JP2024109305A - Bisoprolol-containing patch - Google Patents

Abstract

[Problem] To provide a patch in which the content of bisoprolol is unlikely to decrease even over time. [Solution] A patch comprising 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. [Selected Figures] None

Description

The present invention relates to a patch containing bisoprolol.

Bisoprolol, a highly selective blocker of β1 receptors (β1 blocker) of the sympathetic nervous system, 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 of bisoprolol over time.

JP 2015-051947 A

The inventors have investigated patches containing bisoprolol and found that the content of bisoprolol in the patch decreases over time. A decrease in the content of bisoprolol may affect the performance of bisoprolol, such as the skin permeability. Therefore, an object of the present invention is to provide a patch in which the content of bisoprolol is unlikely to decrease over time. Another object of the present invention is to provide 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.

As a result of intensive research, the inventors discovered that a patch containing 2-mercaptobenzimidazole and a silicic acid compound in the adhesive layer suppresses the decrease in bisoprolol content over time, leading to the completion of the present invention.

That is, the present invention includes the following [1] to [5].
[1] A patch comprising a support and an adhesive layer,
The adhesive layer comprises bisoprolol or a pharma- ceutically acceptable salt thereof, an adhesive base, 2-mercaptobenzimidazole, and a silicic acid compound.
[2] The patch according to [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 patch according to [1] or [2], wherein the content of the silicic acid compound in the adhesive layer is 3.5% by mass to 15% by mass, based on the total mass of the adhesive layer.
[4] The patch according to any one of [1] to [3], wherein the silicic acid compound is light anhydrous silicic acid.
[5] The patch according to any one of [1] to [4], wherein the adhesive base is a rubber-based adhesive base.

The present invention provides a patch in which the content of bisoprolol is unlikely to decrease over time.

The following describes the present invention in detail by showing an embodiment of the present invention.

The patch according to one embodiment of the present invention comprises an adhesive layer on a support, and the adhesive layer contains bisoprolol or a pharma- ceutically acceptable salt thereof, an adhesive base, 2-mercaptobenzimidazole, and a silicic acid compound.

A method according to one embodiment of the present invention is a method for improving the storage stability of bisoprolol or a pharma- ceutical salt thereof in a patch having an adhesive layer on a support, the adhesive layer containing an adhesive base and bisoprolol or a pharma-ceutical salt thereof, and including the inclusion of 2-mercaptobenzimidazole and a silicic acid compound in the adhesive layer.

The support may be any material capable of maintaining the shape of the patch, particularly the adhesive layer. Examples of the material for 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, woven fabrics, knitted fabrics, nonwoven fabrics, and laminates thereof. There are no particular limitations on the thickness of the support, but it is usually preferable that it be about 2 μm to 3000 μm.

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 may be 15 g/ ^m2 to 400 g/ ^m2 , and may be 20 g/ ^m2 to 300 g/ ^m2 , 25 g/ ^m2 to 200 g/ ^m2 , or 30 g/ ^m2 to 100 g/ ^m2 . If the mass per unit area of the adhesive layer exceeds 400 g/ ^m2 , the patch is likely to fall off when putting on or taking off clothes. If the mass per unit area of the adhesive layer is less than 15 g/ ^m2 , the adhesiveness of the patch is likely to decrease.

The pharma- ceutically acceptable salt of bisoprolol means an acid addition salt of bisoprolol that can be used as a medicine. Examples of organic acids include formic acid, acetic acid, adipic acid, citric acid, tartaric acid, methanesulfonic acid, fumaric acid, and maleic acid. Examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. The pharma-ceutically acceptable salt of bisoprolol is preferably bisoprolol fumarate. Bisoprolol or a pharma-ceutically acceptable salt thereof may be anhydrous or hydrated.

The content of bisoprolol can be 1% by mass to 20% by mass based on the total mass of the adhesive layer, 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. Note that the above mass % refers to the mass % of bisoprolol in free form when the adhesive layer contains a pharma- ceutical acceptable salt of bisoprolol.

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 one or more 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.

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, etc., and one of these may be used alone or two or more may be used in combination.

The rubber-based adhesive base in this embodiment is preferably at least one selected from the group consisting of styrene-isoprene-styrene block copolymer and polyisobutylene, as this tends to enable the adhesive layer to exert more sufficient adhesive strength.

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

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.

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 way.

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 types in combination.

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, acrylic polymers contained in acrylic resin alkanolamine liquid, etc. Specific examples of such acrylic adhesive bases include 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 series (manufactured by Henkel) such as 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 Examples of such products include the GELVA series (manufactured by Henkel), such as GELVA (registered trademark) GMS 3083, GELVA (registered trademark) GMS 3253; the MAS series (manufactured by Cosmedi Pharmaceutical Co., Ltd.), such as MAS811 (trade name) and MAS683 (trade 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.).

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.

Silicone-based adhesive bases are compounds that have an organopolysiloxane skeleton. Examples of silicone-based adhesive bases 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, BIO-PSA (registered trademark), 7-4501 Silicone Adhesive, BIO-PSA (registered trademark), 7-4502 Silicone Adhesive, BIO-PSA (registered trademark), 7-4401 Silicone Adhesive, BIO-PSA (registered trademark), 7-4402 Silicone Adhesive and other BIO-PSA series (manufactured by DuPont Toray Specialty Materials Co., Ltd.), Dow Corning (registered trademark) Examples include 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.

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.

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 adhesive layer.

Examples of the silicate compound include silicon dioxide, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminometasilicate, talc, bentonite, and kaolin. The silicate compound may be used alone or in combination of two or more. Among them, silicon dioxide is preferable as the silicate compound according to the present embodiment. Specific examples of silicon dioxide include light anhydrous silicic acid and hydrous silicon dioxide, and of these, light anhydrous silicic acid is particularly preferable. The content of the silicate 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 adhesive layer.

The adhesive layer may further contain other additives as desired. Examples of other additives include tackifier resins, plasticizers, absorption promoters, solubilizers, fillers, fragrances, etc.

Tackifying resins are components that adjust the adhesiveness of the adhesive layer. Examples of tackifying resins include petroleum-based resins, terpene-based resins, rosin-based resins, phenol-based resins, and xylene-based resins. Examples of petroleum-based resins 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 of which are product names manufactured by Yasuhara Chemical Co., Ltd.), and Tamanol 901 (product 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.) (product 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, or may be 30% by mass to 65% by mass, based on the total mass of the adhesive layer.

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 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 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.

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, and ethers (e.g., aliphatic ethers, polyoxyethylene alkyl ethers). These absorption enhancers may have unsaturated bonds and may have a cyclic, linear, or branched chemical structure. 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 alone or in combination of two or more.

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.).

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

Fatty alcohol means a fatty alcohol having 6 to 20 carbon atoms. Examples of fatty alcohols include lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, and cetyl alcohol. Examples of polyhydric alcohols include propylene glycol.

Aliphatic ether means an ether having an aliphatic group (e.g., an alkyl group, an alkenyl group) having 6 to 20 carbon atoms. An example of a polyoxyethylene alkyl ether is polyoxyethylene lauryl ether.

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.

When the 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 adhesive layer.

The solubilizer is a component that facilitates dissolving 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, sorbitan monolaurate), fatty acid amides (e.g., lauric acid diethanolamide), 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 solubilizer, the content of the solubilizer can be 2% by mass to 40% by mass based on the total mass of the adhesive layer.

Examples of fillers 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 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 adhesive layer.

The patch may further comprise 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 comes into contact with the adhesive layer is preferably release-treated with silicone, fluorinated polyolefin, or the like.

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; 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.

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.) at 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 dried and removed to form an adhesive layer of a predetermined thickness. 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 patch can be obtained by cutting into a desired shape and size. In this case, the release liner is removed when the patch is applied. The area of the patch may be 5 cm ² to 100 cm ² , or may be 5 cm ² to 50 cm ^2. The shape and size 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.

Test Example 1: Evaluation of the reduction in bisoprolol content 1. Preparation of a patch According to the compounding ratios in Tables 1 to 4 below, each component was thoroughly mixed in toluene to obtain a solution of an adhesive composition. The obtained solution of the adhesive composition was spread on a release liner (a polyethylene terephthalate film subjected to a release treatment), and then the toluene was dried and removed to form an adhesive layer with a mass per unit area of 37 g/ ^m2 . A support layer (a polyethylene terephthalate film) was laminated on the opposite surface of the obtained adhesive layer to obtain an adhesive layer laminated in the order of support layer/adhesive layer/release liner.

2. Measurement of bisoprolol content The bisoprolol content was measured using the patch before storage, which was cut into an area of ^2.5 cm2, and the patch sealed in a package and stored in a thermostatic chamber at 60°C for one month, according to the following procedure.
After removing the release liner, the patch was placed in a 50 mL test tube, to which 10 mL of a tetrahydrofuran solution containing propyl paraoxybenzoate as an internal standard substance was added, and the solution was dissolved by shaking for 30 minutes and ultrasonic treatment for 30 minutes. The solution was then diluted 5-fold with a 0.2% aqueous phosphoric acid solution, mixed for 10 minutes, and then filtered through a 0.45 μm membrane filter to obtain a sample solution.
The bisoprolol contained in the sample solution and standard sample solution was then eluted and detected for 15 minutes by high performance liquid chromatography (HPLC) using the mobile phase listed below. The bisoprolol concentration in the sample solution was then quantified using the calibration curve obtained from the standard sample solution, and the bisoprolol content contained in the patch was calculated. The bisoprolol content in the patch before storage and after storage at 60°C for one month was calculated by correcting for the actual measured mass of the 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°C
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 storage for one month at 60°C were calculated respectively. The reduction amount was calculated by subtracting the theoretical value of the bisoprolol content in the patch after storage for one month at 60°C from the theoretical value of the bisoprolol content in the patch before storage.

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 bisoprolol content 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 bisoprolol content during storage.

Claims (5)

A patch comprising a support and an adhesive layer,
The adhesive layer comprises bisoprolol or a pharma- ceutically acceptable salt thereof, an adhesive base, 2-mercaptobenzimidazole, and a silicic acid compound. The patch according to claim 1, wherein the content of 2-mercaptobenzimidazole in the adhesive layer is 0.05% by mass to 1% by mass based on the total mass of the adhesive layer. The patch according to claim 1 or 2, wherein the content of the silicate compound in the adhesive layer is 3.5% by mass to 15% by mass based on the total mass of the adhesive layer. The patch according to claim 1 or 2, wherein the silicic acid compound is light anhydrous silicic acid. The patch according to claim 1 or 2, wherein the adhesive base is a rubber-based adhesive base.