Rotigotine Stabilization Method

Abstract

The present invention relates to a method for stabilizing rotigotine, comprising stabilizing rotigotine and / or a pharmaceutically acceptable salt thereof 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 thereof and a styrene-based thermoplastic elastomer, wherein the adhesive layer further contains cross-linked polyvinyl pyrrolidone so that the content in the adhesive layer is 3 to 25% by mass.

Description

Technical Field

[0001] The present invention relates to a method for stabilizing rotigotine, and more specifically, to a method for stabilizing rotigotine and / or a pharmaceutically acceptable salt thereof 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 thereof. Background Art

[0002] Rotigotine is the international common name for the compound (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthol. Japanese Patent Publication No. 2011-504902 (Patent Document 1) describes its existence in Type I and Type II polymorphs. Rotigotine is a D1 / D2 / D3 dopamine receptor agonist primarily used to treat symptoms of Parkinson's disease and restless legs syndrome.

[0003] As a preparation for administering rotigotine, for example, the "Nypro (registered trademark) patch" is commercially available in Japan and abroad. Japanese Patent Application Publication No. 2002-509878 (Patent Document 2) describes a transdermal therapeutic system comprising a backing layer inert to the components of the matrix and a self-adhesive matrix layer containing rotigotine, wherein the matrix has a solubility of rotigotine of 5% (w / w) or higher and a water-insoluble acrylate-based or silicone-based polymer adhesive as a base. Furthermore, Japanese Patent Application Publication No. 2015-503541 (Patent Document 3) describes a transdermal therapeutic system comprising a backing layer impermeable to the active substance and a matrix layer containing a pressure-sensitive adhesive, a drug, and cross-linked polyvinyl pyrrolidone particles. Rotigotine is described as the drug, and a silicone polymer is described as the pressure-sensitive adhesive.

[0004] Furthermore, as preparations for administering rotigotine using a rubber-based adhesive, for example, Japanese Patent Application Laid-Open No. 2014-177428 (Patent Document 4) describes a transdermal patch preparation comprising a support and a drug-containing layer, the drug-containing layer comprising a rosin-based resin and a rubber-based adhesive containing a rubber-based adhesive component, and rotigotine or a pharmaceutically acceptable salt thereof. Japanese Patent Application Laid-Open No. 2013-079220 (Patent Document 5) describes a transdermal patch preparation comprising a support and a drug-containing layer, the drug-containing layer comprising a rubber-based adhesive, rotigotine or a salt thereof, and an inhibitor of the production of rotigotine decomposition products.

[0005] Furthermore, as preparations for administering rotigotine, for example, Japanese Patent Application Publication No. 2006-513195 (Patent Document 6) and Japanese Patent Application Publication No. 2012-504609 (Patent Document 7) describe preparations containing rotigotine in an amorphous form. Japanese Patent Application Publication No. 2013-515041 (Patent Document 8) describes a method for stabilizing rotigotine, comprising the step of providing a solid dispersion containing polyvinyl pyrrolidone and amorphous rotigotine using polyvinyl pyrrolidone (non-crosslinked) at a specific weight ratio relative to rotigotine.

[0006] Furthermore, Japanese Patent Application Publication No. 2017-515871 (Patent Document 9) describes a method for producing a percutaneous absorption preparation, wherein rotigotine and an antioxidant are mixed at a specific weight ratio for the purpose of preventing rotigotine crystal precipitation.

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: Japanese Patent Application No. 2011-504902

[0010] Patent Document 2: Japanese Patent Application No. 2002-509878

[0011] Patent Document 3: Japanese Patent Application No. 2015-503541

[0012] Patent Document 4: Japanese Patent Application Laid-Open No. 2014-177428

[0013] Patent Document 5: Japanese Patent Application Laid-Open No. 2013-079220

[0014] Patent Document 6: Japanese Patent Application No. 2006-513195

[0015] Patent Document 7: Japanese Patent Application No. 2012-504609

[0016] Patent Document 8: Japanese Patent Application No. 2013-515041

[0017] Patent Document 9: Japanese Patent Application No. 2017-515871 Summary of the Invention

[0018] Problems to be solved by the invention

[0019] However, the present inventors conducted further studies on rotigotine-containing patches containing rotigotine and / or a pharmaceutically acceptable salt thereof, and found that even when silicone adhesives or acrylic adhesives, which have been commonly used in combination with rotigotine, or when only rubber adhesives such as polyisobutylene are used as adhesive bases contained in the adhesive layer of the patch, the long-term stability of rotigotine and / or its pharmaceutically acceptable salt may not be sufficient under particularly harsh storage conditions, and a higher level of long-term stability is required.

[0020] The present invention has been made in view of the above-mentioned problems, and an object of the present invention is to provide a method for stabilizing rotigotine that can stabilize rotigotine and / or a pharmaceutically acceptable salt thereof in an adhesive layer of a patch containing a styrene-based thermoplastic elastomer at a high level.

[0021] Means for solving problems

[0022] The present inventors have diligently studied to achieve the above-mentioned objectives and, as a result, have discovered that, in a rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from rotigotine and its pharmaceutically acceptable salts (hereinafter referred to as "rotigotine and / or its pharmaceutically acceptable salts") and a styrene-based thermoplastic elastomer, by further incorporating cross-linked polyvinyl pyrrolidone within a specific content range in the adhesive layer, rotigotine and / or its pharmaceutically acceptable salts can be stabilized at a high level even under long-term and harsh conditions. This has led to the completion of the present invention.

[0023] That is, the method for stabilizing rotigotine of the present invention is characterized in that:

[0024] A method for stabilizing rotigotine and / or its pharmaceutically acceptable salt in a rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains rotigotine and / or its pharmaceutically acceptable salt and a styrene-based thermoplastic elastomer, and

[0025] The adhesive layer further contains cross-linked polyvinyl pyrrolidone so that the content in the adhesive layer becomes 3 to 25% by mass.

[0026] In the method for stabilizing rotigotine of the present invention, the content of rotigotine and / or a pharmaceutically acceptable salt thereof in the adhesive layer is preferably 5 to 15% by mass in terms of free rotigotine.

[0027] In the rotigotine stabilization method of the present invention, it is preferred that the mass ratio of the content of the rotigotine and / or its pharmaceutically acceptable salt converted to free rotigotine to the content of the cross-linked polyvinyl pyrrolidone in the adhesive layer (rotigotine free body content of rotigotine and / or its pharmaceutically acceptable salt converted to rotigotine:cross-linked polyvinyl pyrrolidone content) be 15:3 to 5:25.

[0028] Furthermore, in the rotigotine stabilization method of the present invention, the adhesive layer preferably further contains an imidazole antioxidant, and more preferably the content of the imidazole antioxidant in the adhesive layer is 0.05 to 2% by mass.

[0029] Furthermore, in the rotigotine stabilization method of the present invention, it is preferred that the adhesive layer further contain an aliphatic alcohol. It is also preferred that the adhesive layer further contain a petroleum resin and / or a terpene resin.

[0030] Effects of the Invention

[0031] According to the present invention, there is provided a method for stabilizing rotigotine, which is capable of stabilizing rotigotine and / or a pharmaceutically acceptable salt thereof in an adhesive layer of a patch containing a styrene-based thermoplastic elastomer at a high level. DETAILED DESCRIPTION

[0032] The present invention will be described in detail below with reference to preferred embodiments thereof. The rotigotine stabilization method of the present invention is a method for stabilizing rotigotine and / or its pharmaceutically acceptable salt in a rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer comprises rotigotine and / or its pharmaceutically acceptable salt and a styrene-based thermoplastic elastomer, wherein:

[0033] The adhesive layer further contains cross-linked polyvinyl pyrrolidone so that the content in the adhesive layer becomes 3 to 25% by mass.

[0034] The rotigotine-containing patch of the present invention comprises a support layer and an adhesive layer. As the above-mentioned support layer, there is no particular limitation as long as it can support the adhesive layer described below, and a support layer known as a support layer of a patch can be appropriately adopted. As the material of the support layer of the present invention, for example, there can be mentioned: polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, vinyl acetate-vinyl chloride copolymers, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate, polyethylene naphthalate; cellulose derivatives; synthetic resins such as polyurethane, or metals such as aluminum. Among them, from the viewpoint of drug non-adsorbability or drug non-permeability, polyester and polyethylene terephthalate are preferred. As the form of the above-mentioned support layer, for example, there can be mentioned: films; sheets such as sheets, sheet-like porous bodies, sheet-like foams; fabrics such as woven fabrics, knitted fabrics, and non-woven fabrics; foils; and laminates thereof. The thickness of the support layer is not particularly limited, but is preferably within a range of 5 to 1000 μm from the viewpoint of ease of work when applying the patch and ease of production.

[0035] The rotigotine-containing patch of the present invention may further include a release liner on the surface of the adhesive layer opposite the support layer. Examples of such release liners include films or sheets made of the following materials, and laminates thereof: polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, vinyl acetate-vinyl chloride copolymers, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; synthetic resins such as polyurethane; aluminum, paper, etc. These release liners are preferably those whose surface in contact with the adhesive layer has been subjected to a release treatment such as a coating containing an organosilicon compound or a fluorine-containing compound to facilitate release from the adhesive layer.

[0036] <Rotigotine and its pharmaceutically acceptable salts>

[0037] The adhesive layer of the present invention contains at least one drug selected from rotigotine and its pharmaceutically acceptable salts (rotigotine and / or its pharmaceutically acceptable salts) as a drug. In the present invention, the rotigotine contained in the adhesive layer may be in the form of a free form, a pharmaceutically acceptable salt thereof, or a free form obtained by desalting a pharmaceutically acceptable salt of rotigotine during production and / or in the manufactured formulation. It may be one of these or a mixture of two or more. Pharmaceutically acceptable salts of rotigotine include acid addition salts. Examples of acids in these acid addition salts include hydrochloric acid, sulfuric acid, nitric 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. Among these, the adhesive layer of the present invention preferably contains rotigotine in a free form.

[0038] In the rotigotine stabilization method 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 shall apply hereinafter) is preferably 5 to 15% by mass, more preferably 7 to 15% by mass, further preferably 7 to 12% by mass, and still more preferably 8 to 10% by mass, calculated as free rotigotine, relative to the total mass of the adhesive layer (in this specification, the "total mass of the adhesive layer" means the total mass of the adhesive layer in the patch after production (after containing the cross-linked polyvinyl pyrrolidone described below and, if necessary, an imidazole-based antioxidant, an aliphatic alcohol, a petroleum-based resin, and / or a terpene-based resin, the same shall apply hereinafter)). If the content of rotigotine and / or its pharmaceutically acceptable salt is below the above lower limit, the skin permeability of rotigotine tends to decrease. On the other hand, if the content exceeds the above upper limit, rotigotine and / or its pharmaceutically acceptable salt tends to be stabilized even if cross-linked polyvinyl pyrrolidone is not contained in the adhesive layer. In addition, crystals of rotigotine and / or its pharmaceutically acceptable salt tend to precipitate, forming an amorphous form, or the adhesive strength of the adhesive layer tends to be easily reduced.

[0039] <Styrene-based thermoplastic elastomer>

[0040] The adhesive layer of the present invention contains a styrene-based thermoplastic elastomer as an adhesive base. The styrene-based thermoplastic elastomer of the present invention is a thermoplastic styrene-based elastomer that softens and exhibits fluidity when heated and returns to a rubbery elastic state when cooled. Among them, styrene-based block copolymers are preferred from the perspective of imparting sufficient adhesiveness and temporal stability.

[0041] As the above-mentioned styrene-based block copolymer, specifically, styrene-butadiene block copolymer, styrene-butadiene-styrene block copolymer (SBS), styrene-isoprene block copolymer, styrene-isoprene-styrene block copolymer (SIS), 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, etc., can be used alone or in combination of two or more. It should be noted that, in the above, "ethylene / butylene" represents a copolymer block of ethylene and butene, and "ethylene / propylene" represents a copolymer block of ethylene and propylene. Among them, as the styrene-based thermoplastic elastomer of the present invention, more preferably styrene-isoprene-styrene block copolymer.

[0042] 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 preparation properties of the patch (particularly the cohesive strength of the adhesive layer) tend to be reduced. On the other hand, if the viscosity-average molecular weight exceeds the upper limit, the compatibility with other components contained in the adhesive layer tends to be reduced, making the production of the patch difficult.

[0043] In the rotigotine stabilization method of the present invention, the content of the styrene-based thermoplastic elastomer in the adhesive layer is preferably 5 to 80% by mass, more preferably 5 to 50% by mass, more preferably 10 to 40% by mass, and even more preferably 10 to 30% by mass, relative to the total mass of the adhesive layer. If the content of the styrene-based thermoplastic elastomer is less than the lower limit, the cohesive force and shape retention of the adhesive layer tend to decrease. On the other hand, if the content exceeds the upper limit, the cohesive force of the adhesive layer tends to increase excessively, resulting in a decrease in the adhesive force and compatibility of the adhesive layer.

[0044] Cross-linked polyvinyl pyrrolidone

[0045] In the rotigotine stabilization method of the present invention, the adhesive layer containing at least rotigotine and / or a pharmaceutically acceptable salt thereof and a styrene-based thermoplastic elastomer contains cross-linked polyvinyl pyrrolidone (also referred to as "cross-linked PVP").

[0046] As the cross-linked polyvinyl pyrrolidone of the present invention, cross-linked N-vinyl pyrrolidone polymers can be mentioned. As the above-mentioned N-vinyl pyrrolidone polymer, it can be a homopolymer or a copolymer, for example, a homopolymer of N-vinyl pyrrolidone, a copolymer of N-vinyl pyrrolidone and a polyfunctional monomer can be mentioned. Among them, as the cross-linked polyvinyl pyrrolidone of the present invention, a cross-linked homopolymer of 1-vinyl-2-pyrrolidone (also referred to as "cross-linked polyvinyl pyrrolidone") is preferred. As cross-linked polyvinyl pyrrolidone, commercially available products such as Coridon CL, Coridon CL-M (manufactured by BASF Japan Co., Ltd.); Polyplasticone XL, Polyplasticone XL-10, Polyplasticone INF-10 (manufactured by ISP Japan Co., Ltd.) can also be used.

[0047] The amount of cross-linked polyvinyl pyrrolidone contained in the adhesive layer must be an amount that is 3 to 25% by mass relative to the total mass of the adhesive layer. If the content of cross-linked polyvinyl pyrrolidone in the adhesive layer is lower than the lower limit, the rotigotine stabilization effect of rotigotine and / or its pharmaceutically acceptable salt for a long period of time under particularly harsh conditions cannot be fully exerted. On the other hand, if the upper limit is exceeded, the skin permeability of rotigotine is reduced, or the compatibility in the adhesive layer composition during production is reduced, making production difficult. From the same viewpoint, the content of cross-linked polyvinyl pyrrolidone in the adhesive layer is more preferably 3 to 20% by mass, more preferably 3 to 15% by mass, and even more preferably 4 to 15% by mass.

[0048] In the rotigotine stabilization method of the present invention, the mass ratio of the content of rotigotine and / or its pharmaceutically acceptable salt as free rotigotine to the content of cross-linked polyvinyl pyrrolidone in the adhesive layer (rotigotine free body content of rotigotine and / or its pharmaceutically acceptable salt:cross-linked polyvinyl pyrrolidone content) is preferably 15:3 to 5:25, more preferably 15:3 to 5:20, and even more preferably 15:3 to 5:15. If the content of the cross-linked polyvinyl pyrrolidone relative to rotigotine and / or its pharmaceutically acceptable salt is below the lower limit, crystals of rotigotine and / or its pharmaceutically acceptable salt tend to precipitate. On the other hand, if the content exceeds the upper limit, achieving excellent skin permeability of rotigotine tends to be difficult.

[0049] Furthermore, when the amount of cross-linked polyvinyl pyrrolidone contained in the adhesive layer is less than 4% by mass (preferably 3.95% by mass or less) relative to the total mass of the adhesive layer, it is also preferred that the mass ratio in the adhesive layer (rotigotine free form content of rotigotine and / or its pharmaceutically acceptable salt: cross-linked polyvinyl pyrrolidone content) be 15:3 to 12:3 or 7:3 to 5:15 (more preferably 7:3 to 5:15 from the viewpoint of inhibiting crystal precipitation or amorphous formation of rotigotine and / or its pharmaceutically acceptable salt).

[0050] <Antioxidants>

[0051] As a method for stabilizing rotigotine of the present invention, it is preferred that the adhesive layer further contain an antioxidant. In the present invention, by containing an antioxidant in addition to cross-linked polyvinyl pyrrolidone in the adhesive layer, a higher level of stability over time tends to be achieved.

[0052] Examples of the antioxidant include imidazole-based antioxidants (such as 2-mercaptobenzimidazole). These may be used alone or in combination of two or more. Among these, 2-mercaptobenzimidazole is particularly preferred.

[0053] In this case, the content of the antioxidant contained in the adhesive layer (when it is a combination of two or more, it is the total content of these antioxidants, and the same applies hereinafter. The content of the imidazole-based antioxidant is preferred, and the content of 2-mercaptobenzimidazole is more preferred) is preferably 0.05 to 2% by mass, more preferably 0.05 to 1.5% by mass, and even more preferably 0.05 to 1.0% by mass relative to the total mass of the adhesive layer. If the content of the antioxidant is less than the lower limit, there is a tendency that the further stabilization effect obtained by the antioxidant cannot be fully exerted. On the other hand, if it exceeds the upper limit, there is a possibility that the physical properties of the adhesive layer, such as the adhesion, may be reduced.

[0054] <Petroleum-based resins, terpene-based resins>

[0055] In the rotigotine stabilization method of the present invention, it is preferred that the adhesive layer further contain at least one selected from petroleum resins and terpene resins (petroleum resin and / or terpene resin). In the rotigotine stabilization method of the present invention, the adhesive layer containing the petroleum resin and / or terpene resin tends to achieve a high level of skin permeability and suppress the formation of rotigotine analogs, thereby further improving the stability over time.

[0056] (Petroleum-based resin)

[0057] Examples of the petroleum resins of the present invention include: C5-based 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-based synthetic petroleum resins (copolymers of at least two of indene, styrene, methylindene, and α-methylstyrene, etc.), and dicyclopentadiene-based synthetic petroleum resins (copolymers of dicyclopentadiene as a main component with isoprene and / or 1,3-pentadiene). In addition, from the viewpoint of another classification, for example, alicyclic petroleum resins (alicyclic saturated hydrocarbon resins, etc.), alicyclic hydrogenated petroleum resins, aliphatic petroleum resins (aliphatic hydrocarbon resins, etc.), aliphatic hydrogenated petroleum resins, aromatic petroleum resins, more specifically, Alcon P-70, Alcon P-85, Alcon P-90, Alcon P-100, Alcon P-115, Alcon P-125 (the above are trade names, manufactured by Arakawa Chemical Industries, Ltd.), and Escolex 8000 (trade name, manufactured by Esso Petrochemical Co., Ltd.) As the petroleum resin of the present invention, one of these may be used alone, or two or more thereof may be used in combination. Among them, alicyclic saturated hydrocarbon resins are more preferred from the viewpoints of easily obtaining suitable adhesion to the skin, having a good feel during use due to less odor, and further suppressing the formation of rotigotine analogs.

[0058] In the present invention, the alicyclic saturated hydrocarbon resin refers to 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 1,500, more preferably 1,200 to 1,400.

[0059] (Terpene resin)

[0060] Examples of the terpene resin of the present invention include pinene polymers (α-pinene polymers, β-pinene polymers, etc.), terpene polymers, dipentene polymers, terpene-phenol polymers, aromatic modified terpene polymers, and pinene-phenol copolymers. More specifically, examples include YS Regin (YS Regin PXN (1150N, 300N), YS Regin PX100, and YS Regin PX200. 0, YS Regin TO125, YS Regin TO105, etc.), Clearon P105, Clearon M115, Clearon K100 (these are trade names, manufactured by Yashara Chemical Co., Ltd.), and Tamanol 901 (trade name, manufactured by Arakawa Chemical Industries, Ltd.). Any one of these may be used alone or in combination of two or more. Among these, as the terpene resin of the present invention, pinene polymers are more preferred from the viewpoints of obtaining suitable adhesion to the skin and having a good feel during use due to low odor, etc.

[0061] In the present invention, the content of the petroleum resin and / or terpene resin contained in the adhesive layer (the content of the petroleum resin or terpene resin, or the total content when both are contained, the same shall apply hereinafter) is preferably 5 to 80% by mass, more preferably 10 to 70% by mass, further 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 resin and / or terpene resin is below the lower limit, the adhesive strength or adhesion to the skin of the adhesive layer may be reduced, or the effect of inhibiting the production of rotigotine analogs may not be fully exerted. On the other hand, if the content exceeds the upper limit, the transdermal absorption of the drug or the shape retention of the adhesive layer may be reduced.

[0062] <Aliphatic alcohols>

[0063] As a method for stabilizing rotigotine of the present invention, it is preferred that the adhesive layer further contain an aliphatic alcohol. In the present invention, the aliphatic alcohol refers to a saturated or unsaturated, linear or branched, monovalent or divalent or higher aliphatic alcohol.

[0064] The aliphatic alcohol of the present invention is preferably a monohydric alcohol. Furthermore, the aliphatic alcohol of the present invention preferably has 3 to 23 carbon atoms, more preferably 12 to 23 carbon atoms, further preferably 17 to 23 carbon atoms, particularly preferably 19 to 21 carbon atoms, and particularly preferably 12 to 20 carbon atoms from the perspective of skin permeability. If the carbon number of 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 thus reducing stability over time. On the other hand, if the carbon number exceeds the upper limit, compatibility with the adhesive base or other components tends to decrease.

[0065] Examples of the aliphatic alcohols of the present invention include isopropyl alcohol, hexyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, octyldodecanol, oleyl alcohol, linolenic alcohol, and hexyldecanol. One of these may be used alone, or two or more may be used in combination. Among these, at least one selected from octyldodecanol and lauryl alcohol is particularly preferred as the aliphatic alcohol of the present invention from the perspectives of the above-mentioned stability over time and compatibility, and from the perspective of a tendency to particularly improve the skin permeability of rotigotine.

[0066] In the present invention, the content of the aliphatic alcohol contained in the adhesive layer, when two or more types are present, is preferably 1 to 15% by mass, more preferably 1 to 10% by mass, further 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 tends to decrease. On the other hand, if the content exceeds the upper limit, the compatibility with the adhesive base and other components tends to decrease.

[0067] <Other ingredients>

[0068] The adhesive layer of the rotigotine-containing patch that is the subject of the rotigotine stabilization method of the present invention may further contain, within a range that does not inhibit the effects of the present invention: other drugs other than rotigotine and its pharmaceutically acceptable salts; other adhesive bases other than the above-mentioned styrene-based thermoplastic elastomers; other tackifiers other than the above-mentioned petroleum-based resins and terpene-based resins; other absorption enhancers other than the above-mentioned aliphatic alcohols; and additives such as adsorbents, desalting agents, plasticizers, solubilizers, fillers, stabilizers, and preservatives.

[0069] (Other drugs)

[0070] 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, ethylene glycol salicylate, valdecoxib, celecoxib, rofecoxib, amfenac, etc.), antipyretic analgesics (acetaminophen, dapoxetine ... phenol, etc.), antihistamines (diphenhydramine, chlorpheniramine, mequitazine, homochlorcyclizine, etc.), antihypertensive drugs (diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril, etc.), anti-Parkinson's disease drugs (pergolide, ropinirole, bromocriptine, selegiline, etc.), bronchodilators (tobutrol, isoproterenol, salbutamol, etc.), antiallergic drugs (ketotifen, loratadine, azelastine, terfenadine, cetirizine, azakast, etc.) , local anesthetics (lidocaine, dibucaine, etc.), neuropathic pain medications (pregabalin, etc.), non-narcotic analgesics (butylmorphine, tramadol, pentazocine), narcotic analgesics (morphine, oxycodone, fentanyl, etc.), urinary tract medications (oxybutynin, tamsulosin, etc.), psychotropic medications (promazine, chlorpromazine, etc.), steroid hormones (estradiol, progesterone, norethindrone, cortisone, hydrocortisone, etc.), antidepressants (sertraline, etc.), The present invention also includes antidementia drugs (such as levofloxacin, fluoxetine, paroxetine, and citalopram), antidementia drugs (such as donepezil, rivastigmine, and galantamine), antipsychotic drugs (such as risperidone and olanzapine), central nervous system stimulants (such as methylphenidate), osteoporosis treatment drugs (such as raloxifene and alendronate), breast cancer prevention drugs (such as tamoxifen), anti-obesity drugs (such as mazindol and nometin), insomnia improvement drugs (such as melatonin), and anti-rheumatic drugs (such as actarit). Any one of these drugs may be used alone, or two or more of them may be used in combination.

[0071] In the present invention, when the adhesive layer further contains these other drugs, the total content thereof, when two or more drugs are present, is preferably 10% by mass or less relative to the total mass of the adhesive layer.

[0072] (Other adhesive bases)

[0073] As other adhesive bases other than the above-mentioned styrene-based thermoplastic elastomer, for example, rubber-based adhesive bases other than the above-mentioned styrene-based thermoplastic elastomer, acrylic-based adhesive bases, and silicone-based adhesive bases can be listed. One of these can be used alone, or two or more can be used in combination.

[0074] Examples of rubber-based adhesive bases other than the above-mentioned styrene-based thermoplastic elastomers include isoprene rubber, polyisobutylene (PIB), and polybutene. One of these may be used alone, or two or more may be used in combination. Among these, polyisobutylene is preferably used from the perspective of further improving the adhesion and cohesive force of the adhesive layer. In this case, the mass ratio of the styrene-based thermoplastic elastomer (more preferably a styrene-isoprene-styrene block copolymer) to the polyisobutylene (mass of the styrene-based thermoplastic elastomer:mass of the PIB) is more preferably 1:2 to 30:1 (more preferably in the range of 1:1 to 10:1).

[0075] Examples of the acrylic adhesive base include acrylic acid-octyl acrylate copolymers, 2-ethylhexyl acrylate-vinyl pyrrolidone copolymers, acrylate-vinyl acetate copolymers, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymers, methyl acrylate-2-ethylhexyl acrylate copolymer resins, 2-ethylhexyl acrylate-methyl acrylate-acrylic acid-glycidyl methacrylate copolymers, 2-ethylhexyl acrylate-vinyl acetate-hydroxyethyl acrylate-glycidyl methacrylate copolymers, 2-ethylhexyl acrylate-diacetone acrylamide-acetoacetoxyethyl methacrylate-methyl methacrylate copolymers, ethyl acrylate-methyl methacrylate copolymers, and acrylic polymers contained in acrylic resin alkanolamine solutions. These may be used alone or in combination of two or more.

[0076] Examples of the above-mentioned silicone adhesive base include polydimethylsiloxane (polymers represented as MQ in ASTM D-1418, etc.), polymethylvinylsiloxane (polymers represented as VMQ in ASTM D-1418, etc.), polymethylphenylsiloxane (polymers represented as PVMQ in ASTM D-1418, etc.), and the like. One of these may be used alone, or two or more may be used in combination.

[0077] In the present invention, when these other adhesive bases are further contained, the content thereof, when two or more types are present, is preferably 10% by mass or less in total relative to the total mass of the adhesive layer.

[0078] (Other tackifiers)

[0079] In the rotigotine-containing patch of the present invention, the tackifier is mixed primarily for the purpose of improving the tackiness of the adhesive base. Examples of the other tackifiers include tackifier resins other than the petroleum resins and terpene resins, such as rosin resins, phenolic resins, and xylene resins. One of these may be used alone, or two or more may be used in combination. In the present invention, when these other tackifiers are further included, their total content, when two or more are present, is preferably 10% by mass or less relative to the total mass of the adhesive layer.

[0080] (Other absorption enhancers (transdermal absorption enhancers))

[0081] Examples of the aforementioned other absorption enhancers include substances other than the aforementioned aliphatic alcohols that have a transdermal absorption-enhancing effect on drugs, such as: fatty acids, fatty acid esters, fatty acid amides, or aliphatic alcohol ethers having 6 to 20 carbon atoms; aromatic organic acids; aromatic alcohols; aromatic organic acid esters or ethers; POE hydrogenated castor oils; lecithins; phospholipids; soybean oil derivatives; and triacetin. These may be used alone or in combination of two or more. In the present invention, when these absorption enhancers are further included, their total content, when two or more are present, is preferably 10% by weight or less relative to the total mass of the adhesive layer.

[0082] (additive)

[0083] [Adsorbent]

[0084] Examples of the adsorbent include hygroscopic inorganic and / or organic substances, more specifically minerals such as talc, kaolin, and bentonite; silicon compounds such as fumed silica (Aerosil (registered trademark) and hydrous 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 polyvinyl pyrrolidone (non-crosslinked PVP), aminoalkyl methacrylate copolymers, carboxyvinyl polymers, and butyl methacrylate / methyl methacrylate copolymers. Any one of these adsorbents may be used alone, or two or more may be used in combination. In the present invention, when the adhesive layer further contains these adsorbents, their total content, when two or more adsorbents are present, is preferably 10% by mass or less relative to the total mass of the adhesive layer.

[0085] [Desalting agent]

[0086] The above-mentioned desalting agent is mixed mainly for the purpose of converting all or part of the alkaline drug into a free form. As such a desalting agent, there is no particular limitation. For example, when the above-mentioned drug is mixed with an acid addition salt of the drug to obtain a preparation containing a free form, it is preferably an alkaline substance, more preferably a desalting agent containing metal ions, or an alkaline desalting agent containing nitrogen atoms. As the above-mentioned desalting agent containing metal ions, there can be listed: sodium acetate (including anhydrous sodium acetate), sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium citrate, sodium lactate, etc., and one of them can be used alone, or two or more can be used in combination. It should be noted that, as the adhesive layer of the present invention, it can also further contain a compound derived from the above-mentioned alkaline drug and the above-mentioned desalting agent (for example, sodium chloride when rotigotine hydrochloride is combined with sodium acetate). In the present invention, when the adhesive layer further contains these desalting agents and compounds derived from basic drugs and desalting agents, their total content, when two or more types are present, is preferably 10% by mass or less relative to the total mass of the adhesive layer.

[0087] [Plasticizer]

[0088] The plasticizer is mixed primarily for the purpose of adjusting the adhesive properties of the adhesive layer, the flow characteristics during 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 paraffin-based processing oils, cycloparaffin-based processing oils, and aromatic processing oils; squalane and squalene; plant 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 polybutene and liquid isoprene rubber; diethylene glycol, polyethylene glycol, propylene glycol, and dipropylene glycol. Any one of these may be used alone, or two or more may be used in combination. Among these, the plasticizer is preferably one or a combination of two or more selected from silicone oil, liquid paraffin, and liquid polybutene. In the present invention, when the adhesive layer further contains these plasticizers, their content, when there are two or more types, is preferably 5 to 30% by mass, more preferably 10 to 20% 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 alleviating local irritation during peeling.

[0089] [Dissolving agents, fillers]

[0090] Examples of the dissolving agent include organic acids such as acetic acid and surfactants. These may be used alone or in combination of two or more. Furthermore, the filler is blended primarily for the purpose of adjusting the adhesive strength of the adhesive layer. Examples of such fillers include aluminum hydroxide, calcium carbonate, magnesium carbonate; silicates such as aluminum silicate or magnesium silicate; silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, and titanium oxide. These may be used alone or in combination of two or more.

[0091] [Stabilizer]

[0092] Examples of the stabilizer include ascorbic acid or a metal salt or ester thereof (preferably a sodium salt or palmitate), isoascorbic acid or a metal salt thereof (preferably a sodium salt), ethylenediaminetetraacetic acid or a metal salt thereof (preferably a calcium disodium salt or a tetrasodium salt), cysteine, acetylcysteine, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, pentaerythritol-tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], 3-mercapto-1,2-propanediol, tocopheryl acetate, thymol, soybean lecithin, rutin, dihydroxybenzoic acid, potassium dichloroisocyanurate, quercetin, hydroquinone, a hydroxymethanesulfinic acid metal salt (preferably a sodium salt), a pyrosulfite metal salt (for example, a sodium salt), a sulfite metal salt (preferably a sodium salt), and a thiosulfate metal salt (preferably a sodium salt). These may be used alone or in combination of two or more. Among the above, examples of metal salts include sodium salts, potassium salts, calcium salts, and magnesium salts, and examples of esters include palmitic acid ester, stearic acid ester, and myristate ester.

[0093] In the present invention, when the adhesive layer further contains these stabilizers, the content thereof, when two or more types are present, is preferably 10% by mass or less in total relative to the total mass of the adhesive layer.

[0094] [Preservative]

[0095] Examples of the preservative include p-hydroxybenzoic acid derivatives, benzyl alcohol, phenol, and cresol. These may be used alone or in combination of two or more.

[0096] When the adhesive layer further contains the above-mentioned additives, the total content thereof, when two or more types are present, is preferably 40% by mass or less, more preferably 30% by mass or less, relative to the total mass of the adhesive layer.

[0097] The adhesive layer of the present invention is not particularly limited, but preferably has a mass per unit area (the area of the attachment surface) (thickness after production) of 20 to 200 g / m 2, more preferably 30 to 100 g / m 2 , more preferably 30 to 70 g / m 2 In addition, the area of the adhesive surface of the adhesive layer of the present invention (the area after manufacturing) can be appropriately adjusted according to the purpose of treatment or the object of application, and is not particularly limited. It is usually 0.5 to 200 cm 2 range.

[0098] The rotigotine stabilization method of the present invention is a method in which the adhesive layer of the rotigotine-containing patch contains cross-linked polyvinyl pyrrolidone in the specific amount.

[0099] The patch containing rotigotine is not particularly limited and can be manufactured by appropriately adopting a known method for manufacturing a patch. For example, first, rotigotine and / or its pharmaceutically acceptable salt, the above-mentioned styrene-based thermoplastic elastomer, and optionally a solvent or the above-mentioned other components are mixed according to a conventional method to obtain a uniform adhesive layer composition. When using free rotigotine as the above-mentioned rotigotine and / or its pharmaceutically acceptable salt, it can be type I crystal, type II crystal, or amorphous form, or a mixture of at least two of type I crystal, type II crystal, and amorphous form. In addition, as the above-mentioned rotigotine and / or its pharmaceutically acceptable salt, substances that dissolve in the above-mentioned solvents can also be used. Examples of the above-mentioned solvents include: anhydrous ethanol, toluene, heptane, methanol, ethyl acetate, hexane, and mixtures of at least two of these.

[0100] Next, the adhesive layer composition is spread on one surface (usually one surface) of the support layer to achieve a desired mass per unit area, and then heated as needed to dry and remove the solvent to form an adhesive layer. The adhesive layer is then cut into a desired shape as needed to obtain the rotigotine-containing patch of the present invention.

[0101] The method for producing the rotigotine-containing patch may further include the step of laminating the release liner to the surface of the adhesive layer opposite to the support layer. Alternatively, the adhesive layer composition may be first spread on one surface of the release liner to achieve a desired mass per unit area to form the adhesive layer. The support layer may then be laminating to the surface of the adhesive layer opposite to the release liner, and the patch may be cut into a desired shape as needed, thereby obtaining the rotigotine-containing patch of the present invention. Furthermore, the obtained patch may be sealed in a storage container (e.g., an aluminum laminate bag) as needed to form a package.

[0102] In the rotigotine stabilization method of the present invention, the method for incorporating cross-linked polyvinyl pyrrolidone into the adhesive layer is not particularly limited. For example, the following method can be used: in the method for producing the rotigotine-containing patch, cross-linked polyvinyl pyrrolidone is added to rotigotine and / or a pharmaceutically acceptable salt thereof, the styrene-based thermoplastic elastomer, and, if necessary, the solvent or other components so that the cross-linked polyvinyl pyrrolidone content becomes the above-mentioned specific amount. Furthermore, the above-mentioned antioxidant, the above-mentioned petroleum-based resin and / or terpene-based resin, the above-mentioned aliphatic alcohol, etc. are optionally added, and the mixture is kneaded according to a conventional method to obtain a uniform adhesive layer composition, which is used as the above-mentioned adhesive layer composition.

[0103] Example

[0104] The present invention will be described in more detail below based on Examples and Comparative Examples, but the present invention is not limited to the following Examples. In each Example and Comparative Example, the skin permeation test and stability evaluation were performed by the following methods.

[0105] Skin permeation test (in vitro hairless mouse skin permeation test)

[0106] First, the skin of the trunk of a hairless mouse was peeled and fat was removed. The stratum corneum side of the fat-removed skin piece was cut into 1.0 cm pieces. 2 A square patch with the release liner removed was used to prepare a sample. The patch was placed in a flow-through diffusion tank with the dermis side in contact with the receptor solution. The tank was filled with the receptor solution (phosphate-buffered saline). Next, warm circulating water was circulated around the periphery to maintain the receptor solution at 32°C. The receptor solution was delivered at a flow rate of approximately 5 mL / hr, and the receptor solution was collected every two hours for 24 hours. The rotigotine concentration in the collected receptor solution was determined by high-performance liquid chromatography using the following formula:

[0107] Rotigotine skin permeation (μg / cm 2 ) = {rotigotine concentration in receptor solution (μg / mL) × flow rate (mL)} / patch area (cm 2 ),

[0108] The amount of rotigotine permeated through the skin per unit area of the adhesive layer was calculated, and the amount of permeation through the skin permeation per hour (skin permeation rate (μg / cm 2 The measurement was performed on two samples, and the average of the maximum values of the skin permeation rates within 24 hours was defined as the maximum skin permeation rate (Jmax).

[0109] <Stability evaluation>

[0110] The patches obtained in each example and comparative example were sealed in aluminum laminated bags to prepare samples, which were stored at 60°C for two weeks. The peeling liner was removed from the patch after storage, and the adhesive layer was dissolved in tetrahydrofuran. The following mobile phase liquid was added to the obtained solution in a manner to make a total amount of 50 mL, and filtered using a filter. The substance thus obtained was used as a sample solution, and a high performance liquid chromatography apparatus (manufactured by Shimadzu Corporation, column: ODS column, mobile phase liquid: a mixed solution of acetonitrile and 0.1% phosphate buffer containing 0.01 mol / L sodium lauryl sulfate (55:45), detection wavelength: 225 nm) was used to determine the peak area of rotigotine in the sample solution. In addition, for the sample before storage (immediately after production), the peak area of rotigotine in the sample solution was also determined in the same manner. Then, the following formula was used:

[0111] Rotigotine content change [mass %] = A / B × 100

[0112] [wherein, A represents the peak area of rotigotine in the sample after storage, and B represents the peak area of rotigotine in the sample before storage]

[0113] The change in rotigotine content (mass %) in the adhesive layer of each patch due to storage was calculated and used as the value for stability evaluation. The peak area appearing near 6.5 was defined as the peak area of rotigotine.

[0114] (Example 1)

[0115] First, 9.0 parts by mass of rotigotine (free form), 13.36 parts by mass of styrene-isoprene-styrene block copolymer, 5.72 parts by mass of polyisobutylene, 48.66 parts by mass of alicyclic saturated hydrocarbon resin, 15.26 parts by mass of liquid paraffin, and 5 parts by mass of octyldodecanol were added with 3 parts by mass of cross-linked polyvinyl pyrrolidone (cross-linked PVP), and the mixture was added to an appropriate amount of solvent (anhydrous ethanol and toluene) and mixed to obtain an adhesive layer composition. Next, the obtained adhesive layer composition was spread on a release liner (polyethylene terephthalate film that had been subjected to a release treatment) and dried to remove the solvent, so that the mass per unit area became 50 g / m 2 A support layer (polyethylene terephthalate film) was laminated on the surface of the obtained adhesive layer opposite to the release liner to obtain a patch having support layer / adhesive layer / release liner laminated in this order.

[0116] (Examples 2 to 6, Comparative Examples 1 to 3)

[0117] Each patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition (excluding the solvent) was changed to the composition shown in Table 1 below.

[0118] The patches obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were subjected to skin permeation tests and stability evaluations (two weeks after production, at 60°C). The results of the stability evaluations are shown in Table 1, along with the composition of the adhesive layer composition (excluding the solvent) of each Example and Comparative Example. The results of the skin permeation tests showed that Examples 1 to 6 achieved sufficiently excellent maximum skin permeation rates (Jmax) [μg / cm 2 / hr] (e.g., 12.5 μg / cm in Example 6) 2 / hr).

[0119] [Table 1]

[0120]

[0121] (Examples 7 to 9)

[0122] Each patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition (excluding the solvent) was changed to the composition shown in Table 2 below.

[0123] Stability evaluation (two weeks after production, 60° C.) was performed on the patches obtained in Examples 7 to 9. The results of the stability evaluation are shown in Table 2 together with the composition of the adhesive layer composition (excluding the solvent) of each example.

[0124] [Table 2]

[0125]

[0126] The results shown in Tables 1 and 2 indicate that in patches containing a specific amount of cross-linked polyvinyl pyrrolidone in the adhesive layer (e.g., Examples 1 to 9), even under harsh conditions of a temperature of 60°C, the rotigotine content in the adhesive layer remained unchanged compared to immediately after production and remained at a high level two weeks after production, confirming that rotigotine was stabilized at a high level. Furthermore, it was confirmed that further inclusion of 2-mercaptobenzimidazole in the adhesive layer (e.g., Examples 2, 5, and 6) resulted in even better stability. On the other hand, although the patches obtained in Comparative Examples 1 to 3 were confirmed to have sufficiently high rotigotine contents after storage, their stability was low compared to the patches obtained by implementing the rotigotine stabilization method of the present invention (e.g., Comparative Example 1). Even when 2-mercaptobenzimidazole was further incorporated as an antioxidant into the adhesive layer (e.g., Comparative Examples 2 and 3), the stability of rotigotine was not improved to the level of the patches obtained by implementing the rotigotine stabilization method of the present invention.

[0127] Industrial applicability

[0128] As described above, the present invention provides a method for stabilizing rotigotine that can stabilize rotigotine and / or a pharmaceutically acceptable salt thereof in an adhesive layer of a patch containing a styrene-isoprene-styrene block copolymer at a high level.

Claims

1. A method for stabilizing rotigotine, comprising stabilizing rotigotine and / or its pharmaceutically acceptable salt in a rotigotine-containing patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains rotigotine and / or its pharmaceutically acceptable salt and a styrene-based thermoplastic elastomer. in, The adhesive layer further contains cross-linked polyvinyl pyrrolidone so as to be 3 to 25% by mass in the adhesive layer, and further contains an alicyclic saturated hydrocarbon resin so as to be 20 to 60% by mass in the adhesive layer. The content of the styrene-based thermoplastic elastomer in the adhesive layer is 10 to 30% by mass relative to the total mass of the adhesive layer. The evaluation criteria for the stability of rotigotine and / or its pharmaceutically acceptable salt are changes in the rotigotine content (in mass %) in the adhesive layer due to storage of the patch. Except for the method of obtaining the following patch, Specifically, the components listed in the table below were added to appropriate amounts of anhydrous ethanol and toluene as solvents and mixed to obtain an adhesive layer composition. The obtained adhesive layer composition was then applied to a release liner, i.e., a polyethylene terephthalate film subjected to a release treatment. The solvent was dried to remove the above-mentioned solvent, and the weight per unit area was 50 g / m 2 An adhesive layer is formed in a manner, and a support layer, i.e., a polyethylene terephthalate film, is laminated on the surface of the adhesive layer opposite to the release liner to obtain a patch laminated in the order of support layer / adhesive layer / release liner.

2. The method for stabilizing rotigotine according to claim 1, wherein the content of rotigotine and / or a pharmaceutically acceptable salt thereof in the adhesive layer is 5 to 15% by mass in terms of free rotigotine.

3. The method for stabilizing rotigotine according to claim 1 or 2, wherein: The mass ratio of the content of the free rotigotine of rotigotine and / or its pharmaceutically acceptable salt to the content of the cross-linked polyvinyl pyrrolidone in the adhesive layer, that is, the rotigotine free body content of rotigotine and / or its pharmaceutically acceptable salt:cross-linked polyvinyl pyrrolidone content, is 15:3 to 5:

25.

4. The method for stabilizing rotigotine according to claim 1 or 2, wherein the adhesive layer further contains an imidazole antioxidant. 5 . The method for stabilizing rotigotine according to claim 4 , wherein the content of the imidazole antioxidant in the adhesive layer is 0.05 to 2% by mass. 6 . The method for stabilizing rotigotine according to claim 1 , wherein the adhesive layer further contains an aliphatic alcohol.

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