Rotigotine-containing patch

Abstract

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 comprises propyl gallate, ascorbyl palmitate, and sodium pyrosulfite.

Description

[Technical Field]

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

[0002] Rotigotine is the international generic name for the compound (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]1-naphthalenol, and is known to exist in two crystalline polymorphs, type I and type II. Rotigotine is a D1 / D2 / D3 dopamine receptor agonist and is mainly used to treat symptoms of Parkinson's disease and restless legs syndrome. As a formulation for administering rotigotine, for example, the transdermal patch "Neupro® Patch" is commercially available both domestically and internationally.

[0003] In transdermal patches containing rotigotine and / or a pharmaceutically acceptable salt thereof, the stability of the active ingredient, rotigotine, is required, as with other formulations. For example, Japanese Patent Publication No. 2014-177428 (Patent Document 1) describes a transdermal patch formulation 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 Publication No. 2013-079220 (Patent Document 2) describes a transdermal patch containing rotigotine, comprising a support, a drug-containing layer, and a release liner, for the purpose of suppressing the generation of rotigotine degradation products, wherein the drug-containing layer contains a rubber-based adhesive, rotigotine or a salt thereof, and an inhibitor of the generation of rotigotine degradation products, and mercaptobenzimidazole and sulfites are listed as the inhibitor of the generation of rotigotine degradation products.

[0005] Furthermore, for example, Japanese Patent Publication No. 2018-118927 (Patent Document 3) describes a transdermal patch formulation comprising a support, a drug-containing adhesive layer, and a release liner, for the purpose of suppressing the decomposition of rotigotine by light, wherein the support is an aluminum-free support with a specific light transmittance, and the drug-containing adhesive layer is further to contain an antioxidant, with examples of such antioxidants including 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, wherein the adhesive layer contains rotigotine and / or a pharmaceutically acceptable salt of rotigotine and an adhesive base, and further containing propyl gallate in the adhesive layer improves the stability of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Publication No. 2014-177428 [Patent Document 2] Japanese Patent Publication No. 2013-079220 [Patent Document 3] Japanese Patent Publication No. 2018-118927 [Patent Document 4] International Publication No. 2024 / 116965 [Overview of the project] [Problems that the invention aims to solve]

[0008] However, in rotigotine-containing patches, it is desirable that the active ingredient, rotigotine and / or its pharmaceutically acceptable salt, be contained as stably as possible. Through further investigation by the inventors, it was found that under harsh storage conditions, such as high temperatures, rotigotine and / or its pharmaceutically acceptable salt may decompose, generating decomposition products (rotigotine decomposition products). Therefore, the inventors found that there is room for further improvement in the stability of rotigotine and / or its pharmaceutically acceptable salt in rotigotine-containing patches, and that a higher level of long-term stability than in 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 that exhibits particularly excellent temporal stability of rotigotine and / or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0010] As a result of diligent research to achieve the above objective, the present inventors have found that in a rotigotine-containing patch comprising a support layer and an adhesive layer, the adhesive layer contains at least one selected from the group consisting of rotigotine and its pharmaceutically acceptable salts (rotigotine and / or its pharmaceutically acceptable salts), and an adhesive base, the adhesive base is a rubber-based adhesive base, and the adhesive layer further contains a combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite as antioxidants, thereby suppressing the generation of rotigotine degradation products to an even higher level than in the prior art, even under harsh storage conditions, and making it possible to provide a rotigotine-containing patch with particularly excellent long-term stability of rotigotine and / or its pharmaceutically acceptable salts. Furthermore, the inventors discovered that this long-term stability is particularly superior to that obtained when only two of the three antioxidants are combined, or when one of the three is replaced with another antioxidant, and that this effect is specifically achieved when these three antioxidants—propyl gallate, ascorbyl palmitate, and sodium pyrosulfite—are combined, thus completing the present invention. The embodiments of the present invention obtained from 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 comprises 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 content of ascorbyl palmitate in the adhesive layer is 0.005 to 0.55% by mass based on the total mass of the adhesive layer, and the rotigotine-containing patch according to any one of [1] to [3].

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

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

[0017] [7] The content of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine in the adhesive layer is 5 to 15% by mass in terms of free rotigotine based on the total mass of the adhesive layer, and the rotigotine-containing patch according to any one of [1] to [6].

[0018] [8] In a rotigotine-containing patch comprising a support layer and an adhesive layer, the adhesive layer contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine and a rubber-based adhesive base, and a method for improving the stability of at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine. A method for improving rotigotine stability, which includes a step of further containing an antioxidant in the adhesive layer, and the antioxidant includes propyl gallate, ascorbyl palmitate, and sodium pyrosulfite.

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

[0020]

[10] Propyl gallate is contained in the adhesive layer such that the content of propyl gallate in the adhesive layer is 0.01 to 1.4% by mass based on the total mass of the adhesive layer, the method for improving the stability of rotigotine according to [8] or [9].

[0021]

[11] Ascorbyl palmitate is contained in the adhesive layer such that the content of ascorbyl palmitate in the adhesive layer is 0.005 to 0.55% by mass based on the total mass of the adhesive layer, the method for improving the stability of rotigotine according to any one of [8] to

[10] .

[0022]

[12] Sodium pyrosulfite is contained in the adhesive layer such that the content of sodium pyrosulfite in the adhesive layer is 0.007 to 1.0% by mass based on the total mass of the adhesive layer, the method for improving the stability of rotigotine according to any one of [8] to

[11] .

[0023]

[13] The antioxidant is contained in the adhesive layer such that the content ratio of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer (content of propyl gallate: content of ascorbyl palmitate: content of sodium pyrosulfite) is, by mass ratio, 1:0.003 to 55:0.005 to 100, the method for improving the stability of rotigotine according to any one of [8] to

[12] .

[0024]

[14] 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 based on the total mass of the adhesive layer in terms of free rotigotine, the method for improving the stability of rotigotine according to any one of [8] to

[13] . [Effects of the Invention]

[0025] According to the present invention, it is possible to provide a rotigotine-containing patch that exhibits particularly excellent long-term stability of rotigotine and / or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0026] The present invention will be described in detail below with reference to its preferred embodiments.

[0027] [Rotigotine-containing patch] The rotigotine-containing patch of the present invention 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.

[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 later, and known support layers for patches can be appropriately used. Examples of materials for the support layer according to 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, polyethylene naphthalate; cellulose derivatives; synthetic resins such as polyurethane; and metals such as aluminum. Among these, polyester is preferred from the viewpoint of non-adsorption and non-permeability of drugs, and polyethylene terephthalate is more preferred. Examples of forms of the support layer include films; sheets, sheet-like porous bodies, sheet-like foams, and other sheets; fabrics such as woven fabrics, knitted fabrics, and nonwoven fabrics; paper; foil; and laminates thereof. Furthermore, the thickness of the support layer is not particularly limited, but from the viewpoint of ease of application and ease of manufacturing, it is preferably in the range of 5 to 1000 μm.

[0029] The rotigotine-containing adhesive of the present invention may further include a release liner on the side of the adhesive layer opposite to the support layer. Examples of materials for such a release liner 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; cellulose derivatives; synthetic resins such as polyurethane; and metals such as aluminum. Examples of the form of the release liner include films, sheets, paper, and laminates thereof made of the above materials. Preferably, such a release liner has a release treatment, such as a silicone compound coating or a fluorine compound coating, applied to the side that comes into contact with the adhesive layer, so that it can be easily peeled off from the adhesive layer.

[0030] <Rotigotine and its pharmaceutically acceptable salts> The adhesive layer according to the present invention contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine (hereinafter, optionally referred to as "rotigotine and / or its pharmaceutically acceptable salt") as a drug. In the present invention, the form of rotigotine contained in the adhesive layer may be a free form or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of rotigotine that has been desalted to a free form during manufacturing and / or in the manufactured formulation, and may be one of these or a mixture of two or more. Examples of pharmaceutically acceptable salts of rotigotine include acid addition salts, and examples of acids for the acid addition salts include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, phosphorous acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, tartaric acid, lauric acid, stearic acid, palmitic acid, oleic acid, myristic acid, lauryl sulfate, linolenic acid, and fumaric acid. The aforementioned 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 a free form.

[0031] In the rotigotine-containing patch of the present invention, the content of rotigotine and / or its pharmaceutically acceptable salt contained in the adhesive layer (the content of rotigotine, the content of its pharmaceutically acceptable salt, or, if both are contained, the total content thereof; 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, based on the total mass of the adhesive layer, in terms of rotigotine free form. If the content of rotigotine and / or its pharmaceutically acceptable salt is below the lower limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends to decrease, while 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] According to the rotigotine-containing patch of the present invention and the method for improving rotigotine stability of the present invention described below, it is possible to sufficiently suppress the generation of degradation products (rotigotine degradation products) of rotigotine and / or its pharmaceutically acceptable salts in the adhesive layer. Examples of such degradation products include, but are not limited to, 7,8-dihydronaphthol, despropyl derivative (depropylrotigotine, Despropyl RTN), a substance whose relative retention time (RRT) to the retention time of rotigotine contained in the adhesive layer is around 0.42 in a chromatogram obtained by performing high-performance liquid chromatography under the conditions described in the <Stability Evaluation> section of the examples below (RRT 0.42), and a substance whose relative retention time (RRT) is around 0.50 (RRT 0.50).

[0033] <Adhesive base> The adhesive layer according to the present invention contains a rubber-based adhesive base as an 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, and one of these may be used alone or two or more may be used in combination.

[0034] Among these, the rubber-based adhesive base according to the present invention is particularly preferably a styrene-based thermoplastic elastomer. The styrene-based thermoplastic elastomer is a styrene-based elastomer that softens and becomes fluid when heated, and returns to a rubbery elastic body when cooled. Of these, a styrene-based block copolymer is preferred from the viewpoint of providing sufficient tackiness and superior long-term stability of rotigotine and / or its pharmaceutically acceptable salt.

[0035] Examples of the styrene-based block copolymer include, specifically, 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, styrene-isobutylene-styrene block copolymer, and others. It may be one of these or a 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. Among these, the styrene-based thermoplastic elastomer according to the present invention is more preferably a styrene-isoprene-styrene block copolymer.

[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 physical properties of the patch (especially the cohesive force of the adhesive layer) tend to decrease, while if it exceeds the upper limit, the compatibility with other components contained in the adhesive layer decreases, making it difficult to manufacture the patch.

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

[0038] Furthermore, from the viewpoint of improving the tackiness and cohesive force of the adhesive layer, 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 the mass ratio of the styrene-based thermoplastic elastomer to the polyisobutylene (mass of styrene-based thermoplastic elastomer:mass of polyisobutylene) is more preferably 1:2 to 30:1 (even more preferably in the range of 1:1 to 10:1).

[0039] The aforementioned polyisobutylene also includes so-called butyl rubber (isobutylene-isoprene rubber), and specifically, as polyisobutylene, for example, Oppanol® N50, N80, N100, N150, B11, B12, B50, B80, B100, B120, B150, B220 (product names, manufactured by BASF), JSR® Butyl 065, 268, 365 (product names, manufactured by JSR Corporation), X_Butyl® RB 100, 101-3, 301, 402 (product names, manufactured by ARLANXEO), Exxon® Butyl 065, 065S, 068, 068S, 268, 268S, 365, 365S (product names, Exxon Examples include Butyl065, 268, and 365 (product names, manufactured by Nippon Butyl Co., Ltd.), manufactured by Mobile Inc.

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

[0041] Furthermore, in the present invention, when the styrene-based thermoplastic elastomer is contained in the adhesive layer as the adhesive base, its content (the total content if the styrene-based thermoplastic elastomer is a combination of two or more types, the same applies hereinafter) is preferably 1 to 50% by mass, more preferably 5 to 40% by mass, even more preferably 5 to 30% by mass, and even more preferably 5 to 20% by mass, relative to the total mass of the adhesive layer. If the content of the styrene-based thermoplastic elastomer is below the lower limit, the cohesive force and shape retention of the adhesive layer tend to decrease, while if it exceeds the upper limit, the cohesive force of the adhesive layer tends to increase excessively, leading to a decrease in adhesive strength and compatibility of the adhesive layer.

[0042] The adhesive layer according to the present invention may also contain, within a range that does not impede the effects of the present invention, at least one other adhesive base selected from the group consisting of acrylic adhesive bases and silicone adhesive bases. Examples of the acrylic adhesive base include those listed as adhesives in the "Dictionary of Pharmaceutical Additives 2016 (edited by the Japan Pharmaceutical Additives Association)," and may be one of these or a combination of two or more. Examples of the silicone adhesive base include silicone rubbers represented as MQ (polydimethylsiloxane), VMQ (polymethylvinylsiloxane), PMQ (polymethylphenylsiloxane), and PVMQ (polyphenylvinylmethylsiloxane) in the ASTM standard (ASTM D 1418), or mixtures of at least one of these and silicone resins other than silicone rubber, such as polyditrimethylsilylsiloxane, and may be one of these or a combination of two or more.

[0043] However, in the adhesive layer according to the present invention, it is preferable that no other adhesive bases other than the rubber-based adhesive base are contained in the adhesive layer, and the content of such other adhesive bases (total content if there are two or more types) is preferably 40% by mass or less, more preferably 30% by mass or less, and even more preferably 20% by mass or less (for example, 0 to 20% by mass, 0 to 10% by mass) relative to the total mass of the 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, based on the total mass of the adhesive layer. If the content of propyl gallate is below the lower limit, the effect of improving the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends not to be fully exhibited. On the other hand, if it exceeds the upper limit, the time-dependent stability tends to decrease, and the cohesive force and adhesive force 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 1 part by mass of the content of rotigotine and / or its pharmaceutically acceptable salt in terms of free rotigotine. When the ratio of the propyl gallate content to the content of rotigotine and / or its pharmaceutically acceptable salt is within the above range, the effect of improving the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends to be particularly exhibited.

[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, based on the total mass of the adhesive layer. If the content of ascorbyl palmitate is below the lower limit, the effect of improving the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends not to be fully exhibited. On the other hand, if it exceeds the upper limit, the time-dependent stability tends to decrease, and the cohesive force and adhesive force 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 parts by mass, and more preferably 0.002 to 0.05 parts by mass, per 1 part by mass of the content of rotigotine and / or its pharmaceutically acceptable salt in terms of free rotigotine. When the ratio of the ascorbyl palmitate content to the content of rotigotine and / or its pharmaceutically acceptable salt is within the above range, the effect of improving the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends to be particularly exhibited.

[0049] The sodium pyrosulfite content 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, based on the total mass of the adhesive layer. If the sodium pyrosulfite content is below the lower limit, the effect of improving the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends not to be fully exhibited. On the other hand, if it exceeds the upper limit, the time-dependent stability tends to decrease, and the cohesive force and adhesive force of the adhesive layer tend to decrease.

[0050] Furthermore, the amount 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 1 part by mass of the rotigotine and / or its pharmaceutically acceptable salt content in terms of rotigotine free form. When the ratio of the sodium pyrosulfite content to the content of rotigotine and / or its pharmaceutically acceptable salt is within the above range, the effect of improving the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends to be particularly pronounced.

[0051] Furthermore, the content ratio of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite contained in the adhesive layer according to the present invention (content of propyl gallate: content of ascorbyl palmitate: content of sodium pyrosulfite) is preferably 1:0.003~55:0.005~100 by mass ratio, 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 time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends to be particularly exhibited.

[0052] The inventors have found that, according to the combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite of the present invention, even at minimum content levels, the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt is exhibited at an extremely high level. Such content levels are preferably such that the total content of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite in the adhesive layer is 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 below the lower limit, the effect of improving the time-dependent stability of rotigotine and / or its pharmaceutically acceptable salt tends not to be fully exerted. On the other hand, if it exceeds the upper limit, the time-dependent stability tends to decrease, and the cohesive force or adhesive force of the adhesive layer tends to decrease.

[0053] The adhesive layer according to the present invention may further contain other antioxidants other than propyl gallate, ascorbyl palmitate, and sodium pyrosulfite, as long as they do not impede the effects of the present invention. Other antioxidants include, for example, ascorbic acid or its metal salts or esters (excluding ascorbyl palmitate), isoascorbic acid or its metal salts, ethylenediaminetetraacetic acid or its metal salts, cysteine, acetylcysteine, 2-mercaptobenzimidazole, dibutylhydroxytoluene, butylhydroxyanisole, pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 3-mercapto-1,2-propanediol, tocopherol, tocopherol acetate, thymol, thioglycolic acid and / or pharmaceutically acceptable salts thereof (such as sodium thioglycolate), rutin, dihydroxybenzoic acid, potassium dichloroisocyanurate, quercetin, hydroquinone, hydroxymethanesulfinate metal salts, sodium bisulfite, etc., and may be used individually or in combination of two or more of these. Examples of metal salts include sodium salts, potassium salts, calcium salts, magnesium salts, and calcium disodium salts. Examples of esters include stearic acid esters and myristic acid esters.

[0054] However, in the adhesive layer according to the present invention, the time-dependent stabilization effect of rotigotine and / or its pharmaceutically acceptable salt by the combination of propyl gallate, ascorbyl palmitate, and sodium pyrosulfite is inhibited, and from the viewpoint of the adhesive strength of the adhesive layer, it is preferable not to contain the above-mentioned other antioxidants in the adhesive layer. The content of such other antioxidants (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 ingredients> The adhesive layer according to the present invention may further contain, to the extent that it does not impair the effects of the present invention, other drugs other than rotigotine and its pharmaceutically acceptable salts; tackifiers; absorption enhancers; skin irritation reducers; and additives such as adsorbents, desalting agents, plasticizers, solvents, fillers, and preservatives.

[0056] (Other drugs) Other drugs besides rotigotine and its pharmaceutically acceptable salts include, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, indomethacin, ketoprofen, felbinac, loxoprofen, ibuprofen, flurbiprofen, tiaprofen, acemetacin, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazon, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, and rof (e.g., ecoxib, amfenac), antipyretic analgesics (e.g., acetaminophen), antihistamines (e.g., diphenhydramine, chlorpheniramine, mequitazine, homochlorcyclidine), antihypertensives (e.g., diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril), antiparkinsonian agents (e.g., pergolide, ropinirole, bromocriptine, selegiline), bronchodilators (e.g., tulobuterol, isoproterenol, salbutamol), antiallergic agents (e.g., keto (Tifen, loratadine, azelastine, terfenadine, cetirizine, acitazanol, 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 medications (oxybutynin, tamsulosin, etc.), psychotropic medications (promazine, chlorpromazine, etc.), antidepressants (sertraline, fluoxetine, paroxetine) Examples include antidementia drugs (such as tin, citalopram), antidementia drugs (such as donepezil, rivastigmine, and galantamine), antipsychotics (such as risperidone and olanzapine), central nervous system stimulants (such as methylphenidate), osteoporosis treatment drugs (such as raloxifene and alendronate), breast cancer preventive drugs (such as tamoxifen), anti-obesity drugs (such as mazindol and sibutramine), insomnia treatment drugs (such as melatonin), and anti-rheumatic drugs (such as actarit). It may be one of these drugs or a combination of two or more.

[0057] If the adhesive layer according to the present invention further contains the other drugs, it is preferable that the content of these drugs (or the total content if there are two or more) be 10% by mass or less of the total mass of the adhesive layer.

[0058] (Adhesion agent) The tackifier is primarily formulated to enhance the tackiness of the adhesive base (especially the rubber-based adhesive base). Examples of such tackifiers include petroleum resins, rosin resins, terpene resins, phenolic resins, and xylene resins. The tackifier may be one of these or a combination of two or more, but it is preferable that a petroleum resin is further included.

[0059] If the tackifier is further contained in the adhesive layer, its content (total content if there are two or more types) is preferably 5 to 80% by mass, more preferably 10 to 80% by mass, and even more preferably 20 to 60% by mass, relative to the total mass of the adhesive layer, from the viewpoint of improving the adhesive strength of the adhesive layer and / or mitigating local irritation during peeling.

[0060] Examples of the petroleum-based resins include C5 synthetic petroleum resins (polymers 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 (polymers of at least two of indene, styrene, methylindene, and α-methylstyrene, etc.), and dicyclopentadiene synthetic petroleum resins (polymers mainly composed of dicyclopentadiene with isoprene and / or 1,3-pentadiene). Furthermore, from another classification perspective, examples include alicyclic petroleum resins (alicyclic saturated hydrocarbon resins, etc.), alicyclic hydrogenated petroleum resins, aliphatic petroleum resins (aliphatic hydrocarbon resins, etc.), aliphatic hydrogenated petroleum resins, and aromatic petroleum resins. More specifically, examples include Alcon P-70, Alcon P-85, Alcon P-90, Alcon P-100, Alcon P-115, Alcon P-125, Alcon M-90, Alcon M-100, Alcon M-115, Alcon M-135 (all trade names, manufactured by Arakawa Chemical Industries, Ltd.), and Escolets 8000 (trade name, manufactured by Esso Petrochemical Co., Ltd.). The petroleum resin according to the present invention may be one of these or a combination of two or more. Among these, alicyclic saturated hydrocarbon resins are more preferable from the viewpoint of easily obtaining suitable adhesion to the skin, having a good feel due to less 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 alicyclic saturated hydrocarbon monomers. 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. Furthermore, the alicyclic saturated hydrocarbon resin preferably has a softening point (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. Furthermore, the alicyclic saturated hydrocarbon resin preferably has a glass transition temperature (glass transition temperature measured by 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 resin used in the following examples satisfies all of the most preferred conditions for weight-average molecular weight, softening point, and glass transition temperature.

[0062] If the adhesive layer according to the present invention further contains the petroleum-based resin (preferably an alicyclic saturated hydrocarbon resin), the content thereof (total content thereof if there are two or more types) 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 adhesive layer. If the content of the petroleum-based resin is below the lower limit, the adhesive strength and adhesion to the skin of the adhesive layer tend to decrease, while if it exceeds the upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt and the shape retention of the adhesive layer tend to decrease.

[0063] (Absorption enhancer) Examples of the absorption enhancers include those that have a transdermal absorption-enhancing effect (skin permeability-enhancing effect) of drugs, such as aliphatic alcohols, fatty acids having 6 to 20 carbon atoms, fatty acid esters, fatty acid amides, or aliphatic alcohol ethers; aromatic organic acids; aromatic alcohols; aromatic organic acid esters or ethers; POE hydrogenated castor oils; lecithins; phospholipids; soybean oil derivatives; and triacetins. The absorption enhancers may be one of these or a combination of two or more, but from the viewpoint of better skin permeability of rotigotine and / or its pharmaceutically acceptable salts, it is preferable that aliphatic alcohols are further contained in the adhesive layer.

[0064] If the absorption enhancer is further contained in the adhesive layer, its content (total content if there are two or more types) is preferably 1 to 15% by mass, and 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 its pharmaceutically acceptable salt.

[0065] The aliphatic alcohol refers to a saturated or unsaturated, linear or branched, monovalent or divalent or higher aliphatic alcohol, and the aliphatic alcohol according to the present invention is preferably monovalent. Furthermore, 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 below the lower limit, the boiling point becomes low, making it difficult to maintain a constant content in the formulation, and the long-term stability of the aliphatic alcohol tends to decrease. On the other hand, if it exceeds the upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends to decrease.

[0066] Examples of the aliphatic alcohols 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, but from the viewpoint of the long-term stability and compatibility of the above aliphatic alcohols, as well as the tendency to particularly improve the skin permeability of rotigotine and / or its pharmaceutically acceptable salt, it is preferable that at least one is selected from the group consisting of octyldodecanol and lauryl alcohol.

[0067] If the adhesive layer according to the present invention further contains the aliphatic alcohol, the content thereof (or the total content thereof if there are two or more types) 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 its pharmaceutically acceptable salt tends not to be sufficiently improved, while if it exceeds the upper limit, the compatibility with the adhesive base and other components tends to decrease.

[0068] (Skin irritation reducing agent) Examples of the skin irritation reducing agent include those that reduce the irritation caused to the skin by drugs or antioxidants, such as cholesterol, cholesterol derivatives, cholesterol analogs, diflucortolone valerate, clobetasol propionate, amcinonides, mometasone furoate, fluocinonides, dexamethasone propionate, beclomethasone propionate, and fluocinolone acetonide. The skin irritation reducing agent may be one of these or a combination of two or more.

[0069] If the skin irritation reducing agent is further contained in the adhesive layer, the content thereof (total content if there are two or more types) is preferably 0.1 to 7% by mass, more preferably 1 to 7% by mass, and even more preferably 3 to 5% by 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 adsorbents include hygroscopic inorganic and / or organic substances, more specifically minerals such as talc, kaolin, and bentonite; silicon compounds such as fumed silica (e.g., Aerosil®) 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 polymers such as polyvinylpyrrolidone (also known as "povidone" or "non-crosslinked PVP"), crosslinked polyvinylpyrrolidone (also known as "crosspovidone" or "crosslinked PVP"), aminoalkyl methacrylate copolymers, carboxyvinyl polymers, and butyl methacrylate methyl methacrylate copolymers. The adsorbent may be one of these or a combination of two or more, but from the viewpoint of better long-term stability of rotigotine and / or its pharmaceutically acceptable salts, it is preferable that crosslinked polyvinylpyrrolidone is further contained in the adhesive layer.

[0071] If the adsorbent is further contained in the adhesive layer, its content (or total content if there are two or more types) is preferably 3 to 25% by mass, and more preferably 3 to 15% by mass, relative to the total mass of the adhesive layer, from the viewpoint of the adhesiveness of the adhesive layer.

[0072] The crosslinked polyvinylpyrrolidone can be a crosslinked N-vinylpyrrolidone polymer. The N-vinylpyrrolidone polymer may be a homopolymer or a copolymer, for example, a homopolymer of N-vinylpyrrolidone or a copolymer of N-vinylpyrrolidone and a polyfunctional monomer. Among these, the crosslinked polyvinylpyrrolidone according to the present invention is preferably a crosslinked homopolymer of 1-vinyl-2-pyrrolidone (also called "crospovidone"). As crospovidone, commercially available products such as Coridone CL, Coridone 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] If the adhesive layer according to the present invention further contains the crosslinked polyvinylpyrrolidone, the content thereof (total content if there are two or more types) 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 below the lower limit, crystals of rotigotine and / or its pharmaceutically acceptable salt tend to precipitate easily. On the other hand, if it exceeds the upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends to decrease, or the compatibility in the adhesive layer composition decreases during manufacturing, making manufacturing difficult.

[0074] Furthermore, the content of cross-linked polyvinylpyrrolidone contained in the adhesive layer is preferably 15:3 to 5:25, more preferably 15:3 to 5:20, and even more preferably 15:3 to 5:15, in terms of the mass ratio of the content of rotigotine and / or its pharmaceutically acceptable salt in terms of free rotigotine (content of rotigotine and / or its pharmaceutically acceptable salt in terms of free rotigotine: content of cross-linked polyvinylpyrrolidone). If the ratio of the cross-linked polyvinylpyrrolidone content to the content of rotigotine and / or its pharmaceutically acceptable salt is below the lower limit, rotigotine crystals tend to precipitate, while if it exceeds the upper limit, the skin permeability of rotigotine and / or its pharmaceutically acceptable salt tends to decrease.

[0075] [Desalination agent] The desalting agent is primarily formulated to convert all or part of a basic drug into a free form. While there are no particular limitations on such a desalting agent, for example, when a formulation containing a free drug is obtained by incorporating an acid addition salt of the drug as the drug, it is preferably a basic substance, and more preferably a metal ion-containing desalting agent or a basic nitrogen atom-containing desalting agent. Examples of the metal ion-containing desalting agent include sodium acetate (including anhydrous sodium acetate), sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium citrate, sodium lactate, etc., and may be one of these or a combination of two or more. Furthermore, the adhesive layer according to the present invention may further contain compounds derived from the basic drug and the desalting agent (for example, sodium chloride produced when rotigotine hydrochloride and sodium acetate are combined). In the present invention, if these desalting agents, as well as compounds derived from basic drugs and desalting agents, are further contained in the adhesive layer, it is preferable that the total content of two or more of these agents is 10% by mass or less of the total mass of the adhesive layer.

[0076] [Plasticizer] The plasticizer is primarily formulated to adjust the adhesive properties of the adhesive layer, the flow characteristics in the manufacture of the adhesive layer, and the transdermal absorption characteristics of the drug. Examples of such plasticizers include silicone oil; petroleum oils such as paraffinic process oils (liquid paraffin, etc.), naphthenic process oils, and aromatic process oils; 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, but it is particularly preferable that it be at least one selected from the group consisting of silicone oil, liquid paraffin, and liquid polybutene.

[0077] If the adhesive layer according to the present invention further contains the plasticizer, the content thereof (total content if there are two or more types) is preferably 1 to 30% by mass and more preferably 5 to 20% by mass of the total mass of the adhesive layer, from the viewpoint of improving the adhesive strength of the adhesive layer and / or mitigating local irritation when peeling off.

[0078] [Soluble agents / fillers] Examples of the solvent include organic acids such as acetic acid and surfactants, and may be one of these or a combination of two or more. The filler is mainly formulated to adjust the adhesive strength of the 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 dioxide, and may be one of these or a combination of two or more.

[0079] [Preservatives] Examples of the preservatives include para-hydroxybenzoic acid derivatives, benzyl alcohol, phenol, cresol, etc., and may be one of these or a combination of two or more.

[0080] The adhesive layer according to the present invention is not particularly limited, but its mass per unit area (area of ​​the adhesive surface) is 20 to 200 g / m². 2 Preferably, it is 30-100 g / m². 2 It is more preferable that the amount be 30-70 g / m². 2 It is even more preferable that this is the case. Furthermore, the area of ​​the adhesive layer to be applied according to the present invention can be appropriately adjusted according to the purpose of treatment and the target of application, and is not particularly limited, but is usually 0.5 to 200 cm². 2 It is within the range of [the specified range].

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

[0082] In the method of the present invention, there are no particular limitations on 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 thereof and the rubber-based adhesive base, and known methods for producing adhesive patches can be appropriately employed. For example, first, propyl gallate, ascorbyl palmitate, and sodium pyrosulfite are added to rotigotine and / or a pharmaceutically acceptable salt thereof, the rubber-based adhesive base, and optionally other adhesive bases, other antioxidants, other components, and an appropriate amount of solvent, and the mixture is kneaded according to a conventional method to obtain a uniform adhesive layer composition.

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

[0084] The order in which the components, namely rotigotine and / or its pharmaceutically acceptable salt, the rubber-based adhesive base, propyl gallate, ascorbyl palmitate, and sodium pyrosulfite, as well as other adhesive bases and other antioxidants as needed, and other components and solvents, is not particularly limited. Furthermore, the amount of each of these components is preferably such that the content of each component in the resulting adhesive layer is such that it matches the content of each component described in the rotigotine-containing patch of the present invention. That is, in the method of the present invention, "total mass of the adhesive layer" refers to the total mass of the adhesive layer in a patch subjected to the rotigotine stability improvement method or a patch manufactured by the method for manufacturing a rotigotine-containing patch, i.e., the adhesive layer also containing 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, by spreading the adhesive layer composition on the surface (usually one surface) of the support layer to a desired mass per unit area, then heating as necessary to dry and remove the solvent to form an adhesive layer, and further cutting as necessary to a desired shape, the stability of rotigotine and / or pharmaceutically acceptable salts of rotigotine can be improved in the resulting rotigotine-containing patch, and the rotigotine-containing patch of the present invention can be obtained.

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

[0087] Furthermore, the resulting patch may be sealed in a storage container (e.g., an aluminum laminate bag) as needed to form a package. [Examples]

[0088] The present invention will be described more specifically below based on examples and comparative examples, but the present invention is not limited to the following examples. In each example and comparative example, skin penetration tests and stability evaluations were performed by the methods described below.

[0089] <Skin permeability test (in vitro hairless mouse skin permeability test)> First, the skin of the body of a hairless mouse was peeled off and the fat was removed. A 1.0 cm section was then placed on the stratum corneum side of the fat-removed skin sample. 2The patch obtained by cutting into a square and removing the release liner was applied to obtain a test sample. This was set in a flow-through type diffusion cell such that the dermis side was in contact with the receptor solution, and the cell was filled with a receptor solution (phosphate buffered saline). Next, while circulating warm circulating water through the outer peripheral portion so that the receptor solution was kept at 32°C, the receptor solution was fed at a flow rate of about 5 mL / hr, and the receptor solution was collected every 2 hours up to 24 hours. The rotigotine concentration in the collected receptor solution was measured by high performance liquid chromatography, and respectively, by the following formula: Rotigotine skin permeation amount (μg / cm 2 ) = {Rotigotine concentration (μg / mL) in the receptor solution × Flow rate (mL)} / Patch area (cm 2 ) The rotigotine skin permeation amount per unit area of the adhesive layer was calculated by the above formula, and the skin permeation amount per hour (skin permeation rate (μg / cm 2 / hr)) was determined. The measurement was performed for two test samples respectively, and the average value of the maximum value within 24 hours of each skin permeation rate was taken as the maximum skin permeation rate (Jmax).

[0090] <Stability evaluation> The patches obtained in each of the examples and comparative examples (patch area of the adhesive surface: 5 cm 2 ) were sealed in an aluminum laminate bag to obtain test samples, which were stored at 60°C for 2 weeks. For the patch after storage, the generation rate [%] of rotigotine degradation products was calculated by the following method and used as the value for stability evaluation.

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

[0092] Using the aforementioned sample solution, high-performance liquid chromatography (manufactured by Shimadzu Corporation) was performed under the following conditions: Column: TSKgel ODS-80TsQA (4.6mm ID × 150mm), 5μm Mobile phase: A mixture of 0.2% phosphate buffer containing 10 mM sodium dodecyl sulfate and acetonitrile (50:50 (v:v)) Detection wavelength: 225nm Column temperature: 40℃ Flow rate: 0.7mL / min Chromatograms were obtained of 7,8-dihydronaphthol, despropyl (depropylrotigotin, Despropyl RTN), RRT 0.42, and RRT 0.50, which are rotigotin degradation products, in the sample solution. The inventors have confirmed that these are rotigotin degradation products produced by the decomposition of rotigotin in the adhesive layer.

[0093] Furthermore, using the standard solution, a chromatogram of rotigotine in the standard solution was obtained using the high-performance liquid chromatography apparatus under the same conditions as described above. The amount of each generated product was calculated from the area under the curve of the rotigotine chromatogram obtained and the area under the curve of the chromatograms of 7,8-dihydronaphthol, despropyl derivative, RRT 0.42, and RRT 0.50 obtained above. In addition, the theoretical content of rotigotine was calculated from the amount of rotigotine incorporated into the adhesive layer, and the generation rates of each rotigotine degradation product in the adhesive layer of each patch after storage at 60°C for 2 weeks were calculated (7,8-dihydronaphthol generation rate [%], despropyl derivative 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 rotigotine contained in the adhesive layer of approximately 0.52 was identified as the peak for 7,8-dihydronaphthol, the peak with a relative retention time (RRT) of approximately 0.65 as the peak for the despropyl derivative, the peak with a relative retention time of approximately 0.42 as the peak for RRT 0.42, and the peak with a relative retention time of approximately 0.50 as the peak for RRT 0.50. In this example, a patch that met all of the following criteria—a 7,8-dihydronaphthol generation rate of 0.01% or less, a despropyl derivative generation rate of 0.14% or less, an RRT 0.42 generation rate of 0.06% or less, and an RRT 0.50 generation rate of 0.06% or less—was evaluated as a patch in which the generation of rotigotine degradation products was extremely suppressed.

[0094] (Example 1) First, 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 cross-linked polyvinylpyrrolidone, and 3.00 parts by mass of other components were added to 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. These were then mixed with an appropriate amount of solvent (anhydrous ethanol and toluene) to obtain an adhesive layer composition. Next, the obtained adhesive layer composition was spread onto a release liner (a polyethylene terephthalate film that has been treated for mold release), and the solvent was dried off to obtain a mass of 50 g / m² per unit area. 2 An adhesive layer was formed in such a manner. A support layer (polyethylene terephthalate film) was laminated onto the surface of the obtained adhesive layer opposite to the release liner, thereby obtaining an adhesive patch laminated in the order of support layer / adhesive layer / release liner.

[0095] (Examples 2-3) Each adhesive patch was obtained in the same manner as in Example 1, except that the composition of the adhesive layer composition (excluding the solvent) was set to the composition shown in Table 1 below.

[0096] The above stability evaluation was performed on each of the patches obtained in Examples 1 to 3. The results of the stability evaluation, i.e., the generation rate of each rotigotine degradation product in the adhesive layer after storage at 60°C for 2 weeks, are shown in Table 1, along with the composition of the adhesive layer of each patch (composition of the adhesive layer composition excluding the solvent). In addition, the above skin permeability test showed that the patches obtained in each example had a sufficiently excellent maximum skin permeability rate (Jmax) [μg / cm²]. 2 I confirmed that [ / hr] was achieved.

[0097] [Table 1]

[0098] (Comparative Examples 1-25) Each adhesive patch was obtained in the same manner as in Example 1, except that the composition of the adhesive layer composition (composition excluding the solvent) was set to the compositions shown in Tables 2 to 6 below.

[0099] The above stability evaluation was performed on each of the patches obtained in Comparative Examples 1 to 25. The results of the stability evaluation, i.e., the generation 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, along with the composition of the adhesive layer of each patch (composition of the adhesive layer composition excluding the solvent). In addition, the patches obtained in each comparative example also showed sufficiently excellent maximum skin penetration rate (Jmax) [μg / cm²] in the above skin penetration test. 2 I confirmed that [ / hr] was achieved.

[0100] [Table 2]

[0101] [Table 3]

[0102] [Table 4]

[0103] [Table 5]

[0104] [Table 6]

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

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

[0107] Furthermore, as is clear from the results shown in Tables 3 to 6, in transdermal patches (e.g., Comparative Examples 6 to 25) in which any 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 been conventionally used as antioxidants for drugs, the generation rate of rotigotine degradation products after 2 weeks of storage at 60°C was higher for at least one of the rotigotine degradation products, although these were also within acceptable limits for formulations. This confirmed that the high level of stability achieved with the transdermal patch of the present invention could not be attained.

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

[0109] As described above, the present invention makes it possible to provide a rotigotine-containing patch that exhibits particularly excellent long-term stability of rotigotine and / or its pharmaceutically acceptable salt.

Claims

1. A rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from the group consisting of rotigotine and pharmaceutically acceptable salts of rotigotine, a rubber-based adhesive base, and an antioxidant, wherein the antioxidant comprises 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. The rotigotine-containing patch according to claim 1 or 2, wherein the propyl gallate content in the adhesive layer is 0.01 to 1.4% by mass relative to the total mass of the adhesive layer.

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

6. The 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 (content of propyl gallate: content of ascorbyl palmitate: content of sodium pyrosulfite) is 1:0.003 to 55:0.005 to 100 by mass ratio.

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

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