Rotigotine-containing patches

Abstract

The rotigotine-containing patch of the present invention comprises a support layer and an adhesive layer, wherein the adhesive layer contains rotigotine and / or a pharmaceutically acceptable salt thereof, and the adhesive layer further contains an alicyclic saturated hydrocarbon resin and at least one aliphatic alcohol selected from lauryl alcohol, octyldodecanol, oleyl alcohol, and myristyl alcohol.

Description

Technical Field

[0001] The present invention relates to a patch containing rotigotine, and more particularly to a patch containing rotigotine and / or a pharmaceutically acceptable salt thereof. 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. Rotigotine is a D1 / D2 / D3 dopamine receptor agonist, mainly used to treat the symptoms of Parkinson's disease and restless legs syndrome.

[0003] As a preparation for administering rotigotine, for example, "Nyupro (registered trademark) patch" is commercially available in Japan and abroad. In addition, Japanese Unexamined Patent Publication No. 2010-159302 (Patent Document 1) describes a transdermal absorption therapeutic system having a self-adhesive matrix layer containing rotigotine as a transdermal administration form for treating restless legs syndrome; Japanese Unexamined Patent Publication No. 2002-509878 (Patent Document 2) describes a transdermal therapeutic system comprising a backing layer inactive with respect to the matrix component and a self-adhesive matrix layer containing rotigotine, wherein the matrix has an acrylate-based or silicone-based polymer adhesive as a base material, the solubility of rotigotine being 5% (w / w) or more and being insoluble in water. Furthermore, International Publication No. 2012 / 084969 (Patent Document 3) describes a percutaneous absorption system comprising an adhesive layer formed of an adhesive composition containing a styrene-based polymer and / or polyisobutylene, rotigotine or a pharmaceutically acceptable salt thereof, polyvinyl pyrrolidone or vinyl pyrrolidone and / or vinyl acetate.

[0004] In addition, for example, Japanese Patent Publication No. 2014-177428 (Patent Document 4) describes a percutaneous absorption patch preparation comprising: a support, and a drug-containing layer, the drug-containing layer containing a rubber-based adhesive containing a rosin-based resin and a rubber-based adhesive component, and rotigotine or a pharmaceutically acceptable salt thereof; Japanese Patent Publication No. 2018-123131 (Patent Document 5) describes a percutaneous absorption patch comprising a support, a drug-containing layer and a release liner, the drug-containing layer containing rotigotine, a polyisobutylene-based adhesive, liquid paraffin and polyvinyl pyrrolidone.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent Application Publication No. 2010-159302

[0008] Patent Document 2: Japanese Patent Application No. 2002-509878

[0009] Patent Document 3: International Publication No. 2012 / 084969

[0010] Patent Document 4: Japanese Patent Application Publication No. 2014-177428

[0011] Patent Document 5: Japanese Patent Application Publication No. 2018-123131 Summary of the invention

[0012] Problems to be solved by the invention

[0013] However, the present inventors have conducted further research on rotigotine-containing patches containing rotigotine and / or its pharmaceutically acceptable salts, and have found the following problem. That is, many agents have been known as adhesive agents or transdermal absorption enhancers of drugs contained in patches, but the present inventors have found that even if such agents are contained, there are cases where sufficient skin permeability of rotigotine is not achieved in existing rotigotine-containing patches containing rotigotine and / or its pharmaceutically acceptable salts.

[0014] The present invention has been made in view of the above-mentioned problems, and an object of the present invention is to provide a patch having excellent skin permeability of rotigotine.

[0015] Means for solving problems

[0016] The present inventors have conducted intensive studies to achieve the above-mentioned object and have found that, in a patch having a support layer and an adhesive layer, by combining at least one selected from rotigotine and its pharmaceutically acceptable salts (hereinafter referred to as "rotigotine and / or its pharmaceutically acceptable salts") in the adhesive layer with an alicyclic saturated hydrocarbon resin and a specific aliphatic alcohol, a particularly high level of skin permeability of rotigotine can be achieved compared to the case of using other adhesive imparting agents or percutaneous absorption accelerators, thereby completing the present invention.

[0017] That is, the rotigotine-containing patch of the present invention is 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.

[0018] The adhesive layer further contains an alicyclic saturated hydrocarbon resin and at least one aliphatic alcohol selected from the group consisting of lauryl alcohol, octyldodecanol, oleyl alcohol, and myristyl alcohol.

[0019] In the rotigotine-containing patch of the present invention, the content of the aliphatic alcohol in the adhesive layer is preferably 1 to 15% by mass relative to the total mass of the adhesive layer. In addition, the content of rotigotine and / or a pharmaceutically acceptable salt thereof in the adhesive layer, calculated as a free form of rotigotine, is also preferably 5 to 15% by mass relative to the total mass of the adhesive layer.

[0020] Furthermore, in the rotigotine-containing patch of the present invention, the content of the alicyclic saturated hydrocarbon resin in the adhesive layer is preferably 5 to 80% by mass relative to the total mass of the adhesive layer, and the adhesive layer further preferably contains a styrene-based thermoplastic elastomer. The content of the styrene-based thermoplastic elastomer in the adhesive layer is more preferably 5 to 50% by mass relative to the total mass of the adhesive layer.

[0021] Furthermore, in the rotigotine-containing patch of the present invention, the adhesive layer preferably further contains a plasticizer, and more preferably the content of the plasticizer in the adhesive layer is 4 to 50% by mass based on the total mass of the adhesive layer.

[0022] Effects of the Invention

[0023] According to the present invention, a rotigotine-containing patch having particularly excellent skin permeability of rotigotine can be provided. DETAILED DESCRIPTION

[0024] The present invention will be described in detail below based on preferred embodiments. The rotigotine-containing patch of the present invention is 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.

[0025] The adhesive layer further contains an alicyclic saturated hydrocarbon resin and at least one aliphatic alcohol selected from the group consisting of lauryl alcohol, octyldodecanol, oleyl alcohol, and myristyl alcohol.

[0026] The patch containing rotigotine of the present invention has 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 later. As the support layer of the patch, a known support layer can be appropriately used. As the material of the support layer involved in the present invention, for example, 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, and polyethylene naphthalate; cellulose derivatives; synthetic resins such as polyurethane, or metals such as aluminum. Among them, polyester and polyethylene terephthalate are preferred from the perspective of drug non-adsorbability or drug non-permeability. As the form of the above-mentioned support layer, for example, films; sheets such as sheets, sheet-like porous bodies, and sheet-like foams; fabrics such as woven fabrics, knitted fabrics, and non-woven fabrics; foils; and their laminates. 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.

[0027] The rotigotine-containing patch of the present invention may further include a release liner on the surface of the adhesive layer opposite to the support layer. Examples of the release liner include polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, vinyl acetate-vinyl chloride copolymers, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; synthetic resins such as polyurethane, or films or sheets formed of materials such as aluminum and paper, and laminates thereof. As these release liners, preferably, the surface on the side in contact with the adhesive layer is subjected to a release treatment such as coating with an organic silicon compound or coating with a fluorine compound so that the release liner can be easily peeled off from the adhesive layer.

[0028] <Rotigotine and its pharmaceutically acceptable salt>

[0029] The adhesive layer of the present invention contains at least one selected from rotigotine and its pharmaceutically acceptable salt as a drug. In the present invention, the form of rotigotine contained in the above-mentioned adhesive layer can be a free body (free body) or a pharmaceutically acceptable salt thereof, or a free body formed by desalting the pharmaceutically acceptable salt of rotigotine in the preparation during the manufacturing process and / or after the manufacturing is completed, or a mixture of one or more of them. As the pharmaceutically acceptable salt of rotigotine, an acid addition salt can be exemplified, and as the acid of the above-mentioned acid addition salt, for example, 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 sulfuric acid, linolenic acid, and fumaric acid can be exemplified. Among them, as the adhesive layer of the present invention, it is preferred to contain rotigotine in the form of a free body.

[0030] In the present invention, the content of rotigotine and / or its pharmaceutically acceptable salt contained in the adhesive layer (the content of rotigotine or the content of the pharmaceutically acceptable salt of rotigotine, or the total content when both are contained, the same below) is preferably 5 to 15% by mass, more preferably 7 to 14% by mass, further preferably 7 to 12% by mass, further more preferably 8 to 12% by mass, and particularly preferably 8 to 10% by mass, based on the total mass of the adhesive layer in terms of free rotigotine. If the content of rotigotine and / or its pharmaceutically acceptable salt is less than the above lower limit, the skin permeability of rotigotine tends to decrease, while if it exceeds the above upper limit, crystals of rotigotine and / or its pharmaceutically acceptable salt are precipitated, an amorphous form is generated, or the adhesive force of the adhesive layer tends to decrease.

[0031] <Alicyclic saturated hydrocarbon resin>

[0032] The adhesive layer of the present invention further contains an alicyclic saturated hydrocarbon resin. In the present invention, the above-mentioned adhesive layer contains the above-mentioned alicyclic saturated hydrocarbon resin and the following specific aliphatic alcohol in combination, thereby achieving a particularly high level of skin permeability. It is known that the above-mentioned alicyclic saturated hydrocarbon resin mainly functions as a tackifier of the adhesive base, but if the adhesive layer of the present invention contains other tackifiers instead of the above-mentioned alicyclic saturated hydrocarbon resin, there is a tendency that the skin permeability of rotigotine decreases.

[0033] The so-called alicyclic saturated hydrocarbon resin involved in the present invention refers to an alicyclic hydrogenated petroleum resin which is a homopolymer or copolymer of an alicyclic saturated hydrocarbon monomer. As the above-mentioned alicyclic saturated hydrocarbon resin, the weight average molecular weight is preferably 1,000 to 1,500, and more preferably 1,200 to 1,400. As the alicyclic saturated hydrocarbon resin involved in the present invention, one of them can be used alone, or two or more of them can be used in combination. As the above-mentioned alicyclic saturated hydrocarbon resin, 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.) can be cited.

[0034] In the present invention, the content of the alicyclic saturated hydrocarbon resin contained in the adhesive layer (when two or more alicyclic saturated hydrocarbon resins are combined, the total content thereof, the same below) is preferably 5 to 80% by mass, more preferably 10 to 70% by mass, further preferably 10 to 60% by mass, further more preferably 20 to 60% by mass, and particularly preferably 20 to 50% by mass relative to the total mass of the adhesive layer. If the content of the alicyclic saturated hydrocarbon resin does not reach the lower limit, there is a tendency that the adhesive force of the adhesive layer or the adhesion to the skin decreases, while on the other hand, if the upper limit is exceeded, there is a tendency that the percutaneous absorbability of rotigotine or the shape retention of the adhesive layer decreases. From the viewpoint of the percutaneous absorbability of rotigotine, the content of the alicyclic saturated hydrocarbon resin is also preferably 10 to 50% by mass.

[0035] <Aliphatic alcohol>

[0036] The adhesive layer of the present invention further contains at least one aliphatic alcohol selected from lauryl alcohol, octyldodecanol, oleyl alcohol, and myristyl alcohol. It should be noted that in the present invention, the aliphatic alcohol refers to a saturated or unsaturated linear or branched aliphatic alcohol having a valence of one or more valences. In a patch containing rotigotine, even if an aliphatic alcohol other than these four is used, there is a tendency that sufficient skin permeability of rotigotine is not exhibited. Furthermore, when an aliphatic alcohol having a carbon number of 6 or less is used, it is difficult to keep the content in the preparation constant due to a low boiling point, and the stability over time tends to decrease.

[0037] In the present invention, the content of the aliphatic alcohol contained in the adhesive layer (when two or more aliphatic alcohols are used in combination, the total content thereof, the same below) is preferably 1 to 15% by mass, more preferably 1 to 10% by mass, further preferably 2 to 10% by mass, further 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 less than the lower limit, the skin permeability of rotigotine tends to decrease, while if it exceeds the upper limit, the compatibility with the adhesive base or other components tends to decrease.

[0038] In addition, in the present invention, the mass ratio of the content of the alicyclic saturated hydrocarbon resin to the content of the aliphatic alcohol contained in the adhesive layer (content of alicyclic saturated hydrocarbon resin: content of aliphatic alcohol) is preferably 17:1 to 2:1, more preferably 12:1 to 3:1, and further preferably 10:1 to 5:1. If the content of the alicyclic saturated hydrocarbon resin relative to the content of the aliphatic alcohol does not reach the above lower limit, there is a tendency for the adhesive force of the adhesive layer or the adhesion to the skin to decrease, while on the other hand, if it exceeds the above upper limit, there is a tendency for the percutaneous absorbability of rotigotine to decrease. From the viewpoint of the percutaneous absorbability of rotigotine, the above mass ratio is also preferably 10:1 to 2:1.

[0039] <Adhesive base>

[0040] The adhesive layer of the present invention contains an adhesive base. The adhesive base is not particularly limited, and examples thereof include rubber adhesive bases, acrylic adhesive bases, and silicone adhesive bases. One of these may be used alone, or two or more may be used in combination. Preferably, at least the rubber adhesive base is contained.

[0041] (Rubber-based adhesive)

[0042] As the above-mentioned rubber-based adhesive base, there can be exemplified: styrene-based thermoplastic elastomer, isoprene rubber, polyisobutylene (PIB), polybutene, etc., one of which can be used alone, or two or more can be used in combination, among which styrene-based thermoplastic elastomer is particularly preferred. The above-mentioned so-called styrene-based thermoplastic elastomer refers to a styrene-based elastomer that softens and exhibits fluidity when heated, and exhibits thermoplasticity that returns to a rubber-like elastomer when cooled. Among them, from the viewpoint of sufficient adhesion imparting and stability over time, styrene-based block copolymers are preferred.

[0043] 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" means a copolymer block of ethylene and butene, and "ethylene / propylene" means a copolymer block of ethylene and propylene. Among them, as the styrene-based thermoplastic elastomer involved in the present invention, styrene-isoprene-styrene block copolymer is more preferably used.

[0044] The viscosity average molecular weight of the styrene-isoprene-styrene block copolymer is preferably 30,000 to 2,500,000, and more preferably 100,000 to 1,700,000. If the viscosity average molecular weight is less than the lower limit, the preparation properties of the patch (especially the cohesive force of the adhesive layer) tend to decrease, while if the viscosity average molecular weight exceeds the upper limit, the compatibility with other components contained in the adhesive layer decreases, resulting in a tendency for the manufacture of the patch to become difficult.

[0045] In the present invention, when the above-mentioned styrene-based thermoplastic elastomer is contained in the above-mentioned adhesive layer as the above-mentioned adhesive base, its content (when two or more of the above-mentioned styrene-based thermoplastic elastomers are combined, it is their total content, the same below) is preferably 5 to 50% by mass, more preferably 10 to 40% by mass, and further preferably 10 to 30% by mass relative to the total mass of the above-mentioned adhesive layer. If the content of the above-mentioned styrene-based thermoplastic elastomer does not reach the above-mentioned lower limit, there is a tendency that the cohesive force or shape retention of the adhesive layer decreases. On the other hand, if it exceeds the above-mentioned upper limit, there is a tendency that the cohesive force of the adhesive layer increases excessively, resulting in a decrease in the adhesive force of the adhesive layer or a decrease in the compatibility.

[0046] In addition, as the above-mentioned rubber-based adhesive base, from the viewpoint of the tendency to further improve the adhesion and cohesive force of the adhesive layer, a combination of a styrene-based thermoplastic elastomer (more preferably a styrene-isoprene-styrene block copolymer) and polyisobutylene is more preferred, and it is further preferred that the mass ratio of the above-mentioned styrene-based thermoplastic elastomer to polyisobutylene (mass of styrene-based thermoplastic elastomer: mass of PIB) is 1:2 to 30:1 (further preferably in the range of 1:1 to 10:1).

[0047] In the present invention, when the adhesive layer contains a rubber-based adhesive base as the adhesive base, its content (the total content when there are two or more types in combination, the same below) is preferably 1 to 60 mass %, more preferably 5 to 50 mass %, and further preferably 10 to 40 mass % relative to the total mass of the adhesive layer.

[0048] (Acrylic adhesive base)

[0049] 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 liquids. Any of these may be used alone or in combination of two or more.

[0050] (Silicone adhesive base)

[0051] Examples of the silicone adhesive base include polydimethylsiloxane (polymers represented by MQ in the description based on ASTM D-1418, etc.), polymethylvinylsiloxane (polymers represented by VMQ in the description based on ASTM D-1418, etc.), polymethylphenylsiloxane (polymers represented by PVMQ in the description based on ASTM D-1418, etc.), and the like. One of these may be used alone or in combination of two or more.

[0052] In the present invention, when the above-mentioned adhesive layer contains the above-mentioned acrylic adhesive base and / or silicone adhesive base as the above-mentioned adhesive base, its content (in the case of a combination of two or more, it is their total content, the same below) is preferably less than 10% by mass relative to the total mass of the above-mentioned adhesive layer.

[0053] <Other ingredients>

[0054] The adhesive layer of the present invention may further contain other drugs other than rotigotine and its pharmaceutically acceptable salts; other adhesion-imparting agents other than the above-mentioned alicyclic saturated hydrocarbon resins; other absorption promoters other than the above-mentioned aliphatic alcohols; and additives such as adsorbents, desalting agents, plasticizers, solubilizers, fillers, stabilizers, and preservatives, within the range not impairing the effects of the present invention.

[0055] (Other drugs)

[0056] Examples of other drugs other than rotigotine and its pharmaceutically acceptable salts include nonsteroidal anti-inflammatory analgesics (diclofenac, indomethacin, ketoprofen, felbinac, cloroprofen, ibuprofen, flurbiprofen, tiaprofen, acemetacin, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, rofecoxib, amfenac, etc.), antipyretic analgesics ( Acetaminophen, etc.), antihistamines (diphenhydramine, chlorpheniramine, mequitazine, homochlorcycline, etc.), antihypertensives (diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril, etc.), anti-Parkinson's drugs (pergolide, ropinirole, bromocriptine, selegiline, etc.), bronchodilators (tobutrol, isoproterenol, salbutamol, etc.), antiallergic drugs (ketotifen, loratadine, azelastine, terfenadine, cetirizine, azlast, etc.) , local anesthetics (lidocaine, dibucaine, etc.), drugs for treating neuropathic pain (pregabalin, etc.), non-narcotic analgesics (butylorphan, tramadol, pentazocine), narcotic analgesics (morphine, oxycodone, fentanyl, etc.), urinary tract agents (oxybutynin, tamsulosin, etc.), psychotropic agents (promazine, chlorpromazine, etc.), steroid hormones (estradiol, progesterone, norethindrone, cortisone, hydrocortisone, etc.), antidepressants (sertraline, fluoxetine, paroxetine, etc.), The invention also includes antidepressants (such as oxetine, citalopram, etc.), anti-dementia drugs (donepezil, rivastigmine, galantamine, etc.), antipsychotic drugs (risperidone, olanzapine, etc.), central nervous system stimulants (methylphenidate, etc.), osteoporosis therapeutic drugs (raloxifene, alendronate, etc.), breast cancer preventive drugs (tamoxifen, etc.), anti-obesity drugs (mazindol, sibutramine, etc.), insomnia improving drugs (melatonin, etc.), and anti-rheumatic drugs (actari, etc.). Any one of these may be used alone or in combination of two or more.

[0057] In the present invention, when the adhesive layer further contains these other drugs, the content thereof, when there are two or more types, is preferably 10% by mass or less in total relative to the total mass of the adhesive layer.

[0058] (Other tackifiers)

[0059] As other tackifiers other than the above-mentioned alicyclic saturated hydrocarbon resins, for example, petroleum resins other than the above-mentioned alicyclic saturated hydrocarbon resins, terpene resins, rosin resins, phenol resins and xylene resins can be mentioned. One of them can be used alone or in combination of two or more.

[0060] As petroleum resins other than the above-mentioned alicyclic saturated hydrocarbon resins, for example, alicyclic hydrogenated petroleum resins, aliphatic petroleum resins (aliphatic hydrocarbon resins, etc.), aliphatic hydrogenated petroleum resins, aromatic petroleum resins, more specifically, Escolex 8000 (trade name, manufactured by Esso Petrochemical Co., Ltd.), etc. As such petroleum resins, one of them may be used alone, or two or more of them may be used in combination.

[0061] Examples of the terpene resin 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 Regent (YS Regent PXN (1150N, 300N), YS Regent PX100 0, YS Retin TO125, YS Retin TO105, etc.), Clearon P105, Clearon M115, Clearon K100 (these are trade names, manufactured by Yashara Chemical Co., Ltd.), Tamanol 901 (trade name, manufactured by Arakawa Chemical Industries, Ltd.), any one of them may be used alone or in combination of two or more.

[0062] Examples of the rosin-based resin include hydrogenated rosin glycerol ester, super light-colored rosin, super light-colored rosin ester, and acid-modified super light-colored rosin. More specifically, examples include PIN CRYSTAL (KE-311, PE-590, KE-359, KE-100, etc.) (trade names, manufactured by Arakawa Chemical Industries, Ltd.), and the like. One of these may be used alone, or two or more of them may be used in combination.

[0063] In the present invention, when the adhesive layer further contains these other tackifiers, 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.

[0064] (Other absorption enhancers (transdermal absorption enhancers))

[0065] As the above-mentioned absorption enhancer, there can be mentioned substances other than the above-mentioned specific aliphatic alcohols that have a drug percutaneous absorption promoting effect, for example, there can be mentioned: aliphatic alcohols other than the above-mentioned specific aliphatic alcohols, fatty acids having 6 to 20 carbon atoms, fatty acid esters, fatty 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; triacetin, and any one of them can be used alone or in combination of two or more.

[0066] Examples of the aliphatic alcohol other than the above-mentioned specific aliphatic alcohol include isopropyl alcohol, hexyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, linolenic alcohol and hexyldecanol. These may be used alone or in combination of two or more.

[0067] As absorption enhancers other than the above-mentioned aliphatic alcohols, for example: fatty acids, fatty acid esters, fatty 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. Any one of these may be used alone or in combination of two or more.

[0068] In the present invention, when the adhesive layer further contains these other absorption enhancers, the content thereof, in the case of two or more types, is preferably 10% by mass or less in total relative to the total mass of the adhesive layer.

[0069] (additive)

[0070] [Adsorbent]

[0071] As the above-mentioned adsorbent, there can be mentioned: hygroscopic inorganic and / or organic substances, more specifically, minerals such as talc, kaolin, bentonite, etc.; silicon compounds such as pyrogenic silica (Aerosil (registered trademark) etc.) and hydrated silica; metal compounds such as zinc oxide and dry aluminum hydroxide gel; weak acids such as lactic acid and acetic acid; sugars such as dextrin; high molecular polymers such as polyvinyl pyrrolidone (non-cross-linked PVP), cross-linked polyvinyl pyrrolidone (also called "cross-linked polyvinyl pyrrolidone", "cross-linked PVP"), aminoalkyl methacrylate copolymers, carboxyvinyl polymers and butyl methacrylate-methyl methacrylate copolymers. One of them can be used alone or in combination of two or more.

[0072] As the cross-linked polyvinyl pyrrolidone, a cross-linked N-vinyl pyrrolidone polymer can be exemplified. As the 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 exemplified. Among them, the cross-linked polyvinyl pyrrolidone involved in the present invention is preferably a cross-linked homopolymer of 1-vinyl-2-pyrrolidone. As the cross-linked polyvinyl pyrrolidone, commercial 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.

[0073] In the present invention, when the adhesive layer further contains these adsorbents, the content thereof, in the case of two or more types, is preferably 10% by mass or less in total relative to the total mass of the adhesive layer.

[0074] In the present invention, the cross-linked polyvinyl pyrrolidone is contained in the adhesive layer (preferably in a mass ratio of 10:3 to 1:3 to the content of rotigotine and / or its pharmaceutically acceptable salt (rotigotine free body conversion content of rotigotine and / or its pharmaceutically acceptable salt: cross-linked polyvinyl pyrrolidone content) to the content of rotigotine and / or its pharmaceutically acceptable salt), thereby suppressing the precipitation of crystals of rotigotine and / or its pharmaceutically acceptable salt. However, from the viewpoint of particularly excellent skin permeability of rotigotine, the cross-linked polyvinyl pyrrolidone is preferably not contained in the adhesive layer, and its content is preferably 10% by mass or less, more preferably 8% by mass or less (for example, 3 to 8% by mass), relative to the total mass of the adhesive layer.

[0075] [Desalting agent]

[0076] The above-mentioned desalting agent is mainly mixed 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 acid addition salt of the mixed drug is used as the above-mentioned drug to obtain a preparation of a drug containing a free form, an alkaline substance is preferred, and a desalting agent containing metal ions and a desalting agent containing basic nitrogen atoms are more preferred. As the above-mentioned desalting agent containing metal ions, examples include: 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 in combination of two or more. It should be noted that, as the adhesive layer involved in the present invention, it may also further contain a compound derived from the above-mentioned alkaline drug and the above-mentioned desalting agent (for example, sodium hydrochloride when rotigotine hydrochloride and sodium acetate are combined). In the present invention, when the adhesive layer further contains these desalting agents and compounds derived from alkaline drugs and desalting agents, their content, in the case of two or more types, is preferably 10% by weight or less in total relative to the total weight of the adhesive layer.

[0077] [Plasticizer]

[0078] The above-mentioned plasticizer is mainly mixed for the purpose of adjusting the adhesive properties of the above-mentioned adhesive layer, the flow characteristics during the manufacturing process of the above-mentioned adhesive layer, the percutaneous absorption characteristics of the above-mentioned drug, etc. As such a plasticizer, for example, there can be cited: silicone oil; petroleum oils such as paraffin-based processing oils, cycloparaffin-based processing oils and aromatic-based processing oils; squalane, squalene; plant oils such as olive oil, camellia oil, castor oil, tall oil and peanut oil; dibasic esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, etc., one of which can be used alone, or two or more can be used in combination. Among them, as the above-mentioned plasticizer, it is preferred to be at least one selected from silicone oil, liquid paraffin, and liquid polybutene. In the present invention, when the adhesive layer further contains these plasticizers, the content thereof is preferably 4 to 50% by mass, more preferably 5 to 30% by mass, further preferably 10 to 20% by mass, and further preferably 15 to 20% by mass, relative to the total mass of the adhesive layer in the case of two or more types, from the viewpoint of improving the adhesive force of the adhesive layer and / or alleviating the local irritation during peeling. From the viewpoint of the percutaneous absorbability of rotigotine, the content of the plasticizer is also preferably 15 to 50% by mass.

[0079] [Dissolving agent, filler]

[0080] As the above-mentioned dissolving agent, for example, organic acids such as acetic acid and surfactants can be mentioned, and one of them can be used alone or in combination of two or more. In addition, the above-mentioned filler is mainly mixed for the purpose of adjusting the adhesive force of the above-mentioned adhesive layer. As such fillers, for example, aluminum hydroxide, calcium carbonate, magnesium carbonate; silicates such as aluminum silicate or magnesium silicate; silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide can be mentioned, and one of them can be used alone or in combination of two or more.

[0081] [Stabilizer]

[0082] Examples of the stabilizer include ascorbic acid or a metal salt or ester thereof (preferably a sodium salt or a 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, 2-mercaptobenzimidazole, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], 3-mercapto-1,2-propanediol, tocopherol 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). One of these may be used alone or two or more of them may be used in combination. Among the above, examples of the metal salt include sodium salt, potassium salt, calcium salt and magnesium salt, and examples of the ester include palmitic acid ester, stearic acid ester and myristic acid ester.

[0083] In the present invention, there is a tendency to further improve the stability over time by further containing the above-mentioned stabilizer in the above-mentioned adhesive layer, but from the viewpoint of particularly excellent skin permeability of rotigotine, the above-mentioned adhesive layer preferably does not contain the above-mentioned stabilizer (for example, 2-mercaptobenzimidazole), and the content thereof is preferably 3% by mass or less, more preferably 2% by mass or less, and even more preferably 0.25% by mass or less (for example, 0.005 to 0.25% by mass), relative to the total mass of the above-mentioned adhesive layer.

[0084] [Preservative]

[0085] Examples of the preservative include p-hydroxybenzoic acid derivatives, benzyl alcohol, phenol, cresol, and the like. These may be used alone or in combination of two or more.

[0086] When the adhesive layer further contains the additives, the content thereof, in the case of two or more types, is preferably 40% by mass or less, more preferably 30% by mass or less, based on the total mass of the adhesive layer.

[0087] The adhesive layer of the present invention is not particularly limited, but the weight per unit area (the area of ​​the bonding surface) is preferably 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 can be appropriately adjusted according to the purpose of treatment or the application object, and is not particularly limited, and is usually 0.5 to 200 cm 2 range.

[0088] The patch containing rotigotine of the present invention is not particularly limited and can be manufactured by appropriately adopting a known method for manufacturing a patch. For example, first, according to a conventional method, rotigotine and / or its pharmaceutically acceptable salt, the alicyclic saturated hydrocarbon resin, the specific aliphatic alcohol, the adhesive base, and the solvent or other components as needed are mixed to obtain a uniform adhesive layer composition. When using rotigotine free body as the above-mentioned rotigotine and / or its pharmaceutically acceptable salt, it can be its type I crystal, type II crystal, amorphous type, or a mixture of at least two of type I crystal, type II crystal, and amorphous type. In addition, as the above-mentioned rotigotine and / or its pharmaceutically acceptable salt, rotigotine and / or its pharmaceutically acceptable salt dissolved in the above-mentioned solvent can also be used. As the above-mentioned solvent, it can be exemplified by: anhydrous ethanol, toluene, heptane, methanol, ethyl acetate, hexane, and a mixed solution of at least two of them.

[0089] Next, the adhesive layer composition is applied onto the surface of the support layer (usually one side) in a manner to obtain a desired mass per unit area, and then heated as necessary to dry and remove the solvent to form an adhesive layer, and then cut into a desired shape as necessary, thereby obtaining the patch of the present invention.

[0090] In addition, the method for producing the rotigotine-containing patch of the present invention may further include a step of laminating the release liner on the surface of the adhesive layer opposite to the support layer, firstly applying the adhesive layer composition to one surface of the release liner in a manner to obtain a desired mass per unit area to form an adhesive layer, laminating the support layer on the surface of the adhesive layer opposite to the release liner, and cutting into a desired shape as needed, thereby obtaining the patch of the present invention. Furthermore, the obtained patch may be sealed in a storage packaging container (e.g., an aluminum laminate bag) as needed to prepare a package.

[0091] Example

[0092] Hereinafter, the present invention will be described in more detail based on Examples and Comparative Examples, but the present invention is not limited to the following Examples. It should be noted that in each Example and Comparative Example, the skin permeation test was performed by the method shown below.

[0093] <Skin permeation test (in vitro hairless mouse skin permeation test)>

[0094] First, the skin of the trunk of a hairless mouse was peeled off and fat was removed to obtain a fat-removed skin sheet. A 1.0 cm-long section was cut on the stratum corneum side of the fat-removed skin sheet. 2The test sample was prepared by placing the test sample in a square shape and attaching the patch with the release liner removed. The test sample was placed in a flow-through diffusion tank in such a way that the dermis side was in contact with the receptor solution, and the tank was filled with the receptor solution (phosphate buffered saline). Then, the receptor solution was kept warm at 32°C, while circulating heated circulating water in the periphery and delivering the receptor solution at a flow rate of about 5 mL / hr, and the receptor solution was collected every 2 hours until 24 hours. The rotigotine concentration in the collected receptor solution was determined by high performance liquid chromatography, according to the following formula:

[0095] Rotigotine skin permeation (μg / cm 2 ) = {rotigotine concentration in receptor solution (μg / mL) × flow rate (mL)} / patch area (cm 2 )

[0096] The amount of rotigotine permeated through the skin per unit area of ​​the adhesive layer was calculated, and the amount of rotigotine permeated through the skin per hour (skin permeation rate (μg / cm 2 The measurement was performed on two test samples, and the average of the maximum values ​​of the skin permeation rates within 24 hours was taken as the maximum skin permeation rate (Jmax).

[0097] (Example 1)

[0098] First, 9.0 parts by mass of rotigotine (free body), 15.4 parts by mass of styrene-isoprene-styrene block copolymer, 6.6 parts by mass of polyisobutylene, 48.4 parts by mass of alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), 17.6 parts by mass of liquid paraffin, and 3 parts by mass of lauryl alcohol were added to an appropriate amount of solvent (anhydrous ethanol and toluene) and mixed to obtain an adhesive layer composition. Then, the obtained adhesive layer composition was applied to a release liner (a film made of polyethylene terephthalate subjected to a release treatment), and the solvent was dried to remove the solvent, and the mass per unit area became 50 g / m 2 The adhesive layer was formed in the manner of. A support layer (polyethylene terephthalate film) was laminated on the surface of the obtained adhesive layer opposite to the release liner, thereby obtaining a patch having support layer / adhesive layer / release liner laminated in this order.

[0099] (Examples 2 to 4, Comparative Examples 1 to 18)

[0100] Each patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition was set to the composition shown in Table 1 or Table 2 below.

[0101] Skin permeation tests were performed on the patches obtained in Examples 1 to 4 and Comparative Examples 1 to 18. The results are shown in Tables 1 and 2, respectively, together with the compositions (excluding the solvent) of the adhesive layer compositions of the Examples and Comparative Examples.

[0102] [Table 1]

[0103]

[0104] [Table 2]

[0105]

[0106] As shown in Tables 1 and 2, in the patch of the present invention using lauryl alcohol, octyldodecanol, oleyl alcohol, or myristyl alcohol (Examples 1 to 4), it was confirmed that excellent skin permeability of rotigotine was achieved, and in particular, compared with the case where other aliphatic alcohols having a carbon number close to or the same carbon number as these were used (for example, Comparative Examples 2 to 4), particularly excellent skin permeability was achieved.

[0107] (Example 5, Comparative Examples 19-20)

[0108] Each patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition was set to the composition shown in the following Table 3. In Table 3, "YS Resin PX1150N (manufactured by Yashara Chemical Co., Ltd.)" was used as the terpene resin, and "KE-311 (manufactured by Arakawa Chemical Industries, Ltd.)" was used as the hydrogenated rosin ester.

[0109] The patches obtained in Example 5 and Comparative Examples 19 to 20 were subjected to skin permeation tests. The results are shown in Table 3 together with the composition (excluding the solvent) of the adhesive layer composition of each Example and Comparative Example.

[0110] [Table 3]

[0111]

[0112] As shown in Table 3, in the patch of the present invention using octyldodecanol and alicyclic saturated hydrocarbon resin (Example 5), it was confirmed that excellent skin permeability of rotigotine was achieved, and sufficient skin permeability was achieved even if an adsorbent and a stabilizer were further contained. On the other hand, when a terpene resin or hydrogenated rosin ester as another tackifier was used instead of the alicyclic saturated hydrocarbon resin (Comparative Examples 19 and 20), it was confirmed that the skin permeability of rotigotine decreased.

[0113] (Examples 6-7)

[0114] Each patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition was set to the composition shown in Table 4 below. Skin permeation tests were performed on the patches obtained in Examples 6 to 7. The results are shown in Table 4 together with the composition (excluding the solvent) of the adhesive layer composition of each example.

[0115] [Table 4]

[0116]

[0117] As shown in Table 4, it was confirmed that the patch of the present invention (Examples 6 to 7) achieved excellent skin permeability of rotigotine even when the content of the aliphatic alcohol according to the present invention was 10 parts by mass or 15 parts by mass.

[0118] (Examples 8 to 10)

[0119] Each patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition was set to the composition shown in Table 5 below. Skin permeation tests were performed on the patches obtained in Examples 8 to 10. The results are shown in Table 5 together with the composition (excluding the solvent) of the adhesive layer composition of each example.

[0120] [Table 5]

[0121]

[0122] As shown in Table 5, it was confirmed that the patch of the present invention (Examples 8 to 10) achieved excellent skin permeability of rotigotine even when the content of rotigotine was 11.3 parts by mass or 13.5 parts by mass.

[0123] (Examples 11 to 15)

[0124] Each patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition was set to be the composition shown in Table 6 below. The skin permeation test was performed on the patches obtained in Examples 11 to 15. The results are shown in Table 6 together with the composition (excluding the solvent) of the adhesive layer composition of each example. In addition, the results of Example 8 are also shown in Table 6.

[0125] [Table 6]

[0126]

[0127] As shown in Table 6, it was confirmed that the patch of the present invention (Examples 11 to 14) achieved excellent skin permeability of rotigotine even when the content of the alicyclic saturated hydrocarbon resin was 12.5 parts by mass or 60 parts by mass, and even when the content of the liquid paraffin was 11.6 parts by mass or 47.5 parts by mass. Furthermore, it was confirmed that the patch of the present invention (Example 15) achieved excellent skin permeability of rotigotine even when it did not contain polyisobutylene.

[0128] Industrial Applicability

[0129] As described above, according to the present invention, a rotigotine-containing patch having particularly excellent skin permeability of rotigotine can be provided.

Claims

1. 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. The adhesive layer further contains an alicyclic saturated hydrocarbon resin, at least one aliphatic alcohol selected from lauryl alcohol, octyldodecanol, oleyl alcohol and myristyl alcohol, a rubber-based adhesive base, and a plasticizer. The above-mentioned alicyclic saturated hydrocarbon resin refers to an alicyclic hydrogenated petroleum resin which is a homopolymer or copolymer of an alicyclic saturated hydrocarbon monomer. The plasticizer is at least one selected from silicone oil, liquid paraffin, and liquid polybutene. The content of rotigotine and / or a pharmaceutically acceptable salt thereof in the adhesive layer, calculated as free rotigotine, is 5 to 15% by mass based on the total mass of the adhesive layer. The content of the alicyclic saturated hydrocarbon resin is 10 to 60% by mass based on the total mass of the adhesive layer. The content of the aliphatic alcohol is 1 to 15% by mass based on the total mass of the adhesive layer. The content of the rubber adhesive base is 1 to 60% by mass relative to the total mass of the adhesive layer, and the rubber adhesive base contains a styrene-isoprene-styrene block copolymer. in, Except for the adhesive layer composed of the following: 2 . The rotigotine-containing patch according to claim 1 , wherein the content of the plasticizer in the adhesive layer is 4 to 50% by mass based on the total mass of the adhesive layer.

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