Method for enhancing storage stability of bisoprolol or pharmaceutically acceptable salt thereof

Abstract

To provide a method for enhancing storage stability of bisoprolol or a pharmaceutically acceptable salt thereof in a patch.SOLUTION: The present invention provides a method for enhancing storage stability of bisoprolol or a pharmaceutically acceptable salt thereof in a patch, where the patch comprises an adhesive layer on a support body, where the adhesive layer is a patch comprising an adhesive base and bisoprolol or a pharmaceutically acceptable salt thereof, and where the method involves incorporating 2-mercaptobenzimidazole and a silicate compound in the adhesive layer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for improving the storage stability of bisoprolol or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] Bisoprolol, a highly selective blocker (β1 blocker) of sympathetic β1 receptors, is used to improve essential hypertension, angina pectoris, and arrhythmia, and is available in tablet and patch forms. For example, Patent Document 1 discloses a patch containing bisoprolol, in which the water content of the adhesive layer is 10,000 ppm or less, and which has excellent stability over time. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2015-051947 A Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have studied the patch containing bisoprolol, and found that the content of bisoprolol in the patch decreases with time.When the content of bisoprolol decreases, it may affect the performance of bisoprolol such as skin permeability.Therefore, the object of the present invention is to provide a method for improving the storage stability of bisoprolol or its pharma-ceutically acceptable salt in the patch that comprises a pressure-sensitive adhesive layer on a support. [Means for solving the problem]

[0005] As a result of intensive research, the inventors discovered that the storage stability of bisoprolol or a pharma- ceutical product thereof in a patch can be improved by incorporating 2-mercaptobenzimidazole and a silicic acid compound in the adhesive layer, and thus completed the present invention.

[0006] That is, the present invention includes the following [1] to [6]. [1] A method for improving the storage stability of bisoprolol or a pharma- ceutically acceptable salt thereof in a patch, comprising: The patch comprises an adhesive layer on a support, the adhesive layer containing an adhesive base and bisoprolol or a pharma- ceutically acceptable salt thereof, A method comprising incorporating 2-mercaptobenzimidazole and a silicic acid compound in the pressure-sensitive adhesive layer. [2] A method for improving the storage stability of bisoprolol or a pharma- ceutically acceptable salt thereof in a patch having an adhesive layer on a support, comprising: A step of mixing an adhesive base, bisoprolol or a pharma- ceutically acceptable salt thereof, 2-mercaptobenzimidazole, and a silicic acid compound to obtain an adhesive composition; forming the pressure-sensitive adhesive composition to obtain the patch; A method comprising: [3] The method according to [1] or [2], wherein the content of 2-mercaptobenzimidazole in the pressure-sensitive adhesive layer is 0.05% by mass to 1% by mass, based on the total mass of the pressure-sensitive adhesive layer. [4] The method according to any one of [1] to [3], wherein the content of the silicic acid compound in the pressure-sensitive adhesive layer is 3.5% by mass to 15% by mass, based on the total mass of the pressure-sensitive adhesive layer. [5] The method according to any one of [1] to [4], wherein the silicic acid compound is light anhydrous silicic acid. [6] The method according to any one of [1] to [5], wherein the adhesive base is a rubber-based adhesive base. Effect of the Invention

[0007] According to the present invention, it is possible to provide a method for improving the storage stability of bisoprolol or a pharma- ceutical acceptable salt thereof in a patch comprising an adhesive layer on a support. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will be described in detail below by showing aspects of the present invention.

[0009] A method according to one aspect of the present invention is a method for improving the storage stability of bisoprolol or a pharma- ceutically acceptable salt thereof in a patch, the patch comprising an adhesive layer on a support, the adhesive layer comprising an adhesive base and bisoprolol or a pharma-ceutically acceptable salt thereof, and including 2-mercaptobenzimidazole and a silicic acid compound in the adhesive layer. Specifically, the method may be carried out by the same method as the method for producing the patch described in paragraph

[0044] .

[0010] A method according to another aspect of the present invention is a method for improving the storage stability of bisoprolol or a pharma- ceutically acceptable salt thereof in a patch having an adhesive layer on a support, comprising the steps of: mixing an adhesive base, bisoprolol or a pharma- ceutically acceptable salt thereof, 2-mercaptobenzimidazole, and a silicic acid compound to obtain an adhesive composition; and forming the adhesive composition to obtain the patch. Specifically, the method may be carried out in the same manner as the method for producing the patch described in paragraph

[0044] .

[0011] A patch according to yet another aspect of the present invention comprises an adhesive layer on a support, the adhesive layer containing bisoprolol or a pharma- ceutically acceptable salt thereof, an adhesive base, 2-mercaptobenzimidazole, and a silicic acid compound.

[0012] The support may be any material capable of maintaining the shape of the patch, particularly the pressure-sensitive adhesive layer. Examples of the material of the support include synthetic resins such as polyethylene, polypropylene, polybutadiene, ethylene-vinyl chloride copolymer, polyvinyl chloride, polyamides such as nylon, polyesters, cellulose derivatives, and polyurethanes. The properties of the support include, for example, films, sheets, sheet-like porous bodies, sheet-like foams, cloths such as woven fabrics, knitted fabrics, and nonwoven fabrics, and laminates thereof. The thickness of the support is not particularly limited, but is usually preferably about 2 μm to 3000 μm.

[0013] The adhesive layer is formed from an adhesive composition obtained by mixing bisoprolol or a pharma- ceutically acceptable salt thereof, an adhesive base, 2-mercaptobenzimidazole, a silicic acid compound, and optional components described below. The mass per unit area of ​​the adhesive layer is not particularly limited, and is preferably 15 g / m. 2 ~400g / m 2 and 20 g / m 2 ~300g / m 2 , 25g / m 2 ~200g / m 2 , or 30 g / m 2 ~100g / m 2 The pressure-sensitive adhesive layer may have a mass per unit area of ​​400 g / m 2 If the mass per unit area of ​​the adhesive layer exceeds 15 g / m, the patch will be easily removed when putting on or taking off clothes. 2 If it is less than this, the adhesiveness of the patch is likely to decrease.

[0014] The pharmaceutically acceptable salt of bisoprolol means the acid addition salt of bisoprolol that can be used as medicine.The organic acid includes formic acid, acetic acid, adipic acid, citric acid, tartaric acid, methanesulfonic acid, fumaric acid, maleic acid, etc.The inorganic acid includes hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.The pharmaceutically acceptable salt of bisoprolol is preferably bisoprolol fumarate.Bisoprolol or its pharmaceutically acceptable salt may be anhydrous or hydrated.

[0015] The content of bisoprolol can be 1% by mass to 20% by mass, and may be 3% by mass to 20% by mass, 3% by mass to 15% by mass, 3% by mass to 12% by mass, or 5% by mass to 8% by mass, based on the total mass of the adhesive layer. Note that the above-mentioned % by mass means the % by mass of bisoprolol in free form when the adhesive layer contains a pharma- ceutically acceptable salt of bisoprolol.

[0016] The adhesive base is for imparting adhesiveness to the adhesive layer, and examples thereof include rubber-based adhesive bases, acrylic-based adhesive bases, and silicone-based adhesive bases. The adhesive base is preferably at least one selected from the group consisting of rubber-based adhesive bases, acrylic-based adhesive bases, and silicone-based adhesive bases. The adhesive base may be any one of rubber-based adhesive bases, acrylic-based adhesive bases, and silicone-based adhesive bases, or a combination thereof. The total content of the adhesive base may be 10% by mass to 95% by mass, or may be 20% by mass to 90% by mass, based on the total mass of the adhesive layer.

[0017] Examples of rubber-based adhesive bases include styrene-butadiene block copolymers, styrene-butadiene-styrene block copolymers, styrene-isoprene block copolymers, styrene-isoprene-styrene block copolymers, polyisobutylene, natural rubber, alkyl vinyl ether (co)polymers, polyisoprene, polybutadiene, and the like. One of these may be used alone, or two or more may be used in combination.

[0018] As the rubber-based adhesive base, from the viewpoint that the adhesive layer tends to exhibit more sufficient adhesive strength, it is preferable to use at least one type selected from the group consisting of styrene-isoprene-styrene block copolymer and polyisobutylene.

[0019] Specific examples of styrene-isoprene-styrene block copolymers include Quintac (registered trademark) 3570C (trade name, manufactured by Zeon Corporation), SIS5002, SIS5229, SIS5505, SIS5505P (trade names, manufactured by JSR Corporation), and SIBSTAR (registered trademark) T102 (trade name, manufactured by Kaneka Corporation). Polyisobutylene also includes so-called butyl rubber (isobutylene-isoprene rubber), and a specific example thereof is Oppanol (registered trademark). ) N50, N80, N100, N150, B11, B12, B50, B80, B100, B120, B150, B220 (trade names, manufactured by BASF), JSR (registered trademark) Butyl 065, 268, 365 (trade names, manufactured by JSR Corporation), X_Butyl (registered trademark) RB100, 101-3, 301, 402 (trade names, manufactured by ARLANXEO), Exxon (registered trademark) Butyl 065, 065S, 068, 068S, 268, 268S, 365, 365S (trade names, manufactured by Exxon Mobile), Butyl 065, 268, 365 (trade names, manufactured by Japan Butyl Co., Ltd.), and the like.

[0020] The content of the rubber-based adhesive base can be 10% by mass to 80% by mass, or may be 15% by mass to 60% by mass, 15% by mass to 40% by mass, or 15% by mass to 30% by mass, based on the total mass of the adhesive layer.

[0021] The acrylic adhesive base is, for example, a (co)polymer of one or more (meth)acrylic acid alkyl esters. Examples of (meth)acrylic acid alkyl esters include butyl (meth)acrylate, isobutyl (meth)acrylate, hexyl (meth)acrylate, octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, and decyl (meth)acrylate. In this specification, the term "(meth)acrylic acid" means either or both of acrylic acid and methacrylic acid, and similar expressions are defined in the same manner.

[0022] The acrylic adhesive base may be a copolymer formed from an alkyl (meth)acrylate ester (main monomer) and a comonomer. Examples of the main monomer include methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate. One of these may be used alone, or two or more may be used in combination. The comonomer may be any component that can be copolymerized with an alkyl (meth)acrylate ester. Examples of the comonomer include hydroxyalkyl (meth)acrylate ester, ethylene, propylene, styrene, vinyl acetate, N-vinylpyrrolidone, (meth)acrylic acid, and (meth)acrylic acid amide. The comonomer may be one type alone, or two or more may be used in combination.

[0023] Specific examples of acrylic adhesive bases include acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and acrylic polymers contained in acrylic resin alkanolamine solution. Specific examples of such acrylic adhesive bases include the DURO-TAK series (manufactured by Henkel) such as DURO-TAK (registered trademark) 387-2510, DURO-TAK (registered trademark) 87-2510, DURO-TAK (registered trademark) 387-2287, DURO-TAK (registered trademark) 87-2287, DURO-TAK (registered trademark) 87-4287, DURO-TAK (registered trademark) 387-2516, DURO-TAK (registered trademark) 87-2516, DURO-TAK (registered trademark) 87-2074, DURO-TAK (registered trademark) 87-900A, DURO-TAK (registered trademark) 87-901A, DURO-TAK (registered trademark) 87-9301, and DURO-TAK (registered trademark) 87-4098; GELVA (registered trademark) GMS 788, GELVA (registered trademark) GMS Examples of such series include the GELVA series (manufactured by Henkel), such as GELVA 3083 and GELVA (registered trademark) GMS 3253; the MAS series (manufactured by Cosmedi Pharmaceutical Co., Ltd.), such as MAS811 (product name) and MAS683 (product name); the Eudragit (registered trademark) series (manufactured by Evonik), the Nikasol (registered trademark) series (manufactured by Nippon Carbide Industries Co., Ltd.), and the Ultrasol (registered trademark) series (manufactured by Aica Kogyo Co., Ltd.).

[0024] The content of the acrylic adhesive base can be 10% by mass to 95% by mass, and may be 20% by mass to 90% by mass, based on the total mass of the adhesive layer.

[0025] The silicone adhesive base is a compound having an organopolysiloxane skeleton, and examples of the silicone adhesive base include dimethylpolysiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane. Specific examples of silicone adhesive bases include MD series such as MD7-4502 Silicone Adhesive and MD7-4602 Silicone Adhesive (manufactured by DuPont Toray Specialty Materials Co., Ltd.); BIO-PSA (registered trademark) 7-4301 Silicone Adhesive, BIO-PSA (registered trademark) 7-4302 Silicone Adhesive, BIO-PSA (registered trademark) 7-4201 Silicone Adhesive, BIO-PSA (registered trademark) 7-4202 Silicone Adhesive, BIO-PSA (registered trademark) 7-4101 Silicone Adhesive, BIO-PSA (registered trademark) 7-4102 Silicone Adhesive, BIO-PSA (registered trademark) 7-4601 Silicone Adhesive, BIO-PSA (registered trademark) 7-4602 Silicone Adhesive, and BIO-PSA (registered trademark) 7-4501 Silicone Examples of such adhesives include the BIO-PSA series (manufactured by DuPont-Toray Specialty Materials Co., Ltd.), such as BIO-PSA (registered trademark) 7-4502 Silicone Adhesive, BIO-PSA (registered trademark) 7-4401 Silicone Adhesive, and BIO-PSA (registered trademark) 7-4402 Silicone Adhesive; Dow Corning (registered trademark) 7-9800A, Dow Corning (registered trademark) 7-9800B, Dow Corning (registered trademark) 7-9700A, and Dow Corning (registered trademark) 7-9700B.

[0026] The content of the silicone-based adhesive base can be 10% by mass to 95% by mass, and may be 20% by mass to 90% by mass, based on the total mass of the adhesive layer.

[0027] The content of 2-mercaptobenzimidazole can be 0.01% by mass to 5% by mass, or may be 0.05% by mass to 3% by mass, 0.05% by mass to 1% by mass, or 0.1% by mass to 0.5% by mass, based on the total mass of the pressure-sensitive adhesive layer.

[0028] Examples of the silicic acid compound include silicon dioxide, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminometasilicate, talc, bentonite, and kaolin. The silicic acid compound may be used alone or in combination of two or more. Among them, silicon dioxide is preferable as the silicic acid compound. Specific examples of silicon dioxide include light anhydrous silicic acid and hydrous silicon dioxide, and among these, light anhydrous silicic acid is particularly preferable. The content of the silicic acid compound can be 1% by mass to 15% by mass, or may be 3.5% by mass to 15% by mass, based on the total mass of the pressure-sensitive adhesive layer.

[0029] In the adhesive layer, the value calculated from the contents (mass%) of 2-mercaptobenzimidazole, silicic acid compound, and bisoprolol based on the total mass of the adhesive layer according to the following formula 1 can be 0.01 to 2.0, or may be 0.02 to 1.6 or 0.03 to 1.2. Note that, when a pharma- ceutical acceptable salt of bisoprolol is contained in the adhesive layer, the above content (mass%) of bisoprolol means the content (mass%) of bisoprolol calculated as a free form. [2-mercaptobenzimidazole content (mass%)] × [silicic acid compound content (mass%)] / [bisoprolol content (mass%)] (Formula 1)

[0030] The adhesive layer may further contain other additives as desired, such as a tackifier resin, a plasticizer, an absorption promoter, a solubilizer, a filler, and a fragrance.

[0031] The tackifier resin is a component that adjusts the adhesiveness of the adhesive layer. Examples of the tackifier resin include petroleum resins, terpene resins, rosin resins, phenolic resins, and xylene resins. Examples of the petroleum resin include alicyclic petroleum resins (alicyclic saturated hydrocarbon resins, etc.), aliphatic petroleum resins (aliphatic hydrocarbon resins, etc.), and aromatic petroleum resins. More specifically, Arcon P-70, Arcon P-85, Arcon P-90, Arcon P-100, Arcon P-115, Arcon P-125, Arcon M-70, Arcon M-85, Arcon M-90, Arcon M-100, Arcon M-115, and Arcon M-125 (all trade names, manufactured by Arakawa Chemical Industries Co., Ltd.), and Escoretz 8000 (trade name, manufactured by Esso Petrochemical Co., Ltd.). Examples of terpene resins include pinene polymers (α-pinene polymer, β-pinene polymer, etc.), terpene polymers, dipentene polymers, terpene-phenol polymers, aromatic modified terpene polymers, and pinene-phenol copolymers. More specific examples include YS Resin (YS Resin PXN (1150N, 300N), YS Resin PX1000, YS Resin TO125, YS Resin TO105, etc.), Clearon P105, Clearon M115, Clearon K100 (all trade names, manufactured by Yasuhara Chemical Co., Ltd.), and Tamanol 901 (trade name, manufactured by Arakawa Chemical Industries, Ltd.). Examples of rosin resins include hydrogenated rosin glycerin ester, very light-colored rosin, very light-colored rosin ester, and acid-modified very light-colored rosin. More specifically, Pine Crystal (KE-311, PE-590, KE-359, KE-100, etc.) (trade name, manufactured by Arakawa Chemical Industries, Ltd.) and the like can be mentioned. The tackifier resin may be one of these alone or two or more of them in combination. Among them, alicyclic saturated hydrocarbon resin, terpene resin, hydrogenated rosin glycerin ester, or a combination thereof is preferable, and alicyclic saturated hydrocarbon resin, terpene resin, or a combination thereof is more preferable. When the adhesive layer contains a tackifier resin, the content of the tackifier resin can be 15% by mass to 80% by mass, and may be 30% by mass to 65% by mass, based on the total mass of the adhesive layer.

[0032] Examples of the plasticizer include liquid paraffin, light liquid paraffin, squalane, squalene, vegetable oils (olive oil, camellia oil, castor oil, tall oil, peanut oil, spearmint oil, eucalyptus oil, jojoba oil, camphor white oil, sunflower oil, orange oil, etc.), fats and oils (dibutyl phthalate, dioctyl phthalate, etc.), and liquid rubber (liquid polybutene, liquid isoprene rubber, etc.). When the adhesive layer contains a plasticizer, the content thereof is, for example, 3% by mass to 50% by mass, 5% by mass to 30% by mass, or 7% by mass to 20% by mass based on the total mass of the adhesive layer.

[0033] The absorption enhancer may be any compound that has been known to have a transdermal absorption enhancing effect. Examples of the absorption enhancer include organic acid esters (e.g., fatty acid esters, cinnamic acid esters), organic acid amides (e.g., fatty acid amides), aliphatic alcohols, polyhydric alcohols, ethers (e.g., aliphatic ethers, polyoxyethylene alkyl ethers), and the like. These absorption enhancers may have unsaturated bonds and may have a cyclic, linear, or branched chemical structure. In addition, the absorption enhancer may be a monoterpene compound, a sesquiterpene compound, or a vegetable oil (e.g., olive oil). These absorption enhancers may be used alone or in combination of two or more.

[0034] Examples of organic acid esters include ethyl acetate, propyl acetate, cetyl lactate, lauryl lactate, methyl salicylate, ethylene glycol salicylate, methyl cinnamate, and fatty acid esters. Examples of fatty acid esters include methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, isopropyl palmitate, and cetyl palmitate. The fatty acid ester may be glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyethylene glycol sorbitan fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, or polyoxyethylene hydrogenated castor oil. Specific examples of fatty acid esters include glycerin monocaprylate, glycerin monocaprate, glycerin monolaurate, glycerin monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20, propylene glycol monolaurate, polyethylene glycol monolaurate, polyethylene glycol monostearate, Span 40, Span 60, Span 80, Span 120 (product names, manufactured by Croda Japan Co., Ltd.), Tween (registered trademark) 20, Tween (registered trademark) 21, Tween (registered trademark) 40, Tween (registered trademark) 60, Tween (registered trademark) 80, and NIKKOL (registered trademark) HCO-60 (product name, manufactured by Nikko Chemicals Co., Ltd.).

[0035] Examples of organic acid amides include fatty acid amides (such as lauric acid diethanolamide), hexahydro-1-dodecyl-2H-azepin-2-one (also called Azone) and its derivatives, and pyrothiodecane.

[0036] The term "aliphatic alcohol" refers to an aliphatic alcohol having 6 to 20 carbon atoms. Examples of the aliphatic alcohol include lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, and cetyl alcohol. Examples of the polyhydric alcohol include propylene glycol.

[0037] The aliphatic ether means an ether having an aliphatic group (for example, an alkyl group, an alkenyl group) having 6 to 20 carbon atoms. An example of the polyoxyethylene alkyl ether is polyoxyethylene lauryl ether.

[0038] Examples of the monoterpene compounds include geraniol, thymol, terpineol, l-menthol, borneol, d-limonene, isoborneol, nerol, and dl-camphor. As the monoterpene compound, peppermint oil may be used.

[0039] When the pressure-sensitive adhesive layer contains an absorption enhancer, the content of the absorption enhancer can be 0.5% by mass to 20% by mass based on the total mass of the pressure-sensitive adhesive layer.

[0040] The solubilizer is a component that makes it easy to dissolve bisoprolol or a pharma- ceutically acceptable salt thereof in the adhesive composition. Examples of the solubilizer include fatty acid polyhydric alcohol esters (e.g., propylene glycol monolaurate, glycerin monolaurate, glycerin monooleate, and sorbitan monolaurate), fatty acid amides (e.g., lauric acid diethanolamide), aliphatic alcohols (e.g., octyldodecanol, isostearyl alcohol, and oleyl alcohol), polyhydric alcohols (e.g., propylene glycol, dipropylene glycol, and polyethylene glycol), and pyrrolidone derivatives (e.g., N-methyl-2-pyrrolidone). When the adhesive layer contains a solubilizer, the content of the solubilizer can be 2% by mass to 40% by mass based on the total mass of the adhesive layer.

[0041] Examples of the filler include powders of metal compounds (aluminum oxide, aluminum hydroxide, zinc oxide, titanium oxide, calcium carbonate, etc.) or organic compounds (cellulose powder, stearates, etc.), or short fibers of resins containing these. When the pressure-sensitive adhesive layer contains a filler, the content of the filler can be 0.1% by mass to 20% by mass based on the total mass of the pressure-sensitive adhesive layer.

[0042] The patch may further include a release liner. The release liner is laminated on the surface of the adhesive layer opposite the support. The release liner tends to reduce adhesion of dirt and the like to the adhesive layer during storage. The surface of the release liner that contacts the adhesive layer is preferably release-treated with silicone, fluorinated polyolefin, or the like.

[0043] The material of the release liner is not particularly limited, and liners generally known to those skilled in the art can be used. Examples of the release liner include paper; polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyolefins such as polyethylene and polypropylene; and films such as polyvinyl chloride, polyvinylidene chloride, nylon, and aluminum. The release liner may be a laminate film of high-quality paper and polyolefin. The material of the release liner is preferably a film made of polypropylene or polyethylene terephthalate.

[0044] The patch can be produced, for example, by the following method, but is not limited thereto, and any known method can be used. First, the components constituting the adhesive layer are mixed in a solvent (toluene, ethyl acetate, etc.) in a predetermined ratio to obtain a uniform solution of the adhesive composition. Next, the solution of the adhesive composition is spread on a peelable film (release liner), and the solvent is then dried and removed to form an adhesive layer of a predetermined thickness. Furthermore, a support is pressed onto the adhesive layer so that the adhesive layer is sandwiched between the release liner and the support. Finally, the patch can be obtained by cutting into the desired shape and dimensions. In this case, the release liner is removed when the patch is applied. The area of ​​the patch is 5 cm 2 ~100cm 2 5 cm 2 ~50cm 2 The shape and dimensions of the patch may be, for example, a rectangle with short sides of 2 cm to 10 cm and long sides of 3 cm to 15 cm, or a circle with a diameter of 1 cm to 8 cm. EXAMPLES

[0045] Test Example 1: Evaluation of the Decrease in Bisoprolol Content 1. Preparation of the Patch Each component was thoroughly mixed in toluene to obtain a solution of the pressure-sensitive adhesive composition so as to have the contents (mass %) shown in Tables 1 to 4 below. After spreading the obtained solution of the pressure-sensitive adhesive composition on a release liner (a polyethylene terephthalate film subjected to a release treatment), toluene was removed by drying to form a pressure-sensitive adhesive layer having a mass per unit area of 37 g / m 2 A support layer (a polyethylene terephthalate film) was laminated on the opposite surface of the obtained pressure-sensitive adhesive layer to obtain a patch laminated in the order of support layer / pressure-sensitive adhesive layer / release liner.

[0046] 2. Measurement of the Content of Bisoprolol The content of bisoprolol was measured by the following procedure using the patch before storage cut into an area of 2.5 cm 2 and the patch enclosed in an aluminum package and stored in a thermostat at 60°C for 1 month. After removing the release liner, the patch was put into a 50 mL test tube, and 10 mL of a tetrahydrofuran solution containing propyl paraoxybenzoate as an internal standard substance was added thereto. After dissolving by shaking for 30 minutes and ultrasonic treatment for 30 minutes, it was diluted 5-fold with a 0.2% aqueous phosphoric acid solution. After mixing for 10 minutes, it was filtered through a 0.45 μm membrane filter to obtain a sample solution. Thereafter, bisoprolol contained in the sample solution and the standard sample solution was eluted for 15 minutes by high performance liquid chromatography (HPLC) using the following mobile phase and detected. Then, using the calibration curve obtained from the standard sample solution, the concentration of bisoprolol in the sample solution was quantified, the content of bisoprolol contained in the patch was calculated, and the content of bisoprolol in the patch before storage and after storage at 60°C for 1 month was calculated by correcting using the actually measured value of the mass of the pressure-sensitive adhesive layer of each patch. <HPLC Analysis Conditions> Column: Inertsil ODS-3 (ODS particle size: 3 μm, inner diameter: 4.6 mm, length: 15 cm) Mobile phase: Aqueous mobile phase (aqueous solution of 20 mM sodium heptanesulfonate and 0.2% phosphoric acid):acetonitrile = 60:40 Measurement wavelength: 225nm Flow rate: 0.8mL / min Sample injection volume: 10 μL Column temperature: 40℃ The theoretical value of the bisoprolol content at the time of preparation of the patch was set to 100, and the theoretical values ​​of the bisoprolol content in the patch before storage and after one month of storage at 60°C were calculated respectively. The reduction amount was calculated by subtracting the theoretical value of the bisoprolol content in the patch after one month of storage at 60°C from the theoretical value of the bisoprolol content in the patch before storage.

[0047] In addition, (B)×(C) / (A) in Tables 1 to 4 is a value calculated from the contents (mass%) of 2-mercaptobenzimidazole, light anhydrous silicic acid, and bisoprolol according to the following formula 2. [2-mercaptobenzimidazole content (mass%)] × [light anhydrous silicic acid content (mass%)] / [bisoprolol content (mass%)] (Formula 2)

[0048] [Table 1]

[0049] [Table 2]

[0050] [Table 3]

[0051] [Table 4]

[0052] As is clear from the results shown in Tables 1 to 4, the patch containing 2-mercaptobenzimidazole and light anhydrous silicic acid was able to suppress the decrease in the content of bisoprolol during storage. Also, as is clear from the results shown in Tables 1 and 2, the patch not containing either 2-mercaptobenzimidazole or light anhydrous silicic acid was unable to suppress the decrease in the content of bisoprolol during storage.

Claims

1. A method for improving the storage stability of bisoprolol or a pharma- ceutically acceptable salt thereof in a patch, comprising: The patch comprises an adhesive layer on a support, the adhesive layer containing an adhesive base and bisoprolol or a pharma- ceutically acceptable salt thereof, The method comprises incorporating 2-mercaptobenzimidazole and a silicic acid compound in the pressure-sensitive adhesive layer.

2. The method according to claim 1, wherein the content of 2-mercaptobenzimidazole in the pressure-sensitive adhesive layer is 0.05% by mass to 1% by mass based on the total mass of the pressure-sensitive adhesive layer.

3. The method according to claim 1 or 2, wherein the content of the silicic acid compound in the pressure-sensitive adhesive layer is 3.5% by mass to 15% by mass, based on the total mass of the pressure-sensitive adhesive layer.

4. The method according to claim 1 or 2, wherein the silicic acid compound is a light anhydrous silicic acid.

5. The method according to claim 1 or 2, wherein the adhesive base is a rubber-based adhesive base.

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