Adhesive containing rotigotine and method for improving stability of rotigotine

Abstract

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

Description

Technical Field

[0001] The present invention relates to an adhesive containing rotigotine and a method for improving the stability of rotigotine. More specifically, it relates to an adhesive containing rotigotine and / or a pharmaceutically acceptable salt thereof, and a method for improving the stability of rotigotine in the adhesive. Background Art

[0002] In Japanese Patent Publication No. 2011-504902 (Patent Document 1), the international common name of rotigotine is described as the compound (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthol, and there are polymorphs of type I and type II. Rotigotine is a D1 / D2 / D3 dopamine receptor agonist and is mainly used for treating 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 at home and abroad. In addition, in Japanese Patent Publication No. 2002-509878 (Patent Document 2), a transdermal therapeutic system is described, which includes a support layer inert to the matrix component and a self-adhesive matrix layer containing rotigotine. The solubility of rotigotine in the above matrix is 5% (w / w) or more, and a non-water-soluble acrylate-based or silicone-based polymer adhesive is used as the base material.

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

[0005] Furthermore, for example, in Japanese Patent Publication No. 2017-515871 (Patent Document 6), a method for manufacturing a transdermal preparation is described, which mixes rotigotine and an antioxidant such as butylated hydroxytoluene in a specific weight ratio for the purpose of preventing the crystallization of rotigotine. In addition, as an adhesive containing the above antioxidant, for example, in Japanese Patent Publication No. 2017-073516 (Patent Document 7) and Japanese Patent Publication No. 2018-198925 (Patent Document 8), an adhesive layer of an adhesive containing fentanyl and butorphanol as drugs contains an antioxidant having a sulfur atom in the molecule.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: Japanese Patent Publication No. 2011-504902

[0009] Patent Document 2: Japanese Patent Publication No. 2002-509878

[0010] Patent Document 3: Japanese Patent Publication No. 2015-503541

[0011] Patent Document 4: Japanese Patent Application Laid-Open No. 2014-177428

[0012] Patent Document 5: Japanese Patent Application Laid-Open No. 2013-079220

[0013] Patent Document 6: Japanese Patent Publication No. 2017-515871

[0014] Patent Document 7: Japanese Patent Publication No. 2017-073516

[0015] Patent Document 8: Japanese Patent Publication No. 2018-198925 Summary of the Invention

[0016] Problems to be Solved by the Invention

[0017] However, with respect to a rotigotine-containing adhesive containing rotigotine and / or a pharmaceutically acceptable salt thereof, the inventors further conducted research and found that due to storage conditions, such as severe storage conditions at high temperatures, the stability of rotigotine and / or a pharmaceutically acceptable salt thereof cannot be said to be sufficient, and sometimes rotigotine and / or a pharmaceutically acceptable salt thereof may be decomposed to produce its decomposition product (rotigotine decomposition product). When a large amount of rotigotine decomposition product is generated, there is a concern that the desired pharmacological effects of rotigotine and / or a pharmaceutically acceptable salt thereof cannot be expected. Therefore, the inventors found that a higher level of stability over time is required.

[0018] The present invention has been completed in view of the above problems, and an object thereof is to provide a rotigotine-containing adhesive patch and a method for improving the stability of rotigotine, which are particularly excellent in the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof.

[0019] Means for Solving the Problems

[0020] The inventors of the present invention repeatedly made intensive studies to achieve the above object, and as a result, it was found that in a rotigotine-containing adhesive patch having a support layer and an adhesive layer, and containing at least one selected from rotigotine and a pharmaceutically acceptable salt thereof (in the present specification, sometimes referred to as "rotigotine and / or a pharmaceutically acceptable salt thereof") and an adhesive base in the adhesive layer, by further containing propyl gallate in the adhesive layer, the generation of rotigotine decomposition products can be suppressed at a high level even when stored under severe conditions, and a rotigotine-containing adhesive patch having particularly excellent stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof can be produced, and thus the present invention has been completed. The aspects of the present invention obtained based on this finding are as follows.

[0021] [1] A rotigotine-containing adhesive patch, which has a support layer and an adhesive layer, and the adhesive layer contains at least one selected from rotigotine and a pharmaceutically acceptable salt of rotigotine, an adhesive base, and propyl gallate.

[0022] [2] The rotigotine-containing adhesive 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.

[0023] [3] The rotigotine-containing adhesive patch according to [1] or [2], wherein the adhesive base is at least one selected from a rubber-based adhesive base, an acrylic-based adhesive base, and a silicone-based adhesive base.

[0024] [4] The rotigotine-containing adhesive patch according to any one of [1] to [3], wherein the content of at least one selected from rotigotine and a pharmaceutically acceptable salt of rotigotine in the adhesive layer, in terms of the free form of rotigotine, is 5 to 15% by mass based on the total mass of the adhesive layer.

[0025] [5] A method for improving the stability of rotigotine

[0026] It is a method for enhancing the stability of at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine in an adhesive patch containing rotigotine. The adhesive patch containing rotigotine has a support layer and an adhesive layer, and the adhesive layer contains at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine and an adhesive base.

[0027] The method includes a step of further adding propyl gallate to the adhesive layer.

[0028] [6] The method for enhancing the stability of rotigotine according to [5], wherein the adhesive layer contains propyl gallate in an amount of 0.01 to 1% by mass based on the total mass of the adhesive layer.

[0029] [7] The method for enhancing the stability of rotigotine according to [5] or [6], wherein the adhesive base is at least one selected from a rubber-based adhesive base, an acrylic-based adhesive base, and a silicone-based adhesive base.

[0030] [8] The method for enhancing the stability of rotigotine according to any one of [5] to [7], wherein the content of at least one selected from 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.

[0031] Effects of the Invention

[0032] According to the present invention, an adhesive patch containing rotigotine and / or a pharmaceutically acceptable salt thereof with particularly excellent stability over time and a method for enhancing the stability of rotigotine can be provided. Detailed Description of the Invention

[0033] Hereinafter, the present invention will be described in detail based on its preferred embodiments.

[0034] [Adhesive Patch Containing Rotigotine]

[0035] The adhesive patch containing rotigotine of the present invention has a support layer and an adhesive layer, and the adhesive layer contains at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine, an adhesive base, and propyl gallate.

[0036] The rotigotine-containing patch of the present invention has a support layer and an adhesive layer. As the above-mentioned support layer, as long as it can support the following adhesive layer, there is no particular limitation, and those well-known as the support layer of a patch can be appropriately used. As the material of the support layer of the present invention, for example, polyolefins such as polyethylene and polypropylene can be cited; 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 them, from the viewpoints of non-adsorbability and non-permeability of drugs, polyester and polyethylene terephthalate are preferred. As the form of the above-mentioned support layer, for example, a film; sheets such as a sheet, a sheet-like porous body, and a sheet-like foam; fabrics such as a woven fabric, a knitted fabric, and a non-woven fabric; a foil; and a laminate thereof can be cited. In addition, as the thickness of the above-mentioned support layer, there is no particular limitation, and from the viewpoints of ease of operation and ease of manufacture when attaching the patch, it is preferably in the range of 5 to 1000 μm.

[0037] As the rotigotine-containing patch of the present invention, a release liner may further be provided on the surface of the adhesive layer opposite to the support layer. As such a release liner, polyolefins such as polyethylene and polypropylene can be cited; ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; synthetic resins such as polyurethane, films, sheets, and laminates thereof made of materials including aluminum, paper, etc. As these release liners, in order to be easily peeled from the adhesive layer, those having a release treatment such as silicone compound coating or fluorine compound coating on the surface in contact with the adhesive layer are preferred.

[0038] <Rotigotine and its pharmaceutically acceptable salts>

[0039] The adhesive layer of the present invention contains at least one selected from rotigotine and its pharmaceutically acceptable salts (rotigotine and / or its pharmaceutically acceptable salts) as a drug. As the form of rotigotine contained in the above adhesive layer in the present invention, it may be free cartilage bodies, or its pharmaceutically acceptable salt, or a substance in which the pharmaceutically acceptable salt of rotigotine is desalted to become free cartilage bodies during manufacture and / or in the manufactured preparation, and it may be one of them or a mixture of two or more. Examples of the pharmaceutically acceptable salts of rotigotine include acid addition salts. Examples of the acid for the above 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, fumaric acid. The above acid addition salt may be one of the addition salts of these acids or two or more. As the adhesive layer of the present invention, preferably, rotigotine is contained in the form of free cartilage bodies.

[0040] In the present invention, as the content of rotigotine and / or its pharmaceutically acceptable salts contained in the above adhesive layer (the content of rotigotine or the content of the pharmaceutically acceptable salt of rotigotine, or the total content in the case where both are contained, the same applies hereinafter), in terms of rotigotine free body conversion, it is preferably 5 to 15% by mass, more preferably 6 to 12% by mass, still more preferably 7 to 10% by mass, and even more preferably 8 to 9% by mass with respect to the total mass of the above adhesive layer. If the content of rotigotine and / or its pharmaceutically acceptable salts is less than the above lower limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salts tends to decrease. On the other hand, if it exceeds the above upper limit, crystal precipitation of rotigotine or the adhesive strength of the adhesive layer tends to easily decrease.

[0041] According to the patch containing rotigotine of the present invention and the method for improving the stability of rotigotine of the present invention below, the generation of decomposition products (rotigotine decomposition products) of rotigotine and / or its pharmaceutically acceptable salts can be sufficiently suppressed. Examples of such decomposition products include, but are not limited to, 7,8 - Dihydro Naphthol, Despropyl RTN, etc.

[0042] <Adhesive base>

[0043] The adhesive layer of the present invention further contains an adhesive base. There is no particular limitation on the above-mentioned adhesive base, and examples thereof include: rubber-based adhesive bases, acrylic-based adhesive bases, and silicone-based adhesive bases. It may be one of them, or a combination of two or more. It is preferably at least one selected from rubber-based adhesive bases, acrylic-based adhesive bases without carboxyl groups, and silicone-based adhesive bases, and more preferably contains at least a rubber-based adhesive base.

[0044] In the adhesive layer of the present invention, the content of the above-mentioned adhesive base (in the case of two or more, it is the total content thereof, the same hereinafter) is preferably 1 to 90% by mass, more preferably 5 to 90% by mass, still more preferably 10 to 90% by mass, and still more preferably 10 to 80% by mass with respect to the total mass of the above-mentioned adhesive layer.

[0045] (Rubber-based adhesive base)

[0046] Examples of the above-mentioned rubber-based adhesive base include: styrene-based thermoplastic elastomers, polyisobutylene, natural rubber, alkyl vinyl ether (co)polymers, polyisoprene, polybutadiene, etc. One of them can be used alone, or two or more can be used in combination. Among them, styrene-based thermoplastic elastomers are particularly preferred. The above-mentioned styrene-based thermoplastic elastomer is a thermoplastic styrene-based elastomer that softens and shows fluidity when heated and shows recovery to a rubber-like elastomer when cooled. Among them, from the viewpoint of imparting sufficient adhesiveness and more excellent temporal stability of rotigotine and / or its pharmaceutically acceptable salts, styrene-based block copolymers are preferred.

[0047] Specific examples of the above-mentioned 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 / butene block copolymer, styrene-ethylene / butene-styrene block copolymer, styrene-ethylene / propylene block copolymer, styrene-ethylene / propylene-styrene block copolymer, styrene-isobutene block copolymer, styrene-isobutene-styrene block copolymer, etc. One of them can be used, or two or more can be used in combination. In addition, in the above, "ethylene / butene" represents a copolymer block of ethylene and butene, and "ethylene / propylene" represents a copolymer block of ethylene and propylene. Among them, as the styrene-based thermoplastic elastomer of the present invention, styrene-isoprene-styrene block copolymer is more preferred.

[0048] As the above-mentioned styrene-isoprene-styrene block copolymer, it is preferably a viscosity average molecular weight of 30,000 to 2,500,000, more preferably 100,000 to 1,700,000. If the viscosity average molecular weight is less than the above lower limit value, the physical properties of the preparation of the adhesive (especially the cohesion of the adhesive layer) tend to decrease. On the other hand, if it exceeds the above upper limit value, the compatibility with other components contained in the adhesive layer decreases, and it becomes difficult to manufacture the adhesive.

[0049] In the present invention, when the above-mentioned styrenic thermoplastic elastomer is contained in the above-mentioned adhesive layer as the above-mentioned adhesive base, as its content (the total content when there are two or more types of the above-mentioned styrenic thermoplastic elastomers in combination, the same applies hereinafter), it is preferably 5 to 50% by mass, more preferably 10 to 40% by mass, and still more preferably 10 to 30% by mass based on the total mass of the adhesive layer. If the content of the above-mentioned styrenic thermoplastic elastomer is less than the above lower limit, the cohesion, shape retention, etc. of the adhesive layer tend to decrease. On the other hand, if it exceeds the above upper limit, the cohesion of the adhesive layer increases excessively, the adhesiveness of the adhesive layer decreases, or the compatibility decreases.

[0050] In addition, as the above-mentioned rubber-based adhesive base, from the viewpoint of further enhancing the adhesiveness and cohesion of the adhesive layer, it is more preferably a combination of the above-mentioned styrenic thermoplastic elastomer (more preferably a styrene-isoprene-styrene block copolymer) and the above-mentioned polyisobutylene. Further preferably, the mass ratio of the above-mentioned styrenic thermoplastic elastomer to the above-mentioned polyisobutylene (mass of styrenic thermoplastic elastomer: mass of polyisobutylene) is 1:2 to 30:1 (more preferably in the range of 1:1 to 10:1).

[0051] As specific examples of styrene-isoprene-styrene block copolymers, the following can be cited: Quintac (registered trademark) 3570C (trade name, manufactured by Zeon Corporation, Japan), SIS5002, SIS5229, SIS5505, SIS5505P (trade name, manufactured by JSR Corporation), SIBSTAR (registered trademark) T102 (trade name, manufactured by Kaneka Corporation), and the like. In addition, polyisobutylene also contains so-called butyl rubber (isobutene-isoprene rubber). As specific examples, the following can be cited: Oppanol (registered trademark) N50, N80, N100, N150, B11, B12, B50, B80, B100, B120, B150, B220 (trade name, manufactured by BASF), JSR (registered trademark) Butyl065, 268, 365 (trade name, manufactured by JSR Corporation), X_Butyl (registered trademark) RB100, 101-3, 301, 402 (trade name, manufactured by ARLANXEO), Exxon (registered trademark) Butyl065, 065S, 068, 068S, 268, 268S, 365, 365S (trade name, manufactured by Exxon Mobile), Butyl065, 268, 365 (trade name, manufactured by Nippon Butyl Co., Ltd., Japan), and the like.

[0052] In the present invention, when the adhesive layer contains a rubber-based adhesive base as the adhesive base, its content (in the case of a combination of two or more, their total content, the same hereinafter) is preferably 1 to 60% by mass, more preferably 5 to 50% by mass, and still more preferably 10 to 40% by mass, based on the total mass of the adhesive layer.

[0053] (Acrylic adhesive base)

[0054] As the acrylic adhesive base of the present invention, for example, those listed as adhesives in the "Pharmaceutical Additive Dictionary 2016" (edited by the Pharmaceutical Additive Society of Japan) can be cited. It can be one of them or a combination of two or more. Preferably, it is an acrylic adhesive base that does not have a carboxyl group, and more preferably, it is an acrylic adhesive base that does not have a functional group. In the present invention, the "acrylic adhesive base that does not have a carboxyl group" and the "acrylic adhesive base that does not have a functional group" respectively mean acrylic polymers that substantially do not have a carboxyl group and a functional group, and preferably the contents of the carboxyl group and the functional group in the polymer are each less than 3% by mass.

[0055] Examples of the above acrylic pressure-sensitive adhesive base resin without a carboxyl group include acrylic 2-ethylhexyl ester-vinylpyrrolidone copolymer, acrylic 2-ethylhexyl ester-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer, acrylic 2-ethylhexyl ester-vinyl acetate copolymer, acrylic 2-ethylhexyl ester-methyl methacrylate-butyl acrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, etc., which are acrylic pressure-sensitive adhesive base resins substantially without functional groups; (meth)acrylic 2-ethylhexyl ester-vinyl acetate-2-hydroxyethyl acrylate copolymer, (meth)acrylic 2-hydroxyethyl ester copolymer, (meth)acrylic 2-hydroxypropyl ester copolymer, (meth)acrylic 3-hydroxypropyl ester copolymer, (meth)acrylic 4-hydroxybutyl ester copolymer, acrylic 2-ethylhexyl ester-vinyl acetate-hydroxyethyl acrylate-glycidyl methacrylate copolymer, etc., which are acrylic pressure-sensitive adhesive base resins having a hydroxyl group. It can be a single one of them or a combination of two or more.

[0056] As the above acrylic pressure-sensitive adhesive base resin without a carboxyl group, commercially available products can be appropriately used. For example, MAS 811 and MAS 683 (manufactured by Cosmedy Pharma Co., Ltd.); 87-900A, 87-901A, 87-9301, 87-4098, 87-9088, 87-9085 of the Duro-Tak (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel Corporation); acrylic polymers contained in GMS 3083, GMS 3253, GMS3235, etc. of the GELVA (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel Corporation); 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 the Duro-Tak (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel Corporation); acrylic polymers contained in GMS788, GMS 737, etc. of the GELVA (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel Corporation), etc.

[0057] When the pressure-sensitive adhesive layer of the present invention contains the above acrylic pressure-sensitive adhesive base resin, as its content (in the case of two or more, it is the total content thereof, the same hereinafter), it is preferably 10 to 90% by mass based on the total mass of the pressure-sensitive adhesive layer, and more preferably 20 to 80% by mass. When the content of the above acrylic pressure-sensitive adhesive base resin is less than the above lower limit, the cohesive force of the pressure-sensitive adhesive layer tends to decrease. On the other hand, when it exceeds the above upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salts tends to decrease.

[0058] (Silicone-based pressure-sensitive adhesive base agent)

[0059] As the silicone-based pressure-sensitive adhesive base agent of the present invention, in the ASTM standard (ASTM D 1418), examples include: silicone rubbers represented as MQ (polydimethylsiloxane), VMQ (polymethylvinylsiloxane), PMQ (polymethylphenylsiloxane), PVMQ (polyphenylvinylmethylsiloxane), mixtures of at least one of them and silicone resins other than silicone rubbers such as polydi-trimethylsilylsiloxane, etc. It can be one of them or a combination of two or more. In addition, when mixing silicone resins other than the above silicone rubbers, it is preferably 0.1 to 20% by mass based on the total mass of the silicone-based pressure-sensitive adhesive base agent.

[0060] In addition, as these silicone-based pressure-sensitive adhesive base agents, commercially available products can be appropriately used. For example, silicone-based pressure-sensitive adhesive base agents provided by DuPont Toray Specialty Materials Co., Ltd. under the following models can be appropriately used: 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.

[0061] Furthermore, as the silicone-based pressure-sensitive adhesive base agent of the present invention, for example, it can be: a substance obtained by dehydrogenating the hydrogen atoms of the methyl groups by blending peroxides and crosslinking the methyl groups when having methyl groups; a substance obtained by bonding a crosslinking agent containing an SiH group siloxane compound and crosslinking the vinyl groups when having vinyl groups; a substance obtained by dehydrating and condensing the silanol groups and crosslinking the silanol groups when having hydroxyl groups (i.e., having silanol groups), etc.

[0062] When the pressure-sensitive adhesive layer of the present invention contains the above-mentioned silicone-based pressure-sensitive adhesive base, its content (in the case of two or more types, the total content thereof, the same applies 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 above-mentioned silicone-based pressure-sensitive adhesive base is less than the above lower limit, the cohesive force of the pressure-sensitive adhesive layer tends to decrease. On the other hand, when it exceeds the above upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salts tends to decrease.

[0063] <Propyl Gallate>

[0064] In the patch containing rotigotine of the present invention, the pressure-sensitive adhesive layer contains propyl gallate. As the content of propyl gallate contained in the pressure-sensitive adhesive layer of the present invention, it is preferably 0.01 to 1% by mass, more preferably 0.05 to 1% by mass, further preferably 0.075 to 0.8% by mass, still further preferably 0.1 to 0.6% by mass, and particularly preferably 0.1 to 0.3% by mass, based on the total mass of the pressure-sensitive adhesive layer. If the content of the above-mentioned propyl gallate is less than the above lower limit, there is a tendency that the effect of improving the stability of rotigotine and / or its pharmaceutically acceptable salts over time cannot be fully exerted. On the other hand, if it exceeds the above upper limit, there is a tendency that the cohesive force or the adhesive force of the pressure-sensitive adhesive layer decreases.

[0065] In addition, as the content of propyl gallate contained in the pressure-sensitive adhesive layer, relative to 1 part by mass of the content of rotigotine in terms of the free rotigotine of rotigotine and / or its pharmaceutically acceptable salts, it is preferably 0.001 to 0.12 part by mass, more preferably 0.005 to 0.115 part by mass, further preferably 0.008 to 0.09 part by mass, still further preferably 0.01 to 0.07 part by mass, and particularly preferably 0.01 to 0.035 part by mass. If the ratio of the content of propyl gallate to the content of rotigotine and / or its pharmaceutically acceptable salts is within the above range, there is a tendency to particularly exert the stability of rotigotine and / or its pharmaceutically acceptable salts over time.

[0066] <Thioglycolic Acid and Its Pharmaceutically Acceptable Salts>

[0067] As the pressure-sensitive adhesive layer of the present invention, from the viewpoint of improving the stability of rotigotine and / or its pharmaceutically acceptable salts over time, it may further contain at least one selected from thioglycolic acid and pharmaceutically acceptable salts of thioglycolic acid (thioglycolic acid and / or its pharmaceutically acceptable salts).

[0068] As the form of thioglycolic acid that can be contained in the above-mentioned adhesive layer in the present invention, it can be in the form of free bodies, or its pharmaceutically acceptable salts, or a substance in which the pharmaceutically acceptable salts of thioglycolic acid are desalted to become free bodies during manufacturing and / or in the manufactured preparation. It can be one of them or a mixture of two or more. Examples of the pharmaceutically acceptable salts of thioglycolic acid include: alkali metal salts, alkaline earth metal salts, salts with ammonia, alkylamines, and alkanolamines. More specifically, for example, 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 salts of thioglycolic acid can be one of these salts or two or more. As the form of thioglycolic acid that can be contained in the adhesive layer of the present invention, it is preferably at least one selected from thioglycolic acid and the alkali metal salts of thioglycolic acid (more preferably sodium salt).

[0069] When the adhesive layer of the present invention further contains thioglycolic acid and / or its pharmaceutically acceptable salts, as the content of thioglycolic acid and / or its pharmaceutically acceptable salts contained in the above-mentioned adhesive layer (the content of thioglycolic acid or the pharmaceutically acceptable salts of thioglycolic acid, or their total content when both are contained, the same hereinafter), calculated in terms of sodium thioglycolate, it is preferably 0.03 to 3% by mass, more preferably 0.05 to 3% by mass, further preferably 0.1 to 3% by mass, still more preferably 0.15 to 3% by mass, and particularly preferably 0.25 to 3% by mass, 0.5 to 3% by mass with respect to the total mass of the above-mentioned adhesive layer. If the content of thioglycolic acid and / or its pharmaceutically acceptable salts is less than the above lower limit, there is a tendency that the effect of improving the stability over time of rotigotine and / or its pharmaceutically acceptable salts by using thioglycolic acid and / or its pharmaceutically acceptable salts is not fully exerted. On the other hand, if it exceeds the above upper limit, there is a tendency for the adhesive strength of the adhesive layer to decrease.

[0070] In addition, as the content of thioglycolic acid and / or its pharmaceutically acceptable salts contained in the above-mentioned adhesive layer calculated in terms of sodium thioglycolate, with respect to 1 part by mass of the content of propyl gallate in the above-mentioned adhesive layer, it is preferably 0.02 to 300 parts by mass, more preferably 0.04 to 60 parts by mass, further preferably 0.1 to 40 parts by mass, still more preferably 0.2 to 30 parts by mass, and particularly preferably 0.8 to 30 parts by mass. If the content of thioglycolic acid and / or its pharmaceutically acceptable salts with respect to the content of propyl gallate is within the above range, there is a tendency that the effect of improving the stability over time of rotigotine and / or its pharmaceutically acceptable salts by using thioglycolic acid and / or its pharmaceutically acceptable salts is particularly exerted.

[0071] Furthermore, as the content of thioglycolic acid and / or its pharmaceutically acceptable salt contained in the above adhesive layer, in terms of the content of sodium thioglycolate, per 1 part by mass of the content of rotigotine and / or its pharmaceutically acceptable salt in terms of free rotigotine, it 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, still more preferably 0.03 to 0.35 parts by mass, and particularly preferably 0.05 to 0.35 parts by mass. 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, there is a tendency for 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 to be particularly exerted.

[0072] However, as the adhesive layer of the present invention, from the viewpoint of suppressing the unpleasant odor during the production of the patch, it is also preferred that it substantially does not contain thioglycolic acid and its pharmaceutically acceptable salt. Substantially not containing the above thioglycolic acid and its pharmaceutically acceptable salt means the following situation, that is, the content of thioglycolic acid and its pharmaceutically acceptable salt in terms of the content of sodium thioglycolate is less than 0.03% by mass (for example, 0.029% by mass or less) relative to the total mass of the above adhesive layer.

[0073] <Other components>

[0074] As the adhesive layer of the present invention, within the range that does not hinder the effects of the present invention, it may further contain other drugs other than rotigotine and its pharmaceutically acceptable salt; other stabilizers other than propyl gallate and thioglycolic acid and its pharmaceutically acceptable salt; tackifiers; absorption promoters; skin irritation reducing agents; additives such as adsorbents, desalting agents, plasticizers, solubilizers, fillers, and preservatives.

[0075] (Other drugs)

[0076] As other drugs other than rotigotine and its pharmaceutically acceptable salts as described above, for example, the following can be cited: non-steroidal anti-inflammatory analgesics (diclofenac, indomethacin, ketoprofen, biphenylacetic acid, loxoprofen, ibuprofen, flurbiprofen, tiaprofenic acid, acemetacin, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, rofecoxib, amfenac, etc.), antipyretics (acetaminophen, etc.), antihistamines (diphenhydramine, chlorpheniramine, mequitazine, homochlorcyclizine, etc.), antihypertensive agents (diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril, etc.), anti-Parkinson's agents (pergolide, ropinirole, bromocriptine, selegiline, etc.), bronchodilators (tulobuterol, isoprenaline, salbutamol, etc.), antiallergic agents (ketotifen, loratadine, azelastine, terfenadine, cetirizine, azelastine, etc.), local anesthetics (lidocaine, dibucaine, etc.), drugs for treating neuropathic pain (pregabalin, etc.), non-narcotic analgesics (buprenorphine, tramadol, pentazocine), narcotic analgesics (morphine, oxycodone, fentanyl, etc.), agents for urinary organs (oxybutynin, tamsulosin, etc.), agents for mental and neurological disorders (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 treatment drugs (raloxifene, alendronate, etc.), breast cancer prevention drugs (tamoxifen, etc.), anti-obesity drugs (mazindol, sibutramine, etc.), insomnia improvement drugs (melatonin, etc.), anti-rheumatic drugs (actarit, etc.). It can be one of them or a combination of two or more of them.

[0077] When the adhesive layer of the present invention further contains the above-mentioned other drugs, as its content (in the case of two or more, their total content), it is preferably 10% by mass or less relative to the total mass of the adhesive layer.

[0078] (Other stabilizers)

[0079] As other stabilizers in addition to propyl gallate, thioglycolic acid, and their pharmaceutically acceptable salts, examples include: ascorbic acid or its metal salts or esters (such as palmitate), isoascorbic acid or its metal salts, ethylenediaminetetraacetic acid or its metal salts, cysteine, acetylcysteine, 2-mercaptobenzimidazole, dibutylhydroxytoluene, butylhydroxyanisole, pentaerythrityl-tetra[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], 3-mercapto-1,2-propanediol, vitamin E, vitamin E acetate, thymol, soy lecithin, rutin, dihydroxybenzoic acid, potassium dichloroisocyanurate, quercetin, hydroquinone, metal salts of hydroxymethanesulfinic acid, metal salts of metabisulfite (such as sodium metabisulfite), metal salts of sulfite, metal salts of thiosulfate other than metal salts of thioglycolic acid. It can be one of them or a combination of two or more. Among the above, as metal salts, examples include: sodium salt, potassium salt, calcium salt, magnesium salt, calcium disodium salt. In addition, as esters, examples include: palmitate, stearate, myristate, etc.

[0080] However, in the adhesive layer of the present invention, when the time-dependent stabilization effect of rotigotine based on propyl gallate and / or its pharmaceutically acceptable salts is hindered, or from the viewpoint of the adhesive strength of the adhesive layer, it is preferably that the above-mentioned other stabilizers are not contained in the above-mentioned adhesive layer. As its content (in the case of two or more, their total content), relative to the total mass of the above-mentioned adhesive layer, it is preferably 3% by mass or less, more preferably 2% by mass or less, and still more preferably 0.25% by mass or less (for example, 0 to 0.25%, 0.005 to 0.25%).

[0081] (Tackifier)

[0082] The above-mentioned tackifier is mainly formulated for the purpose of improving the adhesiveness of the above-mentioned adhesive base (preferably a rubber-based adhesive base). Examples of such tackifiers include: petroleum resins, rosin resins, terpene resins, phenolic resins, and xylene resins. As the above-mentioned tackifier, it can be one of them or a combination of two or more. When the adhesive layer of the present invention contains the above-mentioned rubber-based adhesive base as the above-mentioned adhesive base, it is preferably further contains a petroleum resin.

[0083] When the above-mentioned tackifier is further contained in the above-mentioned adhesive layer, as its content (in the case of two or more, their total content), from the viewpoints of improving the adhesive strength of the above-mentioned adhesive layer and / or alleviating local irritation during peeling, relative to the total mass of the above-mentioned adhesive layer, it is preferably 5 to 80% by mass, more preferably 10 to 80% by mass, and still more preferably 20 to 60% by mass.

[0084] As the above petroleum resin, for example, the following can be cited: C5-based synthetic petroleum resin (copolymer of at least two of isoprene, cyclopentadiene, 1,3-pentadiene, and 1-pentene; copolymer of at least two of 2-pentene and dicyclopentadiene; resin mainly composed of 1,3-pentadiene, etc.), C9-based synthetic petroleum resin (copolymer of at least two of indene, styrene, methyl indene, and α-methyl styrene, etc.), dicyclopentadiene-based synthetic petroleum resin (copolymer of isoprene and / or 1,3-pentadiene mainly composed of dicyclopentadiene). In addition, from the perspective of other classifications, for example, the following can be cited: alicyclic petroleum resin (alicyclic saturated hydrocarbon resin, etc.), alicyclic hydrogenated petroleum resin, aliphatic petroleum resin (aliphatic hydrocarbon resin, etc.), aliphatic hydrogenated petroleum resin, aromatic petroleum resin. More specifically, the following can be cited: Arkon P-70, Arkon P-85, Arkon P-90, Arkon P-100, Arkon P-115, Arkon P-125, Arkon M-90, Arkon M-100, Arkon M-115, Arkon M-135 (the above are trade names, manufactured by Arakawa Chemical Industries, Ltd.), Escorez 8000 (trade name, manufactured by Esso Petrochemical Co., Ltd.). The petroleum resin of the present invention can be one of them or a combination of two or more. Among them, from the viewpoints of easily obtaining suitable adhesiveness to the skin, having a good feeling in use due to less odor, etc., and further suppressing the generation of rotigotine decomposition products, etc., an alicyclic saturated hydrocarbon resin is more preferred.

[0085] In the present invention, the above alicyclic saturated hydrocarbon resin refers to a resin that is a homopolymer or copolymer of an alicyclic saturated hydrocarbon monomer. As the above alicyclic saturated hydrocarbon resin, the weight average molecular weight is preferably 1,000 to 2,300, more preferably 1,000 to 1,800, still more preferably 1,000 to 1,600, still more preferably 1,000 to 1,500, and particularly preferably 1,200 to 1,400.

[0086] When the adhesive layer of the present invention further contains the above petroleum resin (preferably an alicyclic saturated hydrocarbon resin), as its content (in the case of two or more, their total content), relative to the total mass of the adhesive layer, it is preferably 5 to 80% by mass, more preferably 10 to 70% by mass, still more preferably 10 to 60% by mass, and particularly preferably 20 to 60% by mass. If the content of the above petroleum resin is less than the above lower limit, there is a tendency for the adhesive strength of the adhesive layer and the adhesiveness to the skin to decrease. On the other hand, if it exceeds the above upper limit, there is a tendency for the skin permeability of rotigotine and / or its pharmaceutically acceptable salt and the shape retention of the adhesive layer to decrease.

[0087] (Absorption promoter)

[0088] As the above absorption promoter, substances having a percutaneous absorption promoting effect (skin penetration promoting effect) on drugs can be exemplified. For example, 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; glyceryl triacetate can be exemplified. As the above absorption promoter, one of them can be used, or a combination of two or more can be used. From the viewpoint of more excellent skin permeability of rotigotine and / or its pharmaceutically acceptable salts, it is preferable to further contain an aliphatic alcohol in the above adhesive layer.

[0089] When the above absorption promoter is further contained in the above adhesive layer, as its content (total content in the case of two or more), from the viewpoint of more excellent skin permeability of rotigotine and / or its pharmaceutically acceptable salts, it is preferably 1 to 15% by mass, more preferably 3 to 7% by mass, based on the total mass of the above adhesive layer.

[0090] The above aliphatic alcohol refers to a saturated or unsaturated straight-chain or branched-chain monohydric or polyhydric aliphatic alcohol. As the aliphatic alcohol of the present invention, a monohydric alcohol is preferred. In addition, as the number of carbon atoms of the above aliphatic alcohol, it is preferably 3 to 23, more preferably 12 to 23, and still more preferably 12 to 20. If the number of carbon atoms of the above aliphatic alcohol is less than the above lower limit, the boiling point decreases, so it is difficult to keep the content in the preparation fixed, and the stability over time of the aliphatic alcohol tends to decrease. On the other hand, if it exceeds the above upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salts tends to decrease.

[0091] As the above aliphatic alcohol, for example, isopropanol, hexanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, octyldodecanol, oleyl alcohol, (9Z,12Z,15Z)-9,12,15-octadecatriene-1-ol (Linolenylalcohol), hexyl decanol can be exemplified. As the above aliphatic alcohol, one of them can be used, or a combination of two or more can be used. From the viewpoint of having a tendency to particularly enhance the skin permeability of rotigotine and / or its pharmaceutically acceptable salts, in addition to the viewpoints of the stability over time and compatibility of the above aliphatic alcohol, at least one selected from octyldodecanol and lauryl alcohol is preferred.

[0092] When the pressure-sensitive adhesive layer of the present invention further contains the above aliphatic alcohol, as its content (when there are two or more kinds, the total content thereof), relative to the total mass of the pressure-sensitive adhesive layer, it is preferably 1 to 15% by mass, more preferably 1 to 10% by mass, still more preferably 2 to 7% by mass, and particularly preferably 3 to 7% by mass. If the content of the above aliphatic alcohol is less than the above lower limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends not to be sufficiently improved. On the other hand, if it exceeds the above upper limit, the compatibility with the above pressure-sensitive adhesive base and other components tends to decrease.

[0093] (Skin irritation reducing agent)

[0094] Examples of the above skin irritation reducing agent include substances having the effect of reducing the irritation imparted to the skin by drugs and stabilizers, such as cholesterol. The above skin irritation reducing agent may also be a combination of two or more kinds.

[0095] When the pressure-sensitive adhesive layer further contains the above skin irritation reducing agent, as its content (when there are two or more kinds, the total content thereof), from the viewpoint of exerting a sufficient skin irritation reducing effect and sufficiently maintaining the compatibility with the pressure-sensitive adhesive base, relative to the total mass of the pressure-sensitive adhesive layer, it is preferably 0.1 to 7% by mass, more preferably 1 to 7% by mass, still more preferably 3 to 5% by mass.

[0096] (Additive)

[0097] [Adsorbent]

[0098] Examples of the above adsorbent include hygroscopic inorganic and / or organic substances. More specifically, examples include: minerals such as talc, kaolin, and bentonite; silicon compounds such as pyrogenic silica (Aerosil (registered trademark), etc.) and hydrated silica; metal compounds such as zinc oxide and dried aluminum hydroxide gel; weak acids such as lactic acid and acetic acid; sugars such as dextrin; and high molecular polymers such as polyvinylpyrrolidone (non-crosslinked PVP), crosslinked polyvinylpyrrolidone (also referred to as "crosslinked polyvidone", "crosslinked PVP"), aminoalkyl methacrylate copolymer, carboxyvinyl polymer, and butyl methacrylate-methyl methacrylate copolymer. The above adsorbent may be one of them or a combination of two or more kinds. From the viewpoint of more excellent stability over time of rotigotine and / or its pharmaceutically acceptable salt, it is preferred that crosslinked polyvinylpyrrolidone is further contained in the pressure-sensitive adhesive layer.

[0099] When the above-mentioned adsorbent is further contained in the above-mentioned adhesive layer, as its content (in the case of two or more kinds, it is the total content thereof), from the viewpoint of the adhesiveness of the adhesive layer, it is preferably 3 to 25% by mass, more preferably 3 to 15% by mass, relative to the total mass of the adhesive layer.

[0100] Examples of the above-mentioned crosslinked polyvinylpyrrolidone include crosslinked N-vinylpyrrolidone polymers. The above-mentioned N-vinylpyrrolidone polymer may be a homopolymer or a copolymer, and examples thereof include: a homopolymer of N-vinylpyrrolidone, a copolymer of N-vinylpyrrolidone and a polyfunctional monomer. Among them, as the crosslinked polyvinylpyrrolidone of the present invention, a crosslinked homopolymer of 1-vinyl-2-pyrrolidone (also referred to as "crosslinked povidone") is preferred. As crosslinked povidone, commercially available products such as Kollidon CL, Kollidon CL-M (manufactured by BASF Japan Co., Ltd.); Polyplasdone XL, Polyplasdone XL-10, Polyplasdone INF-10 (manufactured by ISP Japan Co., Ltd.) can be used.

[0101] When the above-mentioned crosslinked polyvinylpyrrolidone is further contained in the adhesive layer of the present invention, as its content (in the case of two or more kinds, it is the total content thereof), relative to the total mass of the adhesive layer, it is preferably 3 to 25% by mass, more preferably 3 to 20% by mass, and further preferably 3 to 15% by mass. If the content of the above-mentioned crosslinked polyvinylpyrrolidone is less than the above lower limit, crystallization of rotigotine and / or its pharmaceutically acceptable salt tends to precipitate. On the other hand, if it exceeds the above upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt decreases, or the compatibility in the adhesive layer composition during manufacturing decreases, making it difficult to manufacture.

[0102] In addition, as the content of the crosslinked polyvinylpyrrolidone contained in the above-mentioned adhesive layer, based on the mass ratio of the content of the above-mentioned rotigotine and / or its pharmaceutically acceptable salt in terms of free rotigotine (content of rotigotine free form of rotigotine and / or its pharmaceutically acceptable salt: content of crosslinked polyvinylpyrrolidone), it is preferably 15:3 to 5:25, more preferably 15:3 to 5:20, and further preferably 15:3 to 5:15. If the ratio of the content of crosslinked polyvinylpyrrolidone to the content of rotigotine and / or its pharmaceutically acceptable salt is less than the above lower limit, crystallization of rotigotine tends to occur. On the other hand, if it exceeds the above upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt decreases.

[0103] [Desalting agent]

[0104] The above-mentioned desalting agent is mainly formulated for the purpose of converting all or part of an alkaline drug into a free form. As such a desalting agent, there is no particular limitation. For example, when formulating an acid addition salt of a drug to obtain a preparation containing a free form of the drug as the above-mentioned drug, it is preferably an alkaline substance, more preferably a desalting agent containing metal ions or a desalting agent containing an alkaline nitrogen atom. Examples of the above-mentioned desalting agent containing metal ions include sodium acetate (including anhydrous sodium acetate), sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium citrate, sodium lactate, etc. It can be one of them or a combination of two or more. In addition, as the adhesive layer of the present invention, it may further contain a compound derived from the above-mentioned alkaline drug and the above-mentioned desalting agent (for example, sodium chloride generated when rotigotine hydrochloride is combined with sodium acetate). In the present invention, when the above-mentioned desalting agent and a compound derived from an alkaline drug and a desalting agent are further contained in the above-mentioned adhesive layer, as its content, in the case of two or more, it is preferably 10% by mass or less in total relative to the total mass of the above-mentioned adhesive layer.

[0105] [Plasticizer]

[0106] The above-mentioned plasticizer is mainly formulated for the purpose of adjusting the adhesive physical properties of the above-mentioned adhesive layer, the flow characteristics during the manufacture of the above-mentioned adhesive layer, the transdermal absorption characteristics of the above-mentioned drug, etc. Examples of such a plasticizer include silicone oil; petroleum-based oils such as paraffin-based processing oil, naphthenic-based processing oil, and aromatic-based processing oil; squalane, squalene; vegetable-based oils such as olive oil, camellia oil, castor oil, tall oil, and peanut oil; diesters 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. As the above-mentioned plasticizer, it can be one of them or a combination of two or more, and at least one selected from silicone oil, liquid paraffin, and liquid polybutene is particularly preferred.

[0107] When the above-mentioned plasticizer is further contained in the adhesive layer of the present invention, as its content (in the case of two or more, it is their total content), from the viewpoint of improving the adhesive strength of the adhesive layer and / or alleviating local irritation during peeling, it is preferably 1 to 30% by mass, more preferably 5 to 20% by mass relative to the total mass of the above-mentioned adhesive layer.

[0108] [Solvent, Filler]

[0109] As the above-mentioned solvent, organic acids such as acetic acid, surfactants, etc. can be cited as examples. It can be one of them, or a combination of two or more. In addition, the above-mentioned filler is mainly formulated for the purpose of adjusting the adhesive force of the adhesive layer. As this filler, for example, aluminum hydroxide, calcium carbonate, magnesium carbonate; silicates such as aluminum silicate, magnesium silicate; silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide can be cited. It can be one of them, or a combination of two or more.

[0110] [Preservative]

[0111] As the above-mentioned preservative, for example, p-hydroxybenzoic acid derivatives, benzyl alcohol, phenol, cresol, etc. can be cited as examples. It can be one of them, or a combination of two or more.

[0112] The adhesive layer of the present invention is not particularly limited, and the mass per unit area (the area of the attachment surface) is preferably 20 to 200 g / m 2 , more preferably 30 to 100 g / m 2 , still more preferably 30 to 70 g / m 2 . In addition, the area of the attachment surface of the adhesive layer of the present invention can be appropriately adjusted according to the treatment purpose and the application object, and is not particularly limited. Usually, it is in the range of 0.5 to 200 cm 2 .

[0113] [Method for improving the stability of rotigotine, method for manufacturing a rotigotine-containing patch]

[0114] The method for improving the stability of rotigotine of the present invention is a method for improving the stability of at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine in a rotigotine-containing patch having a support layer and an adhesive layer and the adhesive layer containing at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine and an adhesive base. The method includes a step of further including propyl gallate in the adhesive layer. In addition, since the rotigotine-containing patch of the present invention can be obtained by the method for improving the stability of rotigotine, it can also be regarded as a method for manufacturing a rotigotine-containing patch (hereinafter collectively referred to as the method for improving the stability of rotigotine and the method for manufacturing a rotigotine-containing patch, and simply referred to as "the method of the present invention" as the case may be).

[0115] In the method of the present invention, as a method for further containing propyl gallate in the above-mentioned adhesive layer, there is no particular limitation, and a known method for manufacturing an adhesive can be appropriately adopted. For example, first, propyl gallate is added to rotigotine and / or its pharmaceutically acceptable salt, the above-mentioned adhesive base, and optionally thioglycolic acid and / or its pharmaceutically acceptable salt, the above-mentioned other components, and an appropriate amount of a solvent, and kneaded according to a conventional method to obtain a uniform adhesive layer composition. When using rotigotine free form as the above-mentioned rotigotine and / or its pharmaceutically acceptable salt, it can be its type I crystal, type II crystal, amorphous type, or a mixture of at least two or more of type I crystal, type II crystal, and amorphous type. In addition, as the above-mentioned rotigotine and / or its pharmaceutically acceptable salt, it can be a hydrate, or a substance obtained by dissolving it in the above-mentioned solvent. Examples of the above-mentioned solvent include: absolute ethanol, toluene, heptane, methanol, ethyl acetate, hexane, isopropanol, and a mixed solution of at least two or more of them, etc.

[0116] As the mixing order of each component at this time, that is, rotigotine and / or its pharmaceutically acceptable salt, the above-mentioned adhesive base, propyl gallate, and optionally thioglycolic acid and / or its pharmaceutically acceptable salt, the above-mentioned other components, there is no particular limitation. In addition, as their mixing amounts, it is preferably such that the content of each component in the obtained adhesive layer independently becomes the content of each component described in the above-mentioned rotigotine-containing adhesive of the present invention.

[0117] Subsequently, the above-mentioned adhesive layer composition is spread to obtain the above-mentioned adhesive layer. For example, the above-mentioned adhesive layer composition is spread on the surface (usually one surface) of the above-mentioned support layer until it reaches the required mass per unit area, and then heated as needed to dry and remove the above-mentioned solvent to form an adhesive layer. Furthermore, it is cut into the required shape as needed, whereby the stability of rotigotine can be improved in the obtained rotigotine-containing adhesive, and in addition, the rotigotine-containing adhesive of the present invention can be obtained.

[0118] As the method of the present invention, it can further include a step of attaching the above-mentioned release liner to the surface of the above-mentioned adhesive layer opposite to the above-mentioned support layer. In this case, the above-mentioned adhesive layer composition can be first spread on one surface of the above-mentioned release liner until it reaches the required mass per unit area to form an adhesive layer, and then the above-mentioned support layer is attached to the surface of the above-mentioned adhesive layer opposite to the above-mentioned release liner, and cut into the required shape as needed, whereby the above-mentioned rotigotine-containing adhesive is obtained.

[0119] Furthermore, the obtained adhesive can be sealed in a storage packaging container (such as an aluminum laminated bag) as needed to form a package.

[0120] [Example]

[0121] Hereinafter, the present invention will be described in more detail based on examples and comparative examples, but the present invention is not limited to the following examples. In addition, in each of the examples and comparative examples, the skin permeation test and the stability evaluation are carried out by the methods shown below, respectively.

[0122] <Skin Permeation Test (In Vitro Hairless Mouse Skin Permeation Test)>

[0123] First, the skin of the body part of a hairless mouse is peeled off, and an adhesive patch cut into a square of 1.0 cm 2 and with the release liner removed is attached to the stratum corneum side of the fat-removed skin piece from which fat has been removed to prepare a test sample. The test sample is placed in a dynamic diffusion cell with the dermal side in contact with the receiving solution, and the receiving solution (phosphate buffer saline) is filled in the above cell. Subsequently, while circulating warm circulating water in the peripheral part to keep the receiving solution at 32°C, the receiving solution is fed at a flow rate of about 5 mL / hr, and the receiving solution is collected every 2 hours until 24 hours. The concentration of rotigotine in the collected receiving solution is measured by high performance liquid chromatography, and respectively by the following formula:

[0124] Rotigotine skin permeation amount (μg / cm 2 ) = {Concentration of rotigotine in the receiving solution (μg / mL) × Flow rate (mL)} / Adhesive patch area (cm 2 )

[0125] The rotigotine skin permeation amount per unit area of the adhesive layer is calculated, and the skin permeation amount per 1 hour (skin permeation rate (μg / cm 2 / hr)) is obtained. The measurement is carried out for 2 test samples respectively, and the average value of the maximum values within 24 hours of each skin permeation rate is set as the maximum skin permeation rate (Jmax).

[0126] <Stability Evaluation>

[0127] The adhesive patches obtained in each of the examples and comparative examples are sealed in an aluminum laminated bag to prepare test samples, and they are stored at 60°C for 2 weeks. Regarding the adhesive patches after storage, the generation rate [%] of rotigotine decomposition products is calculated by the method of (1) or (2) below, and is set as the value of the stability evaluation. In addition, according to the methods of (1) and (2) below, equivalent results can be obtained. (1)

[0129] First, remove the release liner from the saved patch, immerse the adhesive layer in 5 mL of tetrahydrofuran and dissolve it, add a dilution solution (a mixed solution of 0.2% phosphate buffer and acetonitrile (50:50 (v:v))) to the resulting solution until the total volume becomes 25 mL and shake it, and filter the obtained solution through a filter to obtain a sample solution. In addition, dissolve rotigotine with a known concentration in the above dilution solution in advance to prepare a standard solution.

[0130] Using the above sample solution, through a high-performance liquid chromatography device (manufactured by Shimadzu Corporation), under the following conditions:

[0131] Column: TSKgel ODS-80TsQA (4.6 mm I.D.×150 mm), 5 μm

[0132] Mobile phase: A mixed solution of 0.2% phosphate buffer containing 10 mM sodium dodecyl sulfate and acetonitrile (50:50 (v:v))

[0133] Detection wavelength: 225 nm

[0134] Column temperature: 40 °C

[0135] Flow rate: 0.7 mL / min

[0136] Obtain chromatograms of 7,8-dihydroxynaphthalene (7,8-DihydroNaphthol) and despropyl rotigotine, which are rotigotine decomposition products, in the sample solution.

[0137] In addition, use the above standard solution, under the same conditions as above, through the above high-performance liquid chromatography device, to obtain a chromatogram of rotigotine in the standard solution. According to the area under the curve of rotigotine in the obtained chromatogram and the areas under the curves of 7,8-dihydroxynaphthalene and despropyl rotigotine in the chromatograms obtained above, calculate the production amounts of 7,8-dihydroxynaphthalene and despropyl rotigotine, respectively. In addition, calculate the theoretical content of rotigotine based on the amount of rotigotine formulated in the adhesive layer, divide the above production amounts by the above theoretical content, and thus calculate the production rates (%) of each rotigotine decomposition product in the adhesive layer of each patch stored at 60 °C for 2 weeks (7,8-dihydroxynaphthalene production rate [%], despropyl rotigotine production rate [%]). In addition, set the peak area that appears near the position of 7.8 minutes as the peak area of 7,8-dihydroxynaphthalene, and set the peak area that appears near the position of 9.7 minutes as the peak area of despropyl rotigotine. (2)

[0139] First, remove the release liner from the saved patch, immerse the adhesive layer in 5 mL of tetrahydrofuran and dissolve it, add 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 to the resulting solution until the total volume becomes 25 mL and shake it. Filter the obtained solution through a filter and use it as a sample solution. In addition, dissolve rotigotine with a known concentration in the above dilution solution in advance to prepare a standard solution.

[0140] Using the above sample solution, with a high-performance liquid chromatography apparatus (manufactured by Shimadzu Corporation), under the following conditions:

[0141] Column: ZORBAX SB-C18 (4.6 mm I.D. × 250 mm), 5 μm

[0142] Mobile phase: Phosphate buffer (pH 5.5) containing 10 mM dipotassium hydrogen phosphate and 0.067% trimethylamine (solution A), acetonitrile (solution B); Solution A:Solution B = 90:10 (0 - 20 minutes) → 20:80 (90 - 100 minutes) → 90:10 (105 - 125 minutes)

[0143] Detection wavelength: 225 nm

[0144] Column temperature: 40 °C

[0145] Flow rate: 1 mL / minute,

[0146] Obtain chromatograms of 7,8 - DihydroNaphthol and Despropyl RTN, which are rotigotine decomposition products, in the sample solution.

[0147] In addition, use the above standard solution, under the same conditions as above, with the above high-performance liquid chromatography apparatus, to obtain a chromatogram of rotigotine in the standard solution. Based on the area under the curve of rotigotine in the obtained chromatogram and the areas under the curves of 7,8 - DihydroNaphthol and Despropyl RTN in the chromatograms obtained above, calculate the production amounts of 7,8 - DihydroNaphthol and Despropyl RTN respectively. In addition, calculate the theoretical content of rotigotine based on the amount of rotigotine formulated in the adhesive layer, divide the above respective production amounts by the above theoretical content, and thereby calculate the production rates (% of 7,8 - DihydroNaphthol production rate, % of Despropyl RTN production rate) of each rotigotine decomposition product in the adhesive layer of each patch stored at 60 °C for 2 weeks. In addition, set the peak area that appears at around 56.8 minutes as the peak area of 7,8 - DihydroNaphthol, and set the peak area that appears at around 44.1 minutes as the peak area of Despropyl RTN.

[0148] (Example 1)

[0149] First, 0.1 part by mass of propyl gallate was added to 9 parts by mass of rotigotine (free cartilage bodies), 11.73 parts by mass of styrene-isoprene-styrene block copolymer, 5.03 parts by mass of polyisobutene, 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. An appropriate amount of solvent (anhydrous ethanol and toluene) was added and mixed to obtain an adhesive layer composition. Subsequently, the obtained 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 so that the mass per unit area became 50 g / m 2 . An adhesive layer was formed in this manner. A support layer (a polyethylene terephthalate film) was laminated on the surface of the obtained adhesive layer opposite to the release liner, and an adhesive patch in which the support layer / adhesive layer / release liner was laminated in sequence was obtained.

[0150] (Examples 2 to 4, Comparative Examples 1 to 5)

[0151] Except that the composition of the adhesive layer composition (composition other than the solvent) was made the composition shown in Table 1 or Table 2 below, each adhesive patch was obtained in the same manner as in Example 1.

[0152] For the adhesive patches obtained in Examples 1 to 4 and Comparative Examples 1 to 5, stability evaluations were respectively carried out (2 weeks after manufacture, 60 °C, method (1) for Comparative Examples 1 to 2, method (2) for Examples 1 to 4 and Comparative Examples 3 to 5). The results of the stability evaluations and the compositions of the adhesive layer compositions (compositions other than the solvent) of the respective examples and comparative examples are respectively shown in Tables 1 and 2. In addition, in each example, through a skin permeation test, it was confirmed that a sufficiently excellent maximum skin permeation rate (Jmax) [μg / cm 2 / hr] was achieved.

[0153] [Table 1]

[0154]

[0155] [Table 2]

[0156]

[0157] From the results shown in Tables 1 to 2, it was found that the adhesive containing propyl gallate in the adhesive layer (for example, Examples 1 to 4) had a sufficiently suppressed production rate of rotigotine decomposition products even after being manufactured under severe conditions of 60°C for 2 weeks, and rotigotine was stabilized at a high level.

[0158] On the other hand, among the adhesives obtained in Comparative Examples 2 to 5, even though they contained components such as sodium metabisulfite that had been previously used as stabilizers for drugs, the production rate of rotigotine decomposition products was higher in at least any one of them compared to the adhesive containing propyl gallate in the adhesive layer. In addition, there were cases where the production rate of rotigotine decomposition products further increased even compared to Comparative Example 1 that did not contain a stabilizer (for example, Comparative Examples 2 and 3).

[0159] Industrial applicability

[0160] As described above, according to the present invention, an adhesive containing rotigotine and / or a pharmaceutically acceptable salt thereof with particularly excellent stability over time, and a method for improving the stability of rotigotine can be provided.

Claims

1. A patch containing rotigotine, which comprises a support layer and an adhesive layer, and the adhesive layer contains at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine, an adhesive base, and propyl gallate.

2. The patch containing rotigotine as claimed in claim 1, wherein, The content of propyl gallate in the adhesive layer is 0.01 to 1% by mass relative to the total mass of the adhesive layer.

3. The patch containing rotigotine according to claim 1 or 2, wherein The adhesive base is at least one selected from rubber-based adhesive bases, acrylic-based adhesive bases, and silicone-based adhesive bases.

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

5. A method for improving the stability of rotigotine which is a method for improving the stability of at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine in a patch containing rotigotine, the patch containing rotigotine comprises a support layer and an adhesive layer, and the adhesive layer contains at least one selected from rotigotine and pharmaceutically acceptable salts of rotigotine and an adhesive base, the method includes a step of further containing propyl gallate in the adhesive layer.

6. The method for improving the stability of rotigotine according to claim 5, wherein, The adhesive layer contains propyl gallate in such a manner that the content is 0.01 to 1% by mass relative to the total mass of the adhesive layer.

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

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

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