, it may be present in the final medical patch in a protonated or partially protonated / or deprotonated or partially deprotonated form, or in the form of an acid addition salt, or if included in a salt form, a portion of it may be present as a free base in the final medical patch. Unless otherwise specified, the amount of active agent in the self-adhesive layer structure refers to the amount of active agent included in the medical patch during manufacture of the medical patch and is calculated based on the active agent itself, ignoring other forms. The active agent starting material included in the medical patch during manufacture of the medical patch may be in the form of particles. The active agent may, for example, be present in the self-adhesive layer structure in the form of particles and / or may be dissolved.

[0024] In this context, the term "particle" refers to a solid, particulate material containing individual particles whose size is negligible compared to the material. In particular, particles are solids, including plastic / deformable solids, including amorphous and crystalline materials. The term "dispersion" refers to a step or combination of steps in which the starting material (e.g., active agent) is not completely dissolved. Dispersion in the sense of the present invention includes the dissolution of a portion of the starting material (e.g., active agent particles), depending on the solubility of the starting material (e.g., the solubility of the active agent in the coating composition).

[0025] There are two main types of medical patches that use (passive) active agent delivery: matrix-type medical patches and reservoir-type medical patches. The release of the active agent in a matrix-type medical patch is primarily controlled by the matrix containing the active agent itself. In contrast, a reservoir-type medical patch typically requires a rate-limiting membrane to control the release of the active agent. In principle, a matrix-type medical patch may also include a rate-limiting membrane. However, matrix-type medical patches have the advantage over reservoir-type medical patches in that they typically do not require a rate-determining membrane and do not suffer from dose dumping due to membrane rupture. In summary, matrix-type medical patches are less complicated to manufacture and easier and more convenient to use.

[0026] In this context, a "matrix-type medical patch" is understood to mean a system or structure in which an active agent is homogeneously dissolved and / or dispersed within a polymeric carrier, i.e., a matrix, forming a matrix layer together with the active agent and any remaining ingredients. In such a system, the matrix layer controls the release of the active agent from the medical patch. Preferably, the matrix layer has sufficient cohesion to be self-supporting so that sealing between other layers is not required. Thus, the active layer may be an active matrix layer, in which the active agent is homogeneously distributed within the polymer matrix. The active matrix layer may also include two active agent-containing matrix layers, which may be laminated together. A matrix-type medical patch may also be in the form of a "drug-in-adhesive" type medical patch, which specifically refers to a system in which the active agent is homogeneously dissolved and / or dispersed within a pressure-sensitive adhesive matrix. In this context, the active matrix layer may be an active pressure-sensitive adhesive layer or an active pressure-sensitive adhesive matrix layer. Medical patches in which the active agent is dissolved and / or dispersed within a polymer gel, e.g., a hydrogel, are also considered to be matrix-type in accordance with the present invention.

[0027] A medical patch having a liquid active agent-containing reservoir is referred to as a "reservoir-type medical patch." In such a system, the release of the active agent is preferably controlled by a rate-limiting membrane. In particular, the reservoir is sealed between a backing layer and a rate-limiting membrane. Thus, the active layer may be an active reservoir layer, preferably containing a liquid reservoir containing an active agent, and the active reservoir layer and the skin-contacting layer may be separated by a rate-limiting membrane. In the active reservoir layer, the active agent is preferably dissolved in a solvent such as ethanol or water, or silicone oil.

[0028] A reservoir-type medical patch is not understood to be a matrix-type within the meaning of the present invention. However, a microreservoir-type medical patch (a two-phase system having deposits (e.g., spheres, droplets) of an inner active agent-containing phase dispersed in an outer polymer phase), which is considered in the art to be a hybrid form of a matrix-type medical patch and a reservoir-type medical patch, which differs from a homogeneous single-phase matrix-type medical patch and a reservoir-type medical patch in the concept of drug transport and drug delivery, is considered to be a matrix-type within the meaning of the present invention.

[0029] Thus, a microreservoir-type medical patch refers to a microreservoir system in which a liquid active agent formulation is dispersed in the form of small droplets ("microreservoirs") in an adhesive matrix. The size of the resulting droplets depends on the stirring conditions and the shear force applied during stirring. The size can be determined by optical microscopy (e.g., with a Leica MZ16 equipped with a camera such as a Leica DSC320) by taking photographs of the microreservoirs at different positions at magnifications between 10x and 400x, depending on the required detection limit. Image analysis software can be used to determine the size of the microreservoirs. Microreservoir systems are disclosed in U.S. Patent Nos. 3,946,106, 4,053,580, 4,814,184, and 5,145,682, the disclosures of each of which are incorporated herein by reference. Particular microreservoir systems are described in International Patent Publication No. WO 0101967, the disclosure of which is incorporated herein by reference. These microreservoir systems include polysiloxane as the base polymer and an amphiphilic solvent for the microreservoir droplets.

[0030] The self-adhesive layer structure may be a pressure-sensitive adhesive layer structure.

[0031] Within the meaning of the present invention, the term "pressure-sensitive adhesive" (also abbreviated as "PSA") refers to a material that adheres, especially with finger pressure, is permanently tacky, exerts strong holding power, and can be removed from smooth surfaces without leaving any residue. This can be obtained from a solvent-containing adhesive coating composition after application onto a film and evaporation of the solvent (e.g., n-heptane or ethyl acetate). In this context, the term "solvent" is understood to mean any liquid substance, preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene, and mixtures thereof. The pressure-sensitive adhesive layer becomes self-adhesive when in contact with the skin. According to a specific embodiment, the self-adhesive layer structure according to the present invention comprises a pressure-sensitive adhesive layer for skin contact, which can be provided in the form of a pressure-sensitive adhesive matrix or in the form of an additional layer, i.e., a pressure-sensitive adhesive skin-contact layer. An adhesive overlay can still be used to improve adhesion.

[0032] Within the meaning of the present invention, the term "active layer" refers to a layer that contains an active agent (active agent-containing layer) and provides a release area. This term encompasses active agent-containing reservoir layers (active reservoir layers) and active agent-containing matrix layers (active matrix layers), particularly active agent-containing microreservoir layers (active microreservoir layers). When the active layer is an active matrix layer, such a layer is present in a matrix-type medical patch. As used herein, the active layer is preferably an active matrix layer and refers to the final solidified layer obtained after coating and drying, for example, a solvent-containing coating composition as described herein. Alternatively, the active matrix layer is obtained after melt coating and cooling. The active matrix layer may also be produced by laminating two or more such solidified layers (e.g., dried or cooled layers) of the same composition to provide a desired areal weight. According to certain embodiments, the matrix layer is a pressure-sensitive adhesive matrix layer.

[0033] Within the meaning of the present invention, the term "skin contact layer" refers to a layer that may be included in a self-adhesive layer structure that directly contacts the patient's skin during administration. In this case, other layers of the self-adhesive layer structure do not contact the skin and are not necessarily self-adhesive. The skin contact layer may be directly attached to the active layer, or a membrane may be disposed between the active layer and the skin contact layer. In this context, the term "membrane" is understood to mean a layer disposed between the active layer and the skin contact layer that is at least semi-permeable to the active agent. The membrane may be a microporous membrane or a non-porous partition membrane. Preferred membranes may be selected from the group consisting of polyethylene membranes, polyurethane-coated polyethylene terephthalate / polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate membranes. The additional skin contact layer is preferably present as an adhesive layer.

[0034] Within the meaning of the present invention, the term "backing layer" refers to a layer that supports the active layer. At least one backing layer in the self-adhesive layer structure of a medical patch, and typically the backing layer of the active layer, is substantially impermeable to the active agent contained therein and any additives during storage and administration, thus preventing activity loss or cross-contamination in accordance with regulatory requirements. According to certain embodiments, the backing layer is also occlusive, meaning 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. Suitable backing layers may be siliconized to improve adhesion between the active layer and the backing layer.

[0035] Additionally, 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 an active agent, has a larger area than the self-adhesive layer structure, and provides an additional area for adhesion to the skin but does not provide a release area for the active agent. This improves the overall adhesiveness of the self-adhesive layer structure of the medical patch. The area of ​​the adhesive overlay adds to the overall size of the medical patch but does not add to the release area. The adhesive overlay may comprise a self-adhesive polymer or a self-adhesive polymer mixture selected from the group consisting of acrylic polymers, polyisobutylene, styrene-isoprene-styrene copolymers, polysiloxanes, and mixtures thereof, which may be the same or different from any polymer or polymer mixture contained in the self-adhesive layer structure. The adhesive overlay comprises a backing layer, which may provide occlusive or non-occlusive properties, and an adhesive layer. According to certain embodiments, the backing layer of the adhesive overlay provides non-occlusive properties.

[0036] Within the meaning of the present invention, the term "areal weight" means g / m 2 Refers to the dry weight of a particular layer, e.g., the active layer, provided in units. Area weight values ​​are subject to a tolerance of ±10%, ±7.5%, or ±5% due to manufacturing variations.

[0037] Unless otherwise indicated, "%" means % by weight.

[0038] Within the meaning of the present invention, the term "polymer" (e.g., polymer I or II) refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, including homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. The polymer may be of any structure, such as a linear polymer, a star polymer, a comb polymer, a brush polymer, or any monomer arrangement in the case of a copolymer, e.g., alternating, statistical, block copolymer, or graft polymer. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. The polymer may have a molecular weight of, for example, more than 2000 daltons, more than 5000 daltons, or more than 10,000 daltons. Correspondingly, compounds with a molecular weight of less than 2000 daltons, less than 5000 daltons, or less than 10,000 daltons are usually called oligomers.

[0039] Within the meaning of the present invention, the term "silicone-based polymer" refers to a non-hybrid polymer (i.e., a polymer that does not contain hybrid species) that contains polysiloxane. Polysiloxanes can be prepared from a solvent-free two-component system or from a solution in an organic solvent. There are two fundamentally different types of polysiloxanes: polysiloxanes with free silanol groups and amine-resistant polysiloxanes, which are distinguished by the fact that the free silanol groups are derivatized with trimethylsilyl groups. The methyl groups can be fully or partially substituted with other alkyl or phenyl radicals. As used herein, polysiloxanes are synthesized from linear difunctional oligomers and branched polyfunctional oligomers, the ratio of which determines the physical properties. A higher content of polyfunctional oligomers results in a higher degree of crosslinking, higher cohesion, and lower adhesion, while a lower content of polyfunctional oligomers results in higher adhesion and lower cohesion. The silicone-based polymer is preferably a mixture of high-viscosity and medium-viscosity polysiloxanes, or high-viscosity and low-viscosity polysiloxanes. According to certain embodiments, the at least one silicone-based polymer is a silicone-based pressure-sensitive adhesive.

[0040] Within the meaning of the present invention, the term "acrylic polymer" refers to a non-hybrid polymer based on acrylates, which may be a polymer obtained from one or more monomers selected from acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, butyl methacrylate, t-octylacrylamide, and vinyl acetate.

[0041] Within the meaning of the present invention, the term "silicone-acrylic hybrid polymer" refers to a hybrid polymer based on silicone and acrylate in the form of a pressure-sensitive adhesive. Silicone-acrylic hybrid pressure-sensitive adhesives are described, for example, in EP2599847 and WO2016 / 130408. It has been found that depending on the solvent in which the silicone-acrylic hybrid PSA is supplied, the arrangement of the silicone and acrylic phases differs, providing a continuous silicone or acrylic external phase and a corresponding discontinuous internal phase. When the silicone-acrylic hybrid PSA is supplied in n-heptane, the composition comprises a continuous silicone external 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 external phase and a discontinuous silicone internal phase.

[0042] Within the meaning 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. It includes hydrocarbon polymers, such as natural and synthetic polyisoprene, polybutylene, polyisobutylene, styrene / butadiene polymers, styrene-isoprene-styrene block copolymers, butyl rubber, polyacrylonitrile, halogen-containing polymers, such as polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, polychlorodiene, and other copolymers thereof. In certain embodiments, the natural or synthetic rubber may be a styrene triblock copolymer or polyisobutylene.

[0043] Within the meaning of the present invention, the term "polyisobutylene" refers to a polymer obtained by polymerization of isobutene.

[0044] Within the meaning of the present invention, the term "styrene-isoprene-styrene block copolymer" refers to a polymer obtained by living ionic copolymerization by sequentially introducing styrene, 2-methyl-1,3-butadiene (isoprene), and styrene into a reactor. The styrene content usually varies between 15 and 40%.

[0045] Within the meaning of the present invention, the term "silicone gel adhesive" refers to an elastic, jelly-like material formed by lightly crosslinking a silicone polymer. It can be prepared from a gel-forming composition, 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, which react with each other in the presence of a hydrosilylation catalyst. According to certain embodiments, silicone gel adhesives are based on a polydimethylsiloxane network, which can be formed by the addition reaction (hydrosilylation) of a vinyl-functional polydimethylsiloxane group (polymer) with a hydrogen-functional siloxane (crosslinker). Therefore, silicone gel adhesives are typically applied using a curable, gel-forming (two-component) composition that solidifies upon curing.

[0046] Within the meaning of the present invention, the term "saturation concentration" refers to the active agent concentration corresponding to an equilibrium state in which the solvent (i.e., polymer II of the skin contact layer) cannot dissolve any additional solute (i.e., the active agent). As a result, the solid solute exists in equilibrium with the solid solution at a defined temperature (room temperature—the uncorrected temperature required in the laboratory where the experiment is performed, typically in the range of 15-35°C, or approximately 18-25°C). The saturation concentration of the active agent can be expressed as a weight percent based on the total weight of the active agent layer or the skin contact layer, respectively. The saturation concentration can be measured, for example, using 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, including upper and lower protective layers sandwiching a donor and acceptor layer separated by a partition membrane permeable to the active agent. The donor layer contains an excess of the active agent, and the acceptor layer is substantially free of the active agent, so that the active agent diffuses from the donor layer through the partition membrane into the acceptor layer until a saturation concentration is reached. The donor layer and acceptor layer are fabricated from the respective polymer IIs of the skin contact layer. The donor layer is supersaturated with the active agent, and the acceptor layer is prepared identically to the donor layer but does not contain the active agent. The prepared sandwich system is stored at room temperature for a period of time, e.g., 7 days, to allow the active agent to diffuse from the donor layer to the acceptor layer. The remaining active agent concentration in the donor layer is then measured by HPLC (high-performance liquid chromatography), ultimately obtaining the saturation concentration of the active agent in each polymer II of the skin contact layer.

[0047] As used herein, the solubility parameter (SP) is defined as a numerical estimate of the sum of all intermolecular attractive forces that is empirically related to the degree of mutual solubility of chemical species. The most convenient method for determining the solubility parameter is the Hildebrand method, which calculates the solubility parameter from commonly available molecular weight, boiling point, and density data for many substances. The formula is SP = (ΔE v / V) 1 / 2where V = molecular weight / density, ΔE v = vaporization energy. For substances with vapor pressures too low to be detected, such as high molecular weight polymers, several methods have been developed that use the sum of atomic and group contributions to vaporization. Such methods for calculating the solubility parameter of a material are described, for example, in Small, J. Applied Chem. Vol. 3, p. 71 (1953). Solubility parameters (calculated by Small's method) of exemplary polymers useful in the practice of the present invention are as follows: Polydimethylsiloxane 14.9 MPa 1 / 2 , Polyisobutylene 15.7MPa 1 / 2 , polyethylene / butylene 16.2MPa 1 / 2 , Polyisoprene 16.6MPa 1 / 2 , polyethylene 16.6MPa 1 / 2 , polybutadiene 16.6MPa 1 / 2 , Polybutadiene-co-styrene (75 / 25~72 / 28) 17.4MPa 1 / 2 , polystyrene 18.6MPa 1 / 2 , Polymethyl methacrylate 19.0 MPa 1 / 2 , Polymethyl acrylate 19.8MPa 1 / 2 .

[0048] Within the meaning 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, and preferably also in 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 polyvinylpyrrolidone include Kollidon® 12PF, Kollidon® 17PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90F, or Povidone K90F, supplied by BASF. Different grades of Kollidon® are defined in terms of the K value, which reflects the average molecular weight of the polyvinylpyrrolidone grade. Kollidon® 12 PF is characterized by a K-value range of 10.2 to 13.8, corresponding to a nominal K-value of 12. Kollidon® 17 PF is characterized by a K-value range of 15.3 to 18.4, corresponding to a nominal K-value of 17. Kollidon® 25 is characterized by a K-value range of 22.5 to 27.0, corresponding to a nominal K-value of 25, and Kollidon® 30 is characterized by a K-value range of 27.0 to 32.4, corresponding to a nominal K-value of 30. Kollidon® 90F is characterized by a K-value range of 81.0 to 97.2, corresponding to a nominal K-value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30, and Kollidon® 90F. In this context, the term "K value" refers to the value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and the USP monograph for "Povidone." For all grades and types of polyvinylpyrrolidone, it is preferred that the amount of peroxide be within certain limits, in particular that the amount of peroxide be 500 ppm or less, more preferably 150 ppm or less, and most preferably 100 ppm or less.

[0049] Within the meaning of the present invention, the term "hexagonal shape" refers to the two-dimensional shape of the self-adhesive layer structure of the backing layer and the active layer, or the backing layer, the active layer, and the skin contact layer, respectively, which can be seen when the self-adhesive layer structure is viewed from above on the backing layer. A hexagonal shape in the sense of the present invention is understood to be any shape that can be formed by one hexagon or an aggregate of two or more hexagons. This means that a hexagonal shape according to the present invention does not necessarily have a hexagonal shape as a whole, but is composed of at least one hexagon. The apex of the hexagon may be pointed or rounded. When two or more hexagons form a hexagonal shape, they may be integrally connected to each other, i.e., separable only by cutting the self-adhesive layer structure, for example, or may be detachably connected to each other, for example, using perforations. The backing layer and the active layer, or the backing layer, the active layer, and the skin contact layer, and optionally also the membrane, are coextensive, i.e., they have the same planar extent and / or share the same boundary. In other words, the backing layer and the active layer, or the backing layer, the active layer and the skin contact layer, and optionally the membrane, each present at least one congruent hexagonal shape.

[0050] Within the meaning of the present invention, the term "hexagon" refers to a polygon with six sides. In a "convex hexagon," each of the six points (vertices) where two pairs of sides of the hexagon meet faces outward. Two adjacent vertices are connected by one of the six sides (common side). Non-adjacent vertices are connected by one of the nine diagonals inside the closed hexagonal chain (boundary) of the convex hexagon. A convex hexagon has the smallest total boundary length compared to other polygons with the same area.

[0051] A convex hexagon can also be described as a six-sided polygon with each interior angle (vertex angle) less than 180°. The sum of the interior angles of a simple (non-self-intersecting) hexagon is 720°. Thus, a (convex) hexagon with vertex angles each equal to 120° is also called an equiangular hexagon. A (convex) hexagon with all sides of equal length is also called an equilateral hexagon. If a (convex) hexagon is both an equilateral and an equiangular hexagon, it is also called a regular hexagon.

[0052] A (convex) hexagon may be symmetric, specifically mirror symmetry or rotational symmetry. In this context, mirror symmetry is also called reflection symmetry and is understood to mean symmetry with respect to reflection. A symmetric feature of such a two-dimensional shape is that when the shape is folded in half on a mirror axis, the two halves are identical, i.e., the two halves are mirror images of each other. A regular hexagon therefore has six axes of symmetry, since there are six ways to fold a regular hexagon so that all of its edges coincide. The nth-order rotational symmetry of a two-dimensional shape about a particular point (also called n-fold rotational symmetry) is understood to mean that the shape remains unchanged when rotated through an angle of 360° / n (180°, 120°, 90°, 72°, 60°, etc.). A regular hexagon therefore has sixth-order rotational symmetry, since it looks the same every time it is partially rotated through a 60° angle.

[0053] Within the meaning of the present invention, the term "parallel polygon" refers to a (convex) hexagon in which all pairs of opposite sides (two sides separated from each other by the same number of sides in both boundary directions, i.e., two sides in a hexagon) are parallel and the lengths of the two sides of each pair of parallel opposite sides are equal. This includes parallel polygons with three different side lengths, or parallel polygons with only two different side lengths, and parallel polygons in which all sides are equal in length. The term "parallel polygon" includes, for example, shapes obtained by elongating a parallelogram or a rhombus, in particular, shapes obtained by separating a parallelogram or a rhombus at two non-adjacent vertices, respectively, and introducing a pair of parallel, opposite sides of equal length. In this context, the term "parallelogram" is understood to mean a simple four-sided polygon with two pairs of parallel sides. If the four sides are of equal length, the parallelogram is also called a "rhombus."

[0054] Within the meaning of the present invention, the term "aspect ratio" refers to the ratio of height to width, where width and length are the distances between two points on the boundary of a (convex) hexagon, with the longer of the two distances considered to be the width. In this context, the width of a (convex) hexagon is understood to mean the length of the longest distance between any two points on the boundary, which is often the length of the longest diagonal of the (convex) hexagon between two diametrically opposed vertices. The height of a (convex) hexagon is the longest distance between any two points on the boundary of the (convex) hexagon, meaning that the line connecting these two points is perpendicular to the line connecting the two points defining the width (see above). The ratio of height to width, if any, corresponds to the ratio of the inscribed circle radius (the radius of the inscribed circle) to the circumscribed circle radius (the radius of the circumscribed circle). The ratio of height to width of a regular hexagon is √3:2.

[0055] Regular hexagons fit together like tiles on a plane to form a honeycomb pattern. The honeycomb pattern consists of regular hexagons placed side by side, tiling the plane, i.e. completely filling the entire surface they span, with no holes between them. This is because when the hexagons are laid out side by side, the angles at which their sides meet at their vertices are 120°, and exactly three hexagons meet at every vertex. The honeycomb pattern appears not only in beehives but also in many places in nature, for example in organic compounds (benzyl rings, proteins).

[0056] Hexagonal tiling, also known as hexagonal tessellation, is a regular tiling of the Euclidean plane in which exactly three hexagons intersect at each vertex. Besides regular hexagons (FIG. 1a), hexagonal tiling can also be achieved using other (hexagonal) parallel polygons, in particular elongated rhombuses (FIG. 1b) and parallel polygons formed by elongating parallelograms (FIG. 1c). Such hexagonal shapes can tile the Euclidean plane by translation. Other hexagonal shapes can tile the plane in different directions. In this context, the term "tiling a plane" is understood to mean the complete coverage of a particular plane (flat or curved). Tiling a plane can be performed with or without overlapping adjacent self-adhesive layer structures according to the present invention. Preferably, overlapping is avoided as much as possible.

[0057] Within the meaning of the present invention, the term "medical patch sheet" refers to a number of medical patches sharing a common release liner. Each medical patch represents an individual dosage unit that can be applied to a patient's skin after peeling from the release liner. The amount of active agent contained in the medical patch refers to the amount of active agent contained in the self-adhesive layer structure of the medical patch. The amount of active agent contained in the medical patch sheet refers to the total amount of active agent contained in all the self-adhesive layer structures of the medical patches that make up the medical patch sheet. Therefore, the release area of ​​the medical patch refers to the area provided by the self-adhesive layer structure of the medical patch, and the release area of ​​the medical patch sheet refers to the area provided by all the self-adhesive layer structures of the medical patches that make up the medical patch sheet.

[0058] Within the meaning of the present invention, the term "release liner" refers to a removable protective layer attached to the active layer or skin-contacting layer of the self-adhesive layer structure(s). The release liner may have any suitable two-dimensional geometric shape, preferably a polygonal shape, particularly a rectangular or square shape. According to certain embodiments, the area of ​​the release liner encompasses the total area of ​​all the self-adhesive layer structures of the medical patch that make up the sheet of the medical patch. According to the present invention, the release liner is coextensive with the self-adhesive layer structures or extends beyond the boundaries formed by all the self-adhesive layer structures in all directions, i.e., the polygonal chains formed by the outer hexagonal edges of the self-adhesive layer structures are completely located within or on the polygonal chains formed by the edges of the release liner. Suitable release liners may be polyethylene terephthalate (PET) or polypropylene (PP) films, optionally coated with silicone or fluoropolymers. These include commercially available release liners such as 3M's Scotchpak® Release Liners 9741 / 9742 / 9744.

[0059] Within the meaning of the present invention, the term "weakened" refers to the result of any action (weakening) that allows for easier separation of two sections of a self-adhesive layer structure or two different self-adhesive layer structures, even though the two sections / self-adhesive layer structures are still connected to each other. Such weakening may include, but is not limited to, folding, scratching, perforating, piercing, puncturing, punching, or cutting. According to certain embodiments, the weakening is performed by perforation. In this context, the term "perforated" is understood to mean having small holes. Perforation may be achieved, for example, by needling or laser cutting.

[0060] Within the meaning of the present invention, the term "fastening bridge" refers to a single point between two or three self-adhesive layer structures, in particular between two or three hexagonal shapes, such as two or three convex hexagons or two or three convex double hexagons, where the layer structures are still connected, even though a major portion of the common edge has been cut or weakened. This is preferably achieved by leaving the connection during the separation process, which can be carried out, for example, by punching or cutting. The fastening bridge(s) enable the self-adhesive layer structures thus connected to be jointly released from the release liner. In addition, the fastening bridge(s) is preferably very thin so that it can be easily cut, for example by pulling on one part of the self-adhesive layer structure, to separate one part from the other.

[0061] Within the meaning of the present invention, the term "patient" refers to a subject who presents with a particular symptom or clinical signs of a condition indicating the need for treatment, who is receiving preventative or prophylactic treatment for a condition, or who has been diagnosed with a condition to be treated. Preferably, the patient suffers from neuropathic pain or mixed neuropathic and / or nociceptive pain, such as arthritic pain or cancer pain.

[0062] The term "neuropathic pain" refers to pain caused by lesions or diseases of the somatosensory nervous system. In this context, the term "chronic neuropathic pain" is understood to mean neuropathic pain lasting at least three months. Most patients with neuropathic pain complain of continuous or intermittent spontaneous pain, such as burning, tingling, or pressure, which may be accompanied by pain elicited by light touch or cold air, among other things. Ectopic activity in nerve terminal neuromas, 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 specifically affects peripheral nerves, i.e., nerves outside the brain and spinal cord. In particular, neuropathic pain in the context of the present invention relates to postoperative neuropathic pain, postherpetic neuralgia, and neuropathic pain associated with diabetic peripheral neuropathy of the hands and feet.

[0063] 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 injury site, radiate to the innervation of nerves located at that site, or radiate to dermatomes (after surgery or injury to deep somatic or visceral tissues). Chronic postoperative pain is the result of nerve damage and may be due to the surgery itself or to other causes of pain, including infection, malignancy, etc.

[0064] In this context, the term "postherpetic neuralgia" is understood to mean pain caused by nerve damage due to a previous infection with herpes zoster, also known as postherpetic neuralgia and commonly referred to as shingles. Symptoms of postherpetic neuralgia are limited or localized to the area of ​​skin affected by shingles, particularly the banded area on the trunk, and usually occur on one side of the body. Less common symptoms of postherpetic neuralgia include itching, numbness, or a "pins and needles" sensation.

[0065] In this context, the term "diabetic peripheral neuropathy," also known as "diabetic nerve pain," is understood to mean pain caused by nerve damage as a result of diabetes. Diabetic nerve pain can affect any nerve, but is most often felt in the extremities, such as the hands and feet.

[0066] Within the meaning of the present invention, the term "joint pain" refers to joint symptoms such as discomfort, pain, or suffering in any of the joints of a patient's body, such as the spine, shoulder, hip, elbow, and knee joints. This particularly includes joint pain caused by arthritis, such as osteoarthritis. In this context, the term "osteoarthritis" is understood to mean a degenerative disease characterized by cartilage erosion, bone hypertrophy, subchondral sclerosis, and changes in the synovial membrane and joint capsule. Clinically, it is characterized by joint pain, stiffness, and functional limitations. Osteoarthritis pain has traditionally been considered nociceptive, although some patients suffer from neuropathic pain. Joint pain may specifically be knee pain, elbow pain, hip pain, shoulder pain, hand or foot pain, or back (lower back) pain.

[0067] Within the meaning of the present invention, the term "cancer pain" relates to neuropathic cancer pain caused by nerve damage due to the cancer itself and / or treatments such as chemotherapy, radiotherapy, surgery, etc. Cancer pain caused by the tumor itself usually contains both nociceptive and neuropathic components, with mixed pain being more common than neuropathic cancer pain caused by cancer treatment. Most chemotherapy-induced cancer pain is purely neuropathic. Neuropathic cancer pain is nerve-related (typically neuron-related) pain characterized as a burning or electrical sensation, but may also manifest as decreased sensation or actual muscle weakness.

[0068] Within the meaning of the present invention, the term "coating composition" refers to a composition comprising all the ingredients of the active layer or the skin contact layer, respectively, which can be coated onto a backing layer or a release liner to form the active layer and the skin contact layer upon drying.

[0069] Within the meaning of the present invention, the term "dissolving" refers to the process of obtaining a solution that is clear to the naked eye and does not contain any particles.

[0070] Within the meaning of the present invention, the term "crosslinking" refers to the process of crosslinking functional groups contained within the inert coating composition.

[0071] Within the meaning of the present invention, and unless otherwise specified, the term "about" refers to an amount that is ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±2% of the disclosed amount. [Brief explanation of the drawings]

[0072] [Figure 1a] 1 shows a hexagonal tiling with regular hexagons. [Figure 1b] 1 shows a hexagonal tiling with parallel polygons obtained by elongating rhombuses. [Figure 1c] 1 shows a hexagonal tiling with parallel polygons obtained by elongating parallelograms. [Figure 2a] 1 shows an exemplary pattern of a medical patch sheet according to the present invention, in which the self-adhesive layer structure is a regular hexagon. [Figure 2b] 1 shows an exemplary pattern of a medical patch sheet according to the present invention, in which the self-adhesive layer structure is a double hexagon formed from two identical regular hexagons that share two adjacent vertices and a common side. [Figure 2c] 1 shows an exemplary pattern of a medical patch sheet according to the present invention, in which the self-adhesive layer structure is selected from a regular hexagon and a double hexagon formed from two identical regular hexagons that share two adjacent vertices and a common side. [Figure 3] 1 shows a portion of an exemplary pattern of a medical patch sheet according to the present invention, in which the self-adhesive layer structures are regular hexagons connected to each other by common fastening bridges, and all adjacent self-adhesive layer structures are connected to each other in groups of three by common fastening bridges located at common vertices. DETAILED DESCRIPTION OF THE INVENTION

[0073] Self-adhesive layer structure The present invention relates to a self-adhesive layer structure for use in a medical patch, particularly for the administration of an active agent contained therein. In some embodiments, the self-adhesive layer structure is a pressure-sensitive adhesive layer structure.

[0074] The self-adhesive layer structure, in particular the pressure-sensitive adhesive layer structure, according to the invention has a hexagonal shape, A) a backing layer; B) an active layer comprising polymer I and an active agent; The backing layer and the active layer are coextensive, providing a hexagonal shape for the self-adhesive layer structure.

[0075] In certain embodiments, the self-adhesive layer structure comprises: A) a backing layer; B) an active layer comprising polymer I and an active agent; C) a skin contact layer; The backing layer, active layer, and skin contact layer are coextensive, providing a hexagonal shape for the self-adhesive layer structure. In such embodiments, the self-adhesive layer structure may or may not include a membrane located between the active layer and the skin-contacting layer. The membrane is preferably a rate-controlling membrane.

[0076] In a particular embodiment, the aforementioned layers of the self-adhesive layer structure according to the invention are directly attached to each other, i.e., the backing layer is directly attached to the active layer, which is optionally attached to an additional skin-contacting layer. Alternatively, the active layer is directly attached to the membrane, which is directly attached to an additional skin-contacting layer on the opposite side. In other words, the self-adhesive layer structure according to the invention comprises the following layers in this order: (1) backing layer, (2) active layer, and optionally (3) skin-contacting layer, or (1) backing layer, (2) active layer, optionally (3) membrane, and optionally (4) skin-contacting layer.

[0077] The additional skin contact layer preferably provides adhesion between the self-adhesive layer structure and the patient's skin during administration. If the self-adhesive layer structure according to the invention does not comprise an additional skin contact layer, sufficient adhesion between the self-adhesive layer structure and the patient's skin during administration is provided by other means, such as an active layer and / or an adhesive overlay.

[0078] The backing layer is particularly substantially impermeable to the active agent and preferably consists of a polyester film or ethylene vinyl acetate copolymer having a thickness of 10 to 20 μm.

[0079] In certain embodiments, the self-adhesive layer structure is for transdermal or topical delivery of an active agent. In certain embodiments, the self-adhesive layer structure is for topical delivery of an active agent.

[0080] The self-adhesive layer structure according to the present invention can be used in a matrix-type medical patch or a reservoir-type medical patch, preferably a matrix-type medical patch. In a specific embodiment, the self-adhesive layer structure according to the present invention is used in a matrix-type medical patch, in which the active agent is homogeneously dissolved and / or dispersed in a polymer carrier, i.e., a matrix, to form a matrix layer together with the active agent and optionally further additives. Therefore, the active layer is preferably an active matrix layer. Therefore, in a specific embodiment of the self-adhesive layer structure according to the present invention, the active layer comprises: (i) Polymer I; (ii) an active agent; and an active matrix layer comprising:

[0081] In a particular embodiment, the self-adhesive layer structure according to the invention is for use in a microreservoir medical patch. The active layer is therefore a microreservoir active layer, in particular (i) an outer phase comprising polymer I; (ii) an inner phase containing an active agent; and Preferably, the inner phase is a dry biphasic layer that forms a precipitate dispersed in the outer phase.

[0082] The self-adhesive layer structure according to the present invention is usually placed on a removable protective layer (release liner), which is removed immediately before application to the patient's skin surface. Therefore, the self-adhesive layer structure or medical patch may further comprise a release liner. The self-adhesive layer structure or medical patch thus protected is usually housed in a seam-sealed pouch. The packaging may be child-resistant and / or easy for the elderly to handle.

[0083] active layer As outlined in more detail above, the self-adhesive layer structure according to the invention comprises, inter alia, an active layer, which comprises: (i) Polymer I; (ii) an active agent; and Includes.

[0084] The active agent is preferably uniformly dispersed within the active layer. In certain embodiments, the active layer is an active matrix layer, and in particular a microreservoir active layer.

[0085] Thus, in certain embodiments of the self-adhesive layer structure, the active layer comprises: (i) an outer phase comprising polymer I; (ii) an inner phase containing an active agent; and The inner phase is a dry biphasic layer that forms a precipitate dispersed in the outer phase. In certain embodiments, the outer phase is hydrophobic and the inner phase is hydrophilic.

[0086] The outer phase of the dried two-phase layer preferably has a composition containing 75% to 100% polymer I. The inner phase preferably has a composition containing an active agent and a hydrophilic agent that forms a solution with the active agent. The hydrophilic agent may be a hydrophilic polymer or polymer mixture, specifically selected from the group consisting of polyvinylpyrrolidone, vinyl caprolactam, copolymers of vinyl acetate and ethylene glycol, copolymers of vinylpyrrolidone and vinyl acetate, copolymers of ethylene and vinyl acetate, polyethylene glycol, polypropylene glycol, acrylic polymers, and modified cellulose, all of which have a K value of 10 to 200.

[0087] The dried two-phase layer further comprises an interfacial mediator, particularly one having a kinematic viscosity of 10 cSt to 100,000 cSt at 25°C. The interfacial mediator can be present in the dried two-phase layer in an amount of 0.1% to 3.5% and is used to reduce the maximum droplet size of dispersed precipitates of the inner phase in the outer phase of the dried two-phase layer. While not wishing to be bound by any theory, this effect is believed to be due to filling voids at the interface between the dispersed inner and outer phases, thereby increasing compatibility of the two distinct phases and promoting maximum separation / dispersion of the inner phase in the outer phase. Suitable interfacial mediators include, for example, silicone oil.

[0088] The polymer I contained in the active layer provides sufficient cohesion of the active layer. According to certain embodiments, the polymer I can also provide sufficient adhesion of the self-adhesive layer structure to the patient's skin during administration. In these embodiments, the polymer I is selected from pressure-sensitive adhesive polymers. Thus, in a preferred embodiment of the present invention, the polymer I is a pressure-sensitive adhesive polymer.

[0089] Polymers suitable as polymer I according to the present invention may be selected from silicone-based polymers, acrylic polymers, silicone-acrylic hybrid polymers, and polymers based on natural or synthetic rubbers, such as polyisobutylene or styrene-isoprene-styrene block copolymers, which are described in more detail below. In certain embodiments, the polymer is selected from silicone-based polymers. In certain embodiments, the polymer is a silicone-based polymer obtained by polycondensation of silanol-endblocked polydimethylsiloxane with a silicate resin.

[0090] Furthermore, in certain embodiments, the area weight of the active layer is between 20 and 400 g / m 2 , 30~200g / m 2 , or 50-120g / m 2 The range is.

[0091] Active Agent According to the present invention, the self-adhesive layer structure comprises an active layer which contains an active agent.

[0092] The active agent may be any compound responsible for the therapeutic effect of the medical patch comprising the self-adhesive layer structure. In particular, the active agent may be a topically active agent or a systemically active agent. In certain embodiments, the active agent is at least one analgesic. Suitable analgesics include, for example, buprenorphine, capsaicin, diclofenac, fentanyl, ibuprofen, or lidocaine.

[0093] According to certain embodiments, the active agent is a TRPV1 agonist, such as capsaicin.

[0094] In one embodiment, the active agent is capsaicin. Thus, the self-adhesive layer structure comprises: A) a backing layer; B) an active layer, (i) Polymer I; (ii) an active layer comprising capsaicin; may include:

[0095] In particular, the self-adhesive layer structure comprises a therapeutically effective amount of capsaicin. In certain embodiments, the self-adhesive layer structure comprises capsaicin in an amount of 0.5 to 180 mg, 1.2 to 90 mg, or 19 to 45 mg. In some embodiments, the self-adhesive layer structure comprises capsaicin in an amount of about 179 mg. In other embodiments, the self-adhesive layer structure comprises capsaicin in an amount of about 60 mg, about 45 mg, about 30 mg, about 25 mg, about 10 mg, or about 1 mg.

[0096] Therefore, a particular active layer according to the present invention may comprise: (i) Polymer I; (ii) capsaicin.

[0097] The active layer must have a density of at least 0.30 mg / cm2 per emitting area. 2 , at least 0.50 mg / cm 2 , or at least 0.60 mg / cm 2 of capsaicin and / or per emission area, 1.0 mg / cm 2 Less than 0.8 mg / cm 2 Less than or equal to 0.7 mg / cm 2 In particular, the active layer may contain less than 0.30 mg / cm of capsaicin per emission area. 2 ~1.0mg / cm 2 , 0.30 mg / cm 2 ~8.0mg / cm 2 , 0.50 mg / cm 2 ~8.0mg / cm 2 , 0.60 mg / cm 2 ~0.8mg / cm 2 , or 0.60 mg / cm 2 ~0.7mg / cm 2 Contains capsaicin.

[0098] In certain embodiments, the active layer comprises capsaicin in an amount of 2-20%, 5-15%, or 5-10% by weight, hi certain embodiments, the active layer comprises capsaicin in an amount of about 8% by weight.

[0099] Additionally, the active layer may comprise at least one silicone-based polymer in an amount of 20 to 90 wt %, or 60 to 90 wt %, based on the total weight of the active layer. It should be understood that the aforementioned weight percent amounts refer to the total amount of the at least one silicone-based polymer. For example, if two silicone-based polymers are present, the total amount in the active layer is 20 to 90 wt %, or 60 to 90 wt %, based on the total weight of the active layer.

[0100] Thus, in one embodiment, the self-adhesive layer structure is for transdermal or topical delivery of capsaicin, particularly for topical delivery of capsaicin.

[0101] Capsaicin ((6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide) is the primary bioactive component of chili peppers and an alkaloid found in the Capsicum family. It is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), better known as the vanilloid receptor. By binding to the TRPV1 receptor, the capsaicin molecule produces a sensation similar to that of excessive heat or abrasion injury. Capsaicin has a role as a non-narcotic analgesic and is currently used to treat several pain syndromes, including neuropathic pain. Such pain is thought to arise from a sensitization response in the peripheral and central nervous systems and can occur as a result of peripheral injury or systemic diseases, such as HIV, varicella-zoster, syphilis, autoimmune diseases, and diabetes. Furthermore, capsaicin has also been demonstrated to have beneficial effects on osteoarthritis pain relief due to its potent 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 the cancer cells.

[0102] The active agent, particularly capsaicin, may be present in the active layer in an amount of 1 to 25% by weight, 2 to 20% by weight, or 5 to 10% by weight.

[0103] skin contact layer As outlined in more detail above, the self-adhesive layer structure according to the present invention may further comprise a skin contact layer. In this case, the backing layer, active layer, and skin contact layer are coextensive, providing the hexagonal shape of the self-adhesive layer structure. In certain embodiments, the skin contact layer is an adhesive, in particular a pressure-sensitive adhesive, that provides adhesion between the self-adhesive layer structure and the patient's skin during administration.

[0104] Surprisingly, it has been found that a self-adhesive layer structure comprising a skin contact layer in which the active agent is poorly soluble, preferably directly attached to the active layer, has advantageous properties in terms of reducing skin irritation, while at the same time improving drug delivery behavior and adhesiveness. In particular, since the active agent is poorly soluble, e.g., its saturation concentration in the skin contact layer is less than 0.1%, only a small amount of the active agent is present on the surface of the skin contact layer, thereby providing medical patches with advantageous properties in terms of preventing undesirable skin reactions and allowing safe application and / or removal. Therefore, such a self-adhesive layer structure has a skin contact layer in which the saturation concentration of the active agent is negligible and a separate active layer (not in contact with the skin), thereby inhibiting the release of the active agent before and / or after the self-adhesive layer structure is applied and maintained on the patient's skin. On the other hand, it has been found that such a self-adhesive layer structure with a skin contact layer can still provide sufficient drug delivery and allow for faster release of the active agent.

[0105] Therefore, such a self-adhesive layer structure including a skin contact layer is particularly characterized by a low solubility of the active agent in the skin contact layer, and in certain embodiments, the saturation concentration of capsaicin in the skin contact layer is less than 0.1 wt %, preferably measured by the "sandwich method". In certain embodiments, the saturation concentration of the active agent in the skin contact layer is less than 0.05 wt %, less than 0.02 wt %, or less than 0.01 wt %. Preferably, the saturation concentration of the active agent in the skin contact layer is about 0 wt %. The saturation concentration relates to the amount of the active agent present in the skin contact layer based on the total weight of the skin contact layer.

[0106] In certain embodiments, the saturation concentration of the active agent in the skin contact layer is below a concentration of the active agent that would cause unintended adverse effects, such as skin irritation, upon brief contact. Such a concentration can be empirically determined through 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 of time, such as 5, 10, 30 seconds, or 1 minute. In particular, different model layers representing a range of active agent concentrations can be tested to determine the highest acceptable saturation concentration that still does not cause unintended adverse effects, such as skin irritation. On the other hand, whether a medical patch having a set of active agent and skin contact layer results in a saturation concentration that does not cause any adverse effects can be determined simply (without using a range of different concentrations) by testing a model adhesive layer saturated with the active agent or such a medical patch, i.e., by applying it to the skin as outlined above.

[0107] The skin contact layer can protect the active agent contained in the active layer from the skin of the patient or other person applying or removing the medical patch before and / or after application. Therefore, the skin contact layer must be substantially free of the active agent. This means that the skin contact layer is usually manufactured as a layer that does not contain the active agent. However, due to the concentration gradient, the active agent will usually migrate from the active layer to the skin contact layer over time until equilibrium is reached. However, this migration is limited by the saturation concentration of the active agent in the skin contact layer. In certain embodiments, the skin contact layer does not allow the active agent to be present at a concentration greater than 0.1% by weight.

[0108] Thus, in certain embodiments, the skin contact layer comprises an active agent in an amount of less than 0.1 wt. % based on the total weight of the skin contact layer. In certain embodiments, the skin contact layer comprises an active agent in an amount of less than 0.01 wt. % based on the total weight of the skin contact layer.

[0109] According to certain embodiments, the skin contact layer comprises polymer II. Polymer II in the skin contact layer has a decisive influence on adhesion and further reduces skin irritation due to its elasticity. In certain embodiments, the skin contact layer comprises polymer II in an amount of at least 95 wt %, at least 99 wt %, or about 100 wt %, based on the total weight of the skin contact layer. In particular, the skin contact layer can consist essentially of polymer II. It should be understood that the aforementioned weight percent amounts refer to the total amount of polymer II. For example, if polymer II is a mixture of polymers, the total amount in the skin contact layer is 50 to 100 wt %, based on the total weight of the skin contact layer.

[0110] Suitable polymers for polymer II according to the present invention are in particular polymers capable of concentrating the active agent 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., polymers in which the active agent is substantially insoluble. Thus, according to certain embodiments, polymer II may be a polymer or a mixture of polymers in which the active agent is substantially insoluble.

[0111] Thus, the solubility parameter of polymer II may be different from the solubility parameter of the active agent, and in particular at least 5.0 MPa higher than the solubility parameter of the active agent. 1 / 2 , at least 6.0 MPa 1 / 2 , at least 8.0 MPa 1 / 2 , or at least 10.0 MPa 1 / 2 In particular, the solubility parameter of polymer II 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 or 15.0 MPa 1 / 2 It may be less than.

[0112] Polymer II may be selected from pressure-sensitive adhesive polymers. Thus, in certain embodiments, polymer II may be a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0113] In certain embodiments, polymer II may be a polymer or a mixture of polymers selected from the group consisting of a silicone-acrylic hybrid polymer, a silicone-based polymer, a silicone gel adhesive, and a polymer based on natural or synthetic rubber, which are described in more detail below. In particular, polymer II may be a polymer or a mixture of polymers selected from the group consisting of a silicone-based polymer and a silicone gel adhesive.

[0114] In some embodiments, polymer II may be a silicone gel adhesive. Such a self-adhesive layer structure may include an additional skin contact layer containing a silicone gel adhesive, which provides improved adhesion when applied to a patient's skin and allows for clean, painless removal. When needed, for example, to move to another location, the self-adhesive layer structure can be removed and reapplied without losing its adhesiveness.

[0115] Polymer II may also be a polymer or a mixture of polymers selected from silicone-based polymers, in particular polysiloxane-based polymers such as amine-compatible polysiloxanes, or polymer II may be a polymer or a mixture of polymers selected from natural or synthetic rubbers, in particular SIS block copolymers and / or styrene triblock copolymers such as polyisobutylene and / or polyisobutylene.

[0116] Polymers suitable as polymer II are commercially available, for example, under the trade name Soft skin adhesives (two-component silicone adhesives that cure upon mixing of the two components). Alternatively, polymers suitable as polymer II are commercially available, for example, under the trade names BIO-PSA (polysiloxane-based pressure-sensitive adhesives), JSR-SIS (SIS block copolymer-based pressure-sensitive adhesives), and Oppanol™ (polyisobutylene).

[0117] Additional polymers may also be added, for example, to increase the adhesion of the skin contact layer.

[0118] According to some embodiments, polymer II included in the skin contact layer is different from polymer I included in the active layer. According to other embodiments, polymer II included in the skin contact layer is the same as polymer I included in the active layer.

[0119] According to a particular embodiment, the area weight of the skin contact layer is between 80 and 500 g / m 2 In certain embodiments, the skin contact layer may have a density of 100 to 350 g / m 2 , 150~320g / m 2 , or 180-280g / m 2 The area weight may be

[0120] Silicone-based polymers Suitable silicone-based polymers are non-curable polymers, typically applied by hot melt or solvent-based processes, and preferably do not undergo further curing to solidify.

[0121] Silicone polymers are based on polysiloxanes. Therefore, they are also called polysiloxane-based polymers. Silicone polymers are generally obtained by polycondensation of silanol-endblocked polydimethylsiloxanes with silicate resins. Amine-compatible silicone polymers can be obtained by reacting silicone polymers with trimethylsilyl groups (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer, thereby improving its stability in the presence of amines. As a result, the remaining silanol functionality is at least partially, preferably mostly or completely, capped with trimethylsiloxy groups.

[0122] Thus, in certain embodiments, the silicone-based polymer is an amine-compatible polysiloxane, preferably obtained by polycondensation of a silanol-endblocked polydimethylsiloxane with a silicate resin, followed by at least partial trimethylsilylation of the remaining silanol functionality.

[0123] In certain embodiments, the silicone-based polymer is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives, ie, a polysiloxane-based pressure-sensitive adhesive or a mixture of polysiloxane-based pressure-sensitive adhesives.

[0124] Polysiloxane-based pressure-sensitive adhesives offer suitable viscosity and rapid adhesion to various skin types, including wet skin, suitable adhesive and cohesive properties, long-lasting adhesion to skin, high flexibility, moisture permeability, and compatibility with many active agents and film substrates. These pressure-sensitive adhesives are based on the resin-in-polymer concept, in which polysiloxane-based pressure-sensitive adhesives are prepared by the condensation reaction of silanol-endblocked polydimethylsiloxane with silica resin (also known as silicate resin). For amine stability, residual silanol functionality is additionally capped with trimethylsiloxy groups. The content of silanol-endblocked polydimethylsiloxane contributes to the viscous component of the viscoelastic behavior and influences the adhesive's wetting and spreading properties. The resin acts as a tackifier and reinforcing agent and contributes to the elastic component. The right balance of silanol-endblocked polydimethylsiloxane and resin provides the desired adhesive properties.

[0125] As previously indicated, the tackiness of silicone-based polymers can be varied by the resin-to-polymer ratio, i.e., the ratio of silanol-endblocked polydimethylsiloxane to silicate resin, preferably ranging from 50:50 to 70:30, or from 55:45 to 65:35. The tackiness increases with increasing amounts of polydimethylsiloxane relative to resin. High-viscosity silicone-based polymers preferably have a resin-to-polymer ratio of 55:45, medium-viscosity silicone-based polymers preferably have a resin-to-polymer ratio of 60:40, and low-viscosity silicone-based polymers preferably have a resin-to-polymer ratio of 65:35.

[0126] According to certain embodiments, the pressure-sensitive adhesive may be obtained by polycondensation of silanol-endblocked polydimethylsiloxane with a silicate resin, preferably in a resin-to-polymer ratio of 50:50 to 70:30, or 55:45, 60:40, or 65:35. Thus, in one embodiment, the silicone-based polymer is a mixture of pressure-sensitive adhesives obtained by polycondensation of silanol-endblocked polydimethylsiloxane with a silicate resin, in a resin-to-polymer ratio of 55:45 or 60:40.

[0127] Furthermore, according to certain embodiments, the silicone-based polymer comprises: Solution viscosity of 450 mPa·s and / or 0.01 rad / s at 25°C and approximately 60% solids in heptane, and complex viscosity of 1×10 at 30°C 8 Poise, Solution viscosity of 500 mPa·s and / or 0.01 rad / s at 25°C and in heptane with a solids content of approximately 60%, and a complex viscosity of 5×10 at 30°C 6 It is a mixture of pressure sensitive adhesives that are poise.

[0128] 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 will recognize that the solids content can be varied by adding an appropriate amount of solvent.

[0129] The high viscosity silicone polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 6 Poise, and the medium viscosity silicone polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 7 Poise, and the low viscosity silicone polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 8The high viscosity amine-compatible silicone polymer preferably has a complex viscosity of about 5×10 poise at 0.01 rad / s and 30° C. 6 Poise, and the medium viscosity amine-compatible silicone polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 8 Poise, and the low viscosity amine compatible silicone polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 9 Preferred polysiloxane-based pressure-sensitive adhesives according to the present invention are characterized by a solution viscosity at 25°C and 60% solids content in n-heptane, preferably greater than about 150 mPa·s, or from about 200 mPa·s to about 700 mPa·s, as measured using a Brookfield RVT viscometer equipped with spindle #5 at 50 RPM. They also have a viscosity of about 1x10 at 0.01 rad / s at 30°C. 9 Less than poise, or about 1x10 5 ~approx. 9x10 8 It may be characterized by its complex viscosity in poise.

[0130] Suitable silicone-based polymers are commercially available under the trade name BIO-PSA. Examples of commercially available silicone-based PSA compositions include the standard Liveo™ BIO-PSA series (7-4400, 7-4500, and 7-4600 series) and the amine-compatible (end-capped) Liveo™ BIO-PSA series (7-4100, 7-4200, and 7-4300 series), which are manufactured and typically supplied in n-heptane or ethyl acetate. For example, BIO-PSA 7-4201 has a solution viscosity of 450 mPa·s at 25°C and a solids content of about 60% in heptane, and a viscosity of 1×10 at 0.01 rad / s at 30°C. 8 BIO-PSA7-4301 is characterized by a complex viscosity in poise. BIO-PSA7-4301 has a solution viscosity of 500 mPas at 25°C and a solids content of approximately 60% in heptane, and a viscosity of 5 x 10 at 0.01 rad / s at 30°C. 6 It has a complex viscosity in poise.

[0131] The polysiloxane-based pressure-sensitive adhesives are obtained according to the following scheme: [ka] Such polysiloxane-based pressure-sensitive adhesives are available under the tradenames Liveo™ BIO-PSA7-4401, BIO-PSA7-4501, or BIO-PSA7-4601, provided in n-heptane (designated by the code "01"), or Liveo™ BIO-PSA7-4402, BIO-PSA7-4502, and BIO-PSA7-4602, provided in ethyl acetate (designated by the code "02"). Typical solids content in the solvent ranges from 60 to 75%. The code "44" indicates a low viscosity resin-to-polymer ratio of 65:35; the code "45" indicates a medium viscosity resin-to-polymer ratio of 60:40; and the code "46" indicates a high viscosity resin-to-polymer ratio of 55:45.

[0132] Amine-compatible pressure-sensitive adhesives based on polysiloxanes can be obtained according to the following scheme: [ka] Such polysiloxane-based amine-compatible pressure-sensitive adhesives are available under the tradenames Liveo™ BIO-PSA7-4101, BIO-PSA-7-4201, or BIO-PSA7-4301, provided in n-heptane (designated by the code "01"), or Liveo™ BIO-PSA7-4102, BIO-PSA7-4202, and BIO-PSA7-4302, provided in ethyl acetate (designated by the code "02"). Typical solids content in the solvent ranges from 60 to 75%. Code "41" indicates a low viscosity resin-to-polymer ratio of 65:35; code "42" indicates a medium viscosity resin-to-polymer ratio of 60:40; and code "43" indicates a high viscosity resin-to-polymer ratio of 55:45.

[0133] acrylic polymer As used herein, the terms acrylic polymer and acrylate polymer refer interchangeably to acrylate-based polymers. According to certain embodiments, the acrylic polymer is an acrylate-based pressure-sensitive adhesive. Acrylate-based pressure-sensitive adhesives are sometimes referred to as acrylate-based pressure-sensitive adhesives or acrylate pressure-sensitive adhesives.

[0134] The acrylate-based pressure-sensitive adhesive may be provided in the form of a solution, preferably having a solids content of 30% to 60%. The acrylate-based pressure-sensitive adhesive may or may not contain functional groups such as hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Corresponding commercial products are available, for example, from Henkel under the trade name DuroTak®. Such acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, butyl acrylate, butyl methacrylate, t-octylacrylamide, and vinyl acetate, and are provided in ethyl acetate, heptane, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene, or xylene, or mixtures thereof.

[0135] The following specific acrylate-based pressure sensitive adhesives are available: Duro-Tak® 387-2287 or Duro-Tak® 87-2287 (a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate, provided as a solution in ethyl acetate without crosslinking agent), Duro-Tak® 387-2516 or Duro-Tak® 87-2516 (a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methylacrylate, supplied as a solution in ethyl acetate, ethanol, n-heptane and methanol with a titanium crosslinker), Duro-Tak® 387-2051 or Duro-Tak® 87-2051 (a copolymer based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate, provided as a solution in ethyl acetate and heptane), Duro-Tak® 387-2353 or Duro-Tak® 87-2353 (a copolymer based on acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate and methyl acrylate, provided as a solution in ethyl acetate and hexane), Duro-Tak™ 87-4098 (a copolymer based on 2-ethylhexyl acrylate and vinyl acetate, provided as a solution in ethyl acetate), - Duro-Tak™ 387-9301 (a copolymer based on methyl acrylate, 2-ethylhexyl acrylate and t-octylacrylamide, provided as a solution in ethyl acetate).

[0136] Thus, the acrylic polymer may be selected from acrylic polymers containing functional groups selected from hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. In certain embodiments, the functional groups are limited to hydroxyl groups. The acrylic polymer may be free of carboxylic acid groups, neutralized carboxylic acid groups, or both, free of acid groups, or free of functional groups.

[0137] Depending on the type of commercially available acrylic polymer used and whether a crosslinker is added to the coating composition, the polymer in the final active or skin-contacting layer may be crosslinked (and preferably crosslinked with an aluminum and / or titanium crosslinker) or may not be crosslinked with a crosslinker.

[0138] Silicone Acrylic Hybrid Polymer As used herein, a silicone acrylic hybrid polymer includes a polymerized hybrid species that includes a silicone-based subspecies and an acrylate-based subspecies polymerized together. Thus, a silicone acrylic hybrid polymer includes a silicone phase and an acrylic phase. According to certain embodiments, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.

[0139] 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 typically 30% to 80%. Those skilled in the art will recognize that the solids content can be altered by adding an appropriate amount of solvent.

[0140] In certain embodiments, the weight ratio of silicone to acrylate in the silicone-acrylic hybrid pressure-sensitive adhesive is 5:95 to 95:5, or 20:80 to 80:20, or 40:60 to 60:40, or the silicone to acrylate ratio is about 50:50. Suitable commercially available silicone-acrylic hybrid pressure-sensitive adhesives include 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 DuPont™ in n-heptane or ethyl acetate. For example, 7-6102 silicone-acrylic hybrid PSA, which has a 50 / 50 silicone / acrylate ratio, is characterized by a solution viscosity of 2,500 cP at about 50% solids content in ethyl acetate at 25° C. and a complex viscosity of 1.0e7 poise at 0.1 rad / s at 30° C. 7-6302 silicone acrylic hybrid PSA with a 50 / 50 silicone / acrylate ratio has a solution viscosity of 1,500 cP at approximately 50% solids content in ethyl acetate at 25°C and a complex viscosity of 4.0e6 poise at 0.1 rad / s at 30°C.

[0141] Depending on the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is provided, the silicone and acrylic phases are arranged differently, providing a continuous silicone or acrylic external phase and a corresponding discontinuous internal phase. When the silicone-acrylic hybrid pressure-sensitive adhesive is provided in n-heptane, the composition comprises a continuous silicone external phase and a discontinuous acrylic internal phase. When the silicone-acrylic hybrid pressure-sensitive adhesive is provided in ethyl acetate, the composition comprises a continuous acrylic external phase and a discontinuous silicone internal phase. After evaporation of the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is provided, the phase arrangement of the resulting pressure-sensitive adhesive film or layer corresponds to that of a solvent-borne adhesive coating composition. For example, in the absence of a substance that can induce a phase reversal 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 external 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 external phase and a discontinuous silicone internal phase. The phase arrangement 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 adhered to a siliconized release liner. If the siliconized release liner cannot be peeled or is barely peeled from the pressure-sensitive adhesive film (laminated to a backing film) due to blocking of the two silicone surfaces, the pressure-sensitive adhesive film contains a continuous silicone outer phase. Blocking occurs due to the adhesion of two silicone layers with similar surface energies. The silicone adhesive spreads well on the siliconized liner and therefore forms a good bond to the liner. If the siliconized release liner is easily peeled, the pressure-sensitive adhesive film contains a continuous acrylic outer phase. The acrylic adhesive spreads poorly due to the different surface energies, resulting in low or no adhesion to the siliconized liner.

[0142] 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 functionality. It should be understood that the silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality may contain only acrylate functionality, only methacrylate functionality, or both acrylate and methacrylate functionality.

[0143] The silicone-acrylic hybrid pressure-sensitive adhesive may comprise the reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone-acrylic hybrid pressure-sensitive adhesive is the product of a chemical reaction between these reactants ((a), (b), and (c)). In particular, the silicone-acrylic hybrid pressure-sensitive adhesive may comprise the reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) a (meth)acrylate monomer, and (c) an initiator (i.e., in the presence of an initiator). That is, the silicone-acrylic hybrid pressure-sensitive adhesive may comprise the product of a chemical reaction between these reactants ((a), (b), and (c)).

[0144] The reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, (b) an ethylenically unsaturated monomer, and (c) an initiator can comprise a continuous silicone external phase and a discontinuous acrylic internal phase, or the reaction product of (a), (b), and (c) can comprise a continuous acrylic external phase and a discontinuous silicone internal phase.

[0145] Silicone acrylic hybrid polymers may include the 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.

[0146] The silicone acrylic hybrid polymer may comprise the reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, where the silicone resin comprises triorganosiloxy units RSiO, where R is an organic group. 1 / 2 and tetrafunctional siloxy units SiO 4 / 2 Each SiO 4 / 2 0.1~0.9R3SiO 1 / 2 Included in the molar ratio of units.

[0147] 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)acrylates, dialkoxyalkylsilyl (meth)acrylates, and mixtures thereof, or contains end-capped alkoxysilyl functional groups. The alkoxysilyl functional groups may preferably be selected from the group consisting of trimethoxysilyl groups, dimethoxymethylsilyl groups, triethoxysilyl groups, diethoxymethylsilyl groups, and mixtures thereof.

[0148] The acrylic polymer may be prepared from a mixture containing a polysiloxane-containing monomer, preferably a mixture containing polydimethylsiloxane mono(meth)acrylate.

[0149] Silicone acrylic hybrid polymers may be prepared by a) reacting a silicone polymer with a silicone resin to form a resultant product, and b) reacting the resultant product of a) with an acrylic polymer containing reactive functional groups, wherein the components are reacted in an organic solvent.

[0150] Silicone acrylic hybrid polymers may be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functional groups to form a resultant product, and b) reacting the resultant product of a) with a silicone polymer, wherein the components are reacted in an organic solvent.

[0151] Silicone acrylic hybrid polymers may be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functional groups to form a resultant product, and b) reacting the resultant product of a) with a silicone resin, wherein the components are reacted in an organic solvent.

[0152] Further suitable acrylic polymers, silicone resins and silicone polymers that can be used to chemically react silicone polymers, silicone resins and acrylic polymers to provide silicone acrylic hybrid polymers in accordance with the previous paragraph are described in detail in WO2010 / 124187. Polymers based on natural or synthetic rubber

[0153] Polymers based on natural or synthetic rubber include hydrocarbon polymers such as (natural and synthetic) polyisoprene, polybutylene, polyisobutylene, styrene / butadiene polymers, styrene-isoprene-styrene block copolymers, butyl rubber, polyacrylonitrile, halogen-containing polymers such as polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, polychlorodiene, and other copolymers thereof, etc. The polymers may be used in particular in combination with a tackifier as defined below.

[0154] According to certain embodiments, the polymer may be a styrenic triblock copolymer selected from the group consisting of styrene-ethylene-styrene (SES) block copolymers, styrene-butadiene-styrene (SBS) block copolymers, styrene-isoprene-styrene (SIS) block copolymers, styrene-ethylene / butylene-styrene (S-EB-S) block copolymers, styrene-ethylene / butylene / propylene-styrene (s-EBS-S) block copolymers, styrene-isoprene / butadiene-styrene (S-IB-S) block copolymers, and mixtures thereof.

[0155] In certain embodiments, the polymer may be at least one SIS block copolymer. The at least one SIS block copolymer may be composed of three blocks of polystyrene, polyisoprene, and polystyrene, and particularly has 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 in a ratio of about 15:85 (%) or about 22:78 (%).

[0156] In other embodiments, the polymer is at least one polyisobutylene, and may be a combination of two different types of polyisobutylene, particularly a combination of a low molecular weight polyisobutylene and a high molecular weight polyisobutylene. In certain embodiments, the ratio of low molecular weight polyisobutylene to high molecular weight polyisobutylene ranges from 75:25 to 90:10.

[0157] Suitable styrene-isoprene-styrene (SIS) block copolymers according to the present invention are commercially available, for example, under the brand name JSR-SIS. Specific SIS block copolymer-based pressure-sensitive adhesives are available under the trade names JSR-SIS5229 and JSR-SIS5002.

[0158] Suitable polyisobutylenes for use herein are available under the trade name Oppanol®. Combinations of high molecular weight polyisobutylene (B100 / B80) and low molecular weight polyisobutylenes (B10, B11, B12, B13) may be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene range from 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 M of 1,110,000. v , and a weight average molecular weight M of 1,550,000 w, and an average molecular weight distribution M of 2.9 w / M n Oppanol® B10 has a viscosity average molecular weight M of 40,000. v , and a weight average molecular weight M of 53,000 w , and an average molecular weight distribution M of 3.2 w / M n 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.

[0159] Silicone Gel Adhesive Silicone gel adhesives are elastic, jelly-like materials formed by lightly crosslinked silicone polymers. Therefore, in contrast to the silicone-based polymers used herein, silicone gel adhesives are based on curable gel-forming compositions. When used in the skin-contacting layer, silicone gel adhesives provide adhesion of medical patches to the skin while simultaneously reducing the problem of skin irritation. Furthermore, drug delivery in medical patches is not adversely affected, and surprisingly, skin permeation behavior is improved.

[0160] Silicone gel adhesives, also called silicone gels, are described, for example, in WO2011 / 022199A2.

[0161] Silicone gel adhesives are generally formed from linear or branched silicones having reactive groups thereon. These reactive groups undergo crosslinking reactions during curing. An example of a crosslinking reaction is a hydrosilylation reaction 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 US Pat. No. 5,656,279, US Pat. No. 5,891,076, EP 0322118, and US Pat. No. 4,991,574, which are incorporated herein by reference. An alternative reaction is condensation curing, in which alkoxy- and / or hydroxy-containing siloxanes are cured with a catalyst, as described in US Pat. No. 4,831,070, which is incorporated herein by reference.

[0162] Generally, silicone gel adhesives are obtained by reacting a gel-forming composition containing (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane containing silicon-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of SiH groups with Si-alkenyl groups. These compositions cure at normal ambient temperatures, but curing can be accelerated by heating to elevated temperatures, e.g., 40-140°C, or by exposure to UV light.

[0163] Suitable alkenyl groups contain 2 to about 6 carbon atoms and are exemplified by, but not limited to, vinyl, allyl, and hexenyl. The alkenyl groups in this component may be located at terminal, 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 monovalent hydrocarbon groups free of aliphatic unsaturation and monovalent halogenated hydrocarbon groups. These groups typically contain 1 to about 20 carbon atoms, alternatively 1 to 8 carbon atoms, and are exemplified by, but not limited to, alkyl groups such as methyl, ethyl, propyl, and butyl; aryl groups such as phenyl; and halogenated alkyl groups such as 3,3,3-trifluoropropyl. Typically, at least 50% of the organic groups in the alkenyl-substituted polydiorganosiloxane are methyl. The structure of the alkenyl-substituted polydiorganosiloxane is typically linear, but may contain some branching due to the presence of trifunctional siloxane units. The viscosity of the alkenyl-substituted polydiorganosiloxane can be any desired one. For example, 2 / s super~100,000mm 2 / s, or 50mm 2 / s~80,000mm 2 / s, or 300 mm 2 / s~3,000mm 2 It can be / s.

[0164] Methods for preparing the alkenyl-substituted polydiorganosiloxanes (i) of the present invention, such as condensation of the corresponding halosilanes or equilibration of cyclic polydiorganosiloxanes, are well known in the art.

[0165] The alkenyl-substituted polydiorganosiloxane can be used in the gel-forming composition in an amount of from 10% to 90%, alternatively from 40% to 90%, alternatively from 50% to 80% by weight, based on the weight of the composition. The amount of alkenyl groups present in the alkenyl-substituted polydiorganosiloxane typically ranges from 0.05 to 1%, alternatively from 0.05 to 1%, based on the weight of the alkenyl-substituted polydiorganosiloxane.

[0166] Organosiloxanes containing silicon-bonded hydrogen atoms (ii) are also known in the art, as described, for example, in U.S. Pat. No. 3,983,298. The hydrogen atoms in this component may be located at terminal, pendant (non-terminal), or both terminal and pendant positions. The remaining silicon-bonded organic groups in this component are independently selected from the group consisting of monovalent hydrocarbon groups and monovalent halogenated hydrocarbon groups free of aliphatic unsaturation. These groups typically contain from 1 to about 20 carbon atoms, alternatively from 1 to 8 carbon atoms, and include, but are not limited to, alkyl groups such as methyl, ethyl, propyl, and butyl; aryl groups such as phenyl; and halogenated alkyl groups such as 3,3,3-trifluoropropyl. In one embodiment of the present invention, at least 50% of the organic groups in the silicon-bonded hydrogen-containing organosiloxane are methyl. The structure of the silicon-bonded hydrogen-containing organosiloxane is typically linear, but may contain some branching due to the presence of trifunctional siloxane units. The viscosity of the organosiloxane containing silicon-bonded hydrogen atoms can be any desired value. For example, 2 / s super~100,000mm 2 / s, or 5mm 2 / s~500mm 2 It can be / s.

[0167] Methods for preparing the organosiloxanes containing silicon-bonded hydrogen atoms of the present invention by cohydrolysis of appropriate chlorosilanes are known in the art, and the following references are all incorporated herein by reference: U.S. Patent No. 2,877,255 to Clark; Japanese Laid Open Patent Application (KOKAI) SHO62 (1987)-39660 to Mogi et al.; and U.S. Patent Nos. 5,446,185 and 5,493,040 to Cobb et al.

[0168] The organosiloxane containing silicon-bonded hydrogen atoms can be used in the gel-forming composition in an amount of from 1 wt. % to 30 wt. %, alternatively from 5 wt. % to 20 wt. %, alternatively from 5 wt. % to 15 wt. %, based on the weight of the composition. In one embodiment, the amount of hydrogen groups present in the organosiloxane containing silicon-bonded hydrogen atoms is from 0.05 wt. % to 1.44 wt. %, based on the weight of the organosiloxane containing silicon-bonded hydrogen atoms.

[0169] In the gel-forming composition, (i) and (ii) are preferably 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.

[0170] The hydrosilylation catalyst (iii) promotes the addition reaction between alkenyl-substituted polydiorganosiloxanes and organosiloxanes containing silicon-bonded hydrogen. Any of the known hydrosilylation catalysts can be used, including platinum group metals, compounds containing platinum group metals, and microencapsulated platinum group metals or compounds containing platinum group metals. These platinum group metals include platinum, rhodium, ruthenium, palladium, osmium, and iridium. Platinum and platinum compounds are preferred catalysts because of their high activity in hydrosilylation reactions. One type of platinum catalyst is the complex of chloroplatinic acid with certain vinyl-containing organosiloxane compounds disclosed by Willig in U.S. Pat. No. 3,419,593 (incorporated herein by reference). A specific catalyst of this type is the reaction product of chloroplatinic acid with 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane.

[0171] The hydrosilylation catalyst is present in an amount sufficient to cure the compositions of the present invention. Typically, the concentration of the catalyst is sufficient to provide from 0.1 ppm to 500 ppm (parts per million), alternatively from 1 ppm to 100 ppm, alternatively from 1 ppm to 50 ppm, of platinum group metal, based on the weight of (i) and (ii).

[0172] In view of the above, in one embodiment of the present invention, a silicone gel adhesive is obtained by reacting (i) a gel-forming composition comprising a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst, wherein (i) and (ii) are preferably 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.

[0173] An optional component is a hydroxy-substituted silicone resin as described in U.S. Patent Application No. 2007-0202245, which is incorporated herein by reference. This resin typically has the formula R3 3SiO 1 / 2 a group having the formula SiO 4 / 2 where R 3 is an alkyl group having 1 to 6 carbon atoms or an alkylene group 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-%, alternatively 5 mol-%. The number ratio of M groups to Q groups is typically in the range of 0.6:1 to 4:1, alternatively 0.6:1 to 1.0:1. Silicone resins typically contain 0.1% to 5% by weight, alternatively 1.0% to 5% by weight, of silicon-bonded hydroxy groups.

[0174] The resin can be used in the gel-forming composition in an amount of 2% to 45% by weight, alternatively 5% to 40% by weight, alternatively 10% to 35% by weight, based on the weight of the gel-forming composition and resin.

[0175] Thus, in one embodiment, the silicone gel adhesive may be a silicate resin-reinforced silicone gel adhesive containing from about 2 to about 45 weight percent of at least one hydroxyl-substituted silicate resin.

[0176] According to certain embodiments, the silicone gel adhesive is a two-part silicone adhesive system that cures upon mixing of the two components. Commercially available examples of such two-part silicone adhesives include Liveo™ Soft Skin Adhesives (e.g., MG7-9700, MG7-9800, MG7-9850, and MG7-9900), which are provided as kits containing components A and B. These are platinum-catalyzed, soft, filler-free, elastomeric silicone adhesives for adhering medical devices to skin with moderate adhesion and gentle release. The two components, A and B, are preferably mixed in a 1:1 ratio.

[0177] The silicone gel adhesive layer can be produced by processes known in the art. For example, the gel can be preformed (e.g., as a sheet) onto a substrate such as a liner by molding, calendaring, extruding, spraying, brushing, hand-spreading, casting, or coating. Alternatively, the silicone gel layer can be produced by applying a gel-forming composition to the substrate by spraying, coating, bar coating, etc. The gel-forming composition applied to the substrate is cured to produce a silicone gel adhesive on the substrate.

[0178] Further additives The self-adhesive layer structure of the present invention, particularly the active layer, may further comprise at least one additive or excipient. The additive or excipient is preferably selected from the group consisting of additional polymers, crosslinkers, crystallization inhibitors, solubilizers, fillers, tackifiers, plasticizers, stabilizers, emollients, skin care substances, permeation enhancers, pH adjusters, and preservatives. Such additives may be present in the active layer in an amount of 0.001 to 15 wt. %, e.g., 1 to 10 wt. %, or 0.01 to 5 wt. %, based on the total weight of the active layer. In certain embodiments, the total amount of all additives is 0.001% to 25% of the matrix layer composition. Hereinafter, when a range of amounts for a particular additive is provided, such range refers to the amount per individual additive.

[0179] It should be noted that in pharmaceutical formulations, formulation components are categorized according to their physicochemical and physiological properties and according to their functions. This particularly means that substances or compounds classified in one category do not exclude being classified in another category of formulation components. For example, a certain polymer may be a crystallization inhibitor but also a tackifier. Some substances, for example, are typical emollients while simultaneously acting as permeation enhancers. Those skilled in the art can determine to which category(ies) of formulation components a substance or compound belongs based on general knowledge. Details regarding excipients and additives are provided below, but these should not be understood as being exclusive. Other substances not explicitly listed herein may also be used in accordance with the present invention, and substances and / or compounds explicitly listed in one category of formulation components are not excluded from use as other formulation components within the meaning of the present invention.

[0180] In certain embodiments, the active layer may further comprise an additional polymer, preferably selected from dimethylpolysiloxane and ethylcellulose. For example, dimethylpolysiloxane, such as dimethicone, is preferably used to increase the adhesiveness of the active layer, and ethylcellulose preferably functions as a viscosity-increasing agent. Other polymers of particular interest include polymers with enhanced water absorption capabilities, since increased water and / or moisture absorption helps maintain / improve the adhesiveness of the self-adhesive layer structure. Therefore, the active layer may further comprise at least one additional polymer selected from polymers that improve the water and / or moisture absorption of the matrix layer. Such polymers are well known in the art. Among them, polyvinylpyrrolidone, particularly soluble polyvinylpyrrolidone, is particularly suitable and preferred. Other polymers, in particular, reduce cold flow and are therefore suitable as additional polymers. Such polymer compositions often exhibit the ability to flow very slowly despite very high viscosity, so that the polymer matrix may exhibit cold flow. Thus, during storage, the matrix may flow to some extent beyond the edges of the backing layer. This is a storage stability issue that can be prevented by adding certain polymers. For example, basic acrylate polymers (e.g., Eudragit E100, a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate) can be used to reduce low-temperature flow. Therefore, the active layer may additionally contain a basic polymer, particularly an amine-functional acrylate such as Eudragit E100. The additional polymer may be present, for example, in an amount of 0 to 20% of the active layer, preferably 0.5 to 5% or 5 to 15% of the active layer.

[0181] In certain embodiments, the active layer may further comprise a crosslinking agent. The crosslinking agent may be selected from the group consisting of aluminum and titanium crosslinkers, such as aluminum acetylacetonate, titanium acetylacetonate, or polybutyl titanate, preferably a titanium crosslinker. The amount of crosslinking agent may range from 0.005 to 1%, preferably 0.01 to 0.1%, of the active layer. The active layer may also comprise a self-crosslinking polymer, i.e., a polymer containing crosslinkable functional groups, such as glycidyl groups, that react upon heating. Thus, the active layer preferably comprises the above-described crosslinking agent and self-crosslinking polymer.

[0182] In certain embodiments, the active layer may further comprise a crystallization inhibitor. Suitable examples of crystallization inhibitors include polyvinylpyrrolidone, vinyl acetate / vinylpyrrolidone copolymers, and cellulose derivatives. The crystallization inhibitor is preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone. The crystallization inhibitor may increase the solubility of the active agent or inhibit the crystallization of the active agent. The crystallization inhibitor may be present in an amount of 0.5 to 10 wt % based on the total weight of the active layer.

[0183] In certain embodiments, the active layer may further comprise a solubilizer. The solubilizer preferably improves the solubility of the active agent in the active layer. Preferred solubilizers include, for example, glycerol esters, polyglycerol esters, propylene glycol esters, and polyoxyethylene esters of medium- and / or long-chain fatty acids, such as glyceryl monolinoleate, medium-chain glycerides, and medium-chain triglycerides, nonionic solubilizers made by reacting castor oil with ethylene oxide, and any mixtures thereof that may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and their derivatives, such as hydroxypropyl cellulose and hypromellose acetate succinate; various cyclodextrins and their derivatives; nonionic triblock copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, known as poloxamers. copolymers; water-soluble derivatives of vitamin E; pharmaceutical-grade or agglomerated 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, refined grades of polyethylene glycol 400, refined grades of polyoxyethylene sorbitan monooleate (such as polysorbate 80), or refined grades of 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, the permeation enhancers mentioned below can also act as solubilizers. Additionally, crystallization inhibitors can also act as solubilizers.

[0184] Fillers such as silica gel, titanium dioxide, and zinc oxide may be used in conjunction with the active layer to affect certain physical parameters such as cohesiveness and bond strength in a desired manner.

[0185] If the active layer needs to be self-adhesive and one or more polymers selected do not provide sufficient self-adhesion, a tackifier is added. The tackifier may be selected from polyvinylpyrrolidone (which can maintain the adhesiveness of the matrix layer due to its ability to absorb water and can therefore be considered a tackifier in the 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. The tackifier may be present in an amount of 5 to 15% of the active layer.

[0186] In certain embodiments, the active layer may further comprise an emollient / plasticizer. Exemplary emollients / plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, and polyethylene glycols.

[0187] In certain embodiments, the active layer may further comprise a stabilizer, 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. A combination of tocopherol and ascorbyl palmitate is also particularly preferred. When the active layer comprises a stabilizer, the amount of stabilizer may be 0.001 to 2% of the active layer.

[0188] In certain embodiments, the active layer may further comprise a skin care substance. Such substances may be used to avoid or reduce skin irritation, as may be detected by a skin response score. Suitable skin care substances include sterol compounds such as cholesterol, dexpanthenol, α-bisabolol, and antihistamines.

[0189] In certain embodiments, the active layer may further comprise a permeation enhancer. A permeation enhancer is a substance that affects the barrier properties of the stratum corneum, thereby increasing the permeability of the active agent. Examples of permeation enhancers include polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives (such as allantoin); polar solvents such as dimethyldecylphosphoxide, methyl cetyl sulfoxide, dimethylourarylamine, dodecylpyrrolidone, isosorbitol, dimethyl acetonide, dimethyl sulfoxide, decylmethyl sulfoxide, and dimethylformamide; salicylic acid, amino acids, benzyl nicotinate, and high molecular weight aliphatic surfactants such as lauryl sulfate. Other agents include oleic acid, linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate, tocopherol linoleate, propyl oleate, isopropyl palmitate, etc. When the active layer further comprises 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. Particularly preferably, the active layer comprises a permeation enhancer selected from diethylene glycol monoethyl ether.

[0190] In certain embodiments, the active layer may further comprise a pH adjuster. Suitable pH adjusters include mild acids and bases, including amine derivatives, inorganic alkali derivatives, and polymers with basic or acidic functionality.

[0191] In certain embodiments, the active layer may further comprise a preservative. Suitable preservatives include parabens, formaldehyde-releasing agents, isothiazolinones, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid, and anisic acid.

[0192] hexagonal shape According to the present invention, the self-adhesive layer structure has a hexagonal shape provided by the backing layer and the active layer, or the backing layer, the active layer and the additional skin-contacting layer, respectively. The hexagonal shape comprises at least one hexagon, All pairs of opposite sides of the hexagon are parallel, The sides of the hexagon have a length of 0.2 to 10 cm.

[0193] The hexagonal shape can include 1 to 10 hexagons, e.g., 1, 2, 3, 4, or 5 hexagons, and preferably the hexagons are adjacent and / or non-overlapping. Two or more hexagons are preferably integrally connected to one another. Preferred hexagonal shapes do not include perforations.

[0194] In certain embodiments, the at least one hexagon is at least one convex hexagon, and the hexagonal shape includes at least one convex hexagon, where pairs of opposing sides of the convex hexagon are all parallel, and the sides of the convex hexagon have a length of 0.2 to 10 cm. In certain embodiments, the hexagonal shape includes one or two convex hexagons, particularly those integrally connected to each other. In certain embodiments, the hexagonal shape is a convex hexagon.

[0195] The hexagonal shape of the self-adhesive layer structure plays a crucial role in making medical patches including the self-adhesive layer structure easy and time-saving to handle. It allows for easy coverage of skin areas without cutting before application, thus reducing the risk of contaminating the cutting tool or fingers with the active agent, and also reducing the risk of contaminating the patch at the cut end. Furthermore, the self-adhesive layer structure can cover uneven or rounded skin surfaces without wrinkling, ensuring complete adhesion, and making it easy to surround complex areas such as fingers and toes. In particular, when the hexagonal shape includes at least one convex hexagon, the hexagonal shape requires only a short side length relative to the provided area, reducing the risk of peeling off the edges of the medical patch.

[0196] In certain embodiments, the hexagonal shape is a double hexagon formed from two identical convex hexagons that share two adjacent vertices at a common side. A double hexagon is obtained by mirroring a single convex hexagon about one of its sides (the mirror axis), where the mirror axis includes the common side. In certain embodiments, the double hexagon can be split at the common side to obtain two equal convex hexagons that can be affixed together or separately. Thus, in certain embodiments, the hexagonal shape is a double hexagon formed from two identical convex hexagons that share two adjacent vertices at a common side, and the common side is perforated to allow for easy separation.

[0197] In certain embodiments, the hexagonal shape is a hexagon or a double hexagon, particularly a convex hexagon or double hexagon formed from two identical convex hexagons sharing two adjacent vertices on a common side, preferably having an area of ​​20 cm or less. 2 Ultra, for example, 24cm 2 Super, 30cm 2 Over 40cm 2 More than 150 cm 2 Less than, for example, 60cm 2 Less than or equal to 35cm 2 is less than.

[0198] Hexagonal shapes, particularly convex hexagons or double hexagons, can have mirror symmetry and / or rotational symmetry. Preferred hexagonal shapes are mirror symmetric with at least one axis of symmetry, for example, two, three, or four axes of symmetry, particularly six axes of symmetry. Alternatively or additionally, preferred hexagonal shapes are rotationally symmetric with at least two, for example, three or four, degrees, particularly six-fold rotational symmetry. Thus, particularly preferred hexagonal shapes are mirror symmetric with at least four axes of symmetry and / or have at least four-fold rotational symmetry, particularly mirror symmetric with six axes of symmetry, and further have six-fold rotational symmetry.

[0199] The hexagon, particularly the convex hexagon according to the present invention, has three pairs of parallel opposite portions, which may be of different or equal lengths.In certain embodiments, the lengths of the two sides of each pair of parallel opposite sides are equal, that is, the hexagon is a parallel polygon.A parallel polygon can be obtained by elongating a parallelogram, which has two-fold rotational symmetry, or by elongating a rhombus, which has two-fold rotational symmetry and is mirror symmetric with two symmetry axes.

[0200] In certain embodiments, the six sides of the hexagon, particularly the convex hexagon, are of equal length, i.e., the hexagon is equilateral. Alternatively, the hexagon is scalene, having three sides of equal length and three other sides of equal length. The three sides of equal length and the other three sides of equal length are preferably alternated. Such a hexagon is preferably mirror-symmetric with three axes of symmetry. In another alternative, the hexagon is non-equilateral, having four sides of equal length and two other sides of equal length. This particularly includes hexagons obtained by elongating a rhombus.

[0201] In certain embodiments, the hexagon is trapezoidal, with the ratio of the shortest side to the longest side being 1:4 or less, 1:3 or less, 1:2 or less, 1:1.5 or less, or about 1:1.

[0202] The sides of the hexagon according to the present invention have a length of 0.2 to 10 cm. In certain embodiments, the sides of the hexagon have a length of 0.3 to 8 cm, 0.5 to 4 cm, 0.8 to 3.5 cm, or 0.9 to 2.0 cm. In further embodiments, the sides of the hexagon have a length of 2.8 to 8 cm, 2.8 to 7.5 cm, 2.8 to 4 cm, 2.8 to 3.5 cm, or 2.8 to 3.2 cm. In certain embodiments, two, three, four, or six sides of the hexagon have a length of about 0.5 cm, about 0.9 cm, about 1.5 cm, about 1.8 cm, about 2.8 cm, or about 3.2 cm. For example, - two sides of the hexagon have a length of about 0.5 cm, about 0.9 cm, or about 1.5 cm, and four sides of the hexagon have a length of about 1.8 cm, about 2.8 cm, or about 3.2 cm; or - three sides of the hexagon have lengths of about 0.5 cm, about 0.9 cm, or about 1.5 cm, and three sides of the hexagon have lengths of about 1.8 cm, about 2.8 cm, or about 3.2 cm; or Four sides of the hexagon have lengths of about 0.5 cm, about 0.9 cm, or about 1.5 cm, and two sides of the hexagon have lengths of about 1.8 cm, about 2.8 cm, or about 3.2 cm.

[0203] The height of the hexagon can range from 0.3 to 17 cm, 0.8 to 12.5 cm, 1.3 to 6 cm, or 1.5 to 3.5 cm. The width of the hexagon can range from 0.4 to 20 cm, 1 to 15 cm, 1.6 to 7 cm, or 1.8 to 4 cm.

[0204] In certain embodiments, the hexagons have an aspect ratio (height to width ratio) of 4:1 or less, 3:1 or less, 2:1 or less, 1.5:1 or less, or √3:2 or less. In certain embodiments, the aspect ratio of the hexagons is √3:2 or less.

[0205] In certain embodiments, the hexagon, particularly the convex hexagon, is equiangular. Such a convex hexagon has each interior angle equal to 120°. Alternatively, the hexagon is irregular, with the smallest angle being 60° or greater, 80° or greater, 90° or greater, or 110° or greater. In particular, the smallest angle is 60° or greater, 80° or greater, 90° or greater, 110° or greater, and less than 120°. In certain embodiments, the hexagon has two interior angles (minor angles) of equal size and four other interior angles (major angles) of equal size, with the minor angles being approximately 90°.

[0206] In a further embodiment, the hexagon, particularly the convex hexagon, is a regular hexagon. Such a regular hexagon is preferably mirror symmetric with six axes of symmetry and further has six-fold rotational symmetry. In one embodiment, the hexagonal shape is a bicontiguous hexagon formed from two identical convex hexagons that share two adjacent vertices on a common side, and the two identical convex hexagons are regular hexagons.

[0207] Furthermore, according to a particular embodiment, the area of ​​the hexagonal shape is 20 cm 2 Ultra, for example, 24cm 2 Super, 30cm 2 Over 40cm 2 More than 150 cm 2 Less than, for example, 60cm 2 Less than or equal to 35cm 2 is less than.

[0208] Medical patches and medical patch sheets According to the present invention, the above-described self-adhesive layer structure is used in a medical patch comprising a self-adhesive layer structure disposed on a release liner, and also in a medical patch sheet comprising multiple self-adhesive layer structures disposed on a release liner.

[0209] The medical patch(es) can be either topical medical patch(es) or transdermal therapeutic system(s). In certain embodiments, the medical patch(es) are topical medical patch(es) specifically for the topical administration of capsaicin.

[0210] In one embodiment, the present invention relates to a medical patch, the medical patch comprising: a self-adhesive layer structure as described herein; a release liner; The release liner may be coextensive with the self-adhesive layer structure or may extend beyond the boundaries of the self-adhesive layer structure in all directions.

[0211] In another embodiment, the present invention relates to a medical patch sheet, the medical patch sheet comprising: two or more self-adhesive layer structures as described herein; a release liner; The release liner may be coextensive with the self-adhesive layer structure or may extend beyond the boundaries of the self-adhesive layer structure in all directions.

[0212] The release liner protects the self-adhesive layer structure(s) and must be removed before application. The self-adhesive layer structure(s) can be easily peeled off the release liner and applied to the patient's skin individually or in combination. In certain embodiments, the release liner in the medical patch sheet is not intended to be separated from the self-adhesive layer structure(s) and remains intact after peeling one or more of the self-adhesive layer structure(s) from the sheet. This is advantageous because it makes it easier to peel the self-adhesive layer structure(s) from the release liner, which expands the area of ​​the layer structure, and eliminates the need to discard a separate release liner for each self-adhesive layer structure. Therefore, in such embodiments, the release liner does not include any means for simultaneously tearing off portions of the release liner.

[0213] When the release liner extends beyond the boundary of the self-adhesive layer structure, the release liner may be covered by a boundary layer structure having the same layer design (i.e., including a backing layer, an active layer containing polymer I and an active agent, and optionally a skin-contacting layer) and the same layer thickness and composition as the self-adhesive layer structure, adjacent to the self-adhesive layer structure and coextensive with the outer boundary of the release liner. Such a medical patch sheet can be conveniently produced by first preparing a sheet of the desired layer structure laminated with a release liner, and then dividing the layer structure through the backing layer, the active layer, and the optional skin-contacting layer (if present) by punching, cutting, or slitting to a controlled depth, while preserving at least a portion of the release liner, to obtain a number of self-adhesive layer structures disposed on the release liner surrounded by the boundary layer structure.

[0214] By using multiple self-adhesive layer structures, the surface of the skin area to be treated can be spread without wrinkles by placing the self-adhesive layer structures side by side, whereby gaps and / or overlaps can be avoided due to the hexagonal shape(s) of the self-adhesive layer structures.

[0215] The number of self-adhesive layer structures provided for peeling from the release liner depends on the size(s) of the self-adhesive layer structures. Suitable sheets of medical patches include 2 to 400, 4 to 300, 6 to 120, or 8 to 30 self-adhesive layer structures. In certain embodiments, medical patch sheets include 2 to 15 or 150 to 300 self-adhesive layer structures. In certain embodiments, medical patch sheets include 3, 4, 5, 6, 7, or 8 self-adhesive layer structures. Alternatively, medical patch sheets may include 150, 180, 200, 240, or 300 self-adhesive layer structures. The self-adhesive layer structures may be equal or different.

[0216] The self-adhesive layer structures can be arranged on the release liner in any pattern, either adjacent to each other (tiled flat surfaces) or with small gaps to facilitate gripping of a single self-adhesive layer structure (see Figures 2a, 2b, and 2c). In certain embodiments, the self-adhesive layer structures are arranged on the release liner in a space-saving manner. In particular, the self-adhesive layer structures are arranged side by side on the release liner. Thus, the self-adhesive layer structures can be arranged in two or more parallel rows relative to the longitudinal axis of the release liner, each row preferably containing 2 to 20, 3 to 12, or 4 to 8 self-adhesive layer structures. For example, the self-adhesive layer structures can be arranged in 20 rows, each row containing 15 self-adhesive layer structures, in particular 15 equal self-adhesive layer structures.

[0217] In a particular embodiment, the self-adhesive layer structures are arranged like tiles on a plane. Preferred self-adhesive layer structures for tiling a plane are parallel polygons, in particular regular hexagons. The self-adhesive layer structures may also have a hexagonal shape selected from a regular hexagon and / or a double hexagon formed by two identical regular hexagons, sharing two adjacent vertices and a common side. The self-adhesive layer structures may be separate from each other or connected to each other.

[0218] In certain embodiments, the self-adhesive layer structures are adjacent to each other by sharing two adjacent vertices and their common edge, and are separated from each other by cutting the common edge to allow them to be peeled independently from the release liner. Alternatively, the active agent-containing layer structures are adjacent to each other by sharing two adjacent vertices and their common edge, and are connected to each other by a weakened common edge to allow them to be easily peeled. In particular, the common edge is perforated to allow them to be easily torn. The medical patch sheet may also include self-adhesive layer structures, such as self-adhesive layer structures that are adjacent to each other by sharing two adjacent vertices and their common edge, some of which are separated from each other by cutting the common edge to allow them to be peeled independently from the release liner, and some of which are connected to each other by a weakened common edge to allow them to be easily torn. For example, the self-adhesive layer structures may be arranged in two or more parallel rows relative to the longitudinal axis of the release liner, each row containing 2 to 20 self-adhesive layer structures, the self-adhesive layer structures being adjacent to each other by sharing two adjacent vertices and a common edge, the rows being separated from each other for independent peeling, and the self-adhesive layer structures within a row being connected to each other by a common edge that is perforated for easy peeling. In certain embodiments, all of the self-adhesive layer structures are separated from each other by cutting the common edge so that they can be independently peeled from the release liner.

[0219] In certain embodiments, the self-adhesive layer structures are connected to one another by at least one, preferably two or more, common fastening bridges for joint release from the release liner. The fastening bridge(s) may provide a single point(s) at which the self-adhesive layer structures are connected to one another, even when adjacent or common edges are at least partially cut and separated from one another. This allows the self-adhesive layer structures connected in this manner to be jointly released from the release liner and applied to the patient's skin, which is particularly advantageous for multiple and / or small-area self-adhesive layer structures. Alternatively, for joint release when there are only a small number of such connected self-adhesive layer structures, some of the fastening bridge(s) can be cut, e.g., torn. In certain embodiments, the common fastening bridge is provided at the vertex and connects at least two, preferably three, self-adhesive layer structures. Alternatively, the common fastening bridge may be provided at a side to connect two self-adhesive layer structures. In a preferred medical patch sheet, all adjacent self-adhesive layer structures are connected to each other two by two common fastening bridges at two adjacent vertices or at their common edges, preferably at two adjacent vertices. In a specific embodiment, all adjacent self-adhesive layer structures are connected to each other three by common fastening bridges at common vertices. This particularly relates to self-adhesive layer structures that tile a plane. Thus, in one embodiment of the medical patch sheet according to the present invention, the self-adhesive layer structures are regular hexagons and are connected to each other by at least one fastening bridge for joint release from the release liner, and all adjacent self-adhesive layer structures are connected to each other three by common fastening bridges at common vertices (as shown in FIG. 3).

[0220] In certain embodiments, the self-adhesive layer structure has a hexagonal shape selected from a total of two or three different shapes. In certain embodiments, the self-adhesive layer structure has a hexagonal shape including a convex hexagon and a double hexagon consisting of two identical convex hexagons that share two adjacent vertices and a common side, particularly a regular hexagon and a double hexagon consisting of two identical regular hexagons. Alternatively, all of the self-adhesive layer structures have the same hexagonal shape. In certain embodiments, the self-adhesive layer structure is a double hexagon formed from two identical convex hexagons that share two adjacent vertices and a common side, particularly a double hexagon formed from two identical regular hexagons. In this context, a (regular) convex hexagon or a double hexagon formed from two identical (regular) convex hexagons is congruent.

[0221] The self-adhesive layer structure of the medical patch sheet according to the present invention may contain the same or different active agent(s).

[0222] In certain embodiments, a medical patch (a single medical patch) contains capsaicin in an amount of about 179 mg, or alternatively about 60 mg, about 45 mg, about 30 mg, about 25.5 mg, about 10 mg, or about 1 mg. Similarly, a medical patch sheet (all medical patches of the sheet as a whole) may contain capsaicin in an amount of about 179 mg or less. A preferred medical patch sheet is: - a structure of three self-adhesive layers, each containing approximately 60 mg of capsaicin, or - four self-adhesive layers, each containing approximately 45 mg of capsaicin, or - six self-adhesive layers, each containing approximately 30 mg of capsaicin, or - Contains seven self-adhesive layer structures, each containing capsaicin in an amount of approximately 25.5 mg. Alternatively, a preferred medical patch sheet comprises up to 300 self-adhesive layer structures, each layer containing capsaicin in an amount of about 0.6 mg, and preferably the self-adhesive layer structures are regular hexagons and connected to each other by a common fastening bridge for bonding and releasing from the release liner, and adjacent self-adhesive layer structures are all connected to each other in groups of three by a common fastening bridge located at a common vertex.

[0223] In certain embodiments, the medical patch (single medical patch) is 0.1 cm 2 ~280cm 2 , 0.6cm 2 ~150cm 2 , or 1.5 cm 2 ~35cm 2 In certain embodiments, the area of ​​the medical patch is 20 cm 2 Ultra, for example 24cm 2 Super, 30cm 2 Over 40cm 2 More than 150 cm 2 Less than, for example, 60cm 2 Less than or equal to 35cm 2 In certain embodiments, the release area of ​​the medical patch sheet (all medical patches making up the entire sheet) is less than 1 cm 2 ~300cm 2 is.

[0224] Treatment method / medical use The medical patch or medical patch sheet according to the present invention may be suitable for use in methods of treatment, in particular methods of treating human patients. The symptoms and diseases to be treated will vary depending on the active agent contained in the patch.

[0225] When the active agent is capsaicin, the medical patch or medical patch sheet according to the present invention is particularly suitable for use in a method for treating neuropathic pain, in particular chronic neuropathic pain, preferably including postherpetic neuralgia, postoperative neuralgia (e.g., pain after inguinal hernia surgery, postthoracotomy pain or postmastectomy pain), posttraumatic neuropathy, polyneuropathy (e.g., pain associated with diabetic neuropathy), chemotherapy-induced neuropathy, tumor neuropathy, HIV-associated neuropathy, alcohol-associated neuropathy, small fiber neuropathy or complex regional pain syndrome, radiculopathy or compression syndromes such as carpal tunnel syndrome, more preferably peripheral neuropathic pain, postherpetic neuralgia of the hands and feet or neuropathic pain associated with diabetic peripheral neuropathy (DPN), postoperative neuropathic pain, joint pain or cancer pain.

[0226] In relation to the above, the medical patch or medical patch sheet (part thereof) according to the present invention is preferably applied to at least one body surface of a patient, particularly to a part selected from the back, buttocks, legs, feet, or hands. The preferred application time of the medical patch or medical patch sheet according to the present invention is less than or about 60 minutes for the back, buttocks, or legs, and less than or about 30 minutes for the feet or hands.

[0227] Manufacturing Process The medical patch(es) or medical patch sheet(s) according to the present invention can be manufactured by a conventional manufacturing process such as a solvent casting method, which includes the steps of preparing a coating composition containing all the components of the active layer, and coating and drying the coating composition.

[0228] In certain embodiments, particularly for capsaicin-containing patches, the process for producing a medical patch or medical patch sheet according to the present invention comprises: A. 1.1) Coating an active agent-containing coating composition, the composition comprising: (i) Polymer I; (ii) an active agent, coating the composition onto a release liner; 1.2) drying the coated coating composition to provide an active agent-containing self-adhesive layer structure; 1.3) laminating the active agent-containing self-adhesive layer structure with a backing layer.

[0229] Polymer I is preferably at least one silicone-based polymer that is non-curable and therefore typically applied by a solution-based process. Therefore, the at least one silicone-based polymer is preferably provided 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 non-alcoholic solvents, most preferably ethyl acetate or n-heptane.

[0230] The active agent is preferably capsaicin, and is uniformly dissolved or dispersed in the coating composition containing the active agent.In 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 coating composition containing capsaicin in the form of droplets (microreservoir system).The amphiphilic solvent may not be mixed with the solvent for silicone polymer, or may only be slightly mixed.

[0231] The coated active agent-containing coating composition is solidified by drying, preferably at a temperature of 20 to 60°C, or 30 to 40°C.

[0232] In the case of patches that additionally include a skin contact layer, these may include: A. 1.1) Coating an active agent-containing coating composition, the composition comprising: (i) Polymer I; (ii) an active agent, coating the composition onto a first foil; 1.2) drying the coated coating composition to form a matrix layer; 1.3) laminating the active layer with a backing layer; 2.1) Coating an inert coating composition, the composition comprising: (i) at least one alkenyl-substituted polydiorganosiloxane; (ii) at least one organosiloxane containing silicon-bonded hydrogen atoms; and (iii) at least one catalyst for the reaction of SiH groups with Si-alkenyl groups; coating the composition onto a second foil; 2.2) crosslinking the inert coating composition at a temperature of 50°C to 150°C or irradiating with ultraviolet light to form a skin contact layer; 2.3) laminating the skin contact layer with a release liner; It can be manufactured using a process comprising the steps of:

[0233] The inert coating composition forms a silicone gel adhesive in the skin contact layer upon curing, i.e., crosslinking of the reactive groups of the silicone polymer. Crosslinking is preferably carried out at temperatures between 40 and 140°C.

[0234] The active layer and the skin contact layer are preferably prepared separately as described above, and then laminated together by removing the foil and then laminating the open sides of the two layers together to obtain a self-adhesive layer structure of a medical patch, or two or more self-adhesive layer structures of a medical patch that constitute a medical patch sheet. Thus, this process further comprises: A. 3.1) Removing the foil from the active layer and the skin contact layer; 3.2) laminating the open side of the active layer to the open side of the skin-contacting layer to obtain an active agent-containing self-adhesive layer structure; The method may include the steps of: The preparation of the active layer may occur before or after the preparation of the skin contact layer, or the preparation of the two layers may occur in parallel.

[0235] The active agent-containing self-adhesive layer structure is then preferably divided into one or more self-adhesive layer structures having a hexagonal shape according to the present invention, for example, by generally punching or cutting the backing layer and the active layer, and optionally the skin contact layer, and preserving the release liner. Thus, the process for producing a medical patch or medical patch sheet according to the present invention further comprises: B. Separating at least one hexagonal shape from the active agent-containing self-adhesive layer structure to obtain a medical patch or medical patch sheet; The steps may include:

[0236] In certain embodiments, the division is performed by punching, in particular by punching with a steel rule die. In some embodiments, the punching tool may be discontinuous to provide a fastening bridge.

[0237] The present invention also relates to a medical patch or medical patch sheet obtainable by the process described above. [Example]

[0238] The present invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is merely illustrative and should not be construed as limiting the present invention in any way. 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.

[0239] Example 1: Preparation of capsaicin-containing medical patch sheet The medical patch according to Example 1 may or may not include an additional skin-contacting layer, and therefore the steps of preparing and coating an inactive coating composition and laminating the resulting inactive layer with the previously prepared capsaicin-containing layer are optional.

[0240] Capsaicin-containing coating composition The formulations of the capsaicin-containing coating compositions are summarized below in Table 1.1. The % solids values ​​refer to the amount in % by weight (Amt).

[0241] [Table 1]

[0242] Preparation of Capsaicin-Containing Coating Compositions Transcutol was first thickened with ethyl cellulose under stirring (100-300 rpm).

[0243] The polysiloxane mixture and silicone oil were placed in a container and stirred (100-300 rpm) for at least 5 minutes before adding the ethylcellulose / Transcutol solution. After stirring (100-300 rpm) for an additional 10 minutes, capsaicin was added. The mixture was then stirred at approximately 250-300 rpm for at least 60 minutes until a homogeneous mixture was obtained.

[0244] Coating of capsaicin-containing coating composition The resulting capsaicin-containing coating composition was coated onto a fluoropolymer-coated polyester film (Scotchpak™ 1022). The solvent was removed at room temperature for approximately 20-30 minutes.

[0245] The coating thickness is determined by removing the solvent so that the area weight of the capsaicin-containing layer is approximately 80 g / m 2 was selected to be.

[0246] The resulting capsaicin-containing microreservoir layer was then laminated with a backing layer (polyester film, 19 μm).

[0247] Optionally, the adhesive foil used in coating and drying the capsaicin-containing layer is removed to obtain a capsaicin-containing self-adhesive layer structure comprising a backing layer and a capsaicin-containing layer, wherein the capsaicin-containing layer is attached to the backing layer.

[0248] Inert Coating Composition The formulation of the reactive coating composition for Example 1 is summarized in Table 1.2 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0249] [Table 2]

[0250] Preparation of Inert Coating Composition Both components were weighed separately and Component A was added to a mixing vessel followed by Component B. The mixture was then mixed at about 200 rpm for about 5 minutes until a homogenous mixture of Components A and B was obtained.

[0251] Coating of the inert coating composition The resulting inert coating composition was coated onto adhesive foil within a time frame of approximately 30 minutes. The coating temperature was set at 120° C. The resulting inert layer was heated at this temperature for approximately 40 minutes.

[0252] The coating thickness is approximately 230.0 g / m² for the inactive (skin contact) layer after solvent removal. 2 was selected to be.

[0253] The resulting inactive (skin contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 125 μm).

[0254] Lamination of a capsaicin-containing layer and an inactive (skin contact) layer The inactive (skin-contact) layer was then laminated with the capsaicin-containing layer. For this purpose, the adhesive foil used for coating and drying the layers was removed, and the resulting open sides of the active-containing layer and the 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 adhered to the backing layer, the inactive (skin-contact) layer is adhered to the capsaicin-containing layer, and this structure is closed by a release liner adhered to the inactive (skin-contact) layer.

[0255] Preparation of medical patches and medical patch sheets Individual medical patches were die-cut from the capsaicin-containing self-adhesive layer structures obtained as described, including either a backing layer and a capsaicin-containing layer, or a backing layer, a capsaicin-containing layer, and an inactive (skin-contacting) layer, without damaging the common release liner.

[0256] The medical patch sheet was then enclosed in a pouch of primary packaging material.

[0257] Examples 2A to 2M and Reference Example: Performance evaluation of placebo medical patches and placebo medical patch sheets Different medical patches and medical patch sheets (but without active agents) according to the present invention were prepared based on the adhesive layer without active agents (Examples 2A to 2M). Similarly, rectangular medical patches measuring 20 cm x 14 cm were prepared (Reference Example).

[0258] Coating Composition The formulations of the coating compositions are summarized in Table 2.1 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0259] Table 2.1

[0260] [Table 3]

[0261] Preparation of medical patches and medical patch sheets Individual medical patches were punched out from the inactive self-adhesive layer structure obtained above, which was placed on a release liner including a backing layer and an inactive layer, without damaging the common release liner, to obtain medical patches and medical patch sheets having the hexagonal shapes shown in Table 2.2.

[0262] The performance of the medical patch and medical patch sheet was then evaluated by applying each medical patch(es) or medical patch sheet to different skin areas, particularly the ankles / fingers, and assessing the coverage of the skin area to be treated (+: low coverage to +++: good coverage) and the occurrence of wrinkles (*: no / few wrinkles to ***: many wrinkles).

[0263] The results are shown in Table 2.2 below.

[0264] [Table 4]

[0265] In general, medical patches / medical patch sheets having a hexagonal shape have improved coverage and reduced wrinkles compared to medical patches having a rectangular shape. Various medical patches / medical patch sheets having a hexagonal shape have performed equally well on substantially flat or cylindrical surfaces such as the back, thigh, lower leg, or arm.

[0266] On uneven or curved surfaces, such as on the ankle or fingers, the single hexagon performed slightly better than the double hexagon. Smaller hexagons provided better coverage and less wrinkling than larger hexagons. The best handling results were achieved with hexagonal shapes with side lengths of 1.55 cm or 1.8 cm. Hexagonal shapes with side lengths of 0.9 cm handled poorly, but provided very good coverage and less wrinkling.

[0267] For curved surfaces, tight coverage can only be achieved by minimizing the overlap of the hexagonal edges.

[0268] Furthermore, the hexagonal shapes connected by fastening bridges have been shown to be very easy to handle: it is possible to separate the hexagons one by one, or groups of hexagons (without using a cutting tool), or even to apply all the hexagons of a medical patch sheet together.

[0269] The selection of the most useful medicinal patch(es) / medical patch sheet will depend on the respective skin area to be treated.

[0270] The invention relates in particular to the following further clauses: 1. A self-adhesive layer structure for use in a medical patch, having a hexagonal shape; A) a backing layer; B) an active layer comprising polymer I and an active agent; the backing layer and the active layer are coextensive, providing the hexagonal shape of the self-adhesive layer structure; the hexagonal shape includes at least one hexagon; All pairs of opposite sides of the hexagon are parallel; The sides of the hexagon have a length of 0.2 to 10 cm. The self-adhesive layer structure.

[0271] 2. The self-adhesive layer structure according to clause 1, wherein the self-adhesive layer structure is a pressure-sensitive adhesive layer structure.

[0272] 3. The self-adhesive layer structure of clause 1 or 2, wherein the at least one hexagon is at least one convex hexagon.

[0273] 4. The self-adhesive layer structure of clause 3, wherein the hexagonal shapes include one or two convex hexagons.

[0274] 5. The self-adhesive layer structure of any one of clauses 1 to 4, wherein the hexagonal shape is a convex hexagon.

[0275] 6. The self-adhesive layer structure of any one of clauses 1 to 4, wherein the hexagonal shape is a double hexagon formed from two identical convex hexagons sharing two adjacent vertices and a common side.

[0276] 7. A self-adhesive layer structure according to clause 6, wherein the common edge is perforated to facilitate separation.

[0277] 8. The self-adhesive layer structure of any one of clauses 1 to 7, wherein the hexagon is a parallelepiped.

[0278] 9. The hexagon is equilateral; or the hexagon is a scalene; has three sides of equal length and three other sides of equal length, or It has four sides of equal length and two other sides of equal length, 9. A self-adhesive layer structure according to any one of clauses 1 to 8.

[0279] 10. The self-adhesive layer structure of any one of clauses 1 to 9, wherein the hexagon is a scalene shape and the ratio of the shortest side to the longest side is 1:4 or less, 1:3 or less, 1:2 or less, 1:1.5 or less, or about 1:1.

[0280] 11. The self-adhesive layer structure of any one of clauses 1 to 10, wherein the sides of the hexagon have a length of 0.3 to 8 cm, 0.5 to 4 cm, 0.8 to 3.5 cm, or 0.9 to 2 cm.

[0281] 12. The self-adhesive layer structure of any of clauses 1 to 11, wherein two, three, four, or six sides of the hexagon have a length of about 0.5 cm, about 0.9 cm, about 1.5 cm, about 1.8 cm, about 2.8 cm, or about 3.2 cm.

[0282] 13. The self-adhesive layer structure of any of clauses 1-12, wherein the hexagons have an aspect ratio of 4:1 or less, 3:1 or less, 2:1 or less, 1.5:1 or less, or √3:2 or less.

[0283] 14. The self-adhesive layer structure of any one of clauses 1 to 13, wherein the hexagons are equilateral.

[0284] 15. The hexagon is an irregular polygon; 14. The self-adhesive layer structure of any of clauses 1-13, wherein the minimum angle is 60° or greater, 80° or greater, 90° or greater, or 110° or greater.

[0285] 16. The self-adhesive layer structure according to any one of clauses 1 to 9 and 11 to 14, wherein the hexagon is a regular hexagon.

[0286] 17. The self-adhesive layer structure according to any one of clauses 1 to 15, wherein the active agent is at least one analgesic agent.

[0287] 18. The self-adhesive layer structure according to clause 17, wherein the active agent is selected from the group consisting of buprenorphine, capsaicin, diclofenac, fentanyl, ibuprofen, and lidocaine.

[0288] 19. The self-adhesive layer structure according to clause 17 or 18, wherein the active agent is capsaicin.

[0289] 20. The self-adhesive layer structure of clause 19, wherein the active layer comprises the capsaicin at a concentration of 2-20 wt%, 5-15 wt%, 5-10 wt%, or about 8 wt%.

[0290] 21. The self-adhesive layer structure according to clause 19 or 20, wherein the self-adhesive layer structure contains the capsaicin in an amount of 0.5 to 180 mg, 1.2 to 90 mg, or 19 to 45 mg.

[0291] 22. The self-adhesive layer structure of any one of clauses 19 to 21, wherein the self-adhesive layer structure comprises the capsaicin in an amount of about 179 mg, about 60 mg, about 45 mg, about 30 mg, about 25.5 mg, about 10 mg, or about 1 mg.

[0292] 23. A self-adhesive layer structure according to any one of clauses 1 to 22 for transdermal or topical delivery of said active agent.

[0293] 24. A self-adhesive layer structure according to any one of clauses 1 to 23, wherein polymer I is a pressure-sensitive adhesive polymer.

[0294] 25. A self-adhesive layer structure according to any one of clauses 1 to 24, wherein polymer I is selected from silicone-based polymers, acrylic polymers, silicone-acrylic hybrid polymers, and polymers based on natural or synthetic rubber.

[0295] 26. A self-adhesive layer structure according to any one of clauses 1 to 25, wherein the polymer I is a silicone-based polymer obtained by polycondensation of a silanol-endblocked polydimethylsiloxane and a silicate resin.

[0296] 27.A) the backing layer; B) the active layer; C) a skin contact layer; 27. The self-adhesive layer structure of any of clauses 1-26, wherein the backing layer, the active layer, and the skin contact layer are coextensive, providing the hexagonal shape of the self-adhesive layer structure.

[0297] 28. A self-adhesive layer structure according to clause 27, wherein the skin contact layer is an adhesive, preferably a pressure sensitive adhesive.

[0298] 29. The self-adhesive layer structure according to clause 27 or 28, wherein the skin contact layer comprises polymer II.

[0299] 30. The self-adhesive layer structure according to clause 29, wherein the polymer II is a polymer or mixture of polymers in which the active agent is substantially insoluble.

[0300] 31. The self-adhesive layer structure according to clause 29 or 30, wherein the polymer II is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0301] 32. A self-adhesive layer structure according to any one of clauses 29 to 31, wherein polymer II is a polymer or a mixture of polymers selected from the group consisting of silicone-acrylic hybrid polymers, silicone-based polymers, silicone gel adhesives, and polymers based on natural or synthetic rubber.

[0302] 33. A self-adhesive layer structure according to any one of clauses 29 to 32, wherein polymer II is a polymer or a mixture of polymers selected from the group consisting of silicone-based polymers and silicone gel adhesives.

[0303] 34. A self-adhesive layer structure according to any one of clauses 29 to 33, wherein the polymer II is a silicone gel adhesive.

[0304] 35. The self-adhesive layer structure of clause 27 or 28, wherein the skin contact layer comprises a silicone gel adhesive.

[0305] 36. The self-adhesive layer structure according to clause 34 or 35, 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 silicon-bonded hydrogen atoms; and (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups.

[0306] 37. A self-adhesive layer structure according to any one of clauses 34 to 36, wherein the silicone gel adhesive is obtained by reacting (i) a gel-forming composition comprising a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

[0307] 38. A self-adhesive layer structure described in any one of clauses 34 to 37, wherein the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive containing about 2 to about 45 wt % or about 20 to about 30 wt % of at least one hydroxyl-substituted silicate resin.

[0308] 39. A self-adhesive layer structure described in any one of clauses 1 to 38, wherein the saturation concentration of the active agent 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.

[0309] 40. The self-adhesive layer structure according to any of clauses 1 to 39, wherein the active layer comprises further excipients or additives selected from the group consisting of additional polymers, crosslinkers, crystallization inhibitors, solubilizers, fillers, tackifiers, plasticizers, stabilizers, emollients, skin care substances, permeation enhancers, pH adjusters, and preservatives.

[0310] 41. The self-adhesive layer structure of clause 40, wherein the active layer comprises an additional polymer selected from dimethylpolysiloxane and ethylcellulose.

[0311] 42. The self-adhesive layer structure of clause 40 or 41, wherein the active layer comprises a permeation enhancer selected from diethylene glycol monoethyl ether.

[0312] 43. A medical patch, 43. The self-adhesive layer structure according to any one of clauses 1 to 42, a release liner; The medical patch, wherein the release liner is coextensive with the self-adhesive layer structure or extends in all directions beyond the boundaries of the self-adhesive layer structure.

[0313] 44. A medical patch sheet, two or more self-adhesive layer structures according to any one of clauses 1 to 42; a release liner; The medical patch sheet, wherein the release liner is coextensive with the self-adhesive layer structure or extends in all directions beyond the boundary formed by the self-adhesive layer structure.

[0314] 45. A medical patch sheet according to clause 44, comprising 2 to 400, 4 to 300, 6 to 120, or 8 to 30 self-adhesive layer structures.

[0315] 46. ​​A medical patch sheet according to clause 45, comprising 2 to 15 or 150 to 300 self-adhesive layer structures.

[0316] 47. A medical patch sheet according to clause 45 or 46, comprising 3, 4, 5, 6, 7 or 8 self-adhesive layer structures.

[0317] 48. The self-adhesive layer structures are arranged in two or more parallel rows relative to the longitudinal axis of the release liner; 48. The medical patch sheet according to any one of clauses 44 to 47, wherein each row preferably comprises 2 to 20, 3 to 12, or 4 to 8 self-adhesive layer structures.

[0318] 49. A medical patch sheet according to any one of clauses 44 to 48, wherein the self-adhesive layer structure is arranged like tiles on a flat surface.

[0319] 50. The self-adhesive layer structures are adjacent to each other by sharing two adjacent vertices and their common edge; separated from one another by cutting the common edge so that they can be independently peeled from the release liner; or 50. A medical patch sheet according to any one of clauses 44 to 49, connected to one another by said common edge weakened to facilitate separation.

[0320] 51. A medical patch sheet as described in clause 50, wherein all of the self-adhesive layer structures are separated from each other by cutting the common edge so that they can be independently peeled from the release liner.

[0321] 52. A medical patch sheet as described in clause 51, wherein the common edge is perforated to facilitate separation.

[0322] 53. A medical patch sheet described in any of clauses 44 to 49, wherein the self-adhesive layer structures are connected to each other by at least one, preferably two or more, common fastening bridges for joint release from the release liner.

[0323] 54. The common fastening bridge is provided at the vertices and connecting at least two, preferably three, self-adhesive layer structures; or 54. A medical patch sheet according to clause 53, provided on the sides and connecting two self-adhesive layer structures.

[0324] 55. A medical patch sheet according to clause 53 or 54, wherein all adjacent self-adhesive layer structures are connected to each other two by two adjacent vertices or at least two common fastening bridges provided on their common edges, preferably on two adjacent vertices.

[0325] 56. A medical patch sheet as described in clauses 53 to 55, wherein all adjacent self-adhesive layer structures are connected to each other in groups of three by common fastening bridges provided at their common vertices.

[0326] 57. A medical patch sheet described in any of clauses 44 to 56, wherein the self-adhesive layer structure has a hexagonal shape selected from a total of two or three different shapes.

[0327] 58. A medical patch sheet as described in clause 47, wherein the self-adhesive layer structure has a hexagonal shape including a convex hexagon and a double hexagon formed from two identical convex hexagons sharing two adjacent vertices and a common side.

[0328] 59. A medical patch sheet described in any one of clauses 44 to 56, wherein all of the self-adhesive layer structures have the same hexagonal shape.

[0329] 60. A medical patch sheet as described in clause 59, wherein the self-adhesive layer structure is a double hexagon formed from two identical convex hexagons sharing two adjacent vertices and their common side.

[0330] 61. A process for producing a medical patch according to clause 43 or a medical patch sheet according to any one of clauses 44 to 60, comprising: A. 1.1) Coating an active agent-containing coating composition, said composition comprising: (i) Polymer I; (ii) an active agent; and coating the composition onto a release liner; 1.2) drying the coated coating composition to provide an active agent-containing self-adhesive layer structure; 1.3) laminating the active agent-containing self-adhesive layer structure with a backing layer; B. dividing at least one hexagonal shape from the active agent-containing self-adhesive layer structure to obtain the medical patch or medical patch sheet; The process comprising the steps of:

Claims

1. A self-adhesive layer structure for use in a medical patch, having a hexagonal shape, A) a backing layer; B) an active layer comprising polymer I and an active agent; the backing layer and the active layer are coextensive, providing the hexagonal shape of the self-adhesive layer structure; the hexagonal shape includes at least one hexagon; All pairs of opposite sides of the hexagon are parallel; The sides of the hexagon have a length of 0.2 to 10 cm. The self-adhesive layer structure.

2. The self-adhesive layer structure according to claim 1 , wherein the self-adhesive layer structure is a pressure-sensitive adhesive layer structure.

3. The self-adhesive layer structure according to claim 1 or 2, wherein the at least one hexagon is at least one convex hexagon.

4. The self-adhesive layer structure of claim 3 , wherein the hexagonal shapes include one or two convex hexagons.

5. The self-adhesive layer structure according to any one of claims 1 to 4, wherein the hexagonal shape is a convex hexagon.

6. The self-adhesive layer structure according to any one of claims 1 to 4, wherein the hexagonal shape is a double hexagon formed from two identical convex hexagons that share two adjacent vertices and a common side.

7. the hexagon is equilateral, or the hexagon is a scalene; has three sides of equal length and three other sides of equal length, or having four sides of equal length and two other sides of equal length, The self-adhesive layer structure according to any one of claims 3 to 6.

8. The self-adhesive layer structure according to any one of claims 1 to 7, wherein the sides of the hexagon have a length of 0.3 to 8 cm, 0.5 to 4 cm, 0.8 to 3.5 cm, or 0.9 to 2 cm.

9. The self-adhesive layer structure according to any one of claims 1 to 8, wherein the hexagon is a regular hexagon.

10. the active agent is capsaicin; 10. The self-adhesive layer structure according to any one of claims 1 to 9, wherein the active layer preferably comprises the capsaicin in a concentration of 1 to 15 wt%, 2 to 12 wt%, 4 to 10 wt%, or about 8 wt%.

11. A medical patch, A self-adhesive layer structure according to any one of claims 1 to 10, a release liner; The medical patch, wherein the release liner is coextensive with the self-adhesive layer structure or extends in all directions beyond the boundaries of the self-adhesive layer structure.

12. A medical patch sheet, Two or more self-adhesive layer structures according to any one of claims 1 to 10; a release liner; The medical patch sheet, wherein the release liner is coextensive with the self-adhesive layer structure or extends in all directions beyond the boundary formed by the self-adhesive layer structure.

13. 13. The medical patch sheet of claim 12, comprising 2 to 400, 4 to 300, 6 to 120, or 8 to 30 self-adhesive layer structures, preferably the self-adhesive layer structures are arranged like tiles on a plane.

14. the self-adhesive layer structures are adjacent to each other by sharing two adjacent vertices and their common edge; separated from one another by cutting the common edge so that they can be independently peeled from the release liner; or 14. The medical patch sheet according to claim 12 or 13, wherein the sheets are connected to each other by the common edges which are weakened to facilitate separation.

15. the self-adhesive layer structures are connected to one another by at least one, and preferably two or more, common fastening bridges for joint release from the release liner; The common fastening bridge preferably comprises: or The medical patch sheet according to any one of claims 12 to 14, which is provided on the sides and connects two self-adhesive layer structures.

16. The medical patch sheet according to any one of claims 12 to 15, wherein the self-adhesive layer structures have a hexagonal shape selected from a total of two or three different shapes, or all of the self-adhesive layer structures have the same hexagonal shape.

17. A process for producing the medical patch according to claim 11 or the medical patch sheet according to any one of claims 12 to 16, comprising: A.1.1) Coating an active agent-containing coating composition, said composition comprising: (i) Polymer I; and (ii) an active agent; and coating the composition onto a release liner; 1.2) drying the coated coating composition to provide an active agent-containing self-adhesive layer structure; 1.3) laminating the active agent-containing self-adhesive layer structure with a backing layer; B. Dividing at least one hexagonal shape from the active agent-containing self-adhesive layer structure to obtain the medical patch or medical patch sheet; The process comprising the steps of:

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