Medical patch containing a skin-irritating active agent

Abstract

The present invention relates to a medical patch for administering an active agent, comprising an active agent-containing layer structure, the active agent-containing layer structure comprising a backing layer, an active agent-containing layer, and a skin contact layer, wherein the skin contact layer is an adhesive layer directly adhered to the active agent-containing layer, and the saturation concentration of the active agent in the skin contact layer is less than 0.1% by weight. The present invention also relates to 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 medical patch for administering an active agent, which comprises an active agent-containing layer and a skin contact layer, and the saturation concentration of the active agent in the skin contact layer is less than 0.1% by weight. Furthermore, the present invention relates to a manufacturing process for the medical patch, as well as a treatment method and use. [Background technology]

[0002] The most common routes of drug delivery are oral and parenteral, with the majority of small molecule drugs traditionally being delivered orally. The oral route has the advantages of a predetermined dosage, portability, and the possibility of patient self-administration, but is often associated with gastrointestinal side effects. Parenteral administration, such as intravenous or subcutaneous administration, is not without limitations, including the need for administration by a trained administrator, the invasive nature of injections that induce pain, and reduced patient acceptance / compliance.

[0003] On the other hand, the skin provides an accessible and convenient site for non-invasive administration of drugs, for example, by administering specific doses of drugs transdermally using a medical patch that is applied to the patient's skin.

[0004] Drugs have long been applied topically to the skin to treat localized conditions, but more recently, transdermal delivery techniques have been developed to treat conditions extending beyond the site of topical application. While topical delivery of compounds and / or drugs is limited to treating localized conditions and avoids systemic effects, transdermal drugs refer to pharmaceutical compounds that are applied to the skin and penetrate not only the stratum corneum but also the epidermis to reach the bloodstream and / or for effects on more distant tissues or organs.

[0005] Drug delivery through the skin offers many advantages over other traditional drug administration routes. First, because the skin is the most extended and most easily accessible organ in the body, numerous application options for medical patches are possible. Therefore, drug delivery through the skin can provide a noninvasive alternative to parenteral routes and avoid issues such as needle phobia. Furthermore, it can reduce the number of doses administered, improving patient compliance and making it suitable for unconscious or vomiting patients and those who rely on self-administration. Second, drug delivery through the skin avoids pre-systemic metabolism, improving bioavailability. Furthermore, the pharmacokinetic profile of drugs is typically more uniform with fewer peaks, minimizing the risk of side effects due to peak concentrations.

[0006] On the other hand, drugs, adhesives, or other excipients contained in medical patches can be irritants, causing application site reactions, including skin inflammation such as irritant contact dermatitis (ICD) or allergic contact dermatitis (ACD). ACD is a type IV cell-mediated hypersensitivity reaction that typically presents with lesions ranging from erythema and papules to small vesicles and bullae. ICD develops when drugs, adhesives, or excipients damage the skin surface at a rate that exceeds the skin's ability to repair itself, resulting in skin lesions similar to ACD. Common application site signs and symptoms include local redness (erythema) or pruritus, sometimes accompanied by swelling (edema). These symptoms are usually mild to moderate and transient. Most are limited to the application site and resolve spontaneously within a few days after patch removal. However, some medical patches can even cause systemic reactions and / or pain, depending on the irritant substances contained in them.

[0007] In fact, the occurrence of such (skin) reactions is not limited to the application site, since contamination with irritating substances can already occur during application of the medical patch. In particular, the irritating substances may come into contact with the fingers or other parts of the hands of the person applying the medical patch, with the subsequent risk of transfer to other particularly sensitive areas of the body, such as the eyes. Because of this risk associated with skin-irritating medical patches, and in particular with the skin-irritating active agents contained in medical patches, their application requires appropriate precautions and is often limited to medical professionals, eliminating the advantage of (otherwise possible) self-administration by patients.

[0008] It is therefore desirable to provide a medical patch for the administration of (irritating) active agents that allows for safe and uncomplicated handling, and in particular a medical patch that avoids contamination with the active agents contained therein, even in the event of unawareness, negligence, carelessness, inattention and / or lack of skill on the part of the person applying the medical patch. Summary of the Invention

[0009] It is an object of the present invention to provide a medical patch that overcomes the drawbacks of current administration of irritating active agents.

[0010] It is a further object of the present invention to provide a medical patch for administering an active agent that can be applied and removed in a safe and uncomplicated manner, particularly to provide a medical patch for administering an active agent that can be applied and removed safely by the patient or other person who is not a medical professional.

[0011] It is a further object of the present invention to provide a medical patch for the administration of active agents that avoids substantial contamination with the active agent, and in particular to provide a medical patch for the administration of irritating active agents that requires little or no precautions during application / removal of the medical patch.

[0012] It is a further object of the present invention to provide a medical patch for the administration of active agents which reduces the problem of undesirable skin reactions.

[0013] It is a further object of the present invention to provide a medical patch for the administration of an active agent that provides a permeation rate sufficient to achieve a therapeutically effective dose and has improved adhesive properties.

[0014] Another object of the present invention is to provide a medical patch for the administration of active agents that can be used in therapeutic methods.

[0015] These and other objects are achieved by the present invention, which, according to one aspect, relates to a medical patch for the administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising: A) a backing layer; B) an active agent-containing layer, (i) an active agent, and (ii) an active agent-containing layer comprising Polymer I; C) a skin contact layer comprising polymer II; wherein the skin contact layer is an adhesive layer that is directly adhered to the active agent-containing layer; The saturation concentration of the active agent in the skin contact layer is less than 0.1% by weight.

[0016] Surprisingly, it has been found that a medical patch according to the present invention, including a skin contact layer in which the active agent is poorly soluble, can still provide sufficient drug delivery. Because the active agent is poorly soluble, e.g., the 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 advantageous properties with respect to undesirable skin reactions and enabling safe application and / or removal. Therefore, such an inventive medical patch, having a skin contact layer with a negligible saturation concentration of the active agent and a separate active agent-containing layer (not in contact with the skin), inhibits the release of the active agent before and / or after the medical patch is applied to and maintained on the patient's skin. In particular, an inventive medical patch having a skin contact layer containing polymer II with a negligible saturation concentration of the active agent and a separate active agent-containing layer containing polymer I, also with a negligible saturation concentration of the active agent, substantially eliminates contamination by the active agent. Thus, the present invention allows even medical patches containing irritating active agents to be touched without any special precautions by non-medical personnel, preferably even by the patients themselves.

[0017] According to one particular aspect, the present invention relates to a medical patch for administering an active agent comprising an active agent-containing self-adhesive layer structure, said active agent-containing self-adhesive layer structure comprising: A) a backing layer; B) an active agent-containing matrix layer, (i) an active agent in an amount of at least 0.5 wt. %, based on the total weight of the active agent-containing matrix layer; (ii) a polymer I selected from the group consisting of silicone-based polymers and polymers based on natural or synthetic rubber, and (iii) an active agent-containing matrix layer containing a solubilizer; and C) a skin contact layer comprising polymer II; wherein the skin contact layer is an adhesive layer that is directly adhered to the active agent-containing layer; The saturation concentration of the active agent in the skin contact layer is less than 0.1% by weight.

[0018] According to a particular embodiment of the invention, the medical patch according to the invention is for use in a method of treatment, in particular for use in a method of treatment of pain, or for use in a method of treatment of neuropathic pain or nociceptive pain, or for use in a method of treatment of arthritis or cancer pain, or for use in a method of treatment of pain associated with a joint condition such as arthritis.

[0019] According to a particular embodiment of the invention, the invention relates to the use of a medical patch according to the invention for the manufacture of a medicament, in particular for the manufacture of a medicament for treating pain, or for the manufacture of a medicament for treating neuropathic pain or nociceptive pain, or for the manufacture of a medicament for the treatment of arthritis or cancer pain, or for the manufacture of a medicament for the treatment of pain associated with a joint condition such as arthritis.

[0020] According to a particular embodiment of the present invention, the present invention relates to a method of treatment, in particular a method of treating pain, or neuropathic pain or nociceptive pain, or arthral pain, or cancer pain, or pain associated with a joint condition such as arthritis, which method of treatment comprises applying to the skin of a patient a medical patch according to the present invention.

[0021] Furthermore, the present invention relates to a method for producing the active agent-containing layer structure of the medical patch according to the present invention.

[0022] definition In the sense 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 an active agent-containing (self-adhesive) 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, which 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.

[0023] In the sense of the present invention, the term "active agent-containing layer structure" refers to an active agent-containing structure that provides a release region for the active agent during administration. The active agent-containing layer structure includes at least a backing layer, an active agent-containing layer containing an active agent, and a skin-contacting layer as described herein. Thus, the active agent-containing layer structure includes a therapeutically effective amount of the active agent. In certain embodiments, the active agent-containing layer structure is an active agent-containing self-adhesive layer structure, and therefore provides adhesion to the skin, so that typically no additional assistance is required for fixation to the skin. As used herein, the term "active agent" refers to a substance delivered by an active agent-containing layer structure that provides a beneficial or desired effect on a subject's physical symptoms, either systemically or locally, at the delivery site. Active agents include biologically or pharmacologically active compounds, also known as active substances, drug substances, active ingredients, or active pharmaceutical ingredients (APIs). In this context, "irritating active agents," especially "skin-irritating active agents," are understood to mean active agents that, upon contact, cause (reversible) inflammation or irritation to body surfaces, including the eyes, respiratory tract, skin, or mucous membranes. The degree of irritation may depend on the concentration, contact time, and personal factors (health status, sensitization). Considering the OECD TG 404 guidelines, the potential (skin) irritation of medical patches can be determined, for example, by subjective in vivo observation followed by quantification to obtain a scoring index, such as the Primary Irritation Index (PII). The following skin irritation scoring system can be used for quantification: Erythema and erosion - 0 (no erythema), 1 (very mild erythema (barely discernible)), 2 (clear erythema), 3 (moderate to severe erythema), 4 (severe erythema (reddish-brown to deep red) and mild crusting (deep damage)); Edema - 0 (no edema), 1 (very mild edema (barely discernible)), 2 (mild edema (edges of area defined by distinct raised areas)), 3 (moderate edema (elevation of ~1 mm)), 4 (severe edema (elevation >1 mm beyond the exposed area)). Skin irritation is usually assumed at a PII ≥ 0.5.

[0024] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of active agent in the active agent-containing layer structure sufficient to provide a desired (therapeutic) effect, such as pain 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 and systemic circulation, but this is usually necessary to provide sufficient driving force for delivery from the TTS to the systemic circulation.

[0025] In the context of the present invention, the terms "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, cocrystals, 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 aforementioned forms.

[0026] The active agent contained in a vehicle such as a solvent may be dissolved or dispersed, or may be partially dissolved and partially dispersed.

[0027] 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 active agent-containing 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 exist 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 it is included in a salt form, a portion of it may exist as a free base in the final medical patch. Unless otherwise specified, the amount of active agent in the active agent-containing layer structure refers to the amount of active agent included in the medical patch during the manufacture of the medical patch, calculated based on the active agent itself, without taking into account other forms. The active agent starting material included in the medical patch during the manufacture of the medical patch may be in the form of particles. The active agent may, for example, be present in the active agent-containing layer structure in the form of particles and / or may be dissolved.

[0028] 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).

[0029] 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-controlling membrane to control the release of the active agent. In principle, a matrix-type medical patch can also include a rate-controlling membrane. However, compared to a reservoir-type medical patch, a matrix-type medical patch has the advantage that it typically does not require a rate-determining membrane and dose dumping due to membrane rupture cannot occur. In summary, a matrix-type medical patch is less complicated to manufacture and easier and more convenient to use.

[0030] 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 no sealing between other layers is required. Thus, the active agent-containing layer may be an active agent-containing matrix layer, in which the active agent is homogeneously distributed within the polymer matrix. The active agent-containing matrix layer may also comprise two active agent-containing matrix layers, which may be laminated together. A matrix-type medical patch may in particular be in the form of a "drug-in-adhesive" type medical patch, which 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 agent-containing matrix layer may be an active agent-containing pressure-sensitive adhesive layer or an active agent-containing 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.

[0031] 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-controlling membrane. In particular, the reservoir is sealed between a backing layer and a rate-controlling membrane. Thus, the active agent-containing 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-controlling membrane. In the active reservoir layer, the active agent is preferably dissolved in a solvent such as ethanol or water, or silicone oil.

[0032] A reservoir-type medical patch is not considered 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, different 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.

[0033] Thus, a microreservoir-type medical patch refers to a microreservoir system in which a liquid active agent formulation is dispersed in the adhesive matrix in the form of small droplets ("microreservoirs"). 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 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. Pat. 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.

[0034] The active agent-containing layer structure may be a pressure-sensitive adhesive layer structure.

[0035] In the context 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-borne 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 is self-adhesive when in contact with the skin. In certain embodiments, the active agent-containing 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.

[0036] In the sense of the present invention, the term "active agent-containing layer" refers to a layer that contains an active agent and provides a release region. This term encompasses active agent-containing reservoir layers and active agent-containing matrix layers, particularly active agent-containing microreservoir layers. When the active agent-containing layer is an active agent-containing matrix layer, such a layer is present in a matrix-type medical patch. As used herein, the active agent-containing layer is preferably an active agent-containing matrix layer, and refers to the final solidified layer obtained after coating and drying, for example, a solvent-containing coating composition as described herein. Alternatively, the active agent-containing matrix layer is obtained after melt coating and cooling. The active agent-containing matrix layer 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. In certain embodiments, the matrix layer is a pressure-sensitive adhesive matrix layer.

[0037] In the sense of the present invention, the term "skin contact layer" refers to the layer contained in the active agent-containing layer structure that comes into direct contact with the patient's skin during administration. Other layers of the active agent-containing layer structure do not come into contact with the skin and are not necessarily self-adhesive. The skin contact layer is either directly adhered to the active agent-containing layer, or a membrane is disposed between the active agent-containing layer and the skin contact layer. In this context, the term "membrane" is understood to mean a layer disposed between the active agent-containing 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 can be selected from the group consisting of polyethylene membranes, polyurethane-coated polyethylene terephthalate / polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate membranes. An additional skin contact layer is present as an adhesive layer.

[0038] The size of the skin contact layer and the active agent-containing layer are usually coextensive and correspond to the release area. However, the area of ​​the skin contact layer may be larger than the area of ​​the active agent-containing layer. In such cases, the release area still refers to the area of ​​the active agent-containing layer.

[0039] In the context of the present invention, the term "backing layer" refers to a layer that supports an active agent-containing layer. At least one backing layer in the active agent-containing layer structure of a medical patch, and typically the backing layer of the active agent-containing 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. In 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 agent-containing layer and the backing layer. Alternatively, suitable backing layers may be non-siliconeized to improve adhesion between the active agent-containing layer and the backing layer.

[0040] Additionally, an adhesive overlay may be present. In this context, the term "adhesive overlay" is understood to mean a layer that does not contain an active agent, has a larger area than the active agent-containing self-adhesive layer structure, and provides an additional area for adhesion to the skin but does not provide an area for release of the active agent. This improves the overall adhesive properties 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 active agent-containing self-adhesive layer structure. The adhesive overlay comprises a backing layer, which may provide occlusive or non-occlusive properties, and an adhesive layer. In certain embodiments, the backing layer of the adhesive overlay provides non-occlusive properties.

[0041] In the sense of the present invention, the term "area weight" refers to the dry weight of a particular layer, e.g., an active agent-containing matrix layer, in g / m 2 Area weight values ​​are subject to a tolerance of ±10% or ±7.5% due to manufacturing variations.

[0042] Unless otherwise indicated, "%" means % by weight.

[0043] In the context of the present invention, the term "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. Polymers can have any structure, such as linear polymers, star polymers, comb polymers, brush polymers, etc., and in the case of copolymers, they can have any monomer arrangement, such as alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can have molecular weights of, for example, more than 2,000 daltons, more than 5,000 daltons, or more than 10,000 daltons. Correspondingly, compounds with molecular weights less than 2,000 daltons, less than 5,000 daltons, or less than 10,000 daltons are usually called oligomers.

[0044] In the sense 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.

[0045] In the context 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.

[0046] In the context 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) containing 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. Polysiloxanes as used herein are synthesized from linear difunctional oligomers and branched polyfunctional oligomers, the ratio of which determines their physical properties. The more polyfunctional oligomers present, the higher the degree of crosslinking, resulting in higher cohesion and reduced adhesion; the less polyfunctional oligomers present, the higher the adhesion and reduced cohesion. Preferably, the silicone-based polymer is a mixture of high-viscosity and medium-viscosity polysiloxanes, or high-viscosity and low-viscosity polysiloxanes. In certain embodiments, the at least one silicone-based polymer is a silicone-based pressure-sensitive adhesive.

[0047] In the context 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. In certain embodiments, silicone gel adhesives are based on polydimethylsiloxane networks, which can be formed by the addition reaction (hydrosilylation) of vinyl-functional polydimethylsiloxane groups (polymer) with hydrogen-functional siloxanes (crosslinkers). Therefore, silicone gel adhesives are typically applied using a curable, gel-forming (two-component) composition that solidifies upon curing.

[0048] In the context 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.

[0049] In the context 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 I of the active agent-containing layer or polymer II of the skin contact layer) cannot dissolve 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 determined in the laboratory where the experiment is performed, typically within 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, comprising upper and lower protective layers sandwiching a donor layer and an acceptor layer separated by a partition membrane permeable to the active agent. Because the donor layer contains an excess of active agent and the acceptor layer is substantially free of active agent, the active agent diffuses from the donor layer through the partition membrane into the acceptor layer until a saturation concentration is reached. The donor and acceptor layers are fabricated from the respective polymer II of the skin contact layer (or the respective polymer I of the active agent-containing layer). The donor layer is supersaturated with the active agent, and the acceptor layer is prepared similarly to the donor layer but does not contain the active agent. The prepared sandwich system is stored at room temperature for a 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 the respective polymer II of the skin contact layer (or the respective polymer I of the active agent-containing layer).

[0050] As used herein, the solubility parameter (SP) is defined as a numerical estimate of the sum of all intermolecular attractive forces 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 / 2 where 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 .

[0051] In the sense of the present invention, the term "solubilizer" refers to an agent that increases the solubility of the active agent in the active agent-containing matrix layer.

[0052] It should be noted that in pharmaceutical formulations, formulation components are classified according to their physicochemical and physiological properties and according to their functions. This particularly means that a substance or compound classified into one category does not exclude being classified into another category of formulation components. Those skilled in the art can determine to which category(ies) of formulation components a substance or compound belongs based on general knowledge. For example, the solubilizers defined above can also act as penetration enhancers. On the other hand, penetration enhancers used in the sense of the present invention do not necessarily increase the solubility of the active agent in the active agent-containing layer.

[0053] In the context 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. Commercially available examples of 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® 12PF is characterized by a K-value range of 10.2 to 13.8, corresponding to a nominal K-value of 12. Kollidon® 17PF 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® 12PF, 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 USP monographs 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, 150 ppm or less, or 100 ppm or less.

[0054] In the context of the present invention, the term "hexagonal shape" refers to the two-dimensional shape of the active agent-containing layer structure comprised by the backing layer and the active agent-containing layer, or the backing layer, the active agent-containing layer, and the skin contact layer, respectively, and can be seen when the active agent-containing layer structure is viewed from above on the backing layer. A hexagonal shape in the context of the present invention is understood to mean any shape that can be formed by one hexagon or an aggregate of two or more hexagons. This means that the 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, for example, cutting the active agent-containing layer structure, or may be detachably connected to each other, for example, using perforations. The backing layer and the active agent-containing layer, or the backing layer, the active agent-containing layer, and the skin contact layer, and optionally 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 agent-containing layer, or the backing layer, the active agent-containing layer and the skin-contacting layer, and optionally the membrane, each provide at least one congruent hexagonal shape.

[0055] In the context 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 edges of the hexagon meet faces outward. Two adjacent vertices are connected by one of the six edges (common edge). 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.

[0056] 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.

[0057] 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.

[0058] In the context 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, as well as 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."

[0059] In the sense 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, the longer of the two distances being considered 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.

[0060] 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).

[0061] Hexagonal tiling, also known as hexagonal tessellation, is a regular tiling of the Euclidean plane, in which three hexagons intersect at each vertex. In addition to regular hexagons, hexagonal tiling can also be achieved using other (hexagonal) parallel polygons, in particular elongated rhombuses and elongated parallelograms. 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 active agent-containing layer structures according to the present invention. Preferably, overlapping is avoided as much as possible.

[0062] In the sense of the present invention, the term "pentagonal shape" refers to the two-dimensional shape of the active agent-containing layer structure, which is comprised of the backing layer and the active agent-containing layer, or the backing layer, the active agent-containing layer, and the skin-contact layer, respectively, and can be seen when the active agent-containing layer structure is viewed from above on the backing layer. A pentagonal shape in the sense of the present invention is understood to mean any shape that can be formed by one pentagon or an assembly of two or more pentagons. This means that the pentagonal shape according to the present invention does not necessarily have a pentagonal shape as a whole, but is composed of at least one pentagon. The vertex of the pentagon may be pointed or rounded. When two or more pentagons form a pentagonal shape, they may be integrally connected to each other, i.e., separable only by, for example, cutting the active agent-containing layer structure, or may be detachably connected to each other, for example, using a perforation. The backing layer and the active agent-containing layer, or the backing layer, the active agent-containing layer, and the skin-contact layer, and optionally 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 agent-containing layer, or the backing layer, the active agent-containing layer and the skin-contacting layer, and optionally the membrane, each provide at least one congruent pentagonal shape.

[0063] In the context of the present invention, the term "pentagon" refers to a five-sided polygon. In a "convex pentagon," each of the five points (vertices) where two pairs of sides of the pentagon meet face outward. A vertex is formed by two of the five sides (adjacent sides). Two adjacent vertices are connected by one of the five sides (common side). Non-adjacent vertices are connected by one of the five diagonals inside the closed pentagonal chain (boundary) of the convex pentagon.

[0064] A convex pentagon may also be described as a five-sided polygon with each interior angle (vertex angle) less than 180°. The sum of the interior angles of a simple (non-self-intersecting) pentagon is 540°. Thus, a (convex) pentagon with vertex angles equal to 108° is also referred to as an equilateral pentagon. A (convex) pentagon with all sides of equal length is also referred to as an equilateral pentagon. If a (convex) pentagon is both an equilateral and an equilateral pentagon, it is also referred to as a regular pentagon. A (convex) pentagon is referred to herein as a non-regular pentagon if at least one of its five vertex angles has a different size and / or at least one of its five sides has a different length.

[0065] A (convex) pentagon may be symmetrical, in particular mirror symmetrical. In this context, mirror symmetry is also called reflection symmetry and is understood to mean symmetry with respect to reflection. The symmetrical function 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 preferred (convex) pentagon according to the present invention has at least one, in particular exactly one, axis of symmetry.

[0066] In the context of the present invention, the terms "type I pentagon" and "type II pentagon" refer to a mirror-symmetric convex pentagon with exactly one axis of symmetry, two 90° interior angles, and three 120° interior angles, one of which is divided in the middle by the axis of symmetry. Furthermore, both "type I pentagons" and "type II pentagons" have one pair of equal-length sides, another pair of equal-length sides (which may be the same or different lengths), and one remaining side divided by the central axis of symmetry (the remaining side may have the same or different length as the pair of equal-length sides and / or the other pair of equal-length sides). Finally, a "type I pentagon" differs from a "type II pentagon" in that, since the two 90° interior angles are adjacent, the pair of equal-length sides is parallel (the sides are parallel to each other as well as the axis of symmetry).

[0067] Irregular pentagons, whose two interior angles sum to 180°, can be combined to form tiles on a plane. There are 15 known monohedral convex pentagon tilings, the most recent of which was discovered in 2015: - Type 1: B+C=180°, A+D+E=360° - Type 2: B+D=180°, c=e - Type 3: A=C=D=120°, a=b, d=c+e -Type 4: B=D=90°, b=c, d=e -Type 5: A=60°, D=120°, a=b, d=e -Type 6: B+D=180°, 2B=E, a=d=e, b=c - Type 7: B+2E=2C+D=360°, b=c=d=e - Type 8: 2B+C=D+2E=360°, b=c=d=e - Type 9: 2A+C=D+2E=360°, b=c=d=e -Type 10: A=90°, B+E=180°, B+2C=360°, a=b=c+e -Type 11: A=90°, C+E=180°, 2B+C=360°, 2a+c=d=e -Type 12: A=90°, C+E=180°, 2B+C=360°, 2a=d=c+e - Type 13: B=E=90°, 2A+D=360°, d=2a=2e -Type 14: A=90°, B≒145.34°, C≒69.32°, D≒124.66°, E≒110.68°, 2a=2c=d=e -Type 15: A=150°, B=60°, C=135°, D=105°, E=90°, a=c=e, b=2a

[0068] This list was shown to be complete by Rao in 2017 (Rao, Michael: "Exhaustive search of convex pentagons which tile the plane.").

[0069] Pentagonal tilings, also known as pentagonal tessellations, are tilings of the plane in which each piece is pentagonal. Regular pentagons do not tile the Euclidean plane, but three pentagons can tile a sphere, and four or more pentagons can tile a hyperboloid. The above types of pentagons that can tile the Euclidean plane monohedral (i.e., with one type of tile) generally have no symmetry, although there are special cases with mirror symmetry. For example, our Type I pentagons are Type I mirror symmetry cases, and our Type II pentagons are Type 3 or Type 4 mirror symmetry cases. A Type I pentagon, in which the length of one pair of parallel sides and the length of the remaining side are equal to √3 times the length of the other pair of parallel sides, can tile the Euclidean plane with a prismatic pentagonal tiling. A Type II pentagon, where the lengths of the remaining sides are √3-1 times the length of one pair of equal sides and √3-1 times the length of the other pair of equal sides, can tile the Euclidean plane with a Cairo pentagon tiling.

[0070] Furthermore, pentagons have a special relationship to hexagons, since some hexagons can be subdivided into pentagons. For example, a convex hexagon can be subdivided into two type 1 pentagons, three or nine type 3 pentagons, or four type 4 pentagons. Thus, a type I pentagon, in which one pair of parallel sides has a length equal to half the length of the other pair of parallel sides and the remaining side length is √3 times the length of the other pair of parallel sides, can provide a monohedral pentagonal tiling with stacked regular hexagons containing two pentagons each. Similarly, a type II pentagon, in which one pair of parallel sides has a length equal to half the length of the remaining side and the remaining side length is 2 / √3 times the length of the remaining side, can provide a monohedral pentagonal tiling with stacked regular hexagons containing three pentagons each.

[0071] In the sense of the present invention, the term "medical patch sheet" refers to a number of medical patches that share 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 a medical patch refers to the amount of active agent contained in the active agent-containing layer structure of the medical patch. The amount of active agent contained in a medical patch sheet refers to the total amount of active agent contained in all active agent-containing layer structures of the medical patches that make up the medical patch sheet. Therefore, the release area of ​​a medical patch refers to the area provided by the active agent-containing layer structure of the medical patch, and the release area of ​​a medical patch sheet refers to the area provided by all active agent-containing layer structures of the medical patches that make up the medical patch sheet.

[0072] In the context of the present invention, the term "release liner" refers to a removable protective layer adhered to the active agent-containing layer or skin-contact layer of the active agent-containing layer structure(s). The release liner may have any suitable two-dimensional geometric shape, preferably a polygonal shape, particularly a rectangular or square shape. Preferably, the area of ​​the release liner encompasses the total area of ​​all active agent-containing layer structures of the medical patch that make up the sheet of the medical patch. The release liner may be coextensive with the active agent-containing layer structures or may extend beyond the boundaries formed by all active agent-containing layer structures in all directions, i.e., the polygonal chain formed by the outer edges of the hexagons and / or pentagons of the active agent-containing layer structures is completely within or on the polygonal chain formed by the sides 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.

[0073] In the sense of the present invention, the term "weakened" refers to the result of an action (weakening) that allows two parts of an active agent-containing layer structure or two different active agent-containing layer structures to be more easily separated, although the two parts / active agent-containing layer structures still adhere to each other. Such weakening can include, but is not limited to, folding, scratching, perforating, piercing, puncturing, punching, or cutting. In certain embodiments, weakening is performed by perforation. In this context, the term "perforated" is understood to mean having small holes. Perforation can be achieved, for example, by needling or laser cutting.

[0074] In the sense of the present invention, the term "fastening bridge" refers to a point between two or three active agent-containing layer structures, particularly between two or three hexagonal and / or pentagonal shapes, where a major portion of the common edge is cut or weakened but they are still connected. Preferably, this is 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 continuous release of the active agent-containing layer structures thus connected 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 a part of the active agent-containing layer structure, to separate one part from the other.

[0075] In the sense 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, nociceptive pain, or mixed neuropathic and nociceptive pain, such as arthritic pain or cancer pain.

[0076] In the context of the present invention, 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 for 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] In the context of the present invention, the term "nociceptive pain" refers to pain caused by structural dysfunction, such as injury to bodily tissue. Nociceptive pain is a normal response to (intense) noxious stimuli and is predictably initiated by the activation of nociceptors, i.e., primary afferent neurons with a high activation threshold that detect signals from damaged tissue or the threat of injury. Depending on the underlying stimulus, nociceptive pain can range from sharp, stabbing, and shock-like to dull, aching, and burning, and lasts only as long as the noxious stimulus is maintained. However, certain pathologies, such as osteoarthritis, can result in persistent or repetitive noxious stimuli, in which changes in the joint cause normal weight bearing to generate sufficient forces to activate nociceptors. Nociceptive pain can be divided into somatic and visceral pain.

[0081] In this context, the term "somatic pain" is understood to mean nociceptive pain arising from nociceptors in the skin, bones, connective tissue, muscles, and joints. Somatic pain can be localized, intermittent, or persistent and can be described as aching, shooting, throbbing, or cramping. Deep somatic pain, especially in muscles and bones, can progress over time to a dull ache.

[0082] In this context, the term "visceral pain" is understood to mean nociceptive pain arising from nociceptors in or near the viscera. In particular, visceral pain is transmitted by individual nociceptors in the circulatory, respiratory, digestive, and genitourinary systems and is typically described as a deep ache, pressure, or colic that often radiates to areas of the skin, which may be tender.

[0083] In the context of the present invention, the term "joint pain," also known as arthralgia, refers to articular symptoms such as discomfort, pain, or suffering in any of the joints of a patient's body, such as the spine, shoulders, hips, elbows, knees, feet, or finger joints. In this context, a joint is understood to be the primary structure of the articular system, which can be thought of as a discontinuity in the skeleton that allows for controlled mobility and can have different structures depending on its functional requirements. Joint pain can be constant or can appear temporarily. Joint pain can be the result of illness or injury, but can also be due to other symptoms or factors. In particular, joint pain tends to affect people with arthritis or other long-term (chronic) medical conditions.

[0084] In the sense of the present invention, the term "articular condition" refers to any disease, disorder, or discomfort that affects or involves a joint(s). The joint condition may be inflammatory, i.e., involving inflammation of the bone or associated tissues. It may involve angiogenesis, i.e., the growth of new capillaries from existing vasculature, and / or arthropathy, i.e., certain abnormal conditions that adversely affect the structure or function of all or part of the joint(s), in particular arthritis.

[0085] In this context, the term "arthritis" is understood to mean a form of arthropathy involving inflammation of one or more joints. Arthritis can be infectious, i.e., caused by bacterial, viral, or fungal infections spread from other parts of the body, or non-infectious, i.e., caused by other factors. This includes rheumatoid arthritis, a long-term autoimmune disease that primarily attacks the joints; juvenile arthritis, an autoimmune, non-infectious, inflammatory joint disease that develops in people under the age of 16; psoriatic arthritis, a long-term inflammatory arthritis caused by psoriasis; gouty or pseudogouty arthritis (a type of inflammatory arthritis caused by needle-shaped crystals of uric acid, monosodium urate crystals or calcium pyrophosphate dihydrate crystals); or osteoarthritis (a degenerative disease characterized by cartilage wear, bone hypertrophy, sclerosis of the subchondral bone, and changes in the synovial membrane and joint capsule). Joint symptoms may result in particular in knee pain, elbow pain, hip pain, shoulder pain, limb pain, or (lower) back pain, which are preferably initially nociceptive but may also contain neuropathic components.

[0086] In the sense 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.

[0087] According to the present invention, the medical patch described herein is preferably suitable for use in a treatment method in which the medical patch is applied for a short period of time (application time) but provides the desired effect of pain relief for a long period of time (effective time). It is preferable that almost the entire amount of the active agent contained in the active agent-containing layer of the medical patch is released within the application time. In certain embodiments, the active agent can desensitize and defunctionalize the corresponding pain receptors within the application time, thereby providing sustained pain relief that lasts within the effective time.

[0088] In the sense of the present invention, the term "short time", i.e. application time, relates to a time period of less than or about 240 minutes, less than or about 180 minutes, less than or about 120 minutes, less than or about 90 minutes, less than or about 60 minutes, less than or about 45 minutes, less than or about 30 minutes, less than or about 15 minutes, or in the range of 30 to 90 minutes.

[0089] In the sense of the present invention, the term "prolonged duration", i.e., duration of effect, relates to a period of at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 3 months, or 1-3 months.

[0090] The interval between two dosage forms, also called the administration interval, should be adapted accordingly.In the sense of the present invention, the term "administration interval" refers to the period between two consecutive administrations of a medical patch, that is, the interval between two consecutive times when the medical patch is applied to the patient's skin.Once the medical patch is applied, it remains on the patient's skin for the application time, and then it is removed.However, the administration interval continues until a new medical patch is applied to the skin.

[0091] As used herein, the term "healthcare professional" is understood to mean a provider of medical treatment and advice based on formal training and experience, particularly one who is trained in the application and removal of medical patches (carrying irritating active agents).

[0092] In the sense of the present invention, the term "coating composition" refers to a composition that contains all the components of the active agent-containing layer or the skin contact layer, respectively, and that can be coated onto an intermediate liner, a backing layer, or a release liner to form the active agent-containing layer and the skin contact layer upon drying (or curing).

[0093] In the sense 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.

[0094] In the sense of the present invention, the term "crosslinking" refers to the process of crosslinking functional groups that may be contained within the coating composition that do not have activity.

[0095] In the context 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]

[0096] [Figure 1a] 1 shows the cumulative permeation amount of the medical patch prepared according to Example 1. [Figure 1b] 1 shows the skin permeation rate of the medical patch prepared according to Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0097] Medical Patch Structure The present invention relates to a medical patch for administering an active agent. The medical patch can be either a topical medical patch or a transdermal therapeutic system. In certain embodiments, the patch is a topical medical patch, particularly for the topical administration of an active agent.

[0098] The medical patch according to the present invention comprises an active agent-containing layer structure, and the active agent-containing layer structure comprises: A) a backing layer; B) an active agent-containing layer, (i) an active agent, and (ii) an active agent-containing layer comprising Polymer I; C) a skin contact layer comprising polymer II; Here, the skin contact layer is an adhesive layer that is directly adhered to the active agent-containing layer.

[0099] Preferably, the aforementioned layers of the medical patch of the present invention are directly adhered to each other, i.e., the backing layer is directly adhered to the active agent-containing layer, which in turn is directly adhered to the skin contact layer. In other words, the medical patch of the present invention comprises the following layers in this order: (1) the backing layer, (2) the active agent-containing layer, and (3) the skin contact layer.

[0100] The backing layer, active agent-containing layer, and skin contact layer may be coextensive, i.e., they may have the same planar extent (size). Alternatively, it may be preferable for the backing layer and / or the skin contact layer to have a larger area than the active agent-containing layer. In this active agent-containing layer structure, the active agent contained in the active agent-containing layer is more securely encapsulated therein.

[0101] The additional skin contact layer preferably provides adhesion between the active agent-containing layer structure and the patient's skin during administration. In some embodiments, the active agent-containing layer structure is a self-adhesive layer structure. When applied to a patient's skin, the active agent-containing layer structure of the present invention, including the additional skin contact layer, provides improved wearability as well as clean, painless removal. When necessary, for example, when changing positions, the medical patch can be peeled off and reapplied without losing adhesion. In addition, the active agent-containing layer structure, which sandwiches the active agent-containing layer between the skin contact layer (in which the active agent is preferably substantially insoluble) and the backing layer (preferably substantially impermeable to the active agent), shields the active agent from the skin of the patient or other person applying / removing the medical patch before and / or after application.

[0102] The medical patch of the present invention may be a matrix-type medical patch or a reservoir-type medical patch, and is preferably a matrix-type medical patch. In certain embodiments, the medical patch of the present invention is a matrix-type medical patch, in which the active agent is uniformly 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. In certain embodiments, the active agent-containing matrix layer may contain at least the active agent and solubilizer dissolved and / or dispersed in the matrix (i.e., polymer I). Therefore, the medical patch of the present invention may be a microreservoir-type medical patch.

[0103] The active agent-containing layer structure of the present invention is usually located on a removable protective layer (release liner), from which it is peeled off just before application to the patient's skin surface. Therefore, according to certain embodiments, the medical patch may further include a release liner. The 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 use.

[0104] Active Agent-Containing Layer As outlined in more detail above, the medical patch according to the present invention comprises an active agent-containing layer structure, which in particular comprises the following active agent-containing layer: (i) an active agent; and (ii) Polymer I.

[0105] According to the present invention, the active agent-containing layer is sandwiched between the skin contact layer and the backing layer, so that it cannot come into contact with the skin of the patient (or other person applying / removing the layer). Therefore, the layers of the active agent-containing layer structure are selected so that the active agent-containing layer is the only layer that allows the active agent to be concentrated to more than 0.1 wt% (i.e., neither the skin contact layer nor the backing layer should contain more than 0.1 wt% of the active agent).

[0106] Thus, in certain embodiments, the saturation concentration of the active agent in the active agent-containing layer is greater than 1 wt%, greater than 5 wt%, greater than 10 wt%, or greater than 20 wt%. In particular, the saturation concentration of the active agent in polymer I of the active agent-containing layer may be greater than 1 wt%, greater than 5 wt%, greater than 10 wt%, or greater than 20 wt%. Alternatively, the saturation concentration of the active agent in polymer I of the active agent-containing layer may be (substantially) less than 1 wt%, or less than 0.1 wt%, and may be increased only locally by the addition of one or more solubilizers.

[0107] Therefore, in certain embodiments, the active agent-containing layer may further comprise a solubilizer, particularly in an amount of 1 to 40% by weight, based on the total weight of the active agent-containing layer. (i) an active agent; and (ii) Polymer I; and (iii) a solubilizing agent.

[0108] Without wishing to be bound by theory, it is believed that the safe and uncomplicated handling of the medical patch of the present invention, which relies on the skin contact layer providing a saturation concentration of the active agent of less than 0.1 wt%, can be further improved by selecting polymer I of the active agent-containing layer to provide a saturation concentration of the active agent of less than 1 wt%, or even less than 0.1 wt%, and adding a solubilizer that forms deposits, such as droplets containing the active agent in a microreservoir system. By only locally increasing the active agent concentration in the active agent-containing layer, the active agent can be maintained within the active agent-containing layer unless the active agent-containing layer structure is in contact with the patient's skin. Therefore, undesirable skin reactions caused by the active agent can be avoided.

[0109] In certain embodiments, the active agent-containing layer is preferably an active agent-containing matrix layer, preferably (i) an active agent, in particular in an amount of at least 0.5 wt. %, based on the total amount of the active agent-containing layer; (ii) polymer I, in particular in an amount of 20 to 99% by weight, or 60 to 99% by weight, based on the total amount of the active agent-containing layer, and optionally (iii) A solubilizer is contained in an amount of, in particular, 1 to 40% by weight based on the total weight of the active agent-containing layer.

[0110] The active agent (and optionally the solubilizer) is preferably uniformly dispersed within the active agent-containing matrix layer. As used herein, an active agent-containing matrix layer is a layer containing an active agent dissolved or dispersed in polymer I, or a layer containing an active agent dissolved in a solubilizer to form an active agent-solubilizer mixture dispersed in the polymer I in the form of deposits (particularly droplets). Thus, the active agent-containing matrix layer may comprise an active agent dissolved in a solubilizer as microreservoir droplets dispersed within the active agent-containing matrix layer. The proportion of microreservoir droplets in the active agent-containing matrix layer is typically less than about 40% by weight, or less than about 35% by weight, or between about 20% and about 30% by weight.

[0111] In certain embodiments, the active agent-containing layer may contain at least 0.5 wt.%, at least 1 wt.%, at least 2 wt.%, or at least 5 wt.%, based on the total weight of the active agent-containing layer. In these or other embodiments, the active agent-containing layer may contain no more than 30 wt.%, no more than 20 wt.%, no more than 15 wt.%, or no more than 10 wt.%, based on the total weight of the active agent-containing layer. In particular, the active agent-containing layer may contain 0.5-30 wt.%, 1-20 wt.%, 2-15 wt.%, or 5-10 wt.% of the active agent.

[0112] In certain embodiments, the active agent-containing layer may comprise Polymer I in an amount of 20% to 99% by weight, or 60% to 90% by weight, based on the total weight of the active agent-containing layer. It should be understood that the aforementioned weight percent amounts refer to the total amount of Polymer I. For example, if Polymer I is a mixture of polymers, the total amount in the active agent-containing layer is 20 to 99% by weight, based on the total weight of the active agent-containing layer.

[0113] Active Agent In accordance with the present invention, the active agent-containing layer comprises an active agent.

[0114] The active agent may be any compound responsible for the therapeutic effect of the medical patch comprising an active agent-containing layer structure comprising an active agent-containing layer. In particular, the active agent may be a topically active agent or a systemically active agent. In certain embodiments, the active agent may be at least one irritating active agent, particularly a skin irritating active agent.

[0115] For example, the active agent may be an analgesic agent, such as a TRPV1 agonist.

[0116] According to certain embodiments, the active agent may be a capsaicin analog. As used herein, the term "capsaicin analog" refers to a chemical compound that provides a pharmacological effect similar to that of capsaicin, particularly in terms of the TRPV1 receptor. Capsaicin ((6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide) is an alkaloid belonging to the Capsicum family and a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), better known as the vanilloid receptor. This receptor is a nonselective cation channel that, when activated during the detection and transmission of noxious stimuli, induces a transient Ca 2+ Intracellular calcium is one of the most versatile second messengers in many intracellular signaling pathways, and when TRPV1 is activated, it allows cations to cross the cell membrane and enter the cell, resulting in neuronal depolarization that stimulates signaling to the brain. Therefore, capsaicin analogs are more precisely understood to mean natural or synthetic molecules that have been clearly demonstrated to be TRPV1 receptor agonists and / or that retain all or part of the aromatic catechol ring in their chemical structure.

[0117] In certain embodiments, the active agent is selected from the group consisting of additional capsaicinoids belonging to the Capsicum family (e.g., dihydrocapsaicin (N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnonanamide), nordihydrocapsaicin (N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-methyloctanamide), homocapsaicin ((6E)-N-(4-hydroxy-3-methoxybenzyl)-8-methyldec-6-enamide), homodihydrocapsaicin (N-[(4-hydroxy-3-methoxyphenyl)methyl]-9-methyldecanamide), or pseudocapsaicin (N-[(4-hydroxy-3-methoxyphenyl)methyl]nonanamide, also known as nonivamide); natural capsaicin analogs (e.g., capsiate ((E)-4-hydroxy-3-methoxybenzyl 8-methylnon-6-enoate), gingerol ((5S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one), piperine ((2E,4E)-5-(2H-1,3-benzodioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one), or resiniferatoxin ([(1R,2R,6R,10S,11R,13R,15R,17R)-13-benzyl-6-hydroxy-4,17-dimethyl-5-oxo-15-(propylene-1-en-2-yl)-12,14,18-trioxapentacyclo[11.4.1.0] 1,10 .0 2,6 .0 11,15]octadeca-3,8-dien-8-yl]methyl 2-(4-hydroxy-3-methoxyphenyl)acetate; and synthetic capsaicin analogs (e.g., arvanil ((5Z,8Z,11Z,14Z)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-5,8,11,14-eicosatetraenamide), civamide ((N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-(Z)-6-nonanamide), N-oleylhomovanilamide (N-(9Z-octadecenyl)-3-methyl- hexadecanamide), Olvanil ((Z)-N-[(4-hydroxy-3-methoxyphenyl)methyl]octadec-9-enamide), Palvanil (N-[(4-hydroxy-3-methoxyphenyl)methyl]hexadecanamide), and phenylacetyllinvanil ([(Z,7R)-18-[(4-hydroxy-3-methoxyphenyl)methylamino]-18-oxooctadec-9-en-7-yl]2-phenylacetate).

[0118] According to certain embodiments, the active agent is resiniferatoxin. Resiniferatoxin (abbreviated RTX) is an ultra-potent irritant found in the latex of Euphorbia plants. With a Scoville heat unit rating of 16 billion, pure resiniferatoxin is approximately 500 to 1,000 times hotter than pure capsaicin. Therefore, RTX is highly toxic, capable of causing chemical burns in minute amounts. When ingested orally, submicrogram amounts (less than one millionth of a gram) can cause intense, burning pain. However, as the most potent TRPV1 agonist currently known, RTX exhibits approximately 500 times greater binding affinity for TRPV1 than capsaicin, allowing it to act as a "molecular scalpel" to ablate sensory neurons and achieve lasting pain relief. RTX has a wide therapeutic window, capable of completely desensitizing pain sensation and neurogenic inflammation without causing unacceptable side effects. Intra-articular RTX is currently undergoing clinical trials to treat moderate to severe knee pain in patients with osteoarthritis. Similar targeted approaches may be useful in managing postoperative pain and pain associated with severe burns.

[0119] Thus, certain active agent-containing layers according to the present invention comprise a capsaicin analog, such as resiniferatoxin. Thus, in certain embodiments, medical patches according to the present invention are for the administration (topical or transdermal) of a capsaicin analog or for the administration (topical or transdermal) of resiniferatoxin.

[0120] In certain embodiments, the medical patch, particularly the active agent-containing layer, does not contain capsaicin.

[0121] The medical patch, particularly the active agent-containing layer, contains a therapeutically effective amount of the active agent. In certain embodiments, the active agent-containing layer contains at least 0.10 mg / cm of active agent per release area. 2 , at least 0.20 mg / cm 2 , at least 0.50 mg / cm 2 , or at least 1.0 mg / cm 2 In these or other embodiments, the active agent-containing layer may contain 12.0 mg / cm of active agent per release area. 2 Less than 10.0 mg / cm 2 Less than 6.0 mg / cm 2 Less than or equal to 3.0 mg / cm 2 In particular, the active agent-containing layer may contain an active agent in an amount of 0.10 to 12.0 mg / cm per release area. 2 , 0.20 to 10.0 mg / cm 2 , 0.50 to 6.0 mg / cm 2 , or 1.0 to 3 mg / cm 2 The active agent may include:

[0122] Polymer I According to the present invention, the active agent-containing layer comprises polymer I. This polymer may provide sufficient cohesive and / or adhesive strength for the active agent-containing layer.

[0123] Polymers suitable for use as polymer I according to the present invention are those that allow the active agent to be concentrated to greater than 0.1% by weight, particularly to therapeutically effective amounts, if necessary, by the use of an appropriate solubilizer. Thus, in some embodiments, the saturation concentration of the active agent in polymer I may be greater than 1%, 5%, 10%, or 20% by weight. In alternative embodiments, the saturation concentration of the active agent in polymer I may be (substantially) less than 1% by weight or less than 0.1% by weight, but may be increased to greater than 1%, 5%, 10%, or 20% by weight by the addition of one or more solubilizers.

[0124] Polymer I may be selected from pressure-sensitive adhesive polymers. Thus, in certain embodiments, polymer I may be a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0125] In certain embodiments, polymer I may be a polymer or a mixture of polymers selected from the group consisting of acrylic polymers, silicone-acrylic hybrid polymers, silicone-based polymers, and polymers based on natural or synthetic rubber. In particular, polymer I may be a polymer or a mixture of polymers selected from the group consisting of silicone-based polymers and polymers based on natural or synthetic rubber.

[0126] In a particular embodiment, polymer I may be a polymer or a mixture of polymers selected from silicone-based polymers, in particular polysiloxane-based polymers. In a more particular embodiment, polymer I may be an amine-compatible polysiloxane.

[0127] In certain embodiments, polymer I may be a polymer or a mixture of polymers selected from natural or synthetic rubber, particularly styrene triblock copolymers and polyisobutylene. Thus, polymer I may be a styrene triblock copolymer, such as an SIS block copolymer, or polymer I may be polyisobutylene. Furthermore, the polymer may be a mixture of a styrene triblock copolymer and polyisobutylene, particularly a mixture of an SIS block copolymer and polyisobutylene.

[0128] Suitable polymers I according to the invention are commercially available, for example, under the trade names BIO-PSA (pressure-sensitive adhesives based on polysiloxanes), JSR-SIS (pressure-sensitive adhesives based on SIS block copolymers) and Oppanol™ (polyisobutylene).

[0129] For example, additional polymers may be added to increase the cohesive strength of the active agent-containing layer.

[0130] According to some embodiments, polymer I contained in the active agent-containing layer is different from polymer II contained in the skin contact layer. According to other embodiments, polymer I contained in the active agent-containing layer is the same as polymer II contained in the skin contact layer. In such embodiments, since the saturation concentration of the active agent in polymer I (as in the skin contact layer, and therefore in polymer II) is negligibly small, the active agent-containing layer further comprises a solubilizer.

[0131] solubilizer The medical patch according to the present invention, and in particular the active agent-containing layer, may advantageously contain a solubilizer.

[0132] As outlined above, the solubilizer is an agent that substantially increases the solubility of the active agent in the active agent-containing layer, for example, by at least 1% per 10% by weight, 5% by weight, 1% by weight, or 0.5% by weight of the solubilizer added to the active agent-containing layer (relative to the amount of active agent in the active agent-containing layer in weight percent). This can be achieved by using a substance or mixture of substances that has a relatively high solubility for the active agent. Thus, in certain embodiments, the solubilizer can be a substance or mixture of substances in which capsaicin or a capsaicin analog has a solubility of at least 30% by weight, at least 40% by weight, or at least 45% by weight.

[0133] The solubilizer may also be released with the active agent to further act as a penetration enhancer. Without wishing to be bound by theory, it is believed that the solubilizer may limit or reduce its affinity with polymer I contained in the active agent-containing layer, thus maintaining a high driving force for the active agent dissolved in the solubilizer to leave the patch (although this only appears after the medical patch is applied to the patient's skin).

[0134] In certain embodiments, the solubilizer may be an amphiphilic solvent. Suitable amphiphilic solvents include butanediol, especially 1,3-butanediol, dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether (DGME), diethylene glycol monobutyl ether, propylene glycol, carboxylic acid esters of triethylene glycol and diethylene glycol, polyethoxylated fatty alcohols of 6 to 18 C atoms, or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, or mixtures thereof, or mixtures of these solvents.

[0135] In certain embodiments, the solubilizer is dipropylene glycol, diethylene glycol monoethyl ether, or dimethyl isosorbide. Diethylene glycol monoethyl ether and dimethyl isosorbide are available, for example, under the trade names Transcutol® and Dottisol®, respectively.

[0136] The solubilizer may also be selected from the group consisting of glycerol esters of medium and / or long chain fatty acids, polyglycerol esters, propylene glycol esters, polyoxyethylene esters (e.g., glyceryl monolinoleate, medium chain glycerides, and medium chain triglycerides), non-ionic solubilizers obtained by reaction of castor oil with ethylene oxide, and mixtures thereof. These mixtures may also include fatty acids or fatty alcohols, cellulose, methylcellulose and their derivatives (e.g., hydroxypropyl cellulose and hypromellose acetate succinate), various cyclodextrins and their derivatives, nonionic triblock copolymers having two hydrophilic chains of polyoxyethylene on either side of a central hydrophobic chain of polyoxypropylene (known as poloxamers), water-soluble vitamin E derivatives, pharmaceutical-grade or agglomerated spherical isomalt, polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam graft copolymers (abbreviated as PVAc-PVCap-PEG and known as Soluplus®), purified grades of naturally derived castor oil, purified grades of polyethylene glycol 400, purified grades of dioxyethylene sorbitan monooleate (e.g., polysorbate 80), purified grades of glucono-delta-lactone, corn and potato starches, and water-soluble polyvinylpyrrolidone, as well as insoluble / crosslinked polyvinylpyrrolidone (e.g., crospovidone) as described herein. Additionally, penetration enhancers and / or crystallization inhibitors, described below, may also act as solubilizers.

[0137] Particularly suitable solubilizers include mixtures of propylene glycol monoesters and diesters of fatty acids, such as those commercially available under the trade name Capryol™, including, for example, propylene glycol monocaprylate (type II), a mixture of propylene glycol caprylate esters with a predominant monoester content of at least 90% monoester and no more than 10% diester (commercially available as Capryol™ 90 and supplied by Gattefosse), and polyethylene glycol ethers, in particular polyethylene glycol fatty alcohol ethers such as those commercially available under the trade name Brij™ (e.g., polyethylene glycol dodecyl ether with an average molecular weight Mn of about 362, commercially available as Brij™ L4).

[0138] A certain minimum amount of solubilizer is advantageous in that it helps prevent the recrystallization of the active agent in the active agent-containing layer. On the other hand, too much solubilizer may impair the cohesiveness of the active agent-containing layer, so a balance must be found. Also, in terms of the beneficial effect of preventing the recrystallization of the active agent, the crystallization inhibitor and the solubilizer may complement each other. Finally, the amount of crystallization inhibitor and / or solubilizer required to effectively prevent the recrystallization of the active agent also depends on the amount of the active agent present in the active agent-containing layer.

[0139] skin contact layer As outlined in more detail above, the medical patch according to the present invention comprises an active agent-containing layer structure, which in particular comprises a skin contact layer, which is an adhesive layer that is directly adhered to the active agent-containing layer.

[0140] The medical patch of the present invention is particularly characterized by a saturation concentration of the active agent in the skin contact layer of less than 0.1% by weight, preferably as determined by the "sandwich method." In certain embodiments, the saturation concentration of the active agent in the skin contact layer is less than 0.05%, less than 0.02%, or less than 0.01% by weight. Preferably, the saturation concentration of the active agent in the skin contact layer is about 0% by weight. The saturation concentration relates to the amount of active agent present in the skin contact layer, based on the total weight of the skin contact layer.

[0141] In certain embodiments, the saturation concentration of the active agent in the skin contact layer is below a concentration of the active agent that causes unintended adverse effects, such as skin irritation, after 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 active agent concentration to the skin for a short period of time, such as 5 seconds, 10 seconds, 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 simply determined (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.

[0142] According to the present invention, the skin contact layer shields the active agent contained in the active agent-containing 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 a concentration gradient, the active agent will usually migrate from the active agent-containing 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. Therefore, the skin contact layer does not allow the active agent to be present at a concentration greater than 0.1% by weight.

[0143] 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.

[0144] In certain embodiments, the skin contact layer may comprise 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. The amount of polymer II in the skin contact layer may range from 50 to 95 wt %, 60 to 99 wt %, or 75 to 100 wt %, based on the total weight of the skin contact layer. In particular, the skin contact layer may consist essentially of polymer II. It should be understood that the aforementioned weight 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.

[0145] Polymer II According to the invention, the skin contact layer comprises polymer II, which may be crucial for the adhesive properties of the skin contact layer and may further reduce skin irritation, especially due to its elasticity.

[0146] Suitable polymers for use as polymer II in the present invention are those capable of concentrating the active agent to 0.1 wt % or less, 0.05 wt % or less, 0.02 wt % or less, or 0.01 wt % or less, i.e., polymers in which the active agent is substantially insoluble. Thus, in certain embodiments, polymer II may be a polymer or a mixture of polymers in which the active agent is substantially insoluble.

[0147] Therefore, the solubility parameter of polymer II must be 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 It may be different, and in particular may be lower than the solubility parameter of the active agent. 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.

[0148] 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.

[0149] 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. 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.

[0150] In some embodiments, Polymer II can be a silicone gel adhesive.

[0151] In other embodiments, polymer II may not be a silicone gel adhesive, and therefore, according to such embodiments, the skin-contacting layer does not include a silicone gel adhesive.

[0152] 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.

[0153] Suitable polymers II according to the present invention 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, suitable polymers II according to the present invention are commercially available, for example, under the trade names BIO-PSA (pressure-sensitive adhesives based on polysiloxanes), JSR-SIS (pressure-sensitive adhesives based on SIS block copolymers), and Oppanol™ (polyisobutylene).

[0154] Additional polymers may also be added, for example, to increase the adhesion of the skin contact layer.

[0155] acrylic polymer The terms acrylic polymer and acrylate polymer refer interchangeably to acrylate-based polymers. In certain embodiments, the acrylic polymer is an acrylate-based pressure-sensitive adhesive. Acrylate-based pressure-sensitive adhesives may also be referred to as acrylate-based pressure-sensitive adhesives or acrylate pressure-sensitive adhesives.

[0156] 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.

[0157] 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).

[0158] 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.

[0159] Depending on the type of commercially available acrylic polymer used and whether a crosslinking agent is added to the coating composition, the polymer in the final active agent-containing or skin-contacting layer may be crosslinked (and preferably crosslinked with an aluminum and / or titanium crosslinker) or not crosslinked with a crosslinker.

[0160] Silicone Acrylic Hybrid Polymer Silicone acrylic hybrid polymers include polymerized hybrid species that include a silicone-based subspecies and an acrylate-based subspecies polymerized together. Thus, the silicone acrylic hybrid polymer includes a silicone phase and an acrylic phase. In certain embodiments, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.

[0161] 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.

[0162] The weight ratio of silicone to acrylate in the silicone acrylic hybrid pressure sensitive adhesive may be from 5:95 to 95:5, or from 20:80 to 80:20, or from 40:60 to 60:40, or the ratio of silicone to acrylate may be about 50:50.

[0163] Commercially available suitable silicone acrylic hybrid pressure-sensitive adhesives include the PSA series 7-6100 and 7-6300 manufactured and supplied by Dow Corning in n-heptane or ethyl acetate (7-610X and 7-630X; X=1 n-heptane-based / X=2 ethyl acetate-based). For example, 7-6102 silicone acrylic hybrid PSA, with a 50 / 50 silicone / acrylate ratio, is characterized by a solution viscosity of 2,500 cP at approximately 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, is characterized by 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.

[0164] 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.

[0165] 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.

[0166] 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)).

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] The acrylic polymer may be prepared from a mixture containing a polysiloxane-containing monomer, preferably a mixture containing polydimethylsiloxane mono(meth)acrylate.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] Silicone-based polymers Silicone-based polymers are non-curing polymers that are typically applied by hot melt or solvent-based processes and preferably do not undergo further curing to solidify.

[0177] 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.

[0178] Thus, in certain embodiments, the silicone-based polymer may be an amine-compatible polysiloxane obtained by polycondensing a silanol-endblocked polydimethylsiloxane with a silicate resin, followed by at least partial trimethylsilylation of the remaining silanol functional groups.

[0179] In certain embodiments, the silicone-based polymer may be a polysiloxane-based pressure-sensitive adhesive or a mixture of polysiloxane-based pressure-sensitive adhesives.

[0180] 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.

[0181] 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.

[0182] According to certain embodiments, the silicone-based polymer 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 certain embodiments, the silicone-based polymer may be a pressure-sensitive adhesive mixture obtained by polycondensation of silanol-endblocked polydimethylsiloxane with a silicate resin in a resin-to-polymer ratio of 55:45 or 60:40.

[0183] Furthermore, according to certain embodiments, the polysiloxane-based polymer may be a mixture of the following pressure-sensitive adhesives: A solution viscosity of 450 mPa·s at approximately 60% solids content in heptane at 25°C and / or 1×10 at 0.01 rad / s at 30°C 8 It has a complex viscosity in poise, A solution viscosity of 500 mPa·s at approximately 60% solids content in heptane at 25°C and / or 5×10 at 0.01 rad / s at 30°C 6 It has a complex viscosity in poise.

[0184] Silicone polymers are typically 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.

[0185] 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 solution viscosities of greater than about 150 mPa·s, or from about 200 mPa·s to about 700 mPa·s at 60% solids content in n-heptane at 25°C, preferably measured at 50 rpm using a Brookfield RVT viscometer with spindle number 5. These also have a viscosity of about 1×10 at 0.01 rad / s at 30°C. 9 Less than poise, or about 1 x 10 5 ~Approx. 9×10 8 It may be characterized by a complex viscosity in poise.

[0186] 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 about 60% solids content in heptane at 25°C and a viscosity of 1×10 at 0.01 rad / s at 30°C. 8 Characterized by a complex viscosity in poise, BIO-PSA7-4301 has a solution viscosity of 500 mPa·s at approximately 60% solids content in heptane at 25°C and a complex viscosity of 5 × 10⁶ poise at 0.01 rad / s at 30°C.

[0187] 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.

[0188] 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.

[0189] Silicone Gel Adhesive Silicone gel adhesives are elastic, jelly-like materials formed by lightly crosslinked silicone polymers. Thus, in contrast to the silicone-based polymers used herein, silicone gel adhesives are based on curable gel-forming compositions. Silicone gel adhesives provide adhesion of medical patches to the skin while simultaneously reducing the problem of skin irritation. Furthermore, the drug delivery of the medical patch is not adversely affected, and surprisingly, the skin permeation behavior is improved.

[0190] Silicone gel adhesives, also called silicone gels, are described, for example, in WO2011 / 022199A2.

[0191] 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.

[0192] In certain embodiments, silicone gel adhesives are obtained by reacting a gel-forming composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane containing silicon-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of SiH groups with Si-alkenyl groups. These compositions cure at normal ambient temperatures, but curing can be accelerated by heating to elevated temperatures, e.g., 40-140°C, or by exposure to UV light.

[0193] 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.

[0194] 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.

[0195] The alkenyl-substituted polydiorganosiloxane can be used in the gel-making composition in an amount of 10 to 90 weight percent, alternatively 40 to 90 weight percent, alternatively 50 to 80 weight percent, 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 weight percent, alternatively 0.05 to 1 weight percent, based on the weight of the alkenyl-substituted polydiorganosiloxane.

[0196] 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.

[0197] 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.

[0198] The organosiloxane containing silicon-bonded hydrogen atoms can be used in the gel-forming composition in an amount of 1 to 30 weight percent, alternatively 5 to 20 weight percent, alternatively 5 to 15 weight percent, based on the weight of the composition. In one embodiment, the amount of hydrogen groups present in the organosiloxane containing silicon-bonded hydrogen atoms is 0.05 to 1.44 weight percent, based on the weight of the organosiloxane containing silicon-bonded hydrogen atoms.

[0199] 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.

[0200] 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.

[0201] 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).

[0202] In view of the above, in certain embodiments, 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.

[0203] An optional component is a hydroxy-substituted silicone resin such as those described in U.S. Patent Application No. 2007-020225, which is incorporated herein by reference. The resin typically has the formula R 3 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 wt. %, alternatively 1.0 to 5 wt. % silicon-bonded hydroxy groups.

[0204] The resin may be used in the gel-forming composition in an amount of from 2 to 45 weight percent, alternatively from 5 to 40 weight percent, alternatively from 10 to 35 weight percent, based on the weight of the gel-forming composition and resin.

[0205] Thus, in certain embodiments, 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.

[0206] In 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.

[0207] 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.

[0208] Polymers based on natural or synthetic rubber 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.

[0209] 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.

[0210] 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 (%).

[0211] 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.

[0212] Suitable SIS block copolymers according to the present invention are commercially available, for example, under the trade name JSR-SIS. Particular SIS block copolymer-based pressure-sensitive adhesives are available under the trade names JSR-SIS5229 and JSR-SIS5002.

[0213] Suitable polyisobutylenes for use in the present invention are commercially available, for example, under the trade name Oppanol®. Combinations of high molecular weight polyisobutylenes (B100, B80) and low molecular weight polyisobutylenes (B10, B11, B12, B13) can be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene range from 100:1 to 1:100, from 95:5 to 40:60, or from 90:10 to 75:25. Specific examples of polyisobutylene combinations are B10 / B100 in an 85 / 15 ratio or B12 / B100 in an 80 / 20 ratio. Oppanol® B100 has a viscosity-average molecular weight Mv of 1,110,000, a weight-average molecular weight Mw of 1,550,000, and an average molecular weight distribution Mw / Mn of 2.9. Oppanol® B10 has a viscosity average molecular weight Mv of 40,000, a weight average molecular weight Mw of 53,000, and an average molecular weight distribution Mw / Mn of 3.2. Oppanol® B12 has a viscosity average molecular weight Mv of 55,000, a weight average molecular weight Mw of 70,000, and an average molecular weight distribution Mw / Mn of 3.2. Suitable polyisobutylene adhesives are also commercially available, for example, under the trade name Duro-Tak® 87-6908.

[0214] Further additives The medical patch according to the present invention, particularly the active agent-containing layer and / or the skin-contacting layer, may further comprise at least one additive or excipient. Such additive or excipient is preferably selected from the group consisting of crystallization inhibitors, fillers, skin care substances, pH adjusters, preservatives, tackifiers, emollients, stabilizers, and penetration enhancers, particularly selected from crystallization inhibitors, tackifiers, emollients, stabilizers, and penetration enhancers. Such additives may be present in the active agent-containing layer or the skin-contacting layer in an amount of 0.001 to 80% by weight, for example, 1 to 20% by weight, or 0.01 to 10% by weight, based on the total weight of the active agent-containing layer.

[0215] It should be noted that in pharmaceutical formulations, formulation components are classified 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 penetration 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 are not to 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.

[0216] In certain embodiments, the medical patch, particularly the active agent-containing 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 can increase the solubility of the active agent or inhibit the crystallization of the active agent.

[0217] In certain embodiments, the medical patch, particularly the active agent-containing layer, may further comprise a viscosity-increasing agent. The addition of such an agent can make the active agent more easily dispersible, particularly in a suitable solubilizing agent. The viscosity-increasing agent may be selected from the group consisting of cellulose derivatives and high molecular weight polyacrylic acids, and any mixtures thereof, particularly ethyl cellulose.

[0218] In certain embodiments, the medical patch, particularly the active agent-containing 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.

[0219] In certain embodiments, the medical patch, particularly the active agent-containing layer and / or the skin-contacting 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.

[0220] In certain embodiments, the medical patch, particularly the active agent-containing layer and / or the skin-contacting layer, may further comprise a pH adjusting agent. Suitable pH adjusting agents include mild acids and bases, including amine derivatives, inorganic alkali derivatives, and polymers with basic or acidic functionality.

[0221] In certain embodiments, the medical patch, particularly the active agent-containing layer and / or the skin-contacting 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.

[0222] In certain embodiments, the medical patch, particularly the skin contact layer, may further comprise a skin care substance. Such substances may be used to avoid or reduce skin irritation, which may be detected by a skin reaction score. Suitable skin care substances include sterol compounds such as cholesterol, dexpanthenol, α-bisabolol, and antihistamines.

[0223] Fillers such as silica gel, titanium dioxide and zinc oxide may be used in conjunction with medical patches, particularly active agent-containing layers, to provide desired effects on certain physical parameters such as cohesive strength and bond strength.

[0224] When the active agent-containing layer structure, particularly the skin-contacting layer, is required to have self-adhesion and one or more polymers that do not provide sufficient self-adhesion are selected, a tackifier is added. The tackifier may be a saturated alicyclic hydrocarbon resin, a hydrogenated rosin glycerol ester, a paraffinum liquidum, or a mixture thereof, particularly a mixture containing a saturated alicyclic hydrocarbon resin and a paraffinum liquidum, or a mixture containing a hydrogenated rosin glycerol ester and a paraffinum liquidum. Furthermore, the tackifier may be selected from polyvinylpyrrolidone (which can maintain the adhesive properties of the matrix layer due to its ability to absorb water and therefore can 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.

[0225] In certain embodiments, the medical patch, particularly the active agent-containing 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 dimethyldecylphosphooxide, 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 agent-containing 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, dimethylpropylene urea, etc.

[0226] Medical patch shapes In some embodiments, the active agent-containing layer structure has a hexagonal or pentagonal shape provided by the backing layer, the active agent-containing layer, and the additional skin-contacting layer, respectively. The hexagonal shape includes at least one hexagon, particularly: All pairs of opposite sides of a hexagon are parallel, The sides of the hexagon have a length of 0.2 to 10 cm. The pentagonal shape includes at least one pentagon, in particular The sides of the pentagon have lengths ranging from 0.2 cm to 12.5 cm.

[0227] The hexagonal shape may include 1 to 10, e.g., 1, 2, 3, 4, or 5, hexagons, preferably, the hexagons are adjacent and / or non-overlapping. The polygonal shape may include 1 to 10, e.g., 1, 2, 3, 4, 6, or 9, pentagons, preferably, the pentagons are adjacent and / or non-overlapping. Two or more hexagons or pentagons are preferably integrally connected to each other. The hexagonal or pentagonal shape may, but need not, include perforations.

[0228] 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 opposite sides of the convex hexagon are all parallel, and the sides of the convex hexagon have a length of 0.2 to 10 cm. The hexagonal shape may particularly include one or two convex hexagons integrally connected to each other. In certain embodiments, the at least one pentagon is at least one convex pentagon, and the pentagonal shape includes at least one convex pentagon, where the sides of the convex pentagon have a length of 0.2 cm to 12.5 cm. The pentagonal shape may particularly include one to three convex pentagons integrally connected to each other. In certain embodiments, the hexagonal shape is a convex hexagon, or the pentagonal shape is a convex pentagon. In some embodiments, the convex pentagon may be a non-regular pentagon. In other embodiments, the convex pentagon may be a regular pentagon.

[0229] The hexagonal or pentagonal shape of the active agent-containing layer structure is advantageous in that the medical patch containing the active agent-containing layer structure is easy to handle and does not require much time.It allows the skin area to be easily covered 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 part.In addition, it can cover uneven or rounded skin surfaces without wrinkles, ensuring complete adhesion, and complex areas such as fingers and toes can be easily surrounded by the active agent-containing layer structure.In particular, when the hexagonal or pentagonal shape includes at least one convex hexagon or pentagon, the hexagonal or pentagonal shape requires only a short side length relative to the provided area, thereby reducing the risk of peeling off the edges of the medical patch.

[0230] In one embodiment, the hexagonal or pentagonal shape is a double hexagon or double pentagon formed from two identical convex hexagons or pentagons, respectively, sharing two adjacent vertices at their common edge. A double hexagon or double pentagon is obtained by mirroring a single convex hexagon or pentagon along one of its edges (the mirror axis), where the mirror axis includes the common edge. A double hexagon or double pentagon can be split at the common edge to obtain two equal convex hexagons or pentagons, which may be applied together or separately. Thus, in a further embodiment, the hexagonal or pentagonal shape is a double hexagon or double pentagon formed from two identical convex hexagons or pentagons sharing two adjacent vertices at their common edge, where the common edge is perforated to allow for easy tearing. In another embodiment, the pentagonal shape is a tri-pentagon formed from three identical convex pentagons, each of which shares a common edge with two adjacent vertices. This tri-pentagon is obtained by mirroring a first convex pentagon along one of its four sides (mirror axis 1), where mirror axis 1 includes the common edge shared by the first and second convex pentagons, and mirroring the second convex pentagon along one of its four other sides (mirror axis 2), where mirror axis 2 includes the common edge shared by the second and third convex pentagons. The tri-pentagon can be divided at the common side to obtain three equal convex pentagons, which may be applied together or separately. Thus, in a particularly preferred embodiment, the pentagonal shape is a tri-pentagon formed from three identical convex pentagons, each of which shares a common edge with two adjacent vertices, where the common side is perforated to allow for easy tearing. Such double or triple pentagons may also exist, for example, in the form of a hexagon, in particular a regular hexagon.

[0231] Hexagonal shapes, particularly convex hexagons or double hexagons, may have mirror symmetry and / or rotational symmetry. The hexagonal shape may be 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, the hexagonal shape may be rotationally symmetric with at least two, for example, three, or four, degrees of symmetry, particularly six-fold rotational symmetry. Thus, in certain embodiments, the hexagonal shape is mirror symmetric with at least four axes of symmetry and / or has at least four-fold rotational symmetry, particularly six-fold rotational symmetry, and even six-fold rotational symmetry. Pentagonal shapes in the form of regular hexagons may have mirror symmetry and / or rotational symmetry. Preferred pentagonal 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 pentagonal shapes have rotational symmetry of at least 2, for example 3 or 4, degree, in particular 6-fold rotational symmetry. Thus, particularly preferred pentagonal shapes have mirror symmetry with at least 4 axes of symmetry and / or have at least 4-fold rotational symmetry, in particular mirror symmetry with 6 axes of symmetry, further having 6-fold rotational symmetry.

[0232] When the active agent-containing layer structure has a hexagonal shape, the hexagon, particularly the convex hexagon, has three pairs of parallel opposing portions, which can be different or equal in length.The lengths of the two sides of each pair of parallel opposing portions can be equal, that is, the hexagon can be a parallel polygon.A parallel polygon can be obtained by elongating a parallelogram with two-fold rotational symmetry, or by elongating a rhombus, which has two-fold rotational symmetry and is mirror symmetric with two symmetry axes.

[0233] In certain embodiments, the six sides of a hexagon, particularly a convex hexagon, or the five sides of a pentagon, particularly a convex pentagon, are of equal length, i.e. the hexagon or pentagon is equilateral.

[0234] Alternatively, the hexagon may be a non-regular hexagon, 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 may be a non-equilateral hexagon, having four sides of equal length and two other sides of equal length. This particularly includes hexagons obtained by elongating a rhombus.

[0235] In certain embodiments, the hexagon is a non-regular hexagon, 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.

[0236] The sides of the hexagon according to the present invention have a length of 0.2 to 10 cm. The sides of the hexagon may also 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 particular, two, three, four, or six sides of the hexagon may 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 can have a length of about 0.5 cm, about 0.9 cm, or about 1.5 cm, and four sides of the hexagon can have a length of about 1.8 cm, about 2.8 cm, or about 3.2 cm; or The three sides of the hexagon can have lengths of about 0.5 cm, about 0.9 cm, or about 1.5 cm, and the three sides of the hexagon can have lengths of about 1.8 cm, about 2.8 cm, or about 3.2 cm; or The four sides of the hexagon can have a length of about 0.5 cm, about 0.9 cm, or about 1.5 cm, and the two sides of the hexagon can have a length of about 1.8 cm, about 2.8 cm, or about 3.2 cm.

[0237] 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.

[0238] In certain embodiments, the hexagons have an aspect ratio (height to width) of 4:1 or less, 3:1 or less, 2:1 or less, 1.5:1 or less, or √3:2 or less. The aspect ratio of the hexagons can also be √3:2 or less.

[0239] Alternatively, the pentagon may be non-equilateral, having four sides of equal length, or the pentagon may be non-equilateral, having two sides of equal length and two other sides of equal length. Such pentagons are preferably mirror-symmetric with one axis of symmetry, and the remaining sides are divided in the middle by the axis of symmetry. Pentagons according to the present invention, particularly convex pentagons, may have the following: - 5 sides of equal length, - 5 sides of different lengths, - two sides of equal length and three sides of different lengths, -Three sides of equal length and two sides of different lengths, -Three sides of equal length and two sides of other lengths, -Four sides of equal length and one side of the other length, or -One pair of sides of equal length and another pair of sides of equal length (the remaining sides have a different length from the pair of sides of equal length and the other pair of sides of equal length).

[0240] In certain embodiments, the pentagon is non-equilateral, and the ratio of a side (any side) to another side (any other side) is about 1:1, or about 1:2 / √3, or about 1:√3, or about 1:2, or about 1:2√3. In some embodiments, the pentagon is non-equilateral, and the ratio of the shortest side to the longest side is 1:2. In other embodiments, the pentagon is non-equilateral, and the ratio of the shortest side to the longest side is 1:2√3.

[0241] The sides of the pentagon according to the present invention have a length of 0.2 to 12.5 cm. The sides of the pentagon may have a length of 0.3 to 10 cm, 0.6 to 5 cm, 0.7 to 4.5 cm, or 0.9 to 2.4 cm. In particular, one, two, three, four, or five sides of the pentagon have a length of about 0.5 cm, about 1 cm, about 1.3 cm, about 1.7 cm, about 2 cm, about 2.5 cm, about 3.1 cm, or about 4.5 cm. For example, - two sides of the pentagon have a length of about 0.5 cm, about 1 cm, or about 1.3 cm, two sides of the pentagon have a length of about 1.3 cm, about 1.7 cm, about 2 cm, or about 2.5 cm, and the remaining side has a length of about 2.5 cm, about 3.1 cm, or about 4.5 cm; or - Two sides of the pentagon have a length of about 1 cm or about 1.3 cm, two sides of the pentagon have a length of about 1.3 cm, about 1.7 cm, or about 2 cm, and the remaining side has a length of about 1.7 cm, about 2 cm, or about 2.4 cm.

[0242] The height of the pentagon may range from 0.4 to 16.5 cm, 0.9 to 8.5 cm, 1.4 to 7.5 cm, or 1.6 to 4.5 cm. The width of the pentagon may range from 0.4 to 15.5 cm, 0.9 to 8 cm, 1.3 to 7 cm, or 1.5 to 4 cm.

[0243] The (convex) pentagon according to the present invention may belong to the above-mentioned types 1 to 15. In particular, the (convex) pentagon may be a type 1 pentagon, a type 3 pentagon, or a type 4 pentagon.

[0244] In certain embodiments, two sides of a pentagon are parallel. In particular, a pentagon has two parallel sides of equal length and two other sides of the same or other equal length. Alternatively, none of the sides of a pentagon are parallel.

[0245] In certain embodiments, the pentagon is mirror-symmetric with at least one axis of symmetry. In certain embodiments, the pentagon is mirror-symmetric with at least one axis of symmetry, having not only two (parallel) sides of equal length, but also two other sides of the same length or other equal length, the remaining sides being divided in the middle by the axis of symmetry, and / or having not only two interior angles of 90°, but also three interior angles of 120°, one of the latter being divided in the middle by the axis of symmetry. The pentagon may be a Type I pentagon or a Type II pentagon.

[0246] In certain embodiments, the hexagon, particularly a convex hexagon, is equiangular. Such a convex hexagon has interior angles each equal to 120°. Alternatively, the hexagon is non-equilibrium, 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, or 110° or greater, but less than 120°. Furthermore, the hexagon may have 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°.

[0247] In yet another 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 a specific embodiment, the hexagonal shape is a bicontiguous hexagon formed by two identical convex hexagons sharing two adjacent vertices on a common side, and the two identical convex hexagons are regular hexagons.

[0248] In certain embodiments, the pentagon, particularly the convex pentagon, is non-equilateral, preferably having one interior angle and another interior angle that sum to 180°. The interior angles that sum to 180° may be adjacent or non-adjacent. In some embodiments, one interior angle is 60° and the other interior angle is 120°. Alternatively, one interior angle and another interior angle are each 90°. A preferred (convex) pentagon according to the present invention has two interior angles that are 90° and at least one interior angle that is 120°. A particularly preferred (convex) pentagon according to the present invention has two interior angles that are 90° and three interior angles that are 120°.

[0249] In some very specific embodiments, the pentagon is a Type I special pentagon having the following properties: -A pentagon is mirror symmetric with exactly one axis of symmetry. -A pentagon has two adjacent interior angles of 90° and three adjacent interior angles of 120°. -A pentagon has two parallel sides of equal length, two other sides of equal length, and one remaining side, where: - the ratio of two parallel sides of equal length to the other two parallel sides of equal length is approximately 1:2; and / or - the ratio of two parallel sides of equal length to the remaining side is approximately 1:2√3; and / or -The ratio of the other two equal-length sides to the remaining side is approximately 1:√3.

[0250] In another very special embodiment, the pentagon is a Type II special pentagon having the following properties: -A pentagon is mirror symmetric with exactly one axis of symmetry. -A pentagon has two adjacent interior angles of 120° and two non-adjacent interior angles of 90° separated by another interior angle of 120°. -A pentagon has two sides of equal length, two other sides of equal length, and one remaining side, where - the ratio of two sides of equal length to two other sides of equal length is approximately 1:√3; and / or - the ratio of the two equal sides to the remaining sides is approximately 1:2; and / or -The ratio of the other two equal-length sides to the remaining side is approximately 1:2 / √3.

[0251] Medical patch sheets In certain embodiments of the present invention, the active agent-containing layer structure may also be used in a sheet of a medical patch comprising multiple active agent-containing layer structures disposed on a release liner, particularly when the active agent-containing layer structure has a hexagonal or pentagonal shape.

[0252] Sheets of such medical patches are two or more active agent-containing layer structures as described above; a release liner; The release liner may be coextensive with the active agent-containing layer structure or may extend in all directions beyond the boundaries of the active agent-containing layer structure.

[0253] By using multiple active agent-containing layer structures, the surface of the skin area to be treated can be filled by fitting the active agent-containing layer structures adjacent to each other like a puzzle without wrinkles, and in this case, if the active agent-containing layer structures have a hexagonal or pentagonal shape, such a shape can avoid gaps and / or overlaps.

[0254] The number of active agent-containing layer structures provided on the medical patch sheet peeled from the release liner depends on the size(s) of the active agent-containing layer structures. A suitable medical patch sheet may contain, for example, 2 to 400, 3 to 300, 4 to 300, 4 to 120, 6 to 120, 6 to 30, or 8 to 30 active agent-containing layer structures. In certain embodiments, the medical patch sheet may contain 2 to 15 or 150 to 300 active agent-containing layer structures. In further embodiments, the medical patch sheet may contain 2, 3, 4, 5, 6, 7, or 8 active agent-containing layer structures. Alternatively, the medical patch sheet may contain 150, 180, 200, 240, or 300 active agent-containing layer structures. The active agent-containing layer structures may be the same or different.

[0255] The active agent-containing layer structures can be arranged in any pattern on the release liner, either adjacent to each other (tiling the surface) or with small gaps between them to allow for easy grasping of a single active agent-containing layer structure. In some embodiments, the active agent-containing layer structures are arranged on the release liner in a space-saving manner. In particular, the active agent-containing layer structures are arranged side by side on the release liner. Thus, the active agent-containing layer structures can be arranged in two or more parallel rows relative to the longitudinal axis of the release liner, each row containing 2 to 20, 3 to 12, or 4 to 8 active agent-containing layer structures. For example, the active agent-containing layer structures can be arranged in 20 rows, each row containing 15 active agent-containing layer structures, particularly 15 identical active agent-containing layer structures. In another example, the active agent-containing layer structures can be arranged in four rows, each row containing 3 to 6 active agent-containing layer structures, particularly 3 to 6 identical active agent-containing layer structures. In other embodiments, the active agent-containing layer structures are arranged in one or more types of repeating geometric patterns, preferably each geometric pattern containing 2 to 15, 3 to 12, or 4 to 9 active agent-containing layer structures. Such types of geometric patterns may include polygons such as hexagons. Thus, the active agent-containing layer structures may be arranged in the form of one or more hexagons, particularly regular hexagons, preferably each (regular) hexagon containing 2, 3, 4, or 9, particularly 2 or 3, active agent-containing layer structures. In certain embodiments, the active agent-containing layer structures may be arranged in the form of one or more regular hexagons, each of which contains two special pentagons of type I described above, or each of which contains three special pentagons of type II described above.

[0256] In a specific embodiment, the active agent-containing layer structure tiles the plane, particularly a single plane, such as a prismatic pentagonal tiling or a chiropteran pentagonal tiling. The active agent-containing layer structure tiling the plane can be a parallel polygon, particularly a regular hexagon. The active agent-containing layer structure can also have a hexagonal shape selected from a regular hexagon and / or a bicontiguous hexagon formed from two identical regular hexagons sharing two adjacent vertices and a common side. Furthermore, the active agent-containing layer structure tiling the plane is a pentagon of types 1 to 15, particularly a pentagon of type 1, or a pentagon of type 3, or a pentagon of type 4, such as the (special) pentagon of type I or type II described above. The active agent-containing layer structure may also have a pentagonal shape selected from a bipentagon formed by two identical convex pentagons sharing a common side with two adjacent vertices, and / or a tripentagon formed by three identical convex pentagons sharing a common side with two adjacent vertices in a pair, which may be in the form of a (regular) hexagon. The active agent-containing layer structures may be separated from each other or connected to each other. They may be adjacent to each other by sharing a common vertex in pairs and / or in three and / or four pairs. When a common vertex is shared only in pairs, this shared vertex may be located on a side of the third pentagon, particularly in the center of the side.

[0257] In certain embodiments, the active agent-containing layer structures are adjacent to each other by sharing a common edge with two adjacent vertices, 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 can be adjacent to each other by sharing a common edge with two adjacent vertices, and are connected to each other by a weakened common edge to allow them to be easily peeled apart. In particular, the common edge can be perforated to allow them to be easily torn apart. Also, the medical patch sheet can include active agent-containing layer structures, such active agent-containing layer structures being adjacent to each other by sharing a common edge with two adjacent vertices, 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 apart. For example, the active agent-containing 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 active agent-containing layer structures, the active agent-containing 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 release, and the active agent-containing 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 active agent-containing layer structures are separated from each other by cutting the common edge for independent release from the release liner.

[0258] In certain embodiments, the active agent-containing layer structures are adjacent to each other by sharing at least one vertex and at least a portion of an adjacent edge, and are separated from each other by cutting the adjacent edge to allow for independent peeling from the release liner. Alternatively, the active agent-containing layer structures are adjacent to each other by sharing at least one vertex and at least a portion of an adjacent edge, and are connected to each other by adjacent edges that are weakened to allow for easy peeling. In particular, the adjacent edges are perforated to allow for easy tearing. In some embodiments, the active agent-containing 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 for independent peeling 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 common edges that are weakened to allow for easy peeling. In particular, the common edge is perforated to allow for easy tearing. The medical patch sheet may also include active agent-containing layer structures, which are adjacent to each other by sharing at least one vertex and at least a portion of an adjacent edge, or two adjacent vertices and their common edge, some of which are separated from each other by cutting the adjacent or common edge for independent peeling from the release liner, and some of which are connected to each other by weakened adjacent or common edges for easy tearing. In certain embodiments, all of the active agent-containing layer structures are separated from each other by cutting the adjacent or common edge for independent peeling from the release liner. For example, the active agent-containing 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 active agent-containing layer structures adjacent to each other by sharing at least one vertex and at least a portion of an adjacent edge and / or two adjacent vertices and their common edge, the rows being separated from each other for independent peeling, and the active agent-containing layer structures within a row being connected to each other by a perforated common edge for easy peeling.In another example, the active agent-containing layer structures may be arranged in the form of two or more regular hexagons, each hexagon containing two, three, or nine active agent-containing layer structures adjacent to each other by sharing at least one vertex and at least a portion of an adjacent side and / or two adjacent vertices and their common side, the hexagons being separated from each other for independent peeling, and the active agent-containing layer structures within a hexagon being connected to each other by a common side that is perforated for easy peeling.

[0259] In certain embodiments, the active agent-containing 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) can provide a single point (a) at which the active agent-containing layer structures are connected to one another, even if adjacent or common edges are at least partially cut and separated from one another. This allows the active agent-containing 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 active agent-containing layer structures. Alternatively, for joint release when the number of such connected active agent-containing layer structures is small, some fastening bridge(s) can be cut, e.g., torn.

[0260] In a further embodiment, a common fastening bridge is provided at a vertex, connecting at least two or at least three active agent-containing layer structures. Alternatively, a common fastening bridge may be provided at a side, connecting two active agent-containing layer structures. In a medical patch sheet, adjacent active agent-containing layer structures are connected to each other in pairs by at least two common fastening bridges provided at two adjacent vertices or their common sides. In particular, adjacent active agent-containing layer structures are connected to each other in groups of three by a common fastening bridge provided at a common vertex. This particularly relates to active agent-containing layer structures that tile a plane. Thus, in one embodiment, the active agent-containing 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 adjacent active agent-containing layer structures are connected to each other in groups of three by a common fastening bridge provided at a common vertex.

[0261] In yet further embodiments, common fastening bridges are provided at the vertices and / or sides, connecting at least two, preferably three or four, active agent-containing layer structures, such as: - two active agent-containing layer structures connected by two common fastening bridges at two adjacent vertices, or - Three active agent-containing layer structures connected by a common fastening bridge at the shared vertices or common vertices of two active agent-containing layer structures on the side of a third active agent-containing layer structure; or -Four self-adhesive layer construction connected by one common fastening bridge at the common vertex.

[0262] In a particular sheet of a medical patch, all adjacent active agent-containing layer structures are connected to each other in pairs by at least two common fastening bridges at two adjacent vertices or their common side, and / or at one vertex and an adjacent side, preferably at two adjacent vertices. In particular, all adjacent active agent-containing layer structures are connected to each other in pairs by common fastening bridges at vertices and / or sides, especially at common vertices. This particularly relates to active agent-containing layer structures that tile a plane. Thus, in a preferred embodiment of the sheet of a medical patch according to the present invention, the active agent-containing layer structures are the above-mentioned Type I or Type II (special) pentagons, connected to each other by at least one fastening bridge for joint release from the release liner, and all adjacent active agent-containing layer structures are connected to each other in pairs by common fastening bridges at the shared vertices of the sides or common vertices.

[0263] In certain embodiments, the active agent-containing layer structure has a hexagonal and / or pentagonal shape selected from a total of two or three different shapes. In further embodiments, the active agent-containing layer structure has a hexagonal shape including a convex hexagon and a double hexagon formed from two identical convex hexagons and sharing a common side with two adjacent vertices, particularly a regular hexagon and a double hexagon formed from two identical regular hexagons. Alternatively, the active agent-containing layer structure has a pentagon including a convex pentagon and a double pentagon formed from two identical convex pentagons and sharing a common side with two adjacent vertices, particularly a (special) pentagon of the above-mentioned type I and a double pentagon formed from two identical (special) pentagons of the above-mentioned type I. Alternatively, all of the active agent-containing layer structures have the same hexagonal or pentagonal shape. In certain embodiments, the active agent-containing layer structure is a doublet hexagon formed by two identical convex hexagons, in particular a doublet hexagon formed by two identical regular hexagons, which share two adjacent vertices and a common side. In this context, a (regular) convex hexagon or a doublet hexagon formed by two identical (regular) convex hexagons is congruent. In certain embodiments, the active agent-containing layer structure is a non-equilateral convex pentagon with two interior angles of 90° and three interior angles of 120°, two parallel sides of equal length and two other sides of equal length, and the ratio of the shortest side to the longest side is about 1:2√3. Alternatively, the active agent-containing layer structure is a non-equilateral convex pentagon with two interior angles of 90° and three interior angles of 120°, two sides of equal length and two other sides of equal length, and the ratio of the shortest side to the longest side is about 1:2. In particular, the active agent-containing layer structure may be a (special) pentagon of type I or type II as described above, arranged in the form of a regular hexagon.

[0264] In certain embodiments, the medical patch sheet (all medical patch sheets as a whole) is 1 cm 2 300cm from 2 It has a discharge area of ​​.

[0265] Treatment method / medical use The medical patch according to the present invention is suitable for use in methods of treatment, particularly in methods of treating human patients.

[0266] In certain embodiments, the medical patch of the present invention is for use in a treatment method in which the medical patch is attached to the patient's skin for preferably less than 90 minutes, less than 60 minutes, or less than 30 minutes. In certain embodiments, the medical patch of the present invention is for use in a treatment method having an administration interval of at least about 1.5 months, at least about 2 months, or at least about 3 months. Therefore, it is preferable that the medical patch be applied only after at least 90 days of drug withdrawal after removing the previous medical patch.

[0267] In certain embodiments, the medical patch of the present invention is used in a method for treating pain. In particular, the medical patch of the present invention is used in a method for treating neuropathic pain, such as chronic neuropathic pain. Neuropathic pain preferably includes postherpetic neuralgia, postoperative neuralgia (e.g., pain after inguinal hernia surgery, pain after thoracotomy, or pain after mastectomy), posttraumatic neuropathy, polyneuropathy (e.g., pain associated with diabetic neuropathy), chemotherapy-induced neuropathy, tumor-induced neuropathy, HIV-associated neuropathy, alcohol-associated neuropathy, small fiber neuropathy or complex regional pain syndrome, radiculopathy, or compression syndromes such as carpal tunnel syndrome. Alternatively, the medical patch of the present invention is used in a method for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy of the hands and feet (DPN), or postoperative neuropathic pain, and / or the medical patch of the present invention is used in a method for treating nociceptive pain, such as acute nociceptive pain, preferably somatic pain or nociceptive pain including visceral pain.

[0268] In a specific embodiment, the medical patch of the present invention is used in a method for treating joint pain or cancer pain. In particular, the medical patch of the present invention is used in a method for treating pain associated with a joint condition, particularly pain associated with arthritis, such as infectious or non-infectious arthritis, preferably pain associated with rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, or osteoarthritis, such as hip arthritis, knee arthritis, ankle arthritis, or finger arthritis.

[0269] In relation to the above, the medical patch according to the present invention is preferably applied to at least one body surface of a patient, particularly a body surface selected from the back, buttocks, waist, legs, knees, feet, or hands. The preferred application time of the medical patch according to the present invention is less than or about 60 minutes for the back, buttocks, waist, or legs, and less than or about 30 minutes for the knees, feet, or hands.

[0270] In certain embodiments, the medical patch of the present invention is not applied / removed by a medical professional, and in particular, the medical patch of the present invention is applied / removed by the patient themselves.

[0271] According to a particular aspect, the present invention relates to the use of the medical patch described herein for the manufacture of a medicament, and in particular to the use of the medical patch described herein for the manufacture of a medicament for treating pain, such as for the manufacture of a medicament for treating neuropathic pain or nociceptive pain, or for the manufacture of a medicament for treating arthritic pain or cancer pain. According to a more specific aspect, the present invention also relates to the use of the medical patch described herein for the manufacture of a medicament for treating pain associated with a joint condition such as arthritis.

[0272] According to a particular aspect, the present invention also relates to a method of treatment, in particular a method of treating pain, such as a method of treating neuropathic pain or nociceptive pain, or a method of treating arthritis or cancer pain, comprising applying to the skin of a patient a medical patch as described herein. According to a more particular aspect, the present invention also relates to a method of treating pain associated with a joint condition such as arthritis, comprising applying to the skin of a patient a medical patch as described herein.

[0273] Manufacturing Process The medical patch according to the present invention may be manufactured using a process comprising the following steps. i. preparing an active agent-containing layer; ii. preparing a skin contact layer; iii. Laminating a skin contact layer onto the active agent-containing layer to obtain an active agent-containing layer structure.

[0274] The active agent-containing layer may be prepared before or after the skin contact layer, or the two layers may be prepared in parallel before lamination. Alternatively, the active agent-containing layer may be prepared first and the skin contact layer may be prepared directly on top of the active agent-containing layer, or the skin contact layer may be prepared first and the active agent-containing layer may be prepared directly on top of the skin contact layer.

[0275] In some embodiments, the present invention relates to a method for producing the active agent-containing layer structure of the medical patch described herein, the method comprising the steps of: 1) At least the following ingredients 1. an active agent, and 2. Polymer I to obtain an active agent-containing coating composition; 2.1) coating an active agent-containing coating composition onto a first intermediate liner; 2.2) drying the coated active agent-containing coating composition to form an active agent-containing layer; and optionally 2.3) Laminating the active agent-containing layer obtained by drying the active agent-containing coating composition coated on the first intermediate liner with a backing layer.

[0276] The method may further comprise the following steps: 3.1) coating an active agent-free coating composition comprising at least Polymer II onto a second intermediate liner; 3.2) drying or curing the coated active agent-free coating composition to form a skin contact layer; and optionally 3.3) Laminating the skin contact layer obtained by drying or curing the active agent-free coating composition coated on the second intermediate liner with a release liner.

[0277] The method may further comprise the following steps: 4.1) removing the first and second intermediate liners from the active agent-containing layer and the skin-contacting layer; 4.2) Laminating the open side of the skin-contacting layer to the open side of the active agent-containing layer to obtain an active agent-containing layer structure.

[0278] In another embodiment, the present invention relates to a method for producing the active agent-containing layer structure of the medical patch described herein, comprising the steps of: 1) At least the following ingredients 1. an active agent, and 2. Polymer I to obtain an active agent-containing coating composition; 2.1) coating an active agent-containing coating composition onto a backing layer; 2.2) drying the coated active agent-containing coating composition to form an active agent-containing layer; and optionally 3.1) coating an active agent-free coating composition comprising at least Polymer II onto a release liner; 3.2) drying or curing the coated active agent-free coating composition to form a skin contact layer; and optionally 4) Laminating the open side of the skin-contacting layer to the open side of the active agent-containing layer to obtain an active agent-containing layer structure.

[0279] The active agent-containing layer and the skin-contacting layer are preferably prepared separately as described above and then laminated together by removing the intermediate liner (if any) and then laminating the open sides of the two layers together to provide the active agent-containing layer structure. Alternatively, an active agent-free coating composition can be directionally coated onto the active agent-containing layer and dried or cured before applying a release liner or backing layer, respectively, or an active agent-containing coating composition can be directionally coated onto the skin-contacting layer and dried.

[0280] In this manufacturing process, in step 1), the components are preferably combined in a solvent to obtain a coating composition. The solvent may be selected from alcoholic solvents, particularly methanol, ethanol, isopropanol, and mixtures thereof, and non-alcoholic solvents, particularly ethyl acetate, n-propyl acetate, hexane, n-heptane, petroleum ether, toluene, and mixtures thereof, and is preferably selected from non-alcoholic solvents such as ethyl acetate or n-heptane.

[0281] The active agent may be uniformly dissolved or dispersed in the active agent-containing coating composition. The active agent may be provided in an amphiphilic solvent, which may be immiscible or only slightly miscible with the solvent of the active agent-containing coating composition.

[0282] Polymer I and / or Polymer II may be non-curable and therefore typically applied by a solvent-based process. Polymer I and / or Polymer II may therefore be provided in a solvent, preferably with a solids content of 40 to 75 wt. The solvent may be selected from alcoholic and non-alcoholic solvents, as described above.

[0283] The coated active agent-containing coating composition and / or active agent-free coating composition can be solidified by drying as described in 2.2) or 3.2) to form the active agent-containing layer or the skin contact layer, respectively. Drying is preferably carried out at a temperature of 20 to 90°C. Alternatively, the skin contact layer may be formed during curing, i.e., crosslinking, which is preferably carried out at a temperature of 40 to 140°C. [Example]

[0284] 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.

[0285] Example 1 The skin permeation rate and availability of capsaicin from two medical patches containing capsaicin were determined in vitro.

[0286] The two patches differed from each other only by the presence or absence of an additional skin-contacting layer, and were therefore identically prepared, except that the steps of preparing an inactive coating composition, coating, and laminating the resulting inactive layer with the previously prepared capsaicin-containing layer were performed on only one of the two patches, but not the other.

[0287] Capsaicin-containing coating composition The formulation of the capsaicin-containing coating composition for both patches is summarized in Table 1.1 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0288] [Table 1]

[0289] Preparation of Capsaicin-Containing Coating Compositions Transcutol was first thickened with ethyl cellulose under stirring (100-300 rpm).

[0290] 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.

[0291] 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.

[0292] 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.

[0293] The resulting capsaicin-containing microreservoir layer was then laminated with a backing layer (polyester film, 19 μm).

[0294] Inert Coating Composition For medical patches containing a skin contact layer, the formulation of the inactive coating composition is summarized in Table 1.2 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0295] [Table 2]

[0296] 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 100 rpm for about 10 minutes until a homogenous mixture of Components A and B was obtained.

[0297] 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.

[0298] The coating thickness is approximately 230.0 g / m² for the inactive (skin contact) layer after solvent removal. 2 was selected to be.

[0299] The resulting inactive (skin contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 125 μm).

[0300] 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.

[0301] Preparation of medical patches Individual medical patches were punched out from the capsaicin-containing self-adhesive layer structure obtained above, and then the medical patches were sealed in pouches of the primary packaging material.

[0302] Skin permeation measurements The permeation amounts of the two medical patches prepared as described above were determined in an in vitro experiment using a 10.0 ml Franz diffusion cell according to the OECD guidelines (adopted April 13, 2004). Split-thickness human skin (female abdomen, date of birth 1981) obtained during cosmetic surgery was used. Heat-separated epidermis was used for all medical patches. A release area of ​​1.171 cm was obtained from the medical patch. 2 The amount of capsaicin permeated into the receptor medium of the Franz cell (0.9% sodium chloride solution containing 0.1% azide saline as an antibacterial agent) at a temperature of 32±1°C was measured, and the corresponding skin permeation rate was calculated.

[0303] The results are shown in Table 1.3 and Figure 1a.

[0304] [Table 3]

[0305] The corresponding skin permeation rates (Δ flux rates) were calculated based on the respective permeated amounts.

[0306] The results are shown in Table 1.4 and Figure 1b.

[0307] [Table 4]

[0308] Exemplary Patches 2A-2D, 3A-3D, 4A-4D, and 5A-5D Based on the results obtained in Example 1 outlined above, further patch concepts that are believed to be particularly suitable, and possible testing thereof, are described herein below.

[0309] Active Agent-Containing Coating Composition Possible formulations of active agent-containing coating compositions 2, 3, 4 and 5 are summarized in Table 2.1 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0310] [Table 5]

[0311] Preparation and Coating of Active Agent-Containing Coating Compositions Preparation and coating of the active agent-containing coating composition can be carried out using methods known to those skilled in the art, for example, substantially as outlined in Example 1, optionally using additional solvent during preparation of the active agent-containing coating composition, which evaporates upon drying of the coated composition.

[0312] Inert Coating Composition The formulations of active agent-free coating compositions a-d are summarized below in Table 2.2. The % solids values ​​refer to the amount in % by weight (Amt).

[0313] [Table 6]

[0314] Preparation and Coating of Active Agent-Free Coating Compositions Preparation and coating of active agent-free coating compositions can be carried out using methods known to those skilled in the art, for example, substantially as outlined in Example 1, optionally using additional solvent during preparation of active agent-containing coating compositions, which evaporates upon drying of the coated composition.

[0315] Lamination of an active drug-containing layer and an inactive (skin-contacting) layer The inactive (skin-contacting) layer can then be laminated with the active agent-containing layer obtained using methods known to those skilled in the art, such as methods substantially as outlined in Example 1. Combinations of Formulations 2-5 and a-c result in patches 2a-2d, 3a-3d, 4a-4d, and 5a-5d.

[0316] Preparation of medical patches Individual medical patches can then be die cut from the resulting active agent-containing layer structure and enclosed in pouches of primary packaging material as described above.

[0317] The present invention relates in particular to the following further items: 1. A medical patch for administering an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising: A) a backing layer; B) an active agent-containing layer, (i) an active agent, and (ii) an active agent-containing layer comprising Polymer I; C) a skin contact layer comprising polymer II; wherein the skin contact layer is an adhesive layer that is directly adhered to the active agent-containing layer; A medical patch, wherein the saturation concentration of the active agent in the skin contact layer is less than 0.1% by weight.

[0318] 2. The medical patch according to item 1, wherein the saturation concentration of the active agent in the skin contact layer is less than 0.05% by weight, less than 0.02% by weight, or less than 0.01% by weight.

[0319] 3. The medical patch according to item 1 or 2, wherein polymer II is a polymer or a mixture of polymers in which the active agent is substantially insoluble.

[0320] 4. The medical patch according to any one of items 1 to 3, wherein polymer II is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0321] 5. The medical patch according to any one of items 1 to 4, 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 rubber or synthetic rubber.

[0322] 6. The medical patch according to any one of items 1 to 5, wherein polymer II is a polymer or a mixture of polymers selected from the group consisting of silicone-based polymers and silicone gel adhesives.

[0323] 7. The medical patch according to any one of items 1 to 6, wherein the polymer II is selected from silicone-based polymers.

[0324] 8. The medical patch according to item 7, wherein the silicone-based polymer is obtained by polycondensation of silanol-endblocked polydimethylsiloxane and silicate resin, and preferably has a resin to polymer ratio of 50:50 to 70:30, or 55:45, 60:40, or 65:35.

[0325] 9. A medical patch according to item 7 or 8, wherein the silicone-based polymer is a mixture of pressure-sensitive adhesives obtained by polycondensation of silanol-endblocked polydimethylsiloxane and silicate resin, and the resin-to-polymer ratio is 55:45 or 60:40.

[0326] 10. Silicone-based polymers are pressure-sensitive adhesive mixtures, A solution viscosity of 450 mPa·s at approximately 60% solids content in heptane at 25°C and / or 1×10 at 0.01 rad / s at 30°C 8 It has a complex viscosity in poise, A solution viscosity of 500 mPa·s at approximately 60% solids content in heptane at 25°C and / or 5×10 at 0.01 rad / s at 30°C 6 10. The medical patch according to any one of items 7 to 9, having a complex viscosity in poise.

[0327] 11. The medical patch according to any one of items 1 to 10, wherein polymer II is an amine-compatible polysiloxane.

[0328] 12. The medical patch according to item 11, wherein the amine-compatible polysiloxane is obtained by polycondensing a silanol-endblocked polydimethylsiloxane with a silicate resin, followed by at least partial trimethylsilylation of the remaining silanol functionality.

[0329] 13. The medical patch according to any one of items 1 to 6, wherein polymer II is selected from silicone gel adhesives.

[0330] 14. The medical patch according to item 13, 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 SiH groups with Si-alkenyl groups.

[0331] 15. A medical patch according to item 13 or 14, wherein the silicone gel adhesive is obtained by reacting a gel-forming composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane and (ii) a methylhydrogenpolysiloxane having trimethylsilyl end groups in the presence of (iii) a platinum catalyst.

[0332] 16. A medical patch according to any one of items 13 to 15, wherein the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive containing from about 2 to about 45% by weight of at least one hydroxyl-substituted silicone resin.

[0333] 17. The medical patch according to any one of items 1 to 16, wherein the skin contact layer does not contain a silicone gel adhesive.

[0334] 18. The medical patch according to any one of items 1 to 17, wherein the skin contact layer comprises polymer II in an amount of at least 95% by weight, at least 99% by weight, or about 100% by weight, based on the total weight of the skin contact layer.

[0335] 19. The medical patch according to any one of items 1 to 18, wherein the skin contact layer comprises an active agent in an amount of less than 0.1 wt. %, or less than 0.01 wt. %, based on the total weight of the skin contact layer.

[0336] 20. A medical patch according to any one of items 1 to 19, wherein the active agent is an irritating active agent.

[0337] 21. A medical patch according to any one of items 1 to 20, wherein the active agent is a capsaicin analogue.

[0338] 22. The medical patch according to any one of items 1 to 21, wherein the active agent is selected from the group consisting of arvanil, capsiate, civamide, dihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, nordihydrocapsaicin, olvanil, palvanil, piperine, phenylacetylene vanil, and resiniferatoxin.

[0339] 23. A medical patch according to any one of items 1 to 22, wherein the active agent is resiniferatoxin.

[0340] 24. The medical patch according to any one of items 1 to 23, wherein the active agent-containing layer does not contain capsaicin.

[0341] 25. The active agent is at least 0.10 mg / cm 2 , at least 0.20 mg / cm 2 , at least 0.50 mg / cm 2 , or at least 1.0 mg / cm 2 25. The medical patch according to any one of items 1 to 24, wherein the active agent-containing layer is present in an amount of

[0342] 26. The active agent is 12.0 mg / cm 2 Less than 10.0 mg / cm 2 Less than 6.0 mg / cm 2 Less than or equal to 3.0 mg / cm 2 26. The medical patch according to any one of items 1 to 25, wherein the active agent-containing layer is present in an amount of less than 1000 mg / kg.

[0343] 27. The medical patch according to any one of items 1 to 26, wherein the active agent-containing layer contains the active agent in an amount of 0.5 to 30 wt %, 1 to 20 wt %, 2 to 15 wt %, or 5 to 10 wt %, based on the total weight of the active agent-containing layer.

[0344] 28. A medical patch according to any one of items 1 to 27, wherein the active agent-containing layer contains polymer I in an amount of 20 to 99% by weight, or 60 to 90% by weight, based on the total weight of the active agent-containing layer.

[0345] 29. A medical patch according to any one of items 1 to 28, wherein polymer I is a pressure-sensitive adhesive or a mixture of pressure-sensitive adhesives.

[0346] 30. A medical patch according to any one of items 1 to 29, wherein polymer I is a polymer or a mixture of polymers selected from the group consisting of acrylic polymers, silicone-acrylic hybrid polymers, silicone-based polymers, and polymers based on natural or synthetic rubber.

[0347] 31. A medical patch according to any one of items 1 to 30, wherein polymer I is a polymer or a mixture of polymers selected from the group consisting of silicone-based polymers and polymers based on natural or synthetic rubber.

[0348] 32. The medical patch according to any one of items 1 to 31, wherein polymer I is selected from silicone-based polymers.

[0349] 33. A medical patch according to item 32, wherein the silicone-based polymer is obtained by polycondensation of a silanol-endblocked polydimethylsiloxane with a silicate resin, and preferably has a resin to polymer ratio of 50:50 to 70:30, or 55:45, 60:40, or 65:35.

[0350] 34. A medical patch according to item 32 or 33, wherein the silicone-based polymer is a mixture of pressure-sensitive adhesives obtained by polycondensation of silanol-endblocked polydimethylsiloxane and silicate resin, and the resin-to-polymer ratio is 55:45 or 60:40.

[0351] 35. Silicone-based polymers are pressure-sensitive adhesive mixtures, A solution viscosity of 450 mPa·s at approximately 60% solids content in heptane at 25°C and / or 1×10 at 0.01 rad / s at 30°C 8 It has a complex viscosity in poise, A solution viscosity of 500 mPa·s at approximately 60% solids content in heptane at 25°C and / or 5×10 at 0.01 rad / s at 30°C 6 35. The medical patch according to any one of items 32 to 34, having a complex viscosity in poise.

[0352] 36. A medical patch according to any one of items 1 to 35, wherein polymer I is an amine-compatible polysiloxane.

[0353] 37. A medical patch according to item 36, wherein the amine-compatible polysiloxane is obtained by polycondensing a silanol-endblocked polydimethylsiloxane with a silicate resin, followed by at least partial trimethylsilylation of the remaining silanol functionality.

[0354] 38. A medical patch according to any one of items 1 to 37, wherein polymer I is selected from styrene triblock copolymers and polyisobutylene.

[0355] 39. The medical patch according to item 38, wherein the styrene triblock copolymer is selected from the group consisting of styrene-ethylene-styrene (SES) block copolymer, styrene-butadiene-styrene (SBS) block copolymer, styrene-isoprene-styrene (SIS) block copolymer, styrene-ethylene / butylene-styrene (S-EB-S) block copolymer, styrene-ethylene / butylene / propylene-styrene (S-EBP-S) block copolymer, styrene-isoprene / butadiene-styrene (S-IB-S) block copolymer, and mixtures thereof.

[0356] 40. A medical patch according to any one of items 1 to 39, wherein polymer I is an SIS block copolymer or polyisobutylene, or a mixture thereof.

[0357] 41. A medical patch according to item 40, wherein the SIS block copolymer contains polystyrene and polyisoprene blocks in a ratio of 10:90 (%) to 30:70 (%).

[0358] 42. A medical patch according to item 40 or 41, wherein the SIS block copolymer is composed of three blocks of polystyrene, polyisoprene and polystyrene.

[0359] 43. A medical patch according to any one of items 1 to 42, wherein polymer I is a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene.

[0360] 44. A medical patch according to any one of items 1 to 43, wherein polymer I is different from polymer II.

[0361] 45. A medical patch according to any one of items 1 to 43, wherein polymer I is the same as polymer II.

[0362] 46. ​​A medical patch according to any one of items 1 to 45, wherein the active agent-containing layer further comprises a solubilizer.

[0363] 47. The medical patch according to item 46, wherein the solubilizer is a substance or mixture of substances in which the active agent has a saturation concentration of at least 30% by weight.

[0364] 48. A medical patch according to item 46 or 47, wherein the solubilizer is an amphiphilic solvent.

[0365] 49. The medical patch according to item 46 or 47, wherein the solubilizer is dipropylene glycol, diethylene glycol monoethyl ether, or dimethyl isosorbide.

[0366] 50. The medical patch according to any one of items 46 to 49, wherein the active agent-containing layer contains a solubilizer in an amount of 1 to 40% by weight, based on the total weight of the active agent-containing layer.

[0367] 51. The medical patch according to any one of items 1 to 50, wherein the active agent-containing layer and / or the skin-contacting layer further comprises at least one additive or excipient selected from the group consisting of crystallization inhibitors, viscosity-increasing agents, fillers, skin care substances, pH adjusters, preservatives, tackifiers, emollients, stabilizers, and penetration enhancers.

[0368] 52. A medical patch according to any one of items 1 to 51, wherein the backing layer is impermeable to the active agent.

[0369] 53. A medical patch according to any one of items 1 to 52, wherein the medical patch further comprises a release liner.

[0370] 54. The medical patch according to any one of items 1 to 53, wherein the medical patch is a topical medical patch.

[0371] 55. A medical patch according to any one of items 1 to 54, wherein the medical patch is a transdermal therapeutic system.

[0372] 56. A medical patch according to any one of items 1 to 55 for use in a method of treatment, in particular for use in a method of treating pain, or for use in a method of treating neuropathic pain or nociceptive pain, or for use in a method of treating arthralgia or cancer pain, or for use in a method of treating pain associated with a joint condition such as arthritis.

[0373] 57. Use of the medical patch according to any one of items 1 to 55 for the manufacture of a medicament, in particular for the manufacture of a medicament for treating pain, or for the manufacture of a medicament for treating neuropathic pain or nociceptive pain, or for the manufacture of a medicament for treating arthralgia or cancer pain, or for the manufacture of a medicament for treating pain associated with a joint condition such as arthritis.

[0374] 58. A method of treatment, in particular a method of treating pain, or neuropathic pain, or nociceptive pain, or arthralgia, or cancer pain, or pain associated with a joint condition such as arthritis, comprising: A treatment method comprising applying the medical patch according to any one of items 1 to 55 to the skin of a patient.

[0375] 59. A method for producing an active agent-containing layer structure of a medical patch according to any one of items 1 to 55, comprising: 1) At least the following ingredients 1. an active agent, and 2. Polymer I to obtain an active agent-containing coating composition; 2.1) coating an active agent-containing coating composition onto a first intermediate liner or coating an active agent-containing coating composition onto a backing layer; 2.2) drying the coated active agent-containing coating composition to form an active agent-containing layer.

[0376] 60.2.3) The method according to item 59, further comprising a step of laminating an active agent-containing layer obtained by drying the active agent-containing coating composition coated on the first intermediate liner with a backing layer.

[0377] 61.3.1) coating an active agent-free coating composition comprising at least Polymer II onto a second intermediate liner; or coating an active agent-free coating composition comprising at least Polymer II onto a release liner; 3.2) drying or curing the coated active agent-free coating composition to form a skin contact layer.

[0378] 62.3.3) The method of item 61, further comprising a step of laminating a skin contact layer obtained by drying or curing the active agent-free coating composition coated on a second intermediate liner with a release liner.

[0379] 63.4.1) The method of any one of items 59-62, further comprising the step of removing the first and second intermediate liners from the active agent-containing layer and the skin-contacting layer.

[0380] 64.4.2) The method according to any one of items 59 to 63, further comprising the step of laminating the open side of the skin contact layer to the open side of the active agent containing layer to obtain an active agent containing layer structure.

[0381] 65. A medical patch for administering an active agent comprising an active agent-containing self-adhesive layer structure, said active agent-containing self-adhesive layer structure comprising: A) a backing layer; B) an active agent-containing matrix layer, (i) an active agent in an amount of at least 0.5 wt. %, based on the total weight of the active agent-containing matrix layer; (ii) a polymer I selected from the group consisting of silicone-based polymers and polymers based on natural or synthetic rubber, and (iii) an active agent-containing matrix layer containing a solubilizer; and C) a skin contact layer comprising polymer II; The skin contact layer is an adhesive layer that is directly adhered to the active agent-containing layer; A medical patch, wherein the saturation concentration of the active agent in the skin contact layer is less than 0.1% by weight.

Claims

1. A medical patch for administering an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising: A) a backing layer; B) an active agent-containing layer, (i) an active agent, and (ii) the active agent-containing layer comprising Polymer I; C) a skin contact layer comprising polymer II; the skin contact layer is an adhesive layer that is directly adhered to the active agent-containing layer; The medical patch, wherein the saturation concentration of the active agent in the skin contact layer is less than 0.1% by weight.

2. 10. The medical patch of claim 1, wherein the saturation concentration of the active agent in the skin contact layer is less than 0.05% by weight, less than 0.02% by weight, or less than 0.01% by weight.

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

4. The medical patch of any one of claims 1 to 3, wherein the skin contact layer comprises the polymer II in an amount of at least 95 wt%, at least 99 wt%, or about 100 wt%, based on the total weight of the skin contact layer.

5. 5. The medical patch of claim 1, wherein the skin contact layer comprises the active agent in an amount of less than 0.1% by weight, or less than 0.01% by weight, based on the total weight of the skin contact layer.

6. The medical patch of any one of claims 1 to 5, wherein the active agent is an irritating active agent.

7. The medical patch according to any one of claims 1 to 6, wherein the active agent is a capsaicin analogue.

8. The active agent is selected from the group consisting of arvanil, capsiate, civamide, dihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, nordihydrocapsaicin, olvanil, palvanil, piperine, phenylacetylene vanil, and resiniferatoxin, in particular The medical patch according to any one of claims 1 to 7, wherein the active agent is resiniferatoxin.

9. The active agent is at least 0.10 mg / cm ２ , at least 0.20 mg / cm ２ , at least 0.50 mg / cm ２ , or at least 1.0 mg / cm ２ and / or The active agent is 12.0 mg / cm ２ Less than 10.0 mg / cm ２ Less than 6.0 mg / cm ２ or less than 3.0 mg / cm ２ The medical patch according to any one of claims 1 to 8, wherein the active agent-containing layer is present in an amount of less than 1000 mg / kg.

10. 10. The medical patch according to any one of claims 1 to 9, wherein the active agent-containing layer comprises the active agent in an amount of 0.5 to 30 wt%, 1 to 20 wt%, 2 to 15 wt%, or 5 to 10 wt%, based on the total weight of the active agent-containing layer.

11. The medical patch according to any one of claims 1 to 10, wherein the active agent-containing layer comprises the polymer I in an amount of 20 to 99 wt %, or 60 to 90 wt %, based on the total weight of the active agent-containing layer.

12. The medical patch according to any one of claims 1 to 11, wherein the polymer I is a polymer or a mixture of polymers selected from the group consisting of acrylic polymers, silicone-acrylic hybrid polymers, silicone-based polymers, and polymers based on natural or synthetic rubber, in particular the group consisting of silicone-based polymers and polymers based on natural or synthetic rubber.

13. The medical patch according to any one of claims 1 to 12, wherein the active agent-containing layer further comprises a solubilizer, particularly in an amount of 1 to 40% by weight, based on the total weight of the active agent-containing layer.

14. the solubilizer is a substance or mixture of substances in which the active agent has a saturation concentration of at least 30% by weight; and / or The medical patch according to any one of claims 1 to 13, wherein the solubilizing agent is dipropylene glycol, diethylene glycol monoethyl ether, or dimethyl isosorbide.

15. The medical patch according to any one of claims 1 to 14, wherein the medical patch is a topical medical patch or a transdermal therapeutic system.

16. 16. The medical patch according to any one of claims 1 to 15, for use in a method of treatment, in particular for use in a method of treating pain, or for use in a method of treating neuropathic pain or nociceptive pain, or for use in a method of treating arthralgia or cancer pain, or for use in a method of treating pain associated with a joint condition such as arthritis.

17. Use of the medical patch according to any one of claims 1 to 15 for the manufacture of a medicament, in particular for the manufacture of a medicament for treating pain, or for the manufacture of a medicament for treating neuropathic pain or nociceptive pain, or for the manufacture of a medicament for treating joint pain or cancer pain, or for the manufacture of a medicament for treating pain associated with a joint condition such as arthritis.

18. A method of treatment, in particular a method of treating pain, or neuropathic pain, or nociceptive pain, or joint pain, or cancer pain, or pain associated with a joint condition such as arthritis, comprising: A method of treatment comprising applying the medical patch according to any one of claims 1 to 15 to the skin of a patient.

19. A method for producing an active agent-containing layer structure of a medical patch according to any one of claims 1 to 15, comprising the steps of: 1) At least the following ingredients 1. the active agent, and 2. Polymer I to obtain an active agent-containing coating composition; 2.1) coating the active agent-containing coating composition onto a first intermediate liner or coating the active agent-containing coating composition onto the backing layer; 2.2) drying the coated active agent-containing coating composition to form the active agent-containing layer; 2.3) optionally, laminating the active agent-containing layer obtained by drying the active agent-containing coating composition coated on the first intermediate liner with the backing layer.

20. 3.1) Coating an active agent-free coating composition comprising at least the polymer II onto a second intermediate liner; or coating an active agent-free coating composition comprising at least the polymer II onto a release liner; 3.2) drying or curing the coated active agent-free coating composition to form the skin contact layer; 20. The method of claim 19, further comprising the step of: 3.3) optionally laminating the skin contact layer obtained by drying or curing the active agent-free coating composition coated on the second intermediate liner with a release liner.

21. 4.1) optionally removing the first and second intermediate liners from the active agent-containing layer and the skin-contacting layer; 21. The method of claim 19 or 20, further comprising the step of: 4.2) laminating the open side of the skin contact layer to the open side of the active agent containing layer to obtain the active agent containing layer structure.

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