Rotigotine-containing adhesive patch

Abstract

This rotigotine-containing adhesive patch comprises 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 rubber-based adhesive base; and an antioxidant. The antioxidant includes propyl gallate, ascorbyl palmitate, and sodium pyrosulfite.

Description

Rotigotine-containing patch

[0001] The present invention relates to a patch containing rotigotine, and more particularly to a patch containing rotigotine and / or a pharmaceutically acceptable salt thereof.

[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 is known to exist in crystalline polymorphs of Form I and Form II. Rotigotine is a D1 / D2 / D3 dopamine receptor agonist and is primarily used to treat symptoms of Parkinson's disease and restless legs syndrome. As a preparation for administering rotigotine, for example, the adhesive patch "Neupro (registered trademark) Patch" is commercially available both in Japan and overseas.

[0003] In patches containing rotigotine and / or a pharmaceutically acceptable salt thereof, stability of the active ingredient rotigotine is required, as with other preparations. For example, Japanese Patent Application Laid-Open No. 2014-177428 (Patent Document 1) describes a transdermal patch comprising a support, a drug-containing layer, and a release liner, in which 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, for the purpose of suppressing the precipitation of crystalline components derived from rotigotine.

[0004] Furthermore, for example, Japanese Patent Application Laid-Open No. 2013-079220 (Patent Document 2) describes a rotigotine-containing transdermal patch comprising a support, a drug-containing layer, and a release liner, in which the drug-containing layer contains a rubber-based adhesive, rotigotine or a salt thereof, and an inhibitor for the formation of rotigotine degradation products, with the aim of suppressing the formation of rotigotine degradation products, and lists mercaptobenzimidazole and sulfite as the inhibitor for the formation of rotigotine degradation products.

[0005] Furthermore, for example, Japanese Patent Application Laid-Open No. 2018-118927 (Patent Document 3) describes that, for the purpose of suppressing the decomposition of rotigotine by light, in a transdermal patch comprising a support, a drug-containing adhesive layer, and a release liner, the support is an aluminum-free support with a specific light transmittance, and the drug-containing adhesive layer further contains an antioxidant, and examples of the antioxidant include sulfites and ascorbic acid.

[0006] Furthermore, for example, International Publication No. 2024 / 116965 (Patent Document 4) describes a rotigotine-containing patch comprising a support layer and an adhesive layer, the adhesive layer containing rotigotine and / or a pharmaceutically acceptable salt of rotigotine and an adhesive base, in which the adhesive layer further contains propyl gallate, thereby improving the stability of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine.

[0007] JP 2014-177428 A JP 2013-079220 A JP 2018-118927 A WO 2024 / 116965

[0008] However, while it is desirable that the active ingredient, rotigotine and / or a pharmaceutically acceptable salt thereof, be contained in a rotigotine-containing patch as stably as possible, further studies by the present inventors have revealed that, depending on the storage conditions, for example, harsh storage conditions such as high temperatures, rotigotine and / or a pharmaceutically acceptable salt thereof may be decomposed to produce decomposition products (rotigotine degradation products). Therefore, the present inventors have found that there is room for further improvement in the stability of rotigotine and / or a pharmaceutically acceptable salt thereof in a rotigotine-containing patch, and that a higher level of stability over time than that of the prior art is required.

[0009] The present invention has been made in view of the above problems, and aims to provide a rotigotine-containing patch in which rotigotine and / or a pharmaceutically acceptable salt thereof have particularly excellent stability over time.

[0010] As a result of intensive research into achieving the above-mentioned object, the present inventors have found that in a rotigotine-containing patch comprising a support layer and an adhesive layer, the adhesive layer containing at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts thereof (rotigotine and / or a pharmaceutically acceptable salt thereof), and an adhesive base, by using a rubber-based adhesive base and further containing a combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite as antioxidants in the adhesive layer, the generation of rotigotine degradation products can be suppressed to an even higher level than in conventional techniques even when stored under harsh conditions, and a rotigotine-containing patch with particularly excellent stability of rotigotine and / or a pharmaceutically acceptable salt thereof over time can be obtained. Furthermore, the present inventors discovered that this stability over time is particularly superior to when only two of the three antioxidants are combined, or when one of the three antioxidants is replaced with another antioxidant, and that this effect is specifically achieved when these three antioxidants, propyl gallate, ascorbyl palmitate, and sodium metabisulfite, are combined, leading to the completion of the present invention. The aspects of the present invention obtained based on these findings are as follows.

[0011] [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 rubber-based adhesive base, and an antioxidant, wherein the antioxidant includes propyl gallate, ascorbyl palmitate, and sodium pyrosulfite.

[0012] [2] The rotigotine-containing patch according to [1], wherein the total content of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer is 0.02 to 3.0% by mass relative to the total mass of the adhesive layer.

[0013] [3] The rotigotine-containing patch according to [1] or [2], wherein the content of propyl gallate in the adhesive layer is 0.01 to 1.4% by mass relative to the total mass of the adhesive layer.

[0014] [4] The rotigotine-containing patch according to any one of [1] to [3], wherein the content of ascorbyl palmitate in the adhesive layer is 0.005 to 0.55% by mass relative to the total mass of the adhesive layer.

[0015] [5] The rotigotine-containing patch according to any one of [1] to [4], wherein the content of sodium pyrosulfite in the adhesive layer is 0.007 to 1.0% by mass relative to the total mass of the adhesive layer.

[0016] [6] The rotigotine-containing patch according to any one of [1] to [5], wherein the content ratio of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer (propyl gallate content: ascorbyl palmitate content: sodium pyrosulfite content) is 1:0.003-55:0.005-100, in mass ratio.

[0017] [7] The rotigotine-containing patch according to any one of [1] to [6], 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, calculated as rotigotine free form, relative to the total mass of the adhesive layer.

[0018] [8] 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 a support layer and an adhesive layer, the adhesive layer containing at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine and a rubber-based adhesive base, the method comprising the step of further incorporating an antioxidant into the adhesive layer, wherein the antioxidant comprises propyl gallate, ascorbyl palmitate, and sodium pyrosulfite.

[0019] [9] The method for improving rotigotine stability according to [8], wherein the antioxidant is contained in the adhesive layer so that the total content of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer is 0.02 to 3.0% by mass relative to the total mass of the adhesive layer.

[0020]

[10] The method for improving rotigotine stability according to [8] or [9], wherein the adhesive layer contains propyl gallate so that the content of propyl gallate in the adhesive layer is 0.01 to 1.4 mass% relative to the total mass of the adhesive layer.

[0021]

[11] The method for improving rotigotine stability according to any one of [8] to

[10] , wherein ascorbyl palmitate is incorporated into the adhesive layer so that the content of ascorbyl palmitate in the adhesive layer is 0.005 to 0.55% by mass relative to the total mass of the adhesive layer.

[0022]

[12] The method for improving rotigotine stability according to any one of [8] to

[11] , wherein sodium pyrosulfite is incorporated into the adhesive layer so that the content of sodium pyrosulfite in the adhesive layer is 0.007 to 1.0 mass% relative to the total mass of the adhesive layer.

[0023]

[13] The method for improving the stability of rotigotine according to any one of [8] to

[12] , wherein the antioxidants are contained in the adhesive layer so that the content ratio of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer (propyl gallate content: ascorbyl palmitate content: sodium pyrosulfite content) is 1:0.003-55:0.005-100, in mass ratio.

[0024]

[14] The method for improving rotigotine stability according to any one of [8] to

[13] , 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 mass% based on the total mass of the adhesive layer, calculated as rotigotine free form.

[0025] According to the present invention, it is possible to provide a rotigotine-containing patch in which the stability of rotigotine and / or a pharmaceutically acceptable salt thereof over time is particularly excellent.

[0026] The present invention will be described in detail below based on preferred embodiments thereof.

[0027] [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, a rubber-based adhesive base, and an antioxidant.

[0028] 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 employed. 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, polyesters are preferred, and polyethylene terephthalate is more preferred, from the viewpoint of drug non-adsorption and drug impermeability. Examples of the form of the support layer include films; sheets, such as sheets, porous sheets, and foam sheets; fabrics such as woven fabrics, knitted fabrics, and nonwoven fabrics; paper; foil; 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 of the patch and ease of production.

[0029] The rotigotine-containing patch of the present invention may further comprise a release liner on the surface of the adhesive layer opposite to the support layer. Examples of materials for such release liners include polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; synthetic resins such as polyurethane; and metals such as aluminum. Examples of the release liner include films, sheets, and papers made of the above materials, as well as laminates thereof. It is preferable that such release liners have been subjected to a release treatment, such as a coating containing a silicone compound or a coating containing a fluorine compound, on the surface that comes into contact with the adhesive layer to allow for easy release from the adhesive layer.

[0030] <Rotigotine and a pharmaceutically acceptable salt thereof> The adhesive layer according to the present invention contains at least one drug selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine (sometimes referred to as "rotigotine and / or a pharmaceutically acceptable salt thereof" in this specification). The form of rotigotine contained in the adhesive layer according to the present invention may be a free form or a pharmaceutically acceptable salt thereof, or may be a free form obtained by desalting a pharmaceutically acceptable salt of rotigotine during production and / or in a produced formulation, or may be one of these or a mixture of two or more of them. Pharmaceutically acceptable salts of rotigotine include acid addition salts, and examples of the acids in 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 sulfuric acid, linolenic acid, and fumaric acid. The acid addition salt may be one or more of these acid addition salts. Among these, the adhesive layer according to the present invention preferably contains rotigotine in the form of a free form.

[0031] In the rotigotine-containing patch of 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 14% by mass, even more preferably 7 to 12% by mass, and even more preferably 8 to 10% 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 it exceeds the upper limit, rotigotine crystals tend to precipitate more easily and the adhesive strength of the adhesive layer tends to decrease.

[0032] The rotigotine-containing adhesive 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 degradation products) in the adhesive layer. Examples of such decomposition products include, but are not limited to, 7,8-dihydronaphthol, despropyl form (depropyl rotigotine, Despropyl RTN), and substances with a relative retention time (RRT) of around 0.42 (RRT 0.42) and around 0.50 (RRT 0.50) relative to the retention time of rotigotine contained in the adhesive layer in a chromatogram obtained by performing high performance liquid chromatography under the conditions described in <Stability Evaluation> in the Examples below.

[0033] The adhesive layer according to the present invention contains a rubber-based adhesive base as the adhesive base. Examples of the rubber-based adhesive base include styrene-based thermoplastic elastomers, polyisobutylene, natural rubber, alkyl vinyl ether (co)polymers, polyisoprene, and polybutadiene. These may be used alone or in combination of two or more.

[0034] Among these, it is particularly preferable that the rubber-based adhesive base according to the present invention contains a styrene-based thermoplastic elastomer. The styrene-based thermoplastic elastomer is a thermoplastic styrene-based elastomer that softens and becomes fluid when heated and returns to a rubber-like elastic body when cooled. Among these, a styrene-based block copolymer is preferred from the viewpoints of providing sufficient adhesiveness and providing superior stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof.

[0035] 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, and these may be used alone or in combination of two or more. 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. Of these, a styrene-isoprene-styrene block copolymer is more preferred as the styrene-based thermoplastic elastomer according to the present invention.

[0036] 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, whereas if it exceeds the upper limit, the compatibility with other components contained in the adhesive layer tends to decrease, making it difficult to produce the patch.

[0037] The styrene-isoprene-styrene block copolymer is not particularly limited, and commercially available products such as Quintac (registered trademark) 3570C (trade name, manufactured by Zeon Corporation), SIS5002, SIS5229, SIS5505, SIS5505P (trade name, manufactured by JSR Corporation), and SIBSTAR (registered trademark) T102 (trade name, manufactured by Kaneka Corporation) can be used as appropriate.

[0038] Furthermore, from the viewpoint that the adhesiveness and cohesive strength of the adhesive layer tend to be further improved, the rubber-based adhesive base according to the present invention 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).

[0039] The polyisobutylene also includes so-called butyl rubber (isobutylene-isoprene rubber). Specific examples of the polyisobutylene include Oppanol (registered trademark) N50, N80, N100, N150, B11, B12, B50, B80, B100, B120, B150, and B220 (trade names, manufactured by BASF), JSR (registered trademark) Butyl 065, 268, and 365 (trade names, manufactured by JSR Corporation), X_Butyl (registered trademark) RB 100, 101-3, 301, and 402 (trade names, manufactured by ARLANXEO), and Exxon (registered trademark) Butyl 065, 065S, 068, 068S, 268, 268S, 365, and 365S (trade names, manufactured by Exxon and Butyl 065, 268, and 365 (trade names, manufactured by Japan Butyl Co., Ltd.).

[0040] In the present invention, the content of the rubber-based adhesive base contained in the adhesive layer (when two or more types are combined, the total content thereof; the same applies hereinafter) is preferably 1 to 60 mass %, more preferably 5 to 50 mass %, even more preferably 10 to 40 mass %, and even more preferably 10 to 30 mass %, relative to the total mass of the adhesive layer.

[0041]

[0023] In the present invention, when the styrene-based thermoplastic elastomer is contained as the adhesive base in the pressure-sensitive adhesive layer, the content thereof (when two or more types of styrene-based thermoplastic elastomers are used in combination, the total content of these elastomers; the same applies hereinafter) is preferably 1 to 50 mass%, more preferably 5 to 40 mass%, even more preferably 5 to 30 mass%, and even more preferably 5 to 20 mass%, relative to the total mass of the pressure-sensitive adhesive layer. If the content of the styrene-based thermoplastic elastomer is less than 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.

[0042] The adhesive layer according to the present invention may further contain at least one other adhesive base selected from the group consisting of acrylic adhesives and silicone adhesives, as long as the effects of the present invention are not impaired. Examples of the acrylic adhesive include those listed as adhesives in the "Dictionary of Pharmaceutical Additives 2016 (edited by the Japan Pharmaceutical Additives Association)." These may be used alone or in combination of two or more. Examples of the silicone adhesive include silicone rubbers such as MQ (polydimethylsiloxane), VMQ (polymethylvinylsiloxane), PMQ (polymethylphenylsiloxane), and PVMQ (polyphenylvinylmethylsiloxane) in the ASTM standard (ASTM D 1418), as well as mixtures of at least one of these with a silicone resin other than silicone rubber, such as polyditrimethylsilylsiloxane. These may be used alone or in combination of two or more.

[0043] However, in the pressure-sensitive adhesive layer according to the present invention, it is preferable that the pressure-sensitive adhesive layer does not contain any other pressure-sensitive adhesive base other than the rubber-based pressure-sensitive adhesive base, and the content of the other pressure-sensitive adhesive base (the total content if there are two or more types) is preferably 40 mass % or less, more preferably 30 mass % or less, and even more preferably 20 mass % or less (e.g., 0 to 20 mass %, 0 to 10 mass %) relative to the total mass of the pressure-sensitive adhesive layer.

[0044] <Antioxidants> The adhesive layer of the rotigotine-containing patch may contain one or more antioxidants, but in the rotigotine-containing patch of the present invention, the adhesive layer particularly contains a combination of at least propyl gallate, ascorbyl palmitate, and sodium pyrosulfite.

[0045] The content of propyl gallate contained in the adhesive layer according to the present invention is preferably 0.01 to 1.4% by mass, more preferably 0.02 to 1.0% by mass, even more preferably 0.04 to 0.8% by mass, and even more preferably 0.06 to 0.6% by 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, whereas if the content exceeds the upper limit, the stability over time tends to decrease, and the cohesive strength and adhesive strength of the adhesive layer tend to decrease.

[0046] Furthermore, the content of propyl gallate contained in the adhesive layer is preferably 0.001 to 0.28 parts by mass, and more preferably 0.003 to 0.2 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 effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof tends to be particularly pronounced.

[0047] The content of ascorbyl palmitate contained in the adhesive layer according to the present invention is preferably 0.005 to 0.55% by mass, more preferably 0.01 to 0.5% by mass, even more preferably 0.015 to 0.4% by mass, and even more preferably 0.02 to 0.3% by mass, relative to the total mass of the adhesive layer. If the content of ascorbyl palmitate 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, whereas if the content exceeds the upper limit, the stability over time tends to decrease, and the cohesive strength and adhesive strength of the adhesive layer tend to decrease.

[0048] Furthermore, the content of ascorbyl palmitate contained in the adhesive layer is preferably 0.0005 to 0.1 part by mass, and more preferably 0.002 to 0.05 part 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 ascorbyl palmitate to the content of rotigotine and / or a pharmaceutically acceptable salt thereof is within the above range, the effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof tends to be particularly pronounced.

[0049] The content of sodium pyrosulfite contained in the adhesive layer according to the present invention is preferably 0.007 to 1.0% by mass, more preferably 0.01 to 0.8% by mass, even more preferably 0.02 to 0.5% by mass, and even more preferably 0.03 to 0.4% by mass, relative to the total mass of the adhesive layer. If the content of sodium pyrosulfite 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, whereas if the content exceeds the upper limit, the stability over time tends to decrease, and the cohesive strength and adhesive strength of the adhesive layer tend to decrease.

[0050] Furthermore, the content of sodium pyrosulfite contained in the adhesive layer is preferably 0.0007 to 0.2 parts by mass, and more preferably 0.003 to 0.08 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 sodium pyrosulfite to the content of rotigotine and / or a pharmaceutically acceptable salt thereof is within the above range, the effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof tends to be particularly pronounced.

[0051] Furthermore, the content ratio of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite (propyl gallate content: ascorbyl palmitate content: sodium pyrosulfite content) contained in the adhesive layer according to the present invention is preferably 1:0.003-55:0.005-100 by mass, more preferably 1:0.01-25:0.01-40, even more preferably 1:0.018-10:0.025-12.5, even more preferably 1:0.033-5:0.05-6.7, and particularly preferably 1:0.1-1.5:0.2-1.8, or 1:0.15-1:0.3-1.5. When the content ratio is within the above range, the effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof tends to be particularly pronounced.

[0052] The present inventors have found that the combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite according to the present invention exhibits extremely high level of stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof at a content of at least these compounds. As for such a content, the total content of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer is preferably 3.0% by mass or less, more preferably 0.02 to 3.0% by mass, even more preferably 0.022 to 2.95% by mass, even more preferably 0.04 to 2.9% by mass, even more preferably 0.1 to 2.9% by mass, and particularly preferably 0.1 to 1.5% by mass, relative to the total mass of the adhesive layer. If the total content is less than the lower limit, the effect of improving the stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof tends to be insufficient, whereas if the total content exceeds the upper limit, the stability over time tends to decrease, and the cohesive strength and adhesive strength of the adhesive layer tend to decrease.

[0053] The adhesive layer according to the present invention may further contain, as an antioxidant, an antioxidant other than the above-mentioned propyl gallate, ascorbyl palmitate, and sodium pyrosulfite, within a range that does not impair the effects of the present invention. Examples of such other antioxidants include ascorbic acid or metal salts or esters thereof (excluding ascorbyl palmitate), isoascorbic acid or metal salts thereof, ethylenediaminetetraacetic acid or metal salts thereof, 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, thioglycolic acid and / or pharmaceutically acceptable salts thereof (e.g., sodium thioglycolate), rutin, dihydroxybenzoic acid, potassium dichloroisocyanurate, quercetin, hydroquinone, metal hydroxymethanesulfinates, sodium bisulfite, and the like, and these may be used alone or in combination of two or more. In the above, examples of the metal salt include sodium salt, potassium salt, calcium salt, magnesium salt, and calcium disodium salt. Examples of esters include stearic acid esters and myristate esters.

[0054] However, in the adhesive layer according to the present invention, it is preferable that the adhesive layer does not contain the other antioxidants described above, in cases where the effect of the combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite to stabilize 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 of the other antioxidants (the total content if there are two or more types) is preferably 1% by mass or less, more preferably 0.1% by mass or less, and even more preferably 0.01% by mass or less (for example, 0 to 0.01% by mass) relative to the total mass of the adhesive layer.

[0055] <Other Components> The adhesive layer according to the present invention may further contain additives such as other drugs than rotigotine and pharmaceutically acceptable salts thereof; tackifiers; absorption enhancers; skin irritation reducers; adsorbents, demineralizing agents, plasticizers, solubilizers, fillers, and preservatives, within the scope that does not impair the effects of the present invention.

[0056] (Other Drugs) Examples of other drugs other than rotigotine and its pharmaceutically acceptable salts include nonsteroidal anti-inflammatory analgesics (diclofenac, indomethacin, ketoprofen, felbinac, loxoprofen, ibuprofen, flurbiprofen, tiaprofen, acemetacin, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, loxoprofen, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, roxanediol, roxanediol, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycol salicylate, valdecoxib, celecoxib ... sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, sulindac, sulindac, sulindac, sulindac, sulindac, sulindac, sulindac, sulindac, sulindac, ecoxib, amfenac, etc.), antipyretics and analgesics (acetaminophen, etc.), antihistamines (diphenhydramine, chlorpheniramine, mequitazine, homochlorcyclizine, etc.), antihypertensives (diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril, etc.), antiparkinsonian drugs (pelgolide, ropinirole, bromocriptine, selegiline, etc.), bronchodilators (tulobuterol, isoproterenol, salbutamol, etc.), antiallergics (keto thifen, loratadine, azelastine, terfenadine, cetirizine, azazanolast, etc.), local anesthetics (lidocaine, dibucaine, etc.), neuropathic pain medications (pregabalin, etc.), non-narcotic analgesics (buprenorphine, tramadol, pentazocine, etc.), anesthetic analgesics (morphine, oxycodone, fentanyl, etc.), urinary tract agents (oxybutynin, tamsulosin, etc.), psychotropic agents (promazine, chlorpromazine, etc.), antidepressants (sertraline, fluoxetine, paroxetine, etc.) anti-inflammatory drugs (e.g., steroids, steroids, anti-inflammatory drugs), anti-inflammatory drugs (e.g. ...

[0057] When the adhesive layer of the present invention further contains the other drug, the content thereof (when there are two or more kinds, the total content thereof) is preferably 10 mass % or less relative to the total mass of the adhesive layer.

[0058] (Tackifier) ​​The tackifier is blended mainly for the purpose of increasing the adhesiveness of the adhesive base (particularly the 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 it is preferable that a petroleum-based resin is further contained.

[0059] When the pressure-sensitive adhesive layer further contains the tackifier, the content thereof (the total content thereof when 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 pressure-sensitive adhesive layer, from the viewpoint of improving the adhesive strength of the pressure-sensitive adhesive layer and / or mitigating local irritation during peeling.

[0060] Examples of the petroleum-based 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, methylindene, and α-methylstyrene, etc.), and dicyclopentadiene synthetic petroleum resins (copolymers mainly composed of dicyclopentadiene and isoprene and / or 1,3-pentadiene). From the viewpoint of another classification, 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 specific examples include Arcon P-70, Arcon P-85, Arcon P-90, Arcon P-100, Arcon P-115, Arcon P-125, Arcon M-90, Arcon M-100, Arcon M-115, and Arcon M-135 (all trade names, manufactured by Arakawa Chemical Industries, Ltd.), and Escolez 8000 (trade name, manufactured by Esso Petrochemical Corporation). The petroleum resin according to the present invention may be one of these or a combination of two or more of these. Among these, alicyclic saturated hydrocarbon resins are more preferred from the viewpoints of easily achieving favorable adhesion to the skin, providing a good feel in use due to little odor, and further suppressing the generation of rotigotine degradation products.

[0061] 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, even more preferably 1,000 to 1,600, even more preferably 1,000 to 1,500, and particularly preferably 1,200 to 1,400. The alicyclic saturated hydrocarbon resin preferably has a softening point (as measured by ASTM E28-67 (Standard Method of Test For Softening Point By Ring-And-Ball Apparatus)) of 65 to 145°C, more preferably 85 to 130°C, even more preferably 85 to 120°C, even more preferably 85 to 105°C, and particularly preferably 95 to 105°C. The alicyclic saturated hydrocarbon resin preferably has a glass transition temperature (as measured by a differential scanning calorimeter (DSC)) of 30 to 90°C, more preferably 40 to 85°C, even more preferably 40 to 80°C, even more preferably 40 to 65°C, and particularly preferably 55 to 65°C. The alicyclic saturated hydrocarbon resins used in the following examples satisfy the most preferable conditions for the weight average molecular weight, softening point, and glass transition temperature described above.

[0062] When the pressure-sensitive 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% by mass, more preferably 10 to 70% by mass, even more preferably 10 to 60% by mass, and particularly preferably 20 to 60% by mass, relative to the total mass of the pressure-sensitive 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 pressure-sensitive 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 pressure-sensitive adhesive layer tend to decrease.

[0063] (Absorption Enhancer) Examples of the absorption enhancer include those having a transdermal absorption enhancing effect (skin permeation enhancing effect) of a drug, 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 thereof, 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.

[0064] When the absorption enhancer is further contained in the adhesive layer, the content thereof (the total content of two or more types of absorption enhancers) 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.

[0065] The aliphatic alcohol refers to a saturated or unsaturated, linear or branched, monohydric or dihydric or higher aliphatic alcohol, and the aliphatic alcohol according to the present invention is preferably a monohydric alcohol. The number of carbon atoms in the aliphatic alcohol is preferably 3 to 23, more preferably 12 to 23, and even more preferably 12 to 20. If the number of carbon atoms in the aliphatic alcohol is less than the lower limit, the boiling point will be low, making it difficult to maintain a constant content in the formulation, and the stability of the aliphatic alcohol over time will tend to decrease. On the other hand, if the number of carbon atoms in the aliphatic alcohol exceeds the upper limit, the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof will tend to decrease.

[0066] 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 hexyldecanol. The aliphatic alcohol may be one of these or a combination of two or more thereof, but from the viewpoints of the stability over time and compatibility of the aliphatic alcohol, as well as the tendency to particularly improve the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof, at least one selected from the group consisting of octyldodecanol and lauryl alcohol is preferred.

[0067] When the adhesive layer according to the present invention further contains the aliphatic alcohol, the content thereof (the total content when two or more types are contained) 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, relative to the total mass of the adhesive layer. If the content of the aliphatic alcohol is below the lower limit, the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof tends not to be sufficiently improved, whereas if it exceeds the upper limit, the compatibility with the adhesive base and other ingredients tends to be reduced.

[0068] (Skin Irritation Reducer) Examples of the skin irritation reducer include those having an effect of reducing irritation caused by drugs or antioxidants to the skin, such as cholesterol, cholesterol derivatives, cholesterol analogs, diflucortolone valerate, clobetasol propionate, amcinonide, mometasone furoate, fluocinonide, dexamethasone propionate, beclomethasone propionate, fluocinolone acetonide, etc. The skin irritation reducer may be one of these or a combination of two or more of them.

[0069] When the skin irritation reducing agent is further contained in the adhesive layer, the content thereof (the total content thereof when there are two or more types) is preferably 0.1 to 7 mass %, more preferably 1 to 7 mass %, and even more preferably 3 to 5 mass %, relative to the total mass of the adhesive layer, from the viewpoint of achieving a sufficient skin irritation reducing effect and maintaining sufficient compatibility with the adhesive base.

[0070] (Additives) [Adsorbent] Examples of the adsorbent include inorganic and / or organic substances having hygroscopic properties, more specifically, minerals such as talc, kaolin, bentonite, etc.; silicon compounds such as fumed 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 weight polymers such as polyvinylpyrrolidone (also referred to as "povidone" or "non-crosslinked PVP"), crosslinked polyvinylpyrrolidone (also referred to as "crospovidone" or "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 thereof. However, from the viewpoint of better stability over time of rotigotine and / or a pharmaceutically acceptable salt thereof, it is preferable that the adhesive layer further contains crosslinked polyvinylpyrrolidone.

[0071] When the adsorbent is further contained in the pressure-sensitive adhesive layer, the content thereof (when two or more types are contained, the total content thereof) is preferably 3 to 25 mass %, and more preferably 3 to 15 mass %, relative to the total mass of the pressure-sensitive adhesive layer, from the viewpoint of the adhesiveness of the pressure-sensitive adhesive layer.

[0072] The crosslinked polyvinylpyrrolidone may be a crosslinked N-vinylpyrrolidone polymer. The N-vinylpyrrolidone polymer may be a homopolymer or a copolymer, and examples thereof include a homopolymer of N-vinylpyrrolidone and 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 as appropriate.

[0073] 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 it 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.

[0074] Furthermore, the content of crosslinked polyvinylpyrrolidone contained in the adhesive layer is preferably in a mass ratio to the content of rotigotine and / or a pharmaceutically acceptable salt thereof, calculated as the free form of rotigotine (content of rotigotine and / or a pharmaceutically acceptable salt thereof, calculated as the free form of rotigotine:content of crosslinked polyvinylpyrrolidone) of 15:3 to 5:25, more preferably 15:3 to 5:20, and even more preferably 15:3 to 5:15. If the ratio of the content of crosslinked polyvinylpyrrolidone to the content of rotigotine and / or a pharmaceutically acceptable salt thereof is less than the lower limit, crystalline rotigotine tends to precipitate, whereas if it exceeds the upper limit, the skin permeability of rotigotine and / or a pharmaceutically acceptable salt thereof tends to decrease.

[0075] [Desalting Agent] The desalting agent is incorporated primarily for the purpose of converting all or part of a basic drug into a free form. Such a desalting agent is not particularly limited. For example, when an acid addition salt of a drug is incorporated as the drug to obtain a formulation containing the drug in a free form, 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 metal ion-containing desalting agents include sodium acetate (including anhydrous sodium acetate), sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium citrate, and sodium lactate, and these may be used alone or in combination of two or more. The adhesive layer according to the present invention may further contain a compound derived from the basic drug and the desalting agent (e.g., sodium chloride produced when rotigotine hydrochloride is combined with sodium acetate). In the present invention, when these desalting agents, as well as compounds derived from basic drugs and desalting agents, are further contained in the adhesive layer, the total content thereof, when two or more types are contained, is preferably 10 mass% or less relative to the total mass of the adhesive layer.

[0076] [Plasticizer] The plasticizer is blended mainly for the purpose of adjusting the adhesive properties of the pressure-sensitive adhesive layer, the flow characteristics during the production of the pressure-sensitive adhesive layer, the transdermal absorption characteristics of the drug, etc. Examples of such plasticizers include silicone oil; petroleum oils such as paraffinic process oil (liquid paraffin, etc.), 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, and dipropylene glycol. The plasticizer may be one of these or a combination of two or more thereof, but is particularly preferably at least one selected from the group consisting of silicone oil, liquid paraffin, and liquid polybutene.

[0077] When the pressure-sensitive adhesive layer according to the present invention further contains the plasticizer, the content thereof (the total content thereof when two or more types are used) is preferably 1 to 30 mass %, and more preferably 5 to 20 mass %, relative to the total mass of the pressure-sensitive adhesive layer, from the viewpoint of improving the adhesive strength of the pressure-sensitive adhesive layer and / or mitigating local irritation during peeling.

[0078] [Solubilizer / Filler] Examples of the solubilizer include organic acids such as acetic acid and surfactants, and these may be used alone or in combination of two or more. The filler is blended mainly for the purpose of adjusting the adhesive strength of the pressure-sensitive adhesive layer, and 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, and titanium oxide, and these may be used alone or in combination of two or more.

[0079] [Preservatives] Examples of the preservatives include parahydroxybenzoic acid derivatives, benzyl alcohol, phenol, cresol, etc., and these may be used alone or in combination of two or more.

[0080] The pressure-sensitive adhesive layer according to the present invention is not particularly limited, but preferably has a mass per unit area (area of ​​the adhesive surface) of 20 to 200 g / m ２ It is preferable that the density is 30 to 100 g / m ２ More preferably, it is 30 to 70 g / m ２ The area of ​​the adhesive surface of the adhesive layer according to the present invention can be adjusted appropriately depending on the purpose of treatment and the target of application, and is not particularly limited, but is usually 0.5 to 200 cm ２ The range is.

[0081] [Method for Improving Rotigotine Stability, Method for Producing a Rotigotine-Containing Patch] The present invention provides a method for improving the stability of a rotigotine and / or a pharmaceutically acceptable salt of rotigotine in a rotigotine-containing patch comprising a support layer and an adhesive layer, the adhesive layer containing a pharmaceutically acceptable salt of rotigotine and / or a rubber-based adhesive base, the method comprising the step of further incorporating an antioxidant into the adhesive layer, the antioxidant comprising propyl gallate, ascorbyl palmitate, and sodium pyrosulfite. Furthermore, the rotigotine-containing patch of the present invention can also be obtained by this method for improving rotigotine stability, and this can also be used as a method for producing a rotigotine-containing patch (hereinafter, the method for improving rotigotine stability and the method for producing a rotigotine-containing patch will be collectively referred to as the "method of the present invention" in some cases).

[0082] In the method of the present invention, the method for further incorporating antioxidants including propyl gallate, ascorbyl palmitate, and sodium pyrosulfite into the adhesive layer containing rotigotine and / or a pharmaceutically acceptable salt of rotigotine and the rubber adhesive base is not particularly limited, and any known method for manufacturing adhesive patches can be appropriately adopted. For example, first, propyl gallate, ascorbyl palmitate, and sodium pyrosulfite are added to rotigotine and / or a pharmaceutically acceptable salt thereof, the rubber adhesive base, and, if necessary, the other adhesive bases, other antioxidants, the other components, and an appropriate amount of solvent, and the mixture is kneaded in a conventional manner to obtain a uniform adhesive layer composition.

[0083] When the free form of rotigotine is used as the rotigotine and / or pharmaceutically acceptable salt thereof, it may be in the form of Type I crystal, Type II crystal, or amorphous form, or may be a mixture of at least two of Type I crystal, Type II crystal, and amorphous form. Furthermore, the rotigotine and / or pharmaceutically acceptable salt thereof may be a hydrate, or may be dissolved in the solvent. Examples of the solvent include absolute ethanol, toluene, heptane, methanol, ethyl acetate, hexane, isopropanol, and mixtures of at least two of these.

[0084] In this case, the order of blending the components, i.e., rotigotine and / or a pharmaceutically acceptable salt thereof, the rubber-based adhesive base, propyl gallate, ascorbyl palmitate, and sodium pyrosulfite, as well as the other adhesive bases, other antioxidants, and other components and solvents as necessary, is not particularly limited. Furthermore, the blending amount of each of these components is preferably such that the content of each component in the resulting adhesive layer is the respective content described above for the rotigotine-containing patch of the present invention. That is, in the method of the present invention, the "total mass of the adhesive layer" in this specification refers to the total mass of the adhesive layer in a patch that has been subjected to the method for improving rotigotine stability or a patch produced by the method for producing a rotigotine-containing patch, i.e., the adhesive layer that also contains the combination of the three antioxidants according to the present invention.

[0085] Next, the adhesive layer composition is spread to obtain the adhesive layer. For example, the adhesive layer composition is spread on the surface of the support layer (usually on one surface) to a desired mass per unit area, and then heated as necessary to dry and remove the solvent to form an adhesive layer, which is then cut into a desired shape as necessary, thereby improving the stability of rotigotine and / or a pharmaceutically acceptable salt of rotigotine in the obtained rotigotine-containing patch, and also allowing the rotigotine-containing patch of the present invention to be obtained.

[0086] The method of the present invention may further include a step of laminating the release liner on the surface of the adhesive layer opposite the support layer, in which case the adhesive layer composition may first be spread on one surface of the release liner to a desired mass per unit area to form an adhesive layer, and then the support layer may be laminated on the surface of the adhesive layer opposite the release liner, and the rotigotine-containing patch may be obtained by cutting into a desired shape as necessary.

[0087] Furthermore, the obtained patch may be sealed in a storage packaging container (for example, an aluminum laminate bag) to form a package, if necessary.

[0088] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples. In each example and comparative example, a skin permeation test and a stability evaluation were carried out by the following methods.

[0089] <Skin Permeation Test (In Vitro Hairless Mouse Skin Permeation Test)> First, the skin of the trunk of a hairless mouse was peeled off, and fat was removed. A 1.0 cm sample was placed on the stratum corneum side of the fat-removed skin piece. ２The patch was cut into squares of 0.01 mm and the release liner was removed, and the patch was applied to prepare a test sample. This was placed in a flow-through diffusion cell so that the dermis side was in contact with the receptor solution, and the cell was filled with receptor solution (phosphate buffered saline). Next, the receptor solution was delivered at a flow rate of approximately 5 mL / hr while circulating heated circulating water around the periphery so that the receptor solution was kept at 32°C, and the receptor solution was collected every 2 hours for up to 24 hours. The rotigotine concentration in the collected receptor solution was measured by high performance liquid chromatography, and calculated using the following formula: rotigotine skin permeation amount (μg / cm ２ ) = {rotigotine concentration in receptor solution (μg / mL) × flow rate (mL)} / patch area (cm ２ The amount of rotigotine permeated through the skin per unit area of ​​the adhesive layer was calculated using the above formula, and the amount of permeation through the skin per hour (skin permeation rate (μg / cm)) was calculated. ２ The measurement was carried out for two test samples each, and the average of the maximum values ​​of each skin permeation rate within 24 hours was taken as the maximum skin permeation rate (Jmax).

[0090] <Stability Evaluation> The patches (application surface area 5 cm) obtained in each Example and Comparative Example ２ ) was sealed in an aluminum laminate bag to prepare a test sample, which was then stored for 2 weeks at 60° C. After storage, the rate [%] of rotigotine decomposition products was calculated for the patch using the method described below, and this was used as a stability evaluation value.

[0091] First, the release liner was removed from the patch after storage, and the adhesive layer was immersed in 2.5 mL of tetrahydrofuran to dissolve the solution, to which a dilution solution (a mixture of 0.2% phosphate buffer and acetonitrile (50:50 (v:v))) was added so that the total volume became 25 mL. The mixture was shaken and filtered to prepare a sample solution. Separately from these, rotigotine of a known concentration was dissolved in the dilution solution to prepare a standard solution.

[0092] The sample solution was used with a high performance liquid chromatography system (Shimadzu Corporation) under the following conditions: column: TSKgel ODS-80TsQA (4.6 mm I.D. × 150 mm), 5 μm; mobile phase: a mixture 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. Chromatograms of rotigotine degradation products in the sample solution, 7,8-dihydronaphthol, the despropyl form (depropyl rotigotine, despropyl RTN), RRT 0.42, and RRT 0.50, were obtained. The present inventors have confirmed that these are rotigotine degradation products produced by the degradation of rotigotine in the adhesive layer.

[0093] Furthermore, a chromatogram of rotigotine in the standard solution was obtained using the high-performance liquid chromatography system under the same conditions as above, using the standard solution. The amounts of 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, the despropyl form, RRT 0.42, and RRT 0.50 obtained above. The theoretical content of rotigotine was calculated from the amount of rotigotine formulated in the adhesive layer, and the amounts generated were divided by the theoretical content to calculate the rates of generation 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 form generation rate [%], RRT 0.42 generation rate [%], RRT 0.50 generation rate [%]). In the above chromatogram, the peak with a relative retention time (RRT) of around 0.52 relative to the retention time of rotigotine contained in the adhesive layer was designated as the peak of 7,8-dihydronaphthol, the peak with a relative retention time (RRT) of around 0.65 as the peak of the despropyl form, the peak with a relative retention time of around 0.42 as the peak with an RRT of 0.42, and the peak with a relative retention time of around 0.50 as the peak with an RRT of 0.50. In this example, patches that satisfied all of the following criteria: a 7,8-dihydronaphthol occurrence rate of 0.01% or less, a despropyl form occurrence rate of 0.14% or less, an RRT 0.42 occurrence rate of 0.06% or less, and an RRT 0.50 occurrence rate of 0.06% or less were evaluated as patches in which the occurrence of rotigotine degradation products was extremely suppressed.

[0094] Example 1 First, 0.5000 parts by mass of propyl gallate, 0.2000 parts by mass of ascorbyl palmitate, and 0.3600 parts by mass of sodium pyrosulfite were added to 9.00 parts by mass of rotigotine (free form), 11.59 parts by mass of styrene-isoprene-styrene block copolymer, 4.97 parts by mass of polyisobutylene, 42.20 parts by mass of alicyclic saturated hydrocarbon resin, 13.24 parts by mass of liquid paraffin, 5.00 parts by mass of octyldodecanol, 9.94 parts by mass of crosslinked polyvinylpyrrolidone, and 3.00 parts by mass of other components, 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 to remove it, thereby obtaining a pressure-sensitive adhesive layer composition having a mass per unit area of ​​50 g / m ２ A 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 in which the support layer / pressure-sensitive adhesive layer / release liner were laminated in this order.

[0095] Examples 2 and 3 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 the composition shown in Table 1 below.

[0096] The above-mentioned stability evaluation was carried out for each of the patches obtained in Examples 1 to 3. The results of the stability evaluation, i.e., the occurrence rate of each rotigotine degradation product in the adhesive layer after storage at 60°C for 2 weeks, are shown in Table 1 together with the composition of the adhesive layer of each patch (the composition of the adhesive layer composition excluding the solvent). Note that the patches obtained in each Example exhibited a sufficiently excellent maximum skin permeation rate (Jmax) [μg / cm ２ / hr] was achieved.

[0097]

[0098] Comparative Examples 1 to 25 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 the composition shown in Tables 2 to 6 below.

[0099] The above-mentioned stability evaluation was carried out for each of the patches obtained in Comparative Examples 1 to 25. The results of the stability evaluation, i.e., the occurrence rate of each rotigotine degradation product in the adhesive layer after storage at 60°C for 2 weeks, are shown in Tables 2 to 6, respectively, along with the composition of the adhesive layer of each patch (the composition of the adhesive layer composition excluding the solvent). Note that the patches obtained in each Comparative Example also showed a sufficiently excellent maximum skin permeation rate (Jmax) [μg / cm ２ / hr] was achieved.

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] As is clear from the results shown in Table 1, in the patches of the present invention (e.g., Examples 1 to 3) in which a combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite was contained in the adhesive layer, the generation of rotigotine degradation products (7,8-dihydronaphthol, despropyl form, RRT 0.42, RRT 0.50) was sufficiently suppressed and the generation rate was low, confirming that rotigotine was stabilized at a high level, even after storage for 2 weeks under the harsh condition of a temperature of 60°C. In particular, it was confirmed that these patches provided extremely excellent stability of rotigotine when the total content of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer was at least (e.g., Example 3).

[0106] On the other hand, as is clear from the results shown in Table 2, in patches (e.g., Comparative Examples 1 to 5) that do not contain at least one of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer, the rate of generation of rotigotine decomposition products after 2 weeks of storage at 60°C was higher for at least one of the rotigotine decomposition products, although this was within the acceptable range for a formulation, compared to the patches of the present invention that contain all of these ingredients, and it was confirmed that the high level of stability of the patches of the present invention was not achieved.

[0107] Furthermore, as is clear from the results shown in Tables 3 to 6, even in patches (e.g., Comparative Examples 6 to 25) in which any one of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite was replaced with dibutylhydroxytoluene, thymol, butylhydroxyanisole, tocopherol, ethylenediaminetetraacetic acid, 2-mercaptobenzimidazole, ascorbic acid, or sodium thioglycolate, which have conventionally been used as antioxidants for drugs, the rate of generation of rotigotine decomposition products after 2 weeks of storage at 60°C was higher for at least any one of the rotigotine decomposition products, although these were within the acceptable range for a formulation, compared to the patch of the present invention containing a combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer, and it was confirmed that such a high level of stability as that of the patch of the present invention was not achieved.

[0108] These results confirmed that rotigotine is stabilized at a particularly high level in the patch of the present invention, which contains a specific combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite as antioxidants in the adhesive layer.

[0109] As explained above, according to the present invention, it is possible to provide a rotigotine-containing patch in which rotigotine and / or a pharmaceutically acceptable salt thereof have particularly excellent stability over time.

Claims

1. A rotigotine-containing patch comprising a support layer and an adhesive layer, said adhesive layer containing at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, a rubber-based adhesive base, and an antioxidant, said antioxidant including propyl gallate, ascorbyl palmitate, and sodium pyrosulfite.

2. The rotigotine-containing patch according to claim 1, wherein the total content of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer is 0.02 to 3.0% by mass relative to the total mass of the adhesive layer.

3. A rotigotine-containing patch according to claim 1 or 2, wherein the content of propyl gallate in the adhesive layer is 0.01 to 1.4% by mass relative to the total mass of the adhesive layer.

4. A rotigotine-containing patch according to claim 1 or 2, wherein the content of ascorbyl palmitate in the adhesive layer is 0.005 to 0.55% by mass relative to the total mass of the adhesive layer.

5. A rotigotine-containing patch according to claim 1 or 2, wherein the content of sodium pyrosulfite in the adhesive layer is 0.007 to 1.0% by mass relative to the total mass of the adhesive layer.

6. A rotigotine-containing patch according to claim 1 or 2, wherein the content ratio of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer (propyl gallate content: ascorbyl palmitate content: sodium pyrosulfite content) is 1:0.003-55:0.005-100 by mass.

7. A 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, calculated as the free form of rotigotine, relative to the total mass of the adhesive layer.

Images