Bisoprolol-containing patch

Abstract

To provide a patch that prevents bisoprolol analogs from increasing with time.SOLUTION: A patch includes an adhesive layer on a support. The adhesive layer includes bisoprolol or a pharmaceutically acceptable salt thereof, an adhesive base, L-cysteine, and a silicate compound. In the adhesive layer, the value calculated by the formula: L-cysteine content (mass%)×silicate compound content (mass%) / bisoprolol content (mass%) is 0.016-0.5.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a transdermal patch containing bisoprolol. [Background technology]

[0002] Bisoprolol, a highly selective β1 blocker of sympathetic nerve β1 receptors, is used to improve essential hypertension, angina pectoris, and arrhythmias, and is available in tablet and transdermal patch forms. Regarding transdermal patches containing bisoprolol, for example, Patent Document 1 discloses a transdermal patch in which the water content of the adhesive layer is 10,000 ppm or less, and which exhibits excellent long-term stability of bisoprolol. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2015-051947 [Overview of the project] [Problems that the invention aims to solve]

[0004] The present inventors investigated a patch containing bisoprolol and found that the amount of bisoprolol-related substances in the patch increased over time. An increase in bisoprolol-related substances may affect the performance of bisoprolol, such as its skin permeability. Therefore, an object of the present invention is to provide a patch in which the amount of bisoprolol-related substances does not increase easily over time. Another object of the present invention is to provide a method for suppressing the decomposition of bisoprolol or its pharmaceutically acceptable salt in a patch having an adhesive layer on a support. [Means for solving the problem]

[0005] Through diligent research, the inventors discovered that a patch containing L-cysteine ​​and a silicate compound in the adhesive layer, where the content of bisoprolol, L-cysteine, and the silicate compound in the adhesive layer satisfies a predetermined relationship, suppresses the increase of bisoprolol-related substances over time and suppresses the decomposition of bisoprolol or its pharmaceutically acceptable salts, thus completing the present invention.

[0006] In other words, the present invention includes the following [1] to [5]. [1] A patch comprising an adhesive layer on a support, The above adhesive layer contains bisoprolol or a pharmaceutically acceptable salt thereof, an adhesive base, L-cysteine, and a silicate compound. In the above adhesive layer, the following formula: L-cysteine ​​content (mass%) × Silicate compound content (mass%) / Bisoprolol content (mass%) A patch whose calculated value is between 0.016 and 0.5. [2] The adhesive patch according to [1], wherein the L-cysteine ​​content in the adhesive layer is 0.01% to 5% by mass, based on the total mass of the adhesive layer. [3] The adhesive patch according to [1] or [2], wherein the content of the silicate compound in the adhesive layer is 1% by mass to 10% by mass, based on the total mass of the adhesive layer. [4] The transdermal patch according to any one of [1] to [3], wherein the silicic acid compound is light anhydrous silicic acid. [5] The adhesive patch according to any one of [1] to [4], wherein the adhesive base is a rubber-based adhesive base. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a patch in which the amount of bisoprolol-related substances does not increase easily over time. [Modes for carrying out the invention]

[0008] The present invention will be described in detail below with reference to embodiments of the present invention.

[0009] A patch according to one embodiment of the present invention comprises an adhesive layer on a support, the adhesive layer containing bisoprolol or a pharmaceutically acceptable salt thereof, an adhesive base, L-cysteine, and a silicate compound. Furthermore, the value calculated by L-cysteine ​​content (mass%) × silicate compound content (mass%) / bisoprolol content (mass%) is 0.016 to 0.5. Here, the content (mass%) of each component is based on the total mass of the adhesive layer. In the case of a patch containing a pharmaceutically acceptable salt of bisoprolol in the adhesive layer, "bisoprolol content (mass%)" means the mass% of bisoprolol on a free form basis.

[0010] A method according to one embodiment of the present invention is a method for suppressing the decomposition of bisoprolol or a pharmaceutically acceptable salt thereof in a patch comprising an adhesive layer on a support, wherein the adhesive layer contains an adhesive base and bisoprolol or a pharmaceutically acceptable salt thereof, and the method includes containing L-cysteine ​​and a silicate compound in the adhesive layer. Furthermore, the value calculated by L-cysteine ​​content (mass%) × silicate compound content (mass%) / bisoprolol content (mass%) is 0.016 to 0.5. Here, the content (mass%) of each component is based on the total mass of the adhesive layer. In the case of a patch containing a pharmaceutically acceptable salt of bisoprolol in the adhesive layer, "bisoprolol content (mass%)" means the mass% of bisoprolol on a free form basis.

[0011] The support material can be any material capable of maintaining the shape of the adhesive, particularly the adhesive layer. Examples of support material materials include polyethylene, polypropylene, polybutadiene, ethylene-vinyl chloride copolymer, polyvinyl chloride, polyamides such as nylon, polyester, cellulose derivatives, and synthetic resins such as polyurethane. The properties of the support material can be, for example, films, sheets, porous sheets, foamed sheets, woven fabrics, knitted fabrics, nonwoven fabrics, and laminates thereof. The thickness of the support material is not particularly limited, but is usually preferably about 2 μm to 3000 μm.

[0012] The adhesive layer is formed from an adhesive composition obtained by mixing bisoprolol or a pharmaceutically acceptable salt thereof, an adhesive base, L-cysteine, a silicic acid compound, and optional components described below. The mass per unit area of the adhesive layer is not particularly limited and can be 15 g / m 2 ~400 g / m 2 and can be 20 g / m 2 ~300 g / m 2 or 25 g / m 2 ~200 g / m 2 or 30 g / m 2 ~100 g / m 2 It may also be. When the mass per unit area of the adhesive layer exceeds 400 g / m 2 , the patch is likely to fall off when putting on or taking off clothes, etc. When the mass per unit area of the adhesive layer is less than 15 g / m 2 , the adhesiveness of the patch is likely to decrease.

[0013] The pharmaceutically acceptable salt of bisoprolol means those among the acid addition salts of bisoprolol that are available for pharmaceutical use. Examples of organic acids include formic acid, acetic acid, adipic acid, citric acid, tartaric acid, methanesulfonic acid, fumaric acid, maleic acid, etc. Examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. The pharmaceutically acceptable salt of bisoprolol is preferably bisoprolol fumarate. Bisoprolol or a pharmaceutically acceptable salt thereof may be an anhydride or a hydrate.

[0014] The content of bisoprolol can be 1% to 20% by mass based on the total mass of the adhesive layer, and may be 3% to 20% by mass, 3% to 15% by mass, 3% to 12% by mass, or 5% to 8% by mass. In addition, when the patch contains a pharmaceutically acceptable salt of bisoprolol in the adhesive layer, the mass% means the mass% in terms of the free form of bisoprolol.

[0015] The adhesive base is for imparting adhesiveness to the adhesive layer, and examples thereof include rubber-based adhesive bases, acrylic-based adhesive bases, silicone-based adhesive bases, and the like. 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 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 can be 10% to 95% by mass based on the total mass of the adhesive layer, and may be 20% to 90% by mass.

[0016] Examples of the rubber-based adhesive base 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 thereof may be used in combination.

[0017] From the viewpoint that the rubber-based adhesive base according to the present embodiment tends to be able to exhibit more sufficient adhesive force of the adhesive layer, it is preferably at least one selected from the group consisting of styrene-isoprene-styrene block copolymers and polyisobutylene.

[0018] Specific examples of styrene-isoprene-styrene block copolymers include Quintac® 3570C (trade name, manufactured by Zeon Corporation), SIS5002, SIS5229, SIS5505 (trade names, manufactured by JSR Corporation), SIBSTAR® T102 (trade name, manufactured by Kaneka Corporation), and others. Polyisobutylene also includes so-called butyl rubber (isobutylene-isoprene rubber), with specific examples including Oppanol® N50. Examples include N80, N100, N150, B11, B12, B50, B80, B100, B120, B150, B220 (product names, manufactured by BASF), JSR® Butyl065, 268, 365 (product names, manufactured by JSR Corporation), X_Butyl® RB100, 101-3, 301, 402 (product names, manufactured by ARLANXEO), Exxon® Butyl065, 065S, 068, 068S, 268, 268S, 365, 365S (product names, manufactured by Exxon Mobile), Butyl065, 268, 365 (product names, manufactured by Nippon Butyl Co., Ltd.), etc.

[0019] The content of the rubber-based adhesive base can be 10% to 80% by mass, based on the total mass of the adhesive layer, and may also be 15% to 60% by mass, 15% to 40% by mass, or 15% to 30% by mass.

[0020] Acrylic adhesive bases are, for example, (co)polymers of one or more alkyl (meth)acrylate esters. Examples of alkyl (meth)acrylate 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 acrylic acid or methacrylic acid, or both, and similar expressions are defined in the same way.

[0021] The acrylic adhesive base may be a copolymer formed from an alkyl (meth)acrylate (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, and one of these may be used alone or in combination of two or more. The comonomer may be any component that can copolymerize with the alkyl (meth)acrylate. Examples of comonomers include hydroxyalkyl (meth)acrylate, ethylene, propylene, styrene, vinyl acetate, N-vinylpyrrolidone, (meth)acrylic acid, and (meth)acrylamide. The comonomer may be used alone or in combination of two or more.

[0022] Specific examples of acrylic adhesive bases include acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, acrylic acid 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. 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, DURO-TAK(registered trademark) 87-4098, etc.; GELVA(registered trademark) GMS 788, GELVA(registered trademark) GMS Examples include the GELVA series (manufactured by Henkel), such as 3083 and GELVA® GMS 3253; the MAS series (manufactured by Cosmedi Pharmaceutical Co., Ltd.), such as MAS811 (trade name) and MAS683 (trade name); the Eudragit® series (manufactured by Evonik); the Nikazol® series (manufactured by Nippon Carbide Industries, Ltd.); and the Ultrazol® series (manufactured by Aica Industries Co., Ltd.).

[0023] The content of the acrylic adhesive base can be 10% to 95% by mass, or 20% to 90% by mass, based on the total mass of the adhesive layer.

[0024] Silicone-based adhesives are compounds having an organopolysiloxane skeleton. Examples of silicone-based adhesives include dimethylpolysiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane. Specific silicone-based adhesive bases include, for example, the MD series (manufactured by DuPont-Toray Specialty Materials Co., Ltd.), such as MD7-4502 Silicone Adhesive and MD7-4602 Silicone Adhesive; 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 Adhesive. Examples include the BIO-PSA series (manufactured by DuPont-Toray Specialty Materials Co., Ltd.), such as Adhesive, BIO-PSA® 7-4502 Silicone Adhesive, BIO-PSA® 7-4401 Silicone Adhesive, and BIO-PSA® 7-4402 Silicone Adhesive, as well as Dow Corning® 7-9800A, Dow Corning® 7-9800B, Dow Corning® 7-9700A, and Dow Corning® 7-9700B.

[0025] The content of the silicone-based adhesive base can be 10% to 95% by mass, or 20% to 90% by mass, based on the total mass of the adhesive layer.

[0026] The L-cysteine ​​content can be 0.01% to 5% by mass, based on the total mass of the adhesive layer, and may be 0.05% to 3% by mass, 0.05% to 1% by mass, or 0.05% to 0.5% by mass.

[0027] Examples of silicate compounds include silicon dioxide, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminometasilicate, talc, bentonite, and kaolin. One of these silicate compounds may be used alone, or two or more may be used in combination. Among these, silicon dioxide is preferred as the silicate compound in this embodiment. Specific examples of silicon dioxide include light anhydrous silica and hydrated silicon dioxide, of which light anhydrous silica is particularly preferred. The content of the silicate compound can be 1% to 10% by mass, or 2% to 6% by mass, based on the total mass of the adhesive layer.

[0028] The value calculated by multiplying the L-cysteine ​​content (mass%) by the silicate compound content (mass%) / bisoprolol content (mass%) in the adhesive layer is preferably 0.03 to 0.4, and more preferably 0.033 to 0.33.

[0029] The adhesive layer may optionally further contain other additives. Examples of other additives include tackifying resins, plasticizers, absorption enhancers, solvents, fillers, and fragrances.

[0030] Tackifying resins are components that adjust the tackiness of the adhesive layer. Examples of tackifying resins include petroleum resins, terpene resins, rosin resins, phenolic resins, and xylene resins. Examples of petroleum resins include alicyclic petroleum resins (alicyclic saturated hydrocarbon resins, etc.), aliphatic petroleum resins (aliphatic hydrocarbon resins, etc.), and aromatic petroleum resins. More specifically, examples include Alcon P-70, Alcon P-85, Alcon P-90, Alcon P-100, Alcon P-115, Alcon P-125, Alcon M-70, Alcon M-85, Alcon M-90, Alcon M-100, Alcon M-115, Alcon M-125 (all trade names, manufactured by Arakawa Chemical Industries, Ltd.), and Escolets 8000 (trade name, manufactured by Esso Petrochemical Co., Ltd.). Examples of terpene resins include pinene polymers (α-pinene polymers, β-pinene polymers, etc.), terpene polymers, dipentene polymers, terpene-phenol polymers, aromatically modified terpene polymers, and pinene-phenol copolymers. More specifically, examples include YS resins (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 glycerol ester, ultra-pale rosin, ultra-pale rosin ester, and acid-modified ultra-pale rosin. More specifically, examples include Pine Crystal (KE-311, PE-590, KE-359, KE-100, etc.) (trade name, manufactured by Arakawa Chemical Industries, Ltd.). One of these tackifying resins may be used alone, or two or more may be used in combination. Among these, alicyclic saturated hydrocarbon resins, terpene resins, hydrogenated rosin glycerol ester, or a combination thereof is preferred, and alicyclic saturated hydrocarbon resins, terpene resins, or a combination thereof is more preferred. When the adhesive layer contains a tackifying resin, the content of the tackifying resin can be 15% to 80% by mass, or 30% to 65% by mass, based on the total mass of the adhesive layer.

[0031] Examples of plasticizers 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 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, its content is, for example, 3% to 50% by mass, 5% to 30% by mass, or 7% to 20% by mass, based on the total mass of the adhesive layer.

[0032] The absorption enhancer can be any compound conventionally known to have transdermal absorption-enhancing properties. Examples of absorption enhancers include organic acid esters (e.g., fatty acid esters, cinnamic acid esters), organic acid amides (e.g., fatty acid amides), aliphatic alcohols, polyhydric alcohols, and ethers (e.g., aliphatic ethers, polyoxyethylene alkyl ethers). These absorption enhancers may have unsaturated bonds and may have cyclic, linear, or branched chemical structures. The absorption enhancer may also be a monoterpene compound, a sesquiterpene compound, or a vegetable oil (e.g., olive oil). These absorption enhancers may be used individually or in combination of two or more.

[0033] 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. Fatty acid esters may also be glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, 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® 20, Tween® 21, Tween® 40, Tween® 60, Tween® 80, and NIKKOL® HCO-60 (product name, manufactured by Nikko Chemicals Co., Ltd.).

[0034] Examples of organic acid amides include fatty acid amides (e.g., lauric acid diethanolamide), hexahydro-1-dodecyl-2H-azepine-2-one (also known as Azone) and its derivatives, and pyrothiodecane.

[0035] Aliphatic alcohols refer to alcohols with 6 to 20 carbon atoms. Examples of aliphatic alcohols include lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, and cetyl alcohol. An example of a polyhydric alcohol is propylene glycol.

[0036] Aliphatic ethers refer to ethers that have an aliphatic group (e.g., alkyl or alkenyl group) with 6 to 20 carbon atoms. An example of a polyoxyethylene alkyl ether is polyoxyethylene lauryl ether.

[0037] Examples of monoterpene compounds include geraniol, thymol, terpineol, l-menthol, borneol, d-limonene, isoborneol, nerol, and dl-camphor. Peppermint oil may also be used as a monoterpene compound.

[0038] If the adhesive layer contains an absorption accelerator, the amount of the absorption accelerator can be 0.5% to 20% by mass, based on the total mass of the adhesive layer.

[0039] The solvent is a component that facilitates the dissolution of bisoprolol or a pharmaceutically acceptable salt thereof in the adhesive composition. Examples of solvents include fatty acid polyhydric alcohol esters (e.g., propylene glycol monolaurate, glyceryl monolaurate, glyceryl monooleate, sorbitan monolaurate), fatty acid amides (e.g., diethanolamide laurate), aliphatic alcohols (e.g., octyldodecanol, isostearyl alcohol, oleyl alcohol), polyhydric alcohols (e.g., propylene glycol, dipropylene glycol, polyethylene glycol), and pyrrolidone derivatives (e.g., N-methyl-2-pyrrolidone). When the adhesive layer contains a solvent, the solvent content can be 2% to 40% by mass based on the total mass of the adhesive layer.

[0040] Examples of fillers include powders of metal compounds (aluminum oxide, aluminum hydroxide, zinc oxide, titanium dioxide, calcium carbonate, etc.) or organic compounds (cellulose powder, stearate, etc.), or short fibers of resins containing these. When the adhesive layer contains a filler, the filler content can be 0.1% to 20% by mass, based on the total mass of the adhesive layer.

[0041] The adhesive may further include a release liner. The release liner is laminated on the side opposite to the support relative to the adhesive layer. The presence of a release liner tends to reduce the adhesion of dust and other debris to the adhesive layer during storage. Preferably, the surface of the release liner that contacts the adhesive layer is treated with a release agent such as silicone or fluorinated polyolefin.

[0042] 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 release liners include paper; polyester 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 also be a laminated film of fine paper and polyolefin. A film made of polypropylene or polyethylene terephthalate is preferred as the material of the release liner.

[0043] The adhesive patch can be manufactured, for example, by the following method, but is not limited to this, and known methods can be used. First, the components constituting the adhesive layer are mixed in predetermined proportions to obtain a uniform solution (adhesive composition). Next, the adhesive composition is spread on a peelable film (release liner) to a predetermined thickness to form an adhesive layer. Furthermore, the support is pressed onto the adhesive layer so that the adhesive layer is sandwiched between the release liner and the support. Finally, the adhesive patch can be obtained by cutting it to the desired shape and dimensions. In this case, the release liner is removed when the adhesive patch is applied. The area of ​​the adhesive patch is 5 cm². 2 ~100cm 2 It is fine if it is 5cm 2 ~50cm 2 The shape and dimensions of the patch may be, for example, a rectangle with a short side of 2 cm to 10 cm and a long side of 3 cm to 15 cm, or a circle with a diameter of 1 cm to 8 cm. [Examples]

[0044] Test Example 1: Evaluation of the amount of bisoprolol-related substances produced. 1. Preparation of the patch The components were mixed according to Tables 1-3 below to obtain an adhesive composition. The obtained adhesive composition was applied to a release liner (a polyethylene terephthalate film with a release treatment) at a mass of 37 g / m² per unit area. 2 The material was spread out to form an adhesive layer. A support layer (polyethylene terephthalate film) was laminated onto the opposite side of the obtained adhesive layer, resulting in a patch laminated in the order of support layer / adhesive layer / release liner.

[0045] 2. Measurement of bisoprolol-related substances The content of bisoprolol-related substances is 2.5 cm 2 The following procedure was used to measure the size of the patch before storage, which had been cut to the specified area, and the patch that had been stored in its packaging in a 60°C constant temperature chamber for two weeks. After removing the release liner from the patch, it was placed in a 10 mL test tube. 1 mL of tetrahydrofuran was added, and the mixture was shaken for 30 minutes to dissolve. The solution was then diluted 10-fold with a 20% acetonitrile aqueous solution and filtered through a 0.45 μm membrane filter to obtain the sample solution. Bisoprolol and its analogues contained in the sample solution were detected by high-performance liquid chromatography (HPLC) using mobile phases A and B, while changing the ratio of mobile phase A:mobile phase B from 90:10 to 10:90 over 40 minutes. Subsequently, the mixture was eluted at a ratio of 10:90 for 15 minutes, then eluted at a ratio of 90:10 over 5 minutes, and finally eluted at a ratio of 90:10 for 15 minutes. <Analysis conditions> Column: Inertsil ODS-3 (ODS particle size: 3 μm, inner diameter: 4.6 nm, length: 25 cm) Mobile phase: Mobile phase A (aqueous mobile phase: acetonitrile = 90:10), Mobile phase B (aqueous mobile phase: acetonitrile = 30:70) (Aqueous mobile phase: A 20 mM sodium dihydrogen phosphate aqueous solution was prepared to pH 3.0 using phosphoric acid, and then 0.3% triethylamine was added to the solution.) Measurement wavelength: 225nm Flow rate: 0.9mL / min Sample injection volume: 20 μL Column temperature: 40℃ The peak with a relative retention time of 1.57 to the retention time of bisoprolol was identified as the peak corresponding to bisoprolol-related substances. The content (%) of related substances was calculated from the ratio of the peak area of ​​the detected bisoprolol peak to the peak area of ​​the related substance peak. Furthermore, the increase was defined as the difference between the content (%) of related substances before storage and the content (%) after storage at 60°C for two weeks.

[0046] [Table 1]

[0047] [Table 2]

[0048] [Table 3]

[0049] As is clear from the results shown in Tables 1 to 3, adhesive patches with a value calculated as L-cysteine ​​content (mass%) × silicate compound content (mass%) / bisoprolol content (mass%) in the adhesive layer of 0.016 to 0.5 were able to suppress the increase of bisoprolol-related substances during storage.

Claims

1. A patch comprising an adhesive layer on a support, The adhesive layer contains bisoprolol or a pharmaceutically acceptable salt thereof, an adhesive base, L-cysteine, and a silicate compound. In the aforementioned adhesive layer, the following formula applies: L-cysteine ​​content (mass%) × Silicate compound content (mass%) / Bisoprolol content (mass%) A transdermal patch whose calculated value is between 0.016 and 0.

5.

2. The adhesive patch according to claim 1, wherein the L-cysteine ​​content in the adhesive layer is 0.01% by mass to 5% by mass, based on the total mass of the adhesive layer.

3. The adhesive patch according to claim 1 or 2, wherein the content of the silicate compound in the adhesive layer is 1% by mass to 10% by mass, based on the total mass of the adhesive layer.

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

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

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