Method for improving the adhesive layer retention of a rotigotine-containing patch and rotigotine-containing patch with improved retention

Abstract

The method for improving the adhesive layer retention of the ropinirole-containing patch of the present invention is a method for improving the adhesive layer retention of the following patch. The patch has a support layer and an adhesive layer, and the adhesive layer contains at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts and an adhesive. Further, the adhesive layer contains a sodium salt of carbonic acid.

Description

Technical Field

[0001] The present invention relates to a method for improving the adhesive layer holding power of a ropinirole-containing patch and a patch with improved holding power containing ropinirole. More specifically, the present invention relates to a method for improving the adhesive layer holding power of a ropinirole-containing patch containing ropinirole and / or a pharmaceutically acceptable salt thereof and an adhesive, and a ropinirole-containing patch with improved holding power. Background Art

[0002] Ropinirole is known to be a drug useful for the treatment of Parkinson's disease, restless legs syndrome, etc. In recent years, from the viewpoints of reducing the number of drug administrations, improving compliance, and ease of administration and discontinuation of administration, transdermal administration of preparations containing ropinirole and / or a pharmaceutically acceptable salt thereof has been studied.

[0003] For example, International Publication No. 2010 / 134433 (Patent Document 1) describes a transdermal absorption preparation having a support and an adhesive layer containing ropinirole or a pharmaceutically acceptable acid addition salt thereof, and International Publication No. 2012 / 165253 (Patent Document 2) describes a ropinirole-containing patch having a support layer and an adhesive layer containing a specific amount of ropinirole and / or a pharmaceutically acceptable salt thereof.

[0004] Furthermore, International Publication No. 2018 / 155390 (Patent Document 3) describes a patch having a support layer and an adhesive layer containing a mixture of a pharmaceutically acceptable acid addition salt of ropinirole and potassium bicarbonate.

[0005] In addition, International Publication No. 2012 / 165254 (Patent Document 4) describes that free ropinirole plasticizes the adhesive base and reduces the cohesion of the adhesive layer, and it is described in this document that in order to exhibit excellent skin permeability and sufficient adhesiveness of ropinirole, in a ropinirole-containing patch having a support layer and an adhesive layer containing ropinirole and / or a pharmaceutically acceptable salt thereof, the content of ropinirole and / or a pharmaceutically acceptable salt thereof and the mass per unit area of the adhesive layer are set within a specific range, and the above adhesive layer contains a specific amount of alkali metal hydroxide. In addition, as the above alkali metal hydroxide, sodium hydroxide etc. are exemplified.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: International Publication No. 2010 / 134433

[0009] Patent Document 2: International Publication No. 2012 / 165253

[0010] Patent Document 3: WO 2018 / 155390

[0011] Patent Document 4: WO 2012 / 165254 SUMMARY OF THE INVENTION

[0012] PROBLEM TO BE SOLVED BY THE INVENTION

[0013] An adhesive patch continuously administers a drug transdermally by attaching an adhesive layer to the skin, and thus requires various physical properties. For example, the adhesive force of the adhesive layer to the skin (a force usually represented by the force of peeling along the 180° direction or 90° direction), the cohesive force as described in Patent Document 4, the tackiness (usually the degree of stickiness represented by the distance that a ball rolls on the surface of the adhesive layer provided on an inclined plane (rolling ball tack test)), the holding force (resistance to the force of displacement due to the fluidity of the adhesive), etc.

[0014] The present inventors further studied an adhesive patch containing ropinirole, and as a result, found that among the above physical properties, the holding force tends to be particularly reduced in an adhesive patch containing ropinirole and / or a pharmaceutically acceptable salt thereof and an adhesive in the adhesive layer.

[0015] In addition, in order to improve the above holding force, fillers such as calcium carbonate described in Patent Documents 1 to 4 have been used in the past, but the present inventors have found that when these fillers are contained in the above adhesive layer, the skin permeability of ropinirole and / or a pharmaceutically acceptable salt thereof is reduced.

[0016] The present invention has been made in view of the problems of the above prior art, and an object thereof is to provide a method for improving the holding force of an adhesive layer of an adhesive patch containing ropinirole and an adhesive patch containing ropinirole having excellent holding force of the adhesive layer. The method for improving the holding force of the adhesive layer of the adhesive patch containing ropinirole can improve the holding force of the adhesive layer containing ropinirole and / or a pharmaceutically acceptable salt thereof and an adhesive while maintaining the skin permeability of ropinirole and / or a pharmaceutically acceptable salt thereof.

[0017] MEANS FOR SOLVING THE PROBLEM

[0018] The inventors of the present invention have repeatedly conducted in-depth research to achieve the above object, and as a result, it has been found that for a rotigotine-containing patch having a support layer and an adhesive layer, and the adhesive layer containing at least one selected from the group consisting of rotigotine and its pharmaceutically acceptable salts and an adhesive, by further containing a sodium salt of carbonic acid in the above adhesive layer, it has been surprisingly found that, compared with the case of using sodium hydroxide as described in Patent Document 4, the holding power of the above adhesive layer can be sufficiently improved. Furthermore, it has been found that, relative to the reduction in the skin permeability of rotigotine and / or its pharmaceutically acceptable salts in the case of using known calcium carbonate or the like as a filler for the adhesive in the past, the above skin permeability can be sufficiently maintained in the case of using the above sodium salt of carbonic acid, and thus the present invention has been completed.

[0019] That is, the method for improving the holding power of the adhesive layer of the rotigotine-containing patch of the present invention is a method for improving the holding power of the adhesive layer of a rotigotine-containing patch having a support layer and an adhesive layer, and the adhesive layer containing at least one selected from the group consisting of rotigotine and its pharmaceutically acceptable salts and an adhesive.

[0020] This method further contains a sodium salt of carbonic acid in the above adhesive layer.

[0021] In the method for improving the holding power of the adhesive layer of the rotigotine-containing patch of the present invention, the above adhesive is preferably at least one selected from the group consisting of a rubber-based adhesive, an acrylic adhesive without a carboxyl group, and a silicone-based adhesive.

[0022] In addition, in the method for improving the holding power of the adhesive layer of the rotigotine-containing patch of the present invention, the above sodium salt of carbonic acid is preferably at least one selected from the group consisting of sodium carbonate and sodium bicarbonate.

[0023] Furthermore, in the method for improving the holding power of the adhesive layer of the rotigotine-containing patch of the present invention, it is preferred that the above sodium salt of carbonic acid is contained in the above adhesive layer in such a manner that the content relative to the total mass of the above adhesive layer is 0.5 to 33% by mass. In addition, it is also preferred that the above sodium salt of carbonic acid is contained in the above adhesive layer in such a manner that the content relative to 1.0 mole of the content of at least one selected from the group consisting of the above rotigotine and its pharmaceutically acceptable salts in terms of the free form of rotigotine is 0.1 to 5.0 moles.

[0024] In addition, in the method for improving the holding power of the adhesive layer of the rotigotine-containing patch of the present invention, it is preferred that the content of at least one selected from the group consisting of the above rotigotine and its pharmaceutically acceptable salts in terms of the free form of rotigotine relative to the total mass of the above adhesive layer is 5 to 30% by mass.

[0025] The adhesive patch containing ropinirole with improved adhesion retention of the present invention comprises a support layer and an adhesive layer, and the above-mentioned adhesive layer contains at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts, sodium salts of carbonic acid, and an adhesive.

[0026] Effects of the invention

[0027] According to the present invention, it is possible to provide a method for improving the adhesion retention of the adhesive layer of an adhesive patch containing ropinirole and an adhesive patch containing ropinirole with excellent adhesion retention of the adhesive layer. The method for improving the adhesion retention of the adhesive layer of the adhesive patch containing ropinirole can improve the adhesion retention of the adhesive layer containing ropinirole and / or its pharmaceutically acceptable salt and an adhesive while maintaining the skin permeability of ropinirole and / or its pharmaceutically acceptable salt. Detailed implementation manners

[0028] Hereinafter, the present invention will be described in detail according to its preferred implementation manners.

[0029] The method for improving the adhesion retention of the adhesive layer of the adhesive patch containing ropinirole of the present invention (hereinafter, simply referred to as "the method of the present invention" as the case may be) is a method for improving the adhesion retention of the adhesive layer of an adhesive patch containing ropinirole that comprises a support layer and an adhesive layer, and the above-mentioned adhesive layer contains at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts and an adhesive.

[0030] This method further contains sodium salts of carbonic acid in the above-mentioned adhesive layer.

[0031] The adhesive patch containing ropinirole related to the method of the present invention (hereinafter, simply referred to as "the adhesive patch of the present invention" as the case may be) is an adhesive patch that comprises a support layer and an adhesive layer, and the above-mentioned adhesive layer contains at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts and an adhesive.

[0032] As the support layer involved in the present invention, as long as it is a support layer capable of supporting the following adhesive layer, there is no particular limitation, and those publicly known as support layers for adhesives can be appropriately used. As the material of the support layer involved in the present invention, examples include: polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate, polyethylene naphthalate, etc.; cellulose derivatives; synthetic resins such as polyurethane; metals such as aluminum. Among these, from the viewpoints of non-adsorbability and non-permeability of drugs, polyester is preferred. As the form of the above support layer, examples include: film; sheets such as sheet, sheet-like porous body, sheet-like foam; fabrics such as woven fabric, knitted fabric, non-woven fabric; foil; and laminates thereof. In addition, as the thickness of the above support layer, there is no particular limitation, and from the viewpoints of ease of operation and ease of manufacture when attaching the adhesive, it is preferably in the range of 5 to 1000 μm.

[0033] The adhesive involved in the present invention may further include a release liner on the surface opposite to the above support layer of the above adhesive layer. As the release liner, examples include films or sheets containing the following materials and their laminates: polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; synthetic resins such as polyurethane; aluminum, paper, etc. Among these release liners, those preferably having been subjected to release treatment such as silicone compound coating or fluorine compound coating on the surface in contact with the adhesive layer are used to facilitate peeling from the above adhesive layer.

[0034] The adhesive layer involved in the present invention contains, as a drug, at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts (in this specification, referred to as "ropinirole and / or its pharmaceutically acceptable salts" as the case may be).

[0035] As the ropinirole contained in the adhesive layer involved in the present invention, it may be a free form (referred to as "ropinirole free form" in this specification as the case may be), or its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of ropinirole that has been desalted to become a free form during and / or after manufacture of the preparation. It may be a single one of these, or a mixture of two or more.

[0036] As the pharmaceutically acceptable salt of the above ropinirole, a pharmaceutically acceptable acid addition salt of ropinirole (referred to as "ropinirole acid addition salt" in this specification as the case may be) is preferred. As the acid of the above ropinirole acid addition salt, examples include: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphorous acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, tartaric acid, and fumaric acid.

[0037] When the above-mentioned ropinirole acid addition salt is contained in the adhesive layer as a raw material of the patch according to the present invention, since the following sodium salt of carbonic acid is also a weak base, by mixing it during production, all or part of the above-mentioned ropinirole acid addition salt is desalted (neutralized) in the adhesive layer of the preparation during and / or after production to obtain ropinirole in the free base state. As a result, when applying the patch preparation, ropinirole in the free state with higher tissue absorbability can be present in the adhesive layer.

[0038] The content of ropinirole and / or its pharmaceutically acceptable salt according to the present invention (the content of free ropinirole or the content of the pharmaceutically acceptable salt of ropinirole, or the total content of both free ropinirole and the pharmaceutically acceptable salt of ropinirole when both are contained, the same applies hereinafter), in terms of free ropinirole conversion, relative to the total mass of the above-mentioned 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 sodium salt of carbonic acid), and more preferably means the mass obtained by removing the mass of the solvent from the total mass of the following adhesive layer composition), is preferably 5 to 30% by mass, more preferably 5 to 25% by mass, further preferably 5 to 20% by mass, still further preferably 5 to 15% by mass, and particularly preferably 5 to 13.2% by mass. When the content of ropinirole and / or its pharmaceutically acceptable salt is less than the above lower limit, the skin permeability of ropinirole and / or its pharmaceutically acceptable salt (hereinafter, depending on the situation, referred to as "the skin permeability of ropinirole") tends to decrease. On the other hand, when it exceeds the above upper limit, there is a tendency that it is difficult to extend the adhesive layer composition during the formation of the above-mentioned adhesive layer due to the increase in the absolute amount in the adhesive layer, and it is difficult to obtain a uniform preparation.

[0039] The adhesive layer according to the present invention contains an adhesive. Examples of the adhesive according to the present invention include rubber-based adhesives, acrylic adhesives, silicone adhesives, etc. It can be a single one of these, or a combination of two or more. Among these, as the adhesive according to the present invention, it is preferably at least one selected from the group consisting of rubber-based adhesives, acrylic adhesives without carboxyl groups, and silicone adhesives, and more preferably contains at least a rubber-based adhesive.

[0040] In the adhesive layer according to the present invention, as the content of the above-mentioned adhesive (in the case of two or more, the total content thereof, the same applies hereinafter), relative to the total mass of the above-mentioned adhesive layer, it is preferably 10 to 90% by mass, more preferably 17 to 85% by mass, and further preferably 20 to 70% by mass.

[0041] As for the rubber-based adhesive involved in the present invention, natural rubber and synthetic rubber can be cited. From the viewpoint of having a more excellent tendency in the cohesion of the adhesive layer and the skin permeability of ropinirole, it is more preferably at least any one selected from the group consisting of styrene-isoprene-styrene block copolymer (SIS), isoprene rubber, polyisobutylene (PIB), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), polybutene and other synthetic rubbers that do not have hydroxyl groups and carboxyl groups. In the present invention, the "synthetic rubber that does not have hydroxyl groups and carboxyl groups" means that it substantially does not have hydroxyl groups and carboxyl groups, and preferably the content of hydroxyl groups and carboxyl groups in the molecule does not reach 3% by mass of the synthetic rubber.

[0042] When the adhesive layer involved in the present invention contains the above rubber-based adhesive, as its content (in the case of two or more, it is the total content thereof, the same hereinafter), relative to the total mass of the above adhesive layer, it is preferably 10 to 55% by mass, more preferably 15 to 35% by mass. When the content of the above rubber-based adhesive does not reach the above lower limit, the cohesion of the adhesive layer tends to decrease. On the other hand, when it exceeds the above upper limit, the adhesive layer becomes too hard and the adhesiveness of the adherent decreases.

[0043] As for the acrylic-based adhesive involved in the present invention, the acrylic-based adhesives included in the "Pharmaceutical Additive Dictionary 2016 (edited by the Japan Pharmaceutical Additive Association)" can be cited. It can be a single one of these, or a combination of two or more. Preferably, it is an acrylic-based adhesive that does not have a carboxyl group, and more preferably an acrylic-based adhesive that does not have a functional group. In the present invention, the "acrylic-based adhesive that does not have a carboxyl group" means that it substantially does not have a carboxyl group, and preferably the content of the carboxyl group in the polymer does not reach 3% by mass of the acrylic-based polymer. The "acrylic-based adhesive that does not have a functional group" means that it substantially does not have a functional group, and preferably the content of the functional group (including the carboxyl group) in the polymer does not reach 3% by mass of the acrylic-based polymer.

[0044] As the above acrylic binder without a carboxyl group, for example, the following can be mentioned: acrylic-2-ethylhexyl ester / vinylpyrrolidone copolymer, acrylic-2-ethylhexyl ester / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, acrylic-2-ethylhexyl ester / vinyl acetate copolymer, acrylic-2-ethylhexyl ester / methyl methacrylate / butyl acrylate copolymer, ethyl acrylate / methyl methacrylate copolymer, etc., which are acrylic binders substantially without functional groups; (meth)acrylic-2-ethylhexyl ester / vinyl acetate / 2-hydroxyethyl acrylate copolymer, 2-hydroxyethyl (meth)acrylate copolymer, 2-hydroxypropyl (meth)acrylate copolymer, 3-hydroxypropyl (meth)acrylate copolymer, 4-hydroxybutyl (meth)acrylate copolymer, acrylic-2-ethylhexyl ester / vinyl acetate / hydroxyethyl acrylate / glycidyl methacrylate copolymer, etc., which are acrylic binders without a hydroxyl group; It can be a single one of these, or a combination of two or more.

[0045] As the above acrylic binder without a carboxyl group, commercially available products can also be appropriately used. For example, MAS 811 and MAS 683 (manufactured by CosMED Pharmaceutical Co., Ltd.) can be appropriately used; 87-900A, 87-901A, 87-9301, 87-4098, 87-9088, 87-9085 of the Duro-Tak (registered trademark) acrylic binder series (manufactured by Henkel Corporation); acrylic polymers contained in GMS 3083, GMS 3253, GMS 3235, etc. of the GELVA (registered trademark) acrylic binder series (manufactured by Henkel Corporation); or 87-202A, 87-2287, 87-2516, 87-2510, 87-4287, 87-2525, 87-201A, 87-202A, 87-208A, 87-502A, 87-503A, 87-504A of the Duro-Tak (registered trademark) acrylic binder series (manufactured by Henkel Corporation); acrylic polymers contained in GMS788, GMS 737, etc. of the GELVA (registered trademark) acrylic binder series (manufactured by Henkel Corporation), etc.

[0046] When the adhesive layer involved in the present invention contains the above acrylic binder, as its content (in the case of two or more, it is the total content of them, the same hereinafter), relative to the total mass of the above adhesive layer, it is preferably 10 to 90% by mass, more preferably 20 to 85% by mass, and further preferably 20 to 70% by mass. When the content of the above acrylic binder is less than the above lower limit, the cohesion of the adhesive layer tends to decrease. On the other hand, when it exceeds the above upper limit, the skin permeability of ropinirole tends to decrease.

[0047] When the adhesive layer involved in the present invention contains the above-mentioned silicone-based adhesive, examples of the above-mentioned silicone-based pressure-sensitive adhesive include silicone rubbers represented as MQ (polydimethylsiloxane), VMQ (polymethylvinylsiloxane), PMQ (polymethylphenylsiloxane), PVMQ (polyphenylvinylmethylsiloxane) in the ASTM standard (ASTM D 1418), or mixtures of at least one of these and silicone resins other than silicone rubber such as polydi-trimethylsilylsiloxane. It can be a single one of these or a combination of two or more. Furthermore, when mixing the silicone resin other than silicone rubber, it is preferably 0.1 to 20% by mass based on the total mass of the silicone-based pressure-sensitive adhesive.

[0048] In addition, as these silicone-based adhesives, commercially available products can be appropriately used. For example, those provided by DuPont Toray Specialty Materials Co., Ltd. under the following models: BIO-PSA7-410X, BIO-PSA7-420X, BIO-PSA7-430X, BIO-PSA7-440X, BIO-PSA7-450X, BIO-PSA7-460X (each X is independently 1 or 2), BIO-PSA AC7-4201, BIO-PSA AC7-4301, BIO-PSA AC7-4302, MD7-4502, MD7-4602, 7-9700, MG7-9800, MG7-9850; silicone-based adhesives such as BIO-PSA 7-4560 as a hot-melt silicone adhesive, etc.

[0049] Furthermore, as the silicone-based adhesive involved in the present invention, for example, when having a methyl group, it can be crosslinked between the same methyl groups by dehydrogenating the hydrogen atoms of the methyl group by incorporating a peroxide; when having a vinyl group, it can be crosslinked between the same vinyl groups by bonding a crosslinking agent containing a siloxane compound having an SiH group; when having a hydroxyl group (i.e., having a silanol group), it can be crosslinked between the same silanol groups by dehydration condensation, etc.

[0050] When the adhesive layer of the present invention contains the above-mentioned silicone-based adhesive, its content (in the case of two or more, the total content thereof, the same hereinafter) is preferably 10 to 90% by mass, more preferably 20 to 85% by mass, and further preferably 20 to 70% by mass based on the total mass of the adhesive layer. When the content of the above-mentioned silicone-based adhesive is less than the above lower limit, the cohesion of the adhesive layer tends to decrease. On the other hand, when it exceeds the above upper limit, the skin permeability of ropinirole tends to decrease.

[0051] As the adhesive layer related to the present invention, within the range that does not hinder the effects of the present invention, it may further contain other drugs other than ropinirole and its pharmaceutically acceptable salts; absorption promoters (transdermal absorption promoters); additives such as adsorbents, tackifiers, plasticizers, solvents, fillers, stabilizers, preservatives, etc.

[0052] Examples of other drugs other than the above-mentioned ropinirole and its pharmaceutically acceptable salts include: non-steroidal anti-inflammatory analgesics (diclofenac, indomethacin, ketoprofen, biphenylacetic acid, loxoprofen, ibuprofen, flurbiprofen, tiaprofenic acid, acemetacin, sulindac, etodolac, tolmetin, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, ethylene glycol salicylate, valdecoxib, celecoxib, rofecoxib, amfenac, etc.), antihistamines (diphenhydramine, chlorpheniramine, mequitazine, chlorcyclizine, etc.), antihypertensive agents (diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril, etc.), anti-Parkinson's agents (pergolide, bromocriptine, mequitazine, etc.), bronchodilators (tobuterol, isoproterenol, salbutamol, etc.), antiallergic agents (ketotifen, loratadine, azelastine, terfenadine, cetirizine, azelastine, etc.), local anesthetics (lidocaine, dibucaine, etc.), narcotic analgesics (morphine, etc.), urinary organ agents (oxybutynin, tamsulosin, etc.), psychotropic agents (promazine, chlorpromazine, etc.), steroid hormone agents (estradiol, progesterone, norethisterone, cortisone, hydrocortisone, etc.), antidepressants (sertraline, fluoxetine, paroxetine, citalopram, etc.), anti-dementia drugs (donepezil, rivastigmine, galantamine, etc.), antipsychotic drugs (risperidone, olanzapine, etc.), central nervous system stimulants (methylphenidate, etc.), osteoporosis treatment drugs (raloxifene, alendronate, etc.), breast cancer prevention drugs (tamoxifen, etc.), anti-obesity drugs (mazindol, sibutramine, etc.), insomnia improvement drugs (melatonin, etc.), anti-rheumatic drugs (atalurit, etc.). One of these can be used alone, or two or more can be used in combination.

[0053] Examples of the above absorption promoter include isopropyl myristate, isopropyl palmitate, lauryl alcohol, hexyl laurate, myristyl alcohol, oleyl alcohol, isostearyl alcohol, octyldodecanol, benzyl alcohol, glyceryl monooleate (GMO), propylene glycol monolaurate (PGML), polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan tristearate (Tween 65), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monocinnamate (Tween 20), lauric acid diethanolamide (LADA), etc. One of these can be used alone, or two or more of them can be used in combination.

[0054] Examples of the above adsorbent include inorganic and / or organic substances having hygroscopicity. More specifically, examples include minerals such as talc, kaolin, and bentonite; silicon compounds such as fumed silica (Aerosil (registered trademark), etc.) 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 polymer polymers such as polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, crosslinked polyvinylpyrrolidone, carboxyvinyl polymer, and butyl methacrylate / methyl methacrylate copolymer. One of these can be used alone, or two or more of them can be used in combination.

[0055] The above adhesion promoter is mainly compounded for the purpose of improving the adhesive strength of the above adhesive. Examples of such an adhesion promoter include rosin-based resins, terpene-based resins, petroleum-based resins (alicyclic saturated hydrocarbon resins, etc.), phenolic resins, and xylene-based resins. One of these can be used alone, or two or more of them can be used in combination. When such an adhesion promoter is further contained in the above adhesive layer, as its content (in the case of two or more, their total content), from the viewpoint of enhancing the adhesive strength of the above adhesive layer and / or alleviating local irritation during peeling, it is more preferably 10 to 80% by mass, and further preferably 20 to 60% by mass, based on the total mass of the above adhesive layer.

[0056] The above plasticizers are mainly formulated for the purpose of adjusting the adhesive properties of the above adhesive layer, the flow characteristics during the manufacture of the above adhesive layer, the transdermal absorption characteristics of the above drug, etc. Examples of such plasticizers include silicone oil; paraffin-based processing oils such as liquid paraffin, naphthenic-based processing oils, and aromatic-based processing oils; squalane, squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil, and peanut oil; dibutyl phthalate and dioctyl phthalate; liquid rubbers such as liquid polybutene and liquid isoprene rubber; diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, etc. One of these can be used alone, or two or more can be used in combination. Among these, as the above plasticizer, at least one selected from the group consisting of silicone oil, liquid paraffin, and liquid polybutene is preferred. When such a plasticizer is further contained in the above adhesive layer, as its content (in the case of two or more, their total content), from the viewpoint of making the adhesive strength of the patch better, it is more preferably 5 to 60% by mass, and further preferably 7 to 40% by mass relative to the total mass of the above adhesive layer.

[0057] The above solvents are mainly formulated for the purpose of promoting the dissolution of the above drug. Examples of such solvents include organic acids such as acetic acid, aliphatic alcohols, and surfactants. One of these can be used alone, or two or more can be used in combination. Among these, as the above solvent, at least one selected from the group consisting of organic acids and aliphatic alcohols is preferred.

[0058] The above fillers are mainly formulated for the purpose of adjusting the adhesive strength or retention force of the above 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, titanium oxide; One of these can be used alone, or two or more can be used in combination. According to the method of the present invention, even without adding these fillers, an adhesive layer with excellent retention force can be obtained. Therefore, from the viewpoint of maintaining the skin permeability of ropinirole, they can be substantially not added. In this case, more specifically, the amount of the above fillers added (in the case of two or more, their total added amount) is preferably 1% by mass or less, and more preferably 0.1% by mass or less relative to the total mass of the above adhesive layer.

[0059] As the adhesive layer involved in the present invention, within the range that does not hinder the effects of the present invention, components that can also function as desalting agents for pharmaceutically acceptable acid addition salts of ropinirole other than the following sodium salts of carbonic acid may further be used. As such components, for example, metal ion-containing desalting agents and basic nitrogen atom-containing desalting agents can be cited. As the above metal ion-containing desalting agents, strong bases such as sodium hydroxide and potassium hydroxide can be cited, and it can be a single one of these, or a combination of two or more. In addition, weak bases such as sodium acetate (including anhydrous sodium acetate), magnesium hydroxide, sodium citrate, and sodium lactate are also components that can function as desalting agents. According to the method of the present invention, even without incorporating these components, the skin permeability of ropinirole is excellent, and thus they may also be substantially not incorporated. In this case, more specifically, the blending amount of the above components (in the case of two or more, their total blending amount) is preferably 1% by mass or less, more preferably 0.1% by mass or less, relative to the total mass of the above adhesive layer.

[0060] The thickness of the adhesive layer involved in the present invention (the thickness after manufacture (after containing the sodium salt of carbonic acid), the same hereinafter) is not particularly limited. For example, it is preferably a thickness such that the mass per unit area of the above adhesive layer becomes 25 to 250 g / m 2 , more preferably a thickness such that it becomes 50 to 200 g / m 2 , further preferably a thickness such that it becomes 50 to 150 g / m 2 , and even more preferably a thickness such that it becomes 50 to 120 g / m 2 of the thickness. The adhesion area of the adhesive patch involved in the present invention is preferably 1 to 300 cm 2 , more preferably 5 to 30 cm 2 .

[0061] In the method of the present invention, the adhesive layer containing the above ropinirole and / or its pharmaceutically acceptable salt and the above adhesive contains the sodium salt of carbonic acid. In the present invention, "the sodium salt of carbonic acid" is a salt containing an acid selected from the group consisting of carbonic acid and bicarbonate and sodium, and represents a compound in which a carbonate ion (CO 3 2- ) or a bicarbonate ion (HCO 3 - ) is bonded to a sodium ion (Na + ). More specifically, as the sodium salt of carbonic acid involved in the present invention, sodium carbonate and sodium bicarbonate can be cited, and it can be a single one of these, or a combination of two or more.

[0062] In the method of the present invention, it is preferable that the sodium salt of carbonic acid is contained in the adhesive layer such that the content thereof (in the case of two or more, their total content, the same applies hereinafter) relative to the total mass of the adhesive layer is 0.5 to 33% by mass, more preferably 0.5 to 25% by mass, and still more preferably 1 to 20% by mass. When the content of the sodium salt of carbonic acid in the obtained adhesive layer is less than the above lower limit, there is a tendency that the effect of improving the holding power of the adhesive layer cannot be sufficiently exerted. On the other hand, when it exceeds the above upper limit, there is a tendency that the cohesion of the adhesive layer decreases. Furthermore, in the present invention, when the content of the sodium salt of carbonic acid contains the following components derived from the sodium salt of carbonic acid in addition to the content of the sodium salt of carbonic acid, it includes the content calculated as the sodium salt of carbonic acid of this component.

[0063] In addition, in the method of the present invention, it is preferable that the sodium salt of carbonic acid is contained in the adhesive layer such that the content thereof in terms of carbonic acid or bicarbonate (CO 3 or HCO 3 number conversion) is 0.1 to 5.0 moles relative to the content of 1.0 mole of ropinirole and / or its pharmaceutically acceptable salt in terms of free ropinirole. From the viewpoint of sufficiently maintaining the balance between the skin permeability of ropinirole and the effect of improving the holding power of the adhesive layer, it is more preferably contained in the adhesive layer such that it becomes 0.5 to 5.0 moles, and still more preferably 1.0 to 5.0 moles. In addition, from the viewpoint of further sufficiently maintaining the cohesion of the adhesive layer, it is more preferably contained in the adhesive layer such that it becomes 0.2 to 4.0 moles, still more preferably 0.5 to 3.0 moles, and even more preferably 1.0 to 2.0 moles. When the content of the sodium salt of carbonic acid in the obtained adhesive layer is less than the above lower limit, there is a tendency that the skin permeability of ropinirole decreases. On the other hand, when it exceeds the above upper limit, there is a tendency that the cohesion of the adhesive layer decreases.

[0064] As a method for further containing the sodium salt of carbonic acid according to the present invention in the above adhesive layer, for example, the following method can be cited: in the method for manufacturing an adhesive patch containing ropinirole, the above ropinirole and / or its pharmaceutically acceptable salt, the above sodium salt of carbonic acid, and the above adhesive are mixed, and the obtained adhesive layer composition is molded to obtain the above adhesive layer.

[0065] As a method for manufacturing the above-mentioned ropinirole-containing patch, more specifically, for example, the following manufacturing methods can be cited. First, the above-mentioned ropinirole and / or its pharmaceutically acceptable salt, the above-mentioned sodium salt of carbonic acid, and the above-mentioned binder, as well as the above-mentioned other drugs, the above-mentioned absorption enhancer, the above-mentioned additive, and the solvent, etc. as required are mixed to obtain a uniform binder layer composition. Examples of the above-mentioned solvent include: water, absolute ethanol, toluene, hexane, ethyl acetate, cyclohexane, heptane, butyl acetate, ethanol, methanol, xylene, isopropanol, and a mixed solution of two or more of these. Secondly, after spreading the binder layer composition on the surface of the above-mentioned support layer (usually on one surface), the above-mentioned solvent is dried and removed as required to form a binder layer, and then cut into a required shape as required.

[0066] In addition, as a method for manufacturing the above-mentioned ropinirole-containing patch, it can also be the following method: It can further include the step of laminating the release liner on the surface of the binder layer opposite to the support layer. First, the binder layer composition is spread on one surface of the release liner to form the binder layer, and then the support layer is laminated on the surface of the binder layer opposite to the release liner, and cut into a specific shape as required, thereby obtaining the patch.

[0067] Thus, in the obtained ropinirole-containing patch, the skin permeability of ropinirole and / or its pharmaceutically acceptable salt can be prevented from decreasing, and the holding power of the binder layer can be sufficiently improved. Therefore, the present invention also provides a ropinirole-containing patch with improved holding power. As a patch with improved holding power of the binder layer, it includes the above-mentioned support layer and the above-mentioned binder layer, and the above-mentioned binder layer contains the above-mentioned ropinirole and / or its pharmaceutically acceptable salt, the above-mentioned sodium salt of carbonic acid, and the above-mentioned binder.

[0068] In the ropinirole-containing patch with improved holding power of the present invention, as the support layer, the binder layer, ropinirole and / or its pharmaceutically acceptable salt, the sodium salt of carbonic acid, and the binder, including their preferred forms and preferred contents, it corresponds to the ropinirole-containing patch related to the method of the present invention described above.

[0069] When the above-mentioned ropinirole acid addition salt is contained as a raw material of an adhesive in the adhesive layer, as described above, the ropinirole acid addition salt is desalted in whole or in part in the manufacturing process and / or the adhesive layer of the preparation after manufacturing by the sodium salt of carbonic acid which is also a weak base. Therefore, as the adhesive layer in the ropinirole-containing adhesive patch with improved holding power of the present invention obtained in this case, in addition to the above-mentioned adhesive, it is sufficient to contain at least a mixture of the above-mentioned ropinirole acid addition salt and the above-mentioned sodium salt of carbonic acid. As the above-mentioned mixture, as the desalting reaction product of the above-mentioned ropinirole acid addition salt and the above-mentioned sodium salt of carbonic acid, ropinirole free body and components derived from the above-mentioned sodium salt of carbonic acid (components derived from the sodium salt of carbonic acid) may also be contained.

[0070] As the components derived from the above-mentioned sodium salt of carbonic acid, examples include: carbonic acid, carbonate ion, bicarbonate, bicarbonate ion, sodium ion, sodium salt, which may be a single one of these, or a combination of two or more. As the above-mentioned sodium salt, it also depends on the acid of the above-mentioned ropinirole acid addition salt or the type of acid that may be contained in the adhesive layer as needed. For example, examples include: sodium salts of acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphorous acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, tartaric acid, fumaric acid, etc.

[0071] As such a ropinirole-containing adhesive patch with improved holding power, it can be packaged (preferably enclosed) into a packaging container during the period from after manufacturing to before use. As the above-mentioned packaging container, there is no particular limitation, and those that can be usually used as packaging containers for adhesive patches can be appropriately used. For example, it is preferably to use plastic packaging bags, plastic packaging bags formed with a metal layer (such as an aluminum layer), metal packaging bags (such as aluminum packaging bags), etc.

[0072] In addition, as the package obtained by packaging the above-mentioned ropinirole-containing adhesive patch with improved holding power into the above-mentioned packaging container, it may further have a deoxidation means. As the above-mentioned deoxidation means, examples include: a deoxidizer using iron powder enclosed in the above-mentioned packaging container or a deoxidizer mainly composed of vitamin C (more specifically, Agelex series (manufactured by Mitsubishi Gas Chemical Company), Pharmakeep series (manufactured by Mitsubishi Gas Chemical Company), etc.); the above-mentioned packaging container having a layer with a deoxidation function (more specifically, a layer mixed with powders such as aluminum, zinc, manganese, copper, iron, bisulfite, activated carbon, etc.).

[0073] [Examples]

[0074] Hereinafter, the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to the following examples. Furthermore, the skin penetration test and the holding power test of the adhesive patches obtained through each example and comparative example are respectively carried out by the methods shown below.

[0075] <Skin Permeation Test (In Vitro Hairless Mouse Skin Permeation Test)>

[0076] First, the skin of the torso of a hairless mouse was peeled off and the fat was removed. An adhesive patch with a size of 3.14 cm 2 and the release liner removed was attached to the epidermal side. It was set in a flow-through Franz-type permeation test cell with the dermal side in contact with the receiving liquid, and the receiving liquid (PBS) was filled in the above cell. Secondly, while circulating heated circulating water in the peripheral part to keep the receiving liquid at 32°C, the receiving liquid was delivered at a flow rate of about 2.5 ml / hr, and the receiving liquid was taken every 4 hours during the 24-hour period. The concentration of ropinirole (ropinirole hydrochloride) in the taken receiving liquid was measured by high performance liquid chromatography. By the following formula:

[0077] Ropinirole skin permeation amount (μg / cm 2 ) = {Concentration of ropinirole in the receiving liquid (μg / mL) × Flow rate (mL)} / Adhesive patch area (cm 2 ), the ropinirole skin permeation amount per unit area of the adhesive layer was calculated, and the cumulative ropinirole skin permeation amount within 24 hours after the start of attachment was set as the 24-hr cumulative skin permeation amount (μg / cm 2 ).

[0078] <Retention Force Test>

[0079] First, the adhesive patch was cut into a size of 10 mm wide and 50 mm long to prepare test pieces. The release liner was removed from each test piece to expose the adhesive layer surface, and it was placed at the center of one end of a stainless steel plate (made of SUS304) used as a test plate so that the attachment area was 10 mm wide and 25 mm long. A 1-kg roller was reciprocated once for crimping, and the above test piece was attached to the test plate. Immediately after crimping by the roller, the test plate was suspended with the length direction of the test piece as the vertical direction, and a 500-g counterweight was installed at the free end (lower end) of the above test piece. In an environment of 32°C and 65% RH, the elapsed time from the installation of the counterweight until the above test piece peeled off and fell from the test plate was measured. In this retention force test, the conditions other than those shown above were carried out according to the method described in the JIS standard (JIS-Z-0237: 2009).

[0080] (Example 1)

[0081] First, 15.0 parts by mass of ropinirole hydrochloride, 4.2 parts by mass of sodium bicarbonate (equivalent to 1.0 mole relative to 1.0 mole of the molar amount of ropinirole hydrochloride), 13.4 parts by mass of styrene-isoprene-styrene block copolymer (SIS), 9.0 parts by mass of polyisobutylene (PIB), 40.4 parts by mass of an alicyclic saturated hydrocarbon resin, and 18.0 parts by mass of liquid paraffin are added to an appropriate amount of solvents (water, methanol, and toluene) and mixed to obtain an adhesive layer composition. Next, the obtained adhesive layer composition is extended on a release liner (a polyester film subjected to a release treatment) so as to have a thickness of 100 g / m 2 and the solvents are dried and removed to form an adhesive layer. A support layer (a polyester film) is laminated on the surface of the obtained adhesive layer opposite to the release liner, and an adherent laminated in the order of support layer / adhesive layer / release liner is obtained.

[0082] (Comparative Examples 1-2)

[0083] The composition of the adhesive layer composition is as shown in Table 1 below, and other than this, each adherent is obtained in the same manner as in Example 1.

[0084] For the adherents obtained in Example 1 and Comparative Examples 1-2, the above-described skin permeation test and holding force test are respectively carried out. The results are respectively shown in Table 1 below together with the composition (excluding solvents) of each adhesive layer composition. Furthermore, in Table 1, the values in parentheses in the column of ropinirole hydrochloride represent parts by mass in terms of ropinirole free form (hereinafter the same in Tables 2-3).

[0085] [Table 1]

[0086]

[0087] It was clearly confirmed from the results shown in Table 1 that in the adherent containing a sodium salt of carbonic acid in the adhesive layer according to the present invention (for example, Example 1), the skin permeability of ropinirole is excellent in the same manner as in the adherent containing sodium hydroxide (for example, Comparative Example 1). On the other hand, it was confirmed that in the adherent containing calcium carbonate which is also a carbonate like the sodium salt of carbonic acid and is conventionally known as a filler in the adhesive layer (for example, Comparative Example 2), the skin permeability of ropinirole is greatly reduced.

[0088] Furthermore, it was clarified from the results shown in Table 1 that in the adherent containing a sodium salt of carbonic acid in the adhesive layer according to the present invention (for example, Example 1), the holding force is greatly improved compared with the adherent containing sodium hydroxide (for example, Comparative Example 1), and the improvement effect is equal to or better than that of the adherent containing calcium carbonate in the above adhesive layer (for example, Comparative Example 2).

[0089] (Examples 2-3)

[0090] The composition of the adhesive layer composition was as shown in Table 2 below. Except for this, each patch was obtained in the same manner as in Example 1.

[0091] For the patches obtained in Examples 2 to 3, the above-mentioned skin penetration test and adhesion test were carried out respectively. The results are shown in Table 2 below together with the composition (excluding the solvent) of each adhesive layer composition. In addition, the results of Comparative Example 1 and Example 1 are also shown in Table 2. Furthermore, in Table 2, the values in parentheses in the columns of sodium hydroxide and sodium bicarbonate represent the molar ratio relative to 1.0 mole of ropinirole hydrochloride in its free form.

[0092] [Table 2]

[0093]

[0094] It was clearly confirmed from the results shown in Table 2 that in the patches containing the sodium salt of carbonic acid in the adhesive layer according to the present invention, even when the molar ratio relative to 1.0 mole of free ropinirole is 3.0 moles or 5.0 moles (for example, Examples 2 to 3), sufficient skin permeability of ropinirole is maintained in the same manner as when it is 1.0 mole (for example, Example 1), and the adhesion of the adhesive layer is improved.

[0095] (Examples 4 - 5, Comparative Examples 3 - 4)

[0096] The composition of the adhesive layer composition was as shown in Table 3 below. Except for this, each patch was obtained in the same manner as in Example 1. In Table 3, each adhesive is as follows:

[0097] MAS - 811C: an acrylic adhesive substantially having no functional groups (manufactured by CosMED Pharmaceutical Co., Ltd.);

[0098] Bio - PSA - 7 - 4202: Bio - PSA - 7 - 4202, a silicone - based adhesive (manufactured by DuPont Toray Specialty Materials Co., Ltd.).

[0099] For the patches obtained in Examples 4 to 5 and Comparative Examples 3 to 4, the above-mentioned skin penetration test and adhesion test were carried out respectively. The results are shown in Table 3 below together with the composition (excluding the solvent) of each adhesive layer composition. Furthermore, in Table 3, the adhesion values of Examples 4 and 5 are the relative values when the adhesion values of Comparative Examples 3 and 4 are set to 1.

[0100] [Table 3]

[0101]

[0102] It was clearly confirmed from the results shown in Table 3 that even when an acrylic-based adhesive or a silicone-based adhesive was used instead of a rubber-based adhesive (such as SIS and PIB) as the adhesive, in the adhesive layer of the present invention containing a sodium salt of carbonic acid (such as in Examples 4 and 5), while maintaining sufficient skin permeability of ropinirole, the holding power of the adhesive layer was improved.

[0103] From these results, it was confirmed that by further containing a sodium salt of carbonic acid in the adhesive layer containing ropinirole and / or its pharmaceutically acceptable salt and an adhesive, while maintaining sufficient skin permeability of ropinirole and / or its pharmaceutically acceptable salt, the holding power of the above adhesive layer could be sufficiently improved.

[0104] Industrial applicability

[0105] As described above, according to the present invention, it is possible to provide a method for improving the holding power of the adhesive layer of a ropinirole-containing patch, and a ropinirole-containing patch with improved holding power having excellent holding power of the adhesive layer. The method for improving the holding power of the adhesive layer of the ropinirole-containing patch can improve the holding power of the adhesive layer containing ropinirole and / or its pharmaceutically acceptable salt and an adhesive while maintaining sufficient skin permeability of ropinirole and / or its pharmaceutically acceptable salt.

Claims

1. A method for improving the adhesive layer retention of a ropinirole-containing patch, which is a method for improving the retention of the adhesive layer of a ropinirole-containing patch having a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts and an adhesive. Wherein, The adhesive is at least one selected from the group consisting of a rubber-based adhesive, an acrylic adhesive without a carboxyl group, and a silicone-based adhesive. The adhesive layer is further contained with a sodium salt of carbonic acid, and the content of the sodium salt of carbonic acid relative to the total mass of the adhesive layer is 0.5 to 33% by mass. The content of at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts in terms of the free form of ropinirole is 5 to 30% by mass relative to the total mass of the adhesive layer.

2. The method for improving the adhesive layer retention of a ropinirole-containing patch according to claim 1, wherein the sodium salt of carbonic acid is at least one selected from the group consisting of sodium carbonate and sodium bicarbonate.

3. The method for improving the adhesive layer retention of a ropinirole-containing patch according to claim 1 or 2, wherein the sodium salt of carbonic acid is contained in the adhesive layer in such a manner that the content thereof becomes 0.1 to 5.0 moles relative to 1.0 mole of the content of at least one selected from the group consisting of ropinirole and its pharmaceutically acceptable salts in terms of the free form of ropinirole.

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