Rotigotine-containing patch and method for improving rotigotine stability

Abstract

A rotigotine-containing patch that is provided with a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from the group consisting of rotigotine and a pharmaceutically acceptable salt thereof, together with an adhesive base and propyl gallate.

Description

[Technical Field]

[0001] The present invention relates to a rotigotine-containing patch and a method for improving the stability of rotigotine, and more particularly to a patch containing rotigotine and / or a pharmaceutically acceptable salt thereof, and a method for improving the stability of rotigotine in such a patch. [Background technology]

[0002] Rotigotine is the international nonproprietary name for the compound (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]1-naphthalenol, and the existence of crystalline polymorphs I and II is described in JP 2011-504902 A (Patent Document 1). Rotigotine is a D1 / D2 / D3 dopamine receptor agonist and is primarily used to treat the symptoms of Parkinson's disease and restless legs syndrome.

[0003] As a preparation for administering rotigotine, for example, "Neupro (registered trademark) Patch" is commercially available both in Japan and overseas. Furthermore, JP-A 2002-509878 (Patent Document 2) describes a transdermal therapeutic system comprising a backing layer inert to the components of the matrix and a self-adhesive matrix layer containing rotigotine, the matrix being based on a water-insoluble acrylate or silicone polymer adhesive in which the solubility of rotigotine is 5% (w / w) or more.

[0004] Furthermore, Japanese Patent Application Publication No. 2015-503541 (Patent Document 3) describes a transdermal therapeutic system including a backing layer that is impermeable to an active substance, and a matrix layer containing a pressure-sensitive adhesive, a drug, and particles of crosslinked polyvinylpyrrolidone. Rotigotine is described as the drug, and a silicone polymer is described as the pressure-sensitive adhesive. For example, Japanese Patent Application Publication No. 2014-177428 (Patent Document 4) describes a transdermal absorption type patch preparation including a support, a rubber-based pressure-sensitive adhesive base containing a rosin-based resin and a rubber-based tackifying component, and a drug-containing layer containing rotigotine or a pharmaceutically acceptable salt thereof. Japanese Patent Application Publication No. 2013-079220 (Patent Document 5) describes a transdermal absorption type patch including a support, a rubber-based pressure-sensitive adhesive base, rotigotine or a salt thereof, and a drug-containing layer containing an inhibitor for generating a decomposition product of rotigotine.

[0005] Furthermore, for example, Japanese Patent Application Publication No. 2017-515871 (Patent Document 6) describes a method for producing a transdermal absorption preparation in which rotigotine and an antioxidant such as butylhydroxytoluene are mixed at a specific weight ratio for the purpose of preventing rotigotine crystal precipitation. As an adhesive patch containing the antioxidant, for example, in Japanese Patent Application Publication No. 2017-073516 (Patent Document 7) and Japanese Patent Application Publication No. 2018-198925 (Patent Document 8), it is described that an adhesive layer of a patch containing fentanyl or butorphanol as a drug contains an antioxidant having a sulfur atom in the molecule.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

[0007] However, the present inventors have further studied rotigotine-containing patches containing rotigotine and / or a pharmaceutically acceptable salt thereof and found that, depending on storage conditions, for example, harsh storage conditions such as high temperatures, the stability of rotigotine and / or a pharmaceutically acceptable salt thereof may not be sufficient, and rotigotine and / or a pharmaceutically acceptable salt thereof may be decomposed to generate decomposition products (rotigotine degradation products). If a large amount of rotigotine degradation products is generated, the desired medicinal effect of rotigotine and / or a pharmaceutically acceptable salt thereof may not be expected, and therefore, the present inventors have found that a higher level of stability over time is required.

[0008] The present invention has been made in consideration of the above-mentioned problems, and aims to provide a rotigotine-containing patch that has particularly excellent stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof, and a method for improving the stability of rotigotine. [Means for solving the problem]

[0009] As a result of intensive studies to achieve the above object, the present inventors have found that a patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from the group consisting of rotigotine and its pharmaceutically acceptable salts (hereinafter sometimes referred to as "rotigotine and / or its pharmaceutically acceptable salts" in this specification), an adhesive base, and by further containing propyl gallate in the adhesive layer, the generation of rotigotine degradation products can be suppressed at a high level even during storage under harsh conditions, and it is possible to obtain a rotigotine-containing patch having particularly excellent stability over time of rotigotine and / or its pharmaceutically acceptable salts, thus completing the present invention. Aspects of the present invention obtained from such findings are as follows.

[0010] [1] A rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, an adhesive base, and an alicyclic saturated hydrocarbon resin Cholesterol and and propyl gallate.

[0011] [2] The rotigotine-containing patch according to [1], wherein the content of propyl gallate in the adhesive layer is 0.01 to 1% by mass based on the total mass of the adhesive layer.

[0012] [3] The rotigotine-containing patch according to [1] or [2], wherein the adhesive base is at least one selected from the group consisting of a rubber-based adhesive base, an acrylic-based adhesive base, and a silicone-based adhesive base.

[0013] [4] The rotigotine-containing patch according to any one of [1] to [3], wherein the content of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine in the adhesive layer is 5 to 15% by mass in terms of free rotigotine based on the total mass of the adhesive layer.

[0014] [5] A support layer and an adhesive layer, wherein the adhesive layer comprises at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, an adhesive base, and an alicyclic saturated hydrocarbon resin. Cholesterol and a method for improving the stability of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine in a rotigotine-containing patch comprising further incorporating propyl gallate into the pressure-sensitive adhesive layer, Method for improving the stability of rotigotine.

[0015] [6] The method for improving the stability of rotigotine according to [5], wherein propyl gallate is incorporated into the adhesive layer so that the content of propyl gallate relative to the total mass of the adhesive layer is 0.01 to 1 mass %.

[0016] [7] The method for improving rotigotine stability according to [5] or [6], wherein the adhesive base is at least one selected from the group consisting of rubber-based adhesive bases, acrylic-based adhesive bases, and silicone-based adhesive bases.

[0017] [8] The method for improving the stability of rotigotine according to any one of [5] to [7], wherein the content of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine is 5 to 15 mass% relative to the total mass of the adhesive layer, calculated as the free form of rotigotine. [Effects of the Invention]

[0018] According to the present invention, it is possible to provide a rotigotine-containing patch that is particularly excellent in the stability of rotigotine and / or a pharmaceutically acceptable salt thereof over time, and a method for improving the stability of rotigotine. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention will be described in detail below based on preferred embodiments thereof.

[0020] [Rotigotine-containing patch] The rotigotine-containing patch of the present invention comprises a support layer and an adhesive layer, and the adhesive layer contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, an adhesive base, and propyl gallate.

[0021] The rotigotine-containing patch of the present invention comprises a support layer and an adhesive layer. The support layer is not particularly limited as long as it can support the adhesive layer described below, and any known support layer for patches can be appropriately used. Examples of materials for the support layer of the present invention include polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate, and polyethylene naphthalate; cellulose derivatives; synthetic resins such as polyurethane; and metals such as aluminum. Among these, polyester and polyethylene terephthalate are preferred from the viewpoints of drug non-adsorption and drug impermeability. Examples of the form of the support layer include films; sheets, porous sheet-like materials, and foam sheet-like materials; fabrics such as woven fabrics, knitted fabrics, and nonwoven fabrics; foils; and laminates thereof. The thickness of the support layer is not particularly limited, but is preferably within the range of 5 to 1,000 μm from the viewpoints of ease of application and ease of production.

[0022] As the rotigotine-containing patch of the present invention, it may further include a release liner on the surface of the pressure-sensitive adhesive layer opposite to the support layer. Examples of such release liners include polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, vinyl acetate-vinyl chloride copolymers, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; synthetic resins such as polyurethane, and films, sheets, and laminates thereof made of materials such as aluminum and paper. As these release liners, it is preferable that a release treatment such as a silicone compound coating or a fluorine compound coating is applied to the surface in contact with the pressure-sensitive adhesive layer so that it can be easily peeled off from the pressure-sensitive adhesive layer.

[0023] <Rotigotine and pharmaceutically acceptable salts thereof> The pressure-sensitive adhesive layer according to the present invention contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts thereof as a drug (rotigotine and / or pharmaceutically acceptable salts thereof). In the present invention, the form of rotigotine contained in the pressure-sensitive adhesive layer may be a free form or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt of rotigotine may be desalted to a free form during production and / or in the produced preparation, and it may be one of these or a mixture of two or more. Pharmaceutically acceptable salts of rotigotine include acid addition salts, and examples of the acid of the acid addition salts include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, phosphorous acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, tartaric acid, lauric acid, stearic acid, palmitic acid, oleic acid, myristic acid, lauryl sulfate, linolenic acid, and fumaric acid. The acid addition salts may be one or two or more of the addition salts of these acids. Among these, it is preferable that the pressure-sensitive adhesive layer according to the present invention contains rotigotine in a free form.

[0024] In the present invention, the content of rotigotine and / or a pharmaceutically acceptable salt thereof contained in the adhesive layer (the content of rotigotine or the content of a pharmaceutically acceptable salt of rotigotine, or the total content when both are contained; the same applies hereinafter) is preferably 5 to 15% by mass, more preferably 6 to 12% by mass, even more preferably 7 to 10% by mass, and even more preferably 8 to 9% by mass, calculated as the free form of rotigotine, relative to the total mass of the adhesive layer. If the content of rotigotine and / or a pharmaceutically acceptable salt thereof is less than the lower limit, the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof tends to decrease, whereas if the content exceeds the upper limit, crystalline rotigotine may precipitate or the adhesive strength of the adhesive layer may be easily reduced.

[0025] The rotigotine-containing patch of the present invention and the method for improving the stability of rotigotine of the present invention described below can sufficiently suppress the generation of decomposition products of rotigotine and / or its pharmaceutically acceptable salts (rotigotine decomposition products). Examples of such decomposition products include, but are not limited to, 7,8-dihydronaphthol and depropyl rotigotine (despropyl RTN).

[0026] <Adhesive base> The adhesive layer according to the present invention also contains an adhesive base. The adhesive base is not particularly limited and examples thereof include rubber-based adhesive bases, acrylic-based adhesive bases, and silicone-based adhesive bases, and may be one type or a combination of two or more types thereof, but is preferably at least one type selected from the group consisting of rubber-based adhesive bases, acrylic-based adhesive bases having no carboxy group, and silicone-based adhesive bases, and more preferably contains at least a rubber-based adhesive base.

[0027] In the adhesive layer according to the present invention, the content of the adhesive base (when two or more types are used, the total content thereof; the same applies hereinafter) is preferably 1 to 90 mass %, more preferably 5 to 90 mass %, even more preferably 10 to 90 mass %, and even more preferably 10 to 80 mass %, relative to the total mass of the adhesive layer.

[0028] (rubber adhesive base) Examples of the rubber-based adhesive base include styrene-based thermoplastic elastomers, polyisobutylene, natural rubber, alkyl vinyl ether (co)polymers, polyisoprene, polybutadiene, etc., and these may be used alone or in combination of two or more. Among these, styrene-based thermoplastic elastomers are particularly preferred. The styrene-based thermoplastic elastomers are thermoplastic styrene-based elastomers that soften and become fluid when heated and return to a rubber-like elastic body when cooled. Among these, styrene-based block copolymers are preferred from the viewpoints of providing sufficient adhesiveness and superior stability of rotigotine and / or its pharmaceutically acceptable salt over time.

[0029] Specific examples of the styrene-based block copolymer include styrene-butadiene block copolymer, styrene-butadiene-styrene block copolymer, styrene-isoprene block copolymer, styrene-isoprene-styrene block copolymer, styrene-ethylene / butylene block copolymer, styrene-ethylene / butylene-styrene block copolymer, styrene-ethylene / propylene block copolymer, styrene-ethylene / propylene-styrene block copolymer, styrene-isobutylene block copolymer, and styrene-isobutylene-styrene block copolymer. One of these may be used alone, or two or more may be used in combination. In the above, "ethylene / butylene" refers to a copolymer block of ethylene and butylene, and "ethylene / propylene" refers to a copolymer block of ethylene and propylene. Among these, a styrene-isoprene-styrene block copolymer is more preferred as the styrene-based thermoplastic elastomer according to the present invention.

[0030] The styrene-isoprene-styrene block copolymer preferably has a viscosity average molecular weight of 30,000 to 2,500,000, and more preferably 100,000 to 1,700,000. If the viscosity average molecular weight is below the lower limit, the formulation properties of the patch (particularly the cohesive strength of the adhesive layer) tend to decrease, while if it exceeds the upper limit, compatibility with other components contained in the adhesive layer tends to decrease, making it difficult to produce the patch.

[0031] In the present invention, when the styrene thermoplastic elastomer is contained as the adhesive base in the pressure-sensitive adhesive layer, the content thereof (when the styrene thermoplastic elastomer is a combination of two or more types, the total content of the elastomers; the same applies hereinafter) is preferably 5 to 50 mass %, more preferably 10 to 40 mass %, and even more preferably 10 to 30 mass %, of the total mass of the pressure-sensitive adhesive layer. If the content of the styrene thermoplastic elastomer is below the lower limit, the cohesive strength and shape retention of the pressure-sensitive adhesive layer tend to decrease, whereas if it exceeds the upper limit, the cohesive strength of the pressure-sensitive adhesive layer tends to increase excessively, resulting in a decrease in the adhesive strength and compatibility of the pressure-sensitive adhesive layer.

[0032] Furthermore, from the viewpoint that the adhesiveness and cohesive strength of the adhesive layer tend to be further improved, the rubber-based adhesive base is more preferably a combination of the styrene-based thermoplastic elastomer (more preferably a styrene-isoprene-styrene block copolymer) and the polyisobutylene, and it is even more preferable that the mass ratio of the styrene-based thermoplastic elastomer to the polyisobutylene (mass of the styrene-based thermoplastic elastomer:mass of the polyisobutylene) is 1:2 to 30:1 (even more preferably in the range of 1:1 to 10:1).

[0033] Specific examples of the styrene-isoprene-styrene block copolymer include Quintac (registered trademark) 3570C (product name, manufactured by Nippon Zeon Co., Ltd.), SIS5002, SIS5229, SIS5505, SIS5505P (product names, manufactured by JSR Corporation), SIBSTAR (registered trademark) T102 (product name, manufactured by Kaneka Corporation), and the like. In addition, polyisobutylene includes so-called butyl rubber (isobutylene-isoprene rubber). Specific examples include Oppanol (registered trademark) N50, N80, N100, N150, B11, B12, B50, B80, B100, B120, B150, B220 (product names, manufactured by BASF), JSR (registered trademark) Butyl065, 268, 365 (product names, manufactured by JSR Corporation), X_Butyl (registered trademark) RB 100, 101-3, 301, 402 (product names, manufactured by ARLANXEO), Exxon (registered trademark) Butyl065, 065S, 068, 068S, 268, 268S, 365, 365S (product names, manufactured by ExxonMobil), Butyl065, 268, 365 (product names, manufactured by Nippon Butyl Co., Ltd.), and the like.

[0034] In the present invention, when a rubber-based pressure-sensitive adhesive base is contained as the pressure-sensitive adhesive base in the pressure-sensitive adhesive layer, its content (when it is a combination of two or more types, their total content, the same applies hereinafter) is preferably 1 to 60% by mass, more preferably 5 to 50% by mass, and even more preferably 10 to 40% by mass with respect to the total mass of the pressure-sensitive adhesive layer.

[0035] (Acrylic pressure-sensitive adhesive base) Examples of the acrylic adhesive base according to the present invention include those listed as adhesives in the "Dictionary of Pharmaceutical Additives 2016 (edited by the Japan Pharmaceutical Additives Association)." One of these may be used alone, or a combination of two or more may be used. However, an acrylic adhesive base having no carboxy group is preferred, and an acrylic adhesive base having no functional group is more preferred. In the present invention, "an acrylic adhesive base having no carboxy group" and "an acrylic adhesive base having no functional group" respectively refer to an acrylic polymer that is substantially free of carboxy groups and functional groups, preferably in which the contents of carboxy groups and functional groups in the polymer are each less than 3% by mass.

[0036] Examples of the acrylic adhesive base not having a carboxy group include acrylic adhesive bases that are substantially free of functional groups, such as 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer, 2-ethylhexyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-methyl methacrylate-butyl acrylate copolymer, and ethyl acrylate-methyl methacrylate copolymer; and acrylic adhesive bases that have hydroxy groups, such as 2-ethylhexyl (meth)acrylate-vinyl acetate-2-hydroxyethyl acrylate copolymer, 2-hydroxyethyl (meth)acrylate copolymer, 2-hydroxypropyl (meth)acrylate copolymer, 3-hydroxypropyl (meth)acrylate copolymer, 4-hydroxybutyl (meth)acrylate copolymer, and 2-ethylhexyl acrylate-vinyl acetate-hydroxyethyl acrylate-glycidyl methacrylate copolymer, and these may be used alone or in combination of two or more.

[0037] As the acrylic pressure-sensitive adhesive base material having no carboxy group, commercially available products may be appropriately used. For example, MAS 811, MAS 683 (manufactured by Cosmed Pharmaceutical Co., Ltd.); 87-900A, 87-901A, 87-9301, 87-4098, 87-9088, 87-9085 of Duro-Tak (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel); acrylic polymers contained in GMS 3083, GMS 3253, GMS3235, etc. of GELVA (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel), and 87-202A, 87-2287, 87-2516, 87-2510, 87-4287, 87-2525, 87-201A, 87-202A, 87-208A, 87-502A, 87-503A, 87-504A of Duro-Tak (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel); acrylic polymers contained in GMS 788, GMS 737, etc. of GELVA (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel) can be appropriately used.

[0038] When the pressure-sensitive adhesive layer according to the present invention contains the acrylic pressure-sensitive adhesive base material, its content (when there are two or more kinds, the total content thereof, the same hereinafter) is preferably 10 to 90% by mass, more preferably 20 to 80% by mass, based on the total mass of the pressure-sensitive adhesive layer. When the content of the acrylic pressure-sensitive adhesive base material is less than the lower limit, the cohesive force of the pressure-sensitive adhesive layer tends to decrease. On the other hand, when it exceeds the upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends to decrease.

[0039] (Silicone-based pressure-sensitive adhesive base material) As the silicone-based pressure-sensitive adhesive base material according to the present invention, in the ASTM standard (ASTM D 1418), silicone rubbers represented by MQ (polydimethylsiloxane), VMQ (polymethylvinylsiloxane), PMQ (polymethylphenylsiloxane), PVMQ (polyphenylvinylmethylsiloxane), and mixtures of at least one of these and silicone resins other than silicone rubbers such as polyditrimethylsilylsiloxane may be mentioned, and one of these or a combination of two or more may be used. When a silicone resin other than the silicone rubber is mixed, it is preferably 0.1 to 20% by mass based on the total mass of the silicone-based pressure-sensitive adhesive base material.

[0040] In addition, as these silicone-based pressure-sensitive adhesive base materials, commercially available ones may be appropriately used. For example, the following model numbers are provided by DuPont - Toray Specialty Materials Co., Ltd.: BIO-PSA7-410X, BIO-PSA7-420X, BIO-PSA7-430X, BIO-PSA7-440X, BIO-PSA7-450X, BIO-PSA7-460X (each X is independently 1 or 2), BIO-PSA AC7-4201, BIO-PSA AC7-4301, BIO-PSA AC7-4302, MD7-4502, MD7-4602, 7-9700, MG7-9800, MG7-9850; BIO-PSA 7-4560 (hot melt silicone pressure-sensitive adhesive), etc. can be appropriately used.

[0041] Furthermore, as the silicone-based pressure-sensitive adhesive base material according to the present invention, for example, when it has a methyl group, it is crosslinked between the methyl groups by dehydrogenating the hydrogen atoms of the methyl group by blending a peroxide; when it has a vinyl group, it is crosslinked between the vinyl groups by bonding a crosslinking agent composed of a SiH group-containing siloxane compound; when it has a hydroxyl group (i.e., a silanol group), it may be crosslinked between the silanol groups by dehydration condensation, etc.

[0042] When the adhesive layer according to the present invention contains the silicone-based adhesive base, the content thereof (when two or more types are used, the total content thereof; the same applies hereinafter) is preferably 10 to 90 mass %, more preferably 20 to 80 mass %, of the total mass of the adhesive layer. If the content of the silicone-based adhesive base is less than the lower limit, the cohesive strength of the adhesive layer tends to decrease, whereas if it exceeds the upper limit, the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof tends to decrease.

[0043] <Propyl gallate> In the rotigotine-containing adhesive patch of the present invention, the adhesive layer contains propyl gallate. The content of propyl gallate in the adhesive layer according to the present invention is preferably 0.01 to 1 mass%, more preferably 0.05 to 1 mass%, even more preferably 0.075 to 0.8 mass%, even more preferably 0.1 to 0.6 mass%, and particularly preferably 0.1 to 0.3 mass%, relative to the total mass of the adhesive layer. If the content of propyl gallate is below the lower limit, the effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof tends to be insufficient. On the other hand, if the content exceeds the upper limit, the cohesive strength and adhesive strength of the adhesive layer tend to decrease.

[0044] Furthermore, the content of propyl gallate contained in the adhesive layer is preferably 0.001 to 0.12 parts by mass, more preferably 0.005 to 0.115 parts by mass, even more preferably 0.008 to 0.09 parts by mass, even more preferably 0.01 to 0.07 parts by mass, and particularly preferably 0.01 to 0.035 parts by mass, per part by mass of the content of rotigotine and / or a pharmaceutically acceptable salt thereof, calculated as the free form of rotigotine. When the ratio of the content of propyl gallate to the content of rotigotine and / or a pharmaceutically acceptable salt thereof is within the above range, the stability of rotigotine and / or a pharmaceutically acceptable salt thereof over time tends to be particularly excellent.

[0045] <Thioglycolic acid and its pharmaceutically acceptable salts> The adhesive layer according to the present invention may further contain at least one selected from the group consisting of thioglycolic acid and pharmaceutically acceptable salts of thioglycolic acid (thioglycolic acid and / or a pharmaceutically acceptable salt thereof) from the viewpoint of improving the stability of rotigotine and / or a pharmaceutically acceptable salt thereof over time.

[0046] In the present invention, the thioglycolic acid that may be contained in the adhesive layer may be in the free form or a pharmaceutically acceptable salt thereof. It may also be a free form obtained by desalting a pharmaceutically acceptable salt of thioglycolic acid during production and / or in the produced preparation. It may be one of these or a mixture of two or more. Pharmaceutically acceptable salts of thioglycolic acid include alkali metal salts, alkaline earth metal salts, salts with ammonia, alkylamines, and alkanolamines. More specifically, examples of the thioglycolic acid salt include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, dimethylamine salt, diethylamine salt, trimethylamine salt, triethylamine salt, monoethanolamine salt, diethanolamine salt, diisopropanolamine salt, triethanolamine salt, and triisopropanolamine salt. The pharmaceutically acceptable salt of thioglycolic acid may be one of these salts or two or more of them. The form of thioglycolic acid that may be contained in the pressure-sensitive adhesive layer according to the present invention is preferably at least one selected from the group consisting of thioglycolic acid and alkali metal salts (more preferably sodium salts) of thioglycolic acid.

[0047] When the pressure-sensitive adhesive layer according to the present invention further contains thioglycolic acid and / or a pharmaceutically acceptable salt thereof, the content of thioglycolic acid and / or a pharmaceutically acceptable salt thereof contained in the pressure-sensitive adhesive layer (the content of thioglycolic acid or the content of a pharmaceutically acceptable salt of thioglycolic acid, or the total content when both are contained, the same applies hereinafter) is preferably 0.03 to 3% by mass, more preferably 0.05 to 3% by mass, even more preferably 0.1 to 3% by mass, even more preferably 0.15 to 3% by mass, particularly preferably 0.25 to 3% by mass, and 0.5 to 3% by mass in terms of sodium thioglycolate with respect to the total mass of the pressure-sensitive adhesive layer. When the content of thioglycolic acid and / or a pharmaceutically acceptable salt thereof is less than the above lower limit, the effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof by thioglycolic acid and / or a pharmaceutically acceptable salt thereof tends not to be sufficiently exerted. On the other hand, when it exceeds the above upper limit, the adhesive strength of the pressure-sensitive adhesive layer tends to decrease.

[0048] Also, the content of thioglycolic acid and / or a pharmaceutically acceptable salt thereof contained in the pressure-sensitive adhesive layer in terms of sodium thioglycolate is preferably 0.02 to 300 parts by mass, more preferably 0.04 to 60 parts by mass, even more preferably 0.1 to 40 parts by mass, even more preferably 0.2 to 30 parts by mass, and particularly preferably 0.8 to 30 parts by mass with respect to 1 part by mass of the content of propyl gallate in the pressure-sensitive adhesive layer. When the content of thioglycolic acid and / or a pharmaceutically acceptable salt thereof with respect to the content of propyl gallate is within the above range, the effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof by thioglycolic acid and / or a pharmaceutically acceptable salt thereof tends to be particularly exerted.

[0049] Furthermore, the content of thioglycolic acid and / or its pharmaceutically acceptable salt contained in the pressure-sensitive adhesive layer, in terms of sodium thioglycolate, is preferably 0.002 to 0.6 parts by mass, more preferably 0.01 to 0.6 parts by mass, still more preferably 0.015 to 0.6 parts by mass, even more preferably 0.03 to 0.35 parts by mass, and particularly preferably 0.05 to 0.35 parts by mass, relative to 1 part by mass of the content of rotigotine and / or its pharmaceutically acceptable salt in terms of the free rotigotine. When the ratio of the content of thioglycolic acid and / or its pharmaceutically acceptable salt to the content of rotigotine and / or its pharmaceutically acceptable salt is within the above range, the effect of improving the stability over time of rotigotine and / or its pharmaceutically acceptable salt by thioglycolic acid and / or its pharmaceutically acceptable salt tends to be particularly exhibited.

[0050] However, from the viewpoint of suppressing unpleasant odors during the production of the patch, it is also preferable that the pressure-sensitive adhesive layer according to the present invention substantially does not contain either thioglycolic acid or its pharmaceutically acceptable salt. Substantially not containing thioglycolic acid and its pharmaceutically acceptable salt means that the content of thioglycolic acid and its pharmaceutically acceptable salt in terms of sodium thioglycolate is less than 0.03% by mass (for example, 0.029% by mass or less) with respect to the total mass of the pressure-sensitive adhesive layer.

[0051] <Other components> The pressure-sensitive adhesive layer according to the present invention may further contain other drugs other than rotigotine and its pharmaceutically acceptable salt; stabilizers other than propyl gallate and thioglycolic acid and its pharmaceutically acceptable salt; tackifiers; absorption promoters; skin irritation reducers; additives such as adsorbents, desalting agents, plasticizers, solvents, fillers, and preservatives, as long as the effects of the present invention are not inhibited.

[0052] (Other drugs) Examples of other drugs other than rotigotine and its pharmaceutically acceptable salts include, for example, non-steroidal anti-inflammatory drugs (diclofenac, indomethacin, ketoprofen, felbinac, loxoprofen, ibuprofen, flurbiprofen, tiaprofenic acid, acemetacin, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, rofecoxib, anfenac, etc.), antipyretics (acetaminophen, etc.), antihistamines (diphenhydramine, chlorpheniramine, mequitazine, homochlorcyclizine, etc.), antihypertensives (diltiazem, nifedipine, nilvadipine, metoprolol, bisoprolol, trandolapril, etc.), anti-Parkinson's drugs (pergolide, ropinirole, bromocriptine, selegiline, etc.), bronchodilators (terbutaline, isoproterenol, salbutamol, etc.), anti-allergy drugs (ketotifen, loratadine, azelastine, terfenadine, cetirizine, acitazanolast, etc.), local anesthetics (lidocaine, dibucaine, etc.), neuropathic pain therapeutic drugs (pregabalin, etc.), non-narcotic analgesics (buprenorphine, tramadol, pentazocine), narcotic analgesics (morphine, oxycodone, fentanyl, etc.), urinary organ agents (oxybutynin, tamsulosin, etc.), psychotropic drugs (promazine, chlorpromazine, etc.), steroid hormone agents (estradiol, progesterone, norethisterone, cortisone, hydrocortisone, etc.), antidepressants (sertraline, fluoxetine, paroxetine, citalopram, etc.), anti-dementia drugs (donepezil, rivastigmine, galantamine, etc.), antipsychotics (risperidone, olanzapine, etc.), central nervous system stimulants (methylphenidate, etc.), osteoporosis therapeutic drugs (raloxifene, alendronate, etc.), breast cancer preventive drugs (tamoxifen, etc.), anti-obesity drugs (mazindol, sibutramine, etc.), insomnia improvement drugs (melatonin, etc.), anti-rheumatic drugs (actarit, etc.). It may be one of these or a combination of two or more of them.

[0053] When the pressure-sensitive adhesive layer according to the present invention further contains the other drug, the content (when there are two or more kinds, the total content thereof) is preferably 10% by mass or less based on the total mass of the pressure-sensitive adhesive layer.

[0054] (Other stabilizers) Examples of stabilizers other than propyl gallate, thioglycolic acid, and pharmaceutically acceptable salts thereof include ascorbic acid or its metal salts or esters (e.g., palmitic acid ester), isoascorbic acid or its metal salts, ethylenediaminetetraacetic acid or its metal salts, cysteine, acetylcysteine, 2-mercaptobenzimidazole, dibutylhydroxytoluene, butylhydroxyanisole, pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 3-mercapto-1,2-propanediol, tocopherol, tocopherol acetate, thymol, soy lecithin, rutin, dihydroxybenzoic acid, potassium dichloroisocyanurate, quercetin, hydroquinone, metal salts of hydroxymethanesulfinic acid, metal metabisulfites (e.g., sodium pyrosulfite), metal sulfites, and metal thiosulfates other than metal salts of thioglycolic acid. One of these or a combination of two or more thereof may be used. In the above, examples of the metal salts include sodium salts, potassium salts, calcium salts, magnesium salts, and calcium disodium salts. Examples of the esters include palmitic acid esters, stearic acid esters, and myristic acid esters.

[0055] However, in the adhesive layer of the present invention, it is preferable that the adhesive layer does not contain the above-mentioned other stabilizers, in case that the effect of propyl gallate in stabilizing rotigotine and / or a pharmaceutically acceptable salt thereof over time is inhibited, or from the viewpoint of the adhesive strength of the adhesive layer, and the content thereof (the total content if there are two or more types) is preferably 3% by mass or less, more preferably 2% by mass or less, and even more preferably 0.25% by mass or less (e.g., 0 to 0.25% by mass, 0.005 to 0.25% by mass) relative to the total mass of the adhesive layer.

[0056] (tackifier) The tackifier is blended mainly for the purpose of increasing the adhesiveness of the adhesive base (preferably a rubber-based adhesive base). Examples of such tackifiers include petroleum-based resins, rosin-based resins, terpene-based resins, phenol-based resins, and xylene-based resins. The tackifier may be one of these or a combination of two or more of these, but when the adhesive layer according to the present invention contains the rubber-based adhesive base as the adhesive base, it is preferable that a petroleum-based resin is further contained.

[0057] When the adhesive layer further contains the tackifier, the content thereof (the total content thereof if two or more types are contained) is preferably 5 to 80 mass %, more preferably 10 to 80 mass %, and even more preferably 20 to 60 mass %, relative to the total mass of the adhesive layer, from the viewpoint of improving the adhesive strength of the adhesive layer and / or mitigating local irritation during peeling.

[0058] Examples of the petroleum resin include C5 synthetic petroleum resins (copolymers of at least two of isoprene, cyclopentadiene, 1,3-pentadiene, and 1-pentene; copolymers of at least two of 2-pentene and dicyclopentadiene; resins mainly composed of 1,3-pentadiene, etc.), C9 synthetic petroleum resins (copolymers of at least two of indene, styrene, methyl indene, and α-methylstyrene, etc.), and dicyclopentadiene-based synthetic petroleum resins (copolymers of isoprene and / or 1,3-pentadiene mainly composed of dicyclopentadiene). From another classification perspective, examples include alicyclic petroleum resins (such as alicyclic saturated hydrocarbon resins), alicyclic hydrogenated petroleum resins, aliphatic petroleum resins (such as aliphatic hydrocarbon resins), aliphatic hydrogenated petroleum resins, and aromatic petroleum resins. More specifically, examples include Alcon P-70, Alcon P-85, Alcon P-90, Alcon P-100, Alcon P-115, Alcon P-125, Alcon M-90, Alcon M-100, Alcon M-115, Alcon M-135 (the above are trade names, manufactured by Arakawa Chemical Industries, Ltd.), and Escorez 8000 (trade name, manufactured by Esso Petrochemical Co., Ltd.). The petroleum resin according to the present invention may be one of these or a combination of two or more thereof. Among these, from the viewpoints of being easily able to obtain suitable adhesiveness to the skin, having a good feeling in use due to having less odor, etc., and further suppressing the generation of rotigotine degradation products, it is more preferably an alicyclic saturated hydrocarbon resin.

[0059] In the present invention, the alicyclic saturated hydrocarbon resin refers to a resin that is a homopolymer or copolymer of an alicyclic saturated hydrocarbon monomer. The alicyclic saturated hydrocarbon resin preferably has a weight average molecular weight of 1,000 to 2,300, more preferably 1,000 to 1,800, still more preferably 1,000 to 1,600, even more preferably 1,000 to 1,500, and particularly preferably 1,200 to 1,400.

[0060] When the adhesive layer according to the present invention further contains the petroleum-based resin (preferably an alicyclic saturated hydrocarbon resin), the content thereof (the total content when two or more types are contained) is preferably 5 to 80 mass %, more preferably 10 to 70 mass %, even more preferably 10 to 60 mass %, and particularly preferably 20 to 60 mass %, of the total mass of the adhesive layer. If the content of the petroleum-based resin is less than the lower limit, the adhesive strength and adhesion to skin of the adhesive layer tend to decrease, whereas if it exceeds the upper limit, the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof and the shape retention of the adhesive layer tend to decrease.

[0061] (Absorption enhancer) Examples of the absorption enhancer include those having a transdermal absorption-enhancing effect (skin permeation-enhancing effect) of drugs, such as aliphatic alcohols, fatty acids having 6 to 20 carbon atoms, fatty acid esters, fatty acid amides, or aliphatic alcohol ethers; aromatic organic acids; aromatic alcohols; aromatic organic acid esters or ethers; POE hydrogenated castor oils; lecithins; phospholipids; soybean oil derivatives; and triacetin. The absorption enhancer may be one of these or a combination of two or more of them, but from the viewpoint of better skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof, it is preferable that the adhesive layer further contains an aliphatic alcohol.

[0062] When the absorption enhancer is further contained in the adhesive layer, the content thereof (the total content if there are two or more types) is preferably 1 to 15% by mass, more preferably 3 to 7% by mass, relative to the total mass of the adhesive layer, from the viewpoint of better skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof.

[0063] The aliphatic alcohol refers to a saturated or unsaturated, linear or branched, monohydric or polyhydric aliphatic alcohol. As the aliphatic alcohol according to the present invention, it is preferably monohydric. Further, the number of carbon atoms of the aliphatic alcohol is preferably 3 to 23, more preferably 12 to 23, and even more preferably 12 to 20. When the number of carbon atoms of the aliphatic alcohol is less than the lower limit, the boiling point becomes low, making it difficult to keep the content in the preparation constant, and the stability of the aliphatic alcohol over time tends to decrease. On the other hand, when it exceeds the upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends to decrease.

[0064] Examples of the aliphatic alcohol include isopropanol, hexyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, octyldodecanol, oleyl alcohol, linolenyl alcohol, and hexyl decanol. The aliphatic alcohol may be one of these or a combination of two or more. However, from the viewpoint of particularly improving the skin permeability of rotigotine and / or its pharmaceutically acceptable salt in addition to the stability and compatibility of the above aliphatic alcohol over time, it is preferably at least one selected from the group consisting of octyldodecanol and lauryl alcohol.

[0065] When the pressure-sensitive adhesive layer according to the present invention further contains the aliphatic alcohol, its content (when there are two or more, their total content) is preferably 1 to 15% by mass, more preferably 1 to 10% by mass, even more preferably 2 to 7% by mass, and particularly preferably 3 to 7% by mass with respect to the total mass of the pressure-sensitive adhesive layer. When the content of the aliphatic alcohol is less than the lower limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends not to be sufficiently improved. On the other hand, when it exceeds the upper limit, the compatibility with the pressure-sensitive adhesive base and other components tends to decrease.

[0066] (Skin irritation reducer) Examples of the skin irritation reducer include those having an effect of reducing irritation caused by drugs and stabilizers on the skin, such as cholesterol. The skin irritation reducer may be a combination of two or more kinds.

[0067] When the skin irritation reducer is further contained in the pressure-sensitive adhesive layer, the content (when there are two or more kinds, the total content thereof) is preferably 0.1 to 7% by mass, more preferably 1 to 7% by mass, and even more preferably 3 to 5% by mass with respect to the total mass of the pressure-sensitive adhesive layer from the viewpoint of achieving a sufficient skin irritation reducing effect and maintaining sufficient compatibility with the pressure-sensitive adhesive base.

[0068] (Additive) [Adsorbent] Examples of the adsorbent include inorganic and / or organic substances having hygroscopicity. More specifically, minerals such as talc, kaolin, and bentonite; silicon compounds such as fumed silica (e.g., Aerosil (registered trademark)) and hydrous silica; metal compounds such as zinc oxide and dry aluminum hydroxide gel; weak acids such as lactic acid and acetic acid; sugars such as dextrin; and polymer polymers such as polyvinylpyrrolidone (non-crosslinked PVP), crosslinked polyvinylpyrrolidone (also referred to as "crospovidone" and "crosslinked PVP"), aminoalkyl methacrylate copolymer, carboxyvinyl polymer, and butyl methacrylate methyl methacrylate copolymer. The adsorbent may be one of these or a combination of two or more kinds. However, from the viewpoint of better stability over time of rotigotine and / or its pharmaceutically acceptable salts, it is preferable that crosslinked polyvinylpyrrolidone is further contained in the pressure-sensitive adhesive layer.

[0069] When the adsorbent is further contained in the pressure-sensitive adhesive layer, the content (when there are two or more kinds, the total content thereof) is preferably 3 to 25% by mass, more preferably 3 to 15% by mass with respect to the total mass of the pressure-sensitive adhesive layer from the viewpoint of the adhesiveness of the pressure-sensitive adhesive layer.

[0070] The crosslinked polyvinylpyrrolidone may be a crosslinked N-vinylpyrrolidone polymer. The N-vinylpyrrolidone polymer may be a homopolymer or a copolymer, such as a homopolymer of N-vinylpyrrolidone or a copolymer of N-vinylpyrrolidone and a polyfunctional monomer. Among these, the crosslinked polyvinylpyrrolidone according to the present invention is preferably a crosslinked homopolymer of 1-vinyl-2-pyrrolidone (also referred to as "crospovidone"). As the crospovidone, commercially available products such as Kollidon CL and Kollidon CL-M (manufactured by BASF Japan Ltd.), Polyplasdone XL, Polyplasdone XL-10, and Polyplasdone INF-10 (manufactured by ISP Japan Ltd.) may be used.

[0071] When the adhesive layer according to the present invention further contains the crosslinked polyvinylpyrrolidone, the content thereof (the total content when two or more types are used) is preferably 3 to 25% by mass, more preferably 3 to 20% by mass, and even more preferably 3 to 15% by mass, relative to the total mass of the adhesive layer. If the content of the crosslinked polyvinylpyrrolidone is less than the lower limit, crystals of rotigotine and / or a pharmaceutically acceptable salt thereof tend to precipitate easily, whereas if the content exceeds the upper limit, the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof tends to decrease, or compatibility in the adhesive layer composition during production tends to decrease, making production difficult.

[0072] In addition, the content of the crosslinked polyvinylpyrrolidone contained in the pressure-sensitive adhesive layer is preferably in a mass ratio (rotigotine free form equivalent content of rotigotine and / or its pharmaceutically acceptable salt: crosslinked polyvinylpyrrolidone content) of 15:3 to 5:25, more preferably 15:3 to 5:20, and even more preferably 15:3 to 5:15, in terms of the rotigotine free form equivalent content of the rotigotine and / or its pharmaceutically acceptable salt. If the ratio of the content of the crosslinked polyvinylpyrrolidone to the content of the rotigotine and / or its pharmaceutically acceptable salt is less than the lower limit, crystals of rotigotine tend to precipitate. On the other hand, if it exceeds the upper limit, the skin permeability of the rotigotine and / or its pharmaceutically acceptable salt tends to decrease.

[0073] 〔Desalting agent〕 The desalting agent is formulated mainly for the purpose of converting all or part of the basic drug into its free form. Such desalting agents are not particularly limited. For example, when formulating a preparation containing a free form of a drug by blending an acid addition salt of the drug as the drug, it is preferably a basic substance, and more preferably a metal ion-containing desalting agent or a basic nitrogen atom-containing desalting agent. Examples of the metal ion-containing desalting agent include sodium acetate (including anhydrous sodium acetate), sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium citrate, sodium lactate, etc., and it may be one of these or a combination of two or more. Note that the pressure-sensitive adhesive layer according to the present invention may further contain a compound derived from the basic drug and the desalting agent (for example, sodium chloride generated when combining rotigotine hydrochloride and sodium acetate). In the present invention, when these desalting agents, as well as the compounds derived from the basic drug and the desalting agent, are further contained in the pressure-sensitive adhesive layer, the total content, in the case of two or more, is preferably 10% by mass or less based on the total mass of the pressure-sensitive adhesive layer.

[0074] 〔Plasticizer〕 The plasticizer is mainly formulated for the purpose of adjusting the adhesive physical properties of the adhesive layer, the flow characteristics in the production of the adhesive layer, the transdermal absorption characteristics of the drug, etc. Examples of such plasticizers include silicone oil; petroleum-based oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil; squalane, squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil, and peanut oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as liquid polybutene and liquid isoprene rubber; diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, etc. The plasticizer may be one of these or a combination of two or more thereof, but it is particularly preferably at least one selected from the group consisting of silicone oil, liquid paraffin, and liquid polybutene.

[0075] When the adhesive layer according to the present invention further contains the plasticizer, the content (when there are two or more, the total content thereof) is preferably 1 to 30% by mass, more preferably 5 to 20% by mass, based on the total mass of the adhesive layer, from the viewpoint of improving the adhesive strength of the adhesive layer and / or alleviating local irritation during peeling.

[0076] 〔Solvent · Filler〕 Examples of the solvent include organic acids such as acetic acid and surfactants, and it may be one of these or a combination of two or more thereof. The filler is mainly formulated for the purpose of adjusting the adhesive strength of the adhesive layer. Examples of the filler include aluminum hydroxide, calcium carbonate, magnesium carbonate; silicates such as aluminum silicate and magnesium silicate; silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide, and it may be one of these or a combination of two or more thereof.

[0077] 〔Preservative〕 Examples of the preservative include paraoxybenzoic acid derivatives, benzyl alcohol, phenol, cresol, etc., and it may be one of these or a combination of two or more thereof.

[0078] The pressure-sensitive adhesive layer according to the present invention is not particularly limited, but the mass per unit area (the area of the adhesion surface) is 20 to 200 g / m 2 Preferably, it is 30 to 100 g / m 2 More preferably, it is 30 to 70 g / m 2 Even more preferably, it is. Further, the area of the adhesion surface of the pressure-sensitive adhesive layer according to the present invention can be appropriately adjusted according to the purpose of treatment and the application target, and is not particularly limited, but is usually in the range of 0.5 to 200 cm 2 of the range.

[0079] [Method for improving ropinirole stability, method for manufacturing ropinirole-containing patch] The method for improving ropinirole stability of the present invention comprises a support layer and a pressure-sensitive adhesive layer, and in a ropinirole-containing patch in which the pressure-sensitive adhesive layer contains at least one selected from the group consisting of ropinirole and pharmaceutically acceptable salts of ropinirole and a pressure-sensitive adhesive base, it is a method for improving the stability of at least one selected from the group consisting of ropinirole and pharmaceutically acceptable salts of ropinirole, and includes a step of further containing propyl gallate in the pressure-sensitive adhesive layer. Further, since the ropinirole-containing patch of the present invention can be obtained by such a method for improving ropinirole stability, it can also be used as a method for manufacturing a ropinirole-containing patch (hereinafter, the method for improving ropinirole stability and the method for manufacturing a ropinirole-containing patch are collectively referred to as, and sometimes simply referred to as "the method of the present invention").

[0080] In the method of the present invention, the method of further incorporating propyl gallate into the pressure-sensitive adhesive layer is not particularly limited, and a known method for producing an adhesive can be appropriately employed. For example, first, rotigotine and / or a pharmaceutically acceptable salt thereof, and the pressure-sensitive adhesive base, and, if necessary, thioglycolic acid and / or a pharmaceutically acceptable salt thereof and the other components described above, and an appropriate amount of a solvent are added with propyl gallate, and kneaded according to a conventional method to obtain a uniform pressure-sensitive adhesive layer composition. When using rotigotine free form as the rotigotine and / or a pharmaceutically acceptable salt thereof, it may be a type I crystal, a type II crystal, or an amorphous form, or a mixture of at least two or more of type I crystal, type II crystal, and amorphous form. Further, the rotigotine and / or a pharmaceutically acceptable salt thereof may be a hydrate, or may be used in a form dissolved in the solvent. Examples of the solvent include absolute ethanol, toluene, heptane, methanol, ethyl acetate, hexane, isopropanol, and a mixed solution of at least two or more of these.

[0081] At this time, there is no particular limitation on the blending order of each component, that is, rotigotine and / or a pharmaceutically acceptable salt thereof, the pressure-sensitive adhesive base, propyl gallate, and, if necessary, thioglycolic acid and / or a pharmaceutically acceptable salt thereof and the other components. Also, as the blending amounts of these, it is preferable that, independently, the content of each component in the obtained pressure-sensitive adhesive layer is an amount that becomes the content described in the above-mentioned rotigotine-containing adhesive patch of the present invention.

[0082] Next, the pressure-sensitive adhesive layer composition is spread to obtain the pressure-sensitive adhesive layer. For example, after spreading the pressure-sensitive adhesive layer composition on the surface (usually one surface) of the support layer so as to have a desired mass per unit area, if necessary, it is heated to dry and remove the solvent to form a pressure-sensitive adhesive layer, and further, if necessary, cut into a desired shape, whereby the rotigotine stability in the obtained rotigotine-containing adhesive patch can be improved, and the rotigotine-containing adhesive patch of the present invention can be obtained.

[0083] As a method of the present invention, it may further include a step of laminating the release liner on the surface of the pressure-sensitive adhesive layer opposite to the support layer. In this case, the pressure-sensitive adhesive layer composition is first spread on one surface of the release liner so as to have a mass per unit area as desired to form a pressure-sensitive adhesive layer, and then the support layer is laminated on the surface of the pressure-sensitive adhesive layer opposite to the release liner, and if necessary, the rotigotine-containing patch may be obtained by cutting it into a desired shape.

[0084] Furthermore, the obtained patch may be enclosed in a storage packaging container (for example, a bag made of aluminum laminate) as a package if necessary.

Examples

[0085] Hereinafter, the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to the following examples. In each of the examples and comparative examples, the skin permeation test and the stability evaluation were carried out by the methods shown below, respectively.

[0086] <Skin Permeation Test (In Vitro Hairless Mouse Skin Permeation Test)> First, the skin of the body part of a hairless mouse was peeled off and the fat was removed, and a patch obtained by cutting into a 1.0 cm 2 square and removing the release liner was applied as a test sample. This was set in a flow-through type diffusion cell so that the dermal side was in contact with the receptor solution, and the cell was filled with a receptor solution (phosphate buffered saline). Then, while circulating warm circulating water through the outer periphery so that the receptor solution was kept at 32 °C, the receptor solution was fed at a flow rate of about 5 mL / hr, and the receptor solution was collected every 2 hours until 24 hours. The rotigotine concentration in the collected receptor solution was measured by high performance liquid chromatography, and respectively, by the following formula: Rotigotine skin permeation amount (μg / cm 2 ) = {Rotigotine concentration (μg / mL) in the receptor solution × Flow rate (mL)} / Patch area (cm 2 ) Based on this, the amount of rotigotine permeated through the skin per unit area of the adhesive layer was calculated, and the amount of skin permeation per hour (skin permeation rate (μg / cm 2 / hr)) was determined. The measurement was performed for two test samples respectively, and the average value of the maximum value within 24 hours of each skin permeation rate was taken as the maximum skin permeation rate (Jmax).

[0087] <Stability Evaluation> The patches obtained in each example and comparative example were sealed in an aluminum laminate bag to prepare test samples, which were stored at 60°C for 2 weeks. For the patches after storage, the generation rate [%] of rotigotine degradation products was calculated by the following method (1) or (2), and used as the value for stability evaluation. Note that according to the following method (1) and method (2), equivalent results can be obtained from each other.

[0088] (1) First, the release liner was removed from the patch after storage, and the adhesive layer was immersed in 5 mL of tetrahydrofuran to dissolve it. Then, a dilution solution (a mixed solution of 0.2% phosphate buffer and acetonitrile (50:50 (v:v))) was added to the solution until the total volume reached 25 mL, shaken, and the filtered solution was used as the sample solution. Also, rotigotine with a known concentration was dissolved in the above dilution solution in advance to prepare a standard solution.

[0089] Using the sample solution, with a high performance liquid chromatography apparatus (manufactured by Shimadzu Corporation), under the following conditions: Column: TSKgel ODS-80TsQA (4.6 mm I.D.×150 mm), 5 μm Mobile phase: A mixed solution of 0.2% phosphate buffer containing 10 mM sodium dodecyl sulfate and acetonitrile (50:50 (v:v)) Detection wavelength: 225 nm Column temperature: 40°C Flow rate: 0.7 mL / min The chromatograms of 7,8-dihydro naphthol (7,8-Dihydro Naphthol) and despropyl rotigotine (Despropyl RTN), which are rotigotine degradation products, in the sample solution were obtained.

[0090] Also, using the standard solution, under the same conditions as above, a chromatogram of rotigotine in the standard solution was obtained by the high-performance liquid chromatography apparatus. From the area under the curve of rotigotine in the obtained chromatogram and the areas under the curves of 7,8-dihydronaphthol and despropyl rotigotine in the chromatograms obtained above, the generation amounts of 7,8-dihydronaphthol and despropyl rotigotine were calculated respectively. Further, the theoretical content of rotigotine was calculated from the amount of rotigotine formulated in the pressure-sensitive adhesive layer, and by dividing each generation amount by the theoretical content, the generation rates (7,8-Dihydro Naphthol generation rate [%], Despropyl RTN generation rate [%]) of each rotigotine degradation product in the pressure-sensitive adhesive layer of each patch after storage at 60°C for 2 weeks were calculated. The peak area appearing at around 7.8 minutes was taken as the peak area of 7,8-dihydronaphthol, and the peak area appearing at around 9.7 minutes was taken as the peak area of despropyl rotigotine.

[0091] (2) First, the release liner was removed from the patch after storage, and a mixed solution (60:40 (v:v)) of a dilution solution (phosphate buffer (pH 5.5) containing 10 mM dipotassium hydrogen phosphate and 0.067% trimethylamine and acetonitrile) was added to the solution obtained by immersing the pressure-sensitive adhesive layer in 5 mL of tetrahydrofuran and dissolving it until the total volume reached 25 mL, and the mixture was shaken and filtered through a filter to obtain a sample solution. Also, rotigotine with a known concentration was previously dissolved in the dilution solution to obtain a standard solution.

[0092] Using the sample solution, with a high-performance liquid chromatography apparatus (manufactured by Shimadzu Corporation), under the following conditions: Column: ZORBAX SB-C18 (4.6 mm I.D. × 250 mm), 5 μm Mobile phase: Phosphate buffer (pH 5.5) containing 10 mM dipotassium hydrogen phosphate and 0.067% trimethylamine (solution A), acetonitrile (solution B); A solution: B solution = 90:10 (0 to 20 minutes) → 20:80 (90 to 100 minutes) → 90:10 (105 to 125 minutes) Detection wavelength: 225 nm Column temperature: 40℃ Flow rate: 1mL / min chromatograms of 7,8-dihydronaphthol and despropyl rotigotine (despropyl RTN), which are decomposition products of rotigotine, in the sample solution were obtained.

[0093] Using the standard solution, a chromatogram of rotigotine in the standard solution was obtained using the high-performance liquid chromatography system under the same conditions as above. The amounts of 7,8-dihydronaphthol and depropyl rotigotine generated were calculated from the area under the curve of rotigotine in the obtained chromatogram and the areas under the curve of the chromatograms of 7,8-dihydronaphthol and depropyl rotigotine obtained above. The theoretical content of rotigotine was calculated from the amount of rotigotine formulated in the adhesive layer, and the respective amounts generated were divided by the theoretical content to calculate the generation rates of each rotigotine decomposition product in the adhesive layer of each patch after storage at 60°C for 2 weeks (7,8-dihydronaphthol generation rate [%], despropyl RTN generation rate [%]). The peak area appearing at a position around 56.8 minutes was taken as the peak area of 7,8-dihydronaphthol, and the peak area appearing at a position around 44.1 minutes was taken as the peak area of depropyl rotigotine.

[0094] Example 1 First, 0.1 parts by mass of propyl gallate was added to 9 parts by mass of rotigotine (free form), 11.73 parts by mass of styrene-isoprene-styrene block copolymer, 5.03 parts by mass of polyisobutylene, 42.73 parts by mass of alicyclic saturated hydrocarbon resin, 5 parts by mass of octyldodecanol, 3 parts by mass of cholesterol, 10 parts by mass of crosslinked polyvinylpyrrolidone, and 13.41 parts by mass of liquid paraffin, and the mixture was added to an appropriate amount of solvent (absolute ethanol and toluene) and mixed to obtain a pressure-sensitive adhesive layer composition. Next, the obtained pressure-sensitive adhesive layer composition was spread on a release liner (a polyethylene terephthalate film that had been subjected to a release treatment), and the solvent was dried and removed to obtain a pressure-sensitive adhesive layer having a mass per unit area of 50 g / m. 2A support layer (a polyethylene terephthalate film) was laminated on the surface of the resulting pressure-sensitive adhesive layer opposite the release liner, to obtain a patch laminated in this order: support layer / pressure-sensitive adhesive layer / release liner.

[0095] (Examples 2 to 4, Comparative Examples 1 to 5) Each patch was obtained in the same manner as in Example 1, except that the adhesive layer composition (composition excluding the solvent) was adjusted to have the composition shown in Table 1 or Table 2 below.

[0096] The patches obtained in Examples 1 to 4 and Comparative Examples 1 to 5 were each subjected to a stability evaluation (2 weeks after production, at 60°C, using the method in Comparative Examples 1 and 2 (1), and the method in Examples 1 to 4 and Comparative Examples 3 to 5 (2)). The results of the stability evaluation are shown in Tables 1 and 2, respectively, along with the composition of the adhesive layer composition (excluding the solvent) for each Example and Comparative Example. In each Example, a skin permeation test revealed a sufficiently excellent maximum skin permeation rate (Jmax) [μg / cm 2 / hr] was achieved.

[0097] [Table 1]

[0098] [Table 2]

[0099] As is clear from the results shown in Tables 1 and 2, in patches containing propyl gallate in the adhesive layer (e.g., Examples 1 to 4), even under harsh conditions of a temperature of 60°C and two weeks after production, the rate of rotigotine degradation products was sufficiently suppressed, and it was confirmed that rotigotine was stabilized at a high level.

[0100] On the other hand, in the patches obtained in Comparative Examples 2 to 5, even though they contained ingredients such as sodium pyrosulfite, which has traditionally been used as a stabilizer for drugs, the rate of occurrence of at least one of the rotigotine decomposition products was higher than in patches containing propyl gallate in the adhesive layer, and some of them (e.g., Comparative Examples 2 and 3) showed an even higher rate of occurrence of rotigotine decomposition products than in Comparative Example 1, which did not contain a stabilizer. [Industrial Applicability]

[0101] As described above, according to the present invention, it is possible to provide a rotigotine-containing patch that exhibits particularly excellent stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof, and a method for improving the stability of rotigotine.

Claims

1. A rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, a pressure-sensitive adhesive base, an alicyclic saturated hydrocarbon resin, cholesterol, and propyl gallate.

2. The rotigotine-containing patch according to claim 1, wherein the content of propyl gallate in the adhesive layer is 0.01 to 1% by mass based on the total mass of the adhesive layer.

3. The rotigotine-containing patch according to claim 1 or 2, wherein the pressure-sensitive adhesive base is at least one selected from the group consisting of a rubber-based pressure-sensitive adhesive base, an acrylic-based pressure-sensitive adhesive base, and a silicone-based pressure-sensitive adhesive base.

4. The rotigotine-containing patch according to claim 1 or 2, wherein the content of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine in the adhesive layer is 5 to 15% by mass in terms of free rotigotine based on the total mass of the adhesive layer.

5. In a rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, a pressure-sensitive adhesive base, an alicyclic saturated hydrocarbon resin, and cholesterol, a method for improving the stability of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, comprising the step of further containing propyl gallate in the adhesive layer, A method for improving rotigotine stability.

6. The method for improving rotigotine stability according to claim 5, wherein propyl gallate is contained in the adhesive layer such that the content thereof based on the total mass of the adhesive layer is 0.01 to 1% by mass.

7. The method for improving rotigotine stability according to claim 5 or 6, wherein the pressure-sensitive adhesive base is at least one selected from the group consisting of a rubber-based pressure-sensitive adhesive base, an acrylic-based pressure-sensitive adhesive base, and a silicone-based pressure-sensitive adhesive base.

8. The method for improving rotigotine stability according to claim 5 or 6, wherein the content of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine is 5 to 15% by mass in terms of free rotigotine based on the total mass of the adhesive layer.

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