Patches containing bisoprolol

Abstract

The present invention relates to a bisoprolol-containing patch. The present invention provides a bisoprolol-containing patch that maintains good adhesive properties and has high bisoprolol skin permeability. A bisoprolol-containing patch comprises a support and an adhesive layer formed on one surface of the support, wherein the adhesive layer comprises the following components (A) to (C): component (A): a polymer obtained by copolymerizing a monomer component comprising a hydroxyl group-containing monomer and an alkyl (meth)acrylate monomer; component (B): a polymer obtained by copolymerizing a monomer component comprising a methyl methacrylate monomer and a butyl methacrylate monomer; and component (C): bisoprolol.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201680035296.8 and application date on June 17, 2016. Technical Field

[0002] One embodiment of the present invention relates to a patch containing bisoprolol. Background Art

[0003] Patches that adhere to the skin are obtained by forming an adhesive layer on one or both surfaces of a support. Their purpose is to administer drugs from the skin into the body via the adhesive layer, thereby preventing or treating local or systemic diseases.

[0004] For this patch, requirement is to show sufficient adhesiveness when being stuck on skin, and can peel off and remove without polluting skin surface (for example, producing glue residue or being sticky (ベタツキ) etc.) after use.In addition, for patch, expectation is low irritation to skin.

[0005] Disclose the patch of using following acrylic adhesive in patent documentation 1, this acrylic adhesive is by making (methyl) alkyl acrylate and can with this (methyl) alkyl acrylate copolymerization and not containing the monomer of any one in carboxyl and sulfo group to carry out polymerization and obtain.In addition, for the patch of this document, its adhesive layer comprises organic liquid component and can be cross-linked.It is said that above-mentioned patch has the sufficient cohesive force that can not produce glue paste residual when peeling, and the stimulation to skin is little, and has soft sense.But the adhesive that does not have carboxyl and sulfo group disclosed in patent documentation 1 is attached to skin surface for a long time or is attached to the large skin surface of action, sometimes comes off from skin, therefore expects the further improvement of adhesive property.

[0006] Patent Document 2 discloses a patch comprising an adhesive layer containing a cross-linked product of a copolymer of an alkyl (meth)acrylate or a mixture of the alkyl (meth)acrylate and an alkoxyalkyl (meth)acrylate, and a monomer containing a carboxyl group and / or a hydroxyl group. However, when the adhesive layer of the patch contains a copolymer having a carboxyl group and bisoprolol as a drug, there is concern that the carboxyl group may be affected by bisoprolol, hindering drug release from the patch and thereby reducing drug utilization.

[0007] On the other hand, when a copolymer containing a hydroxyl group (hydroxyl group) is included, good adhesion to the skin is exhibited, and there is no concern that the release of bisoprolol from the patch will be impeded. However, the hydroxyl group (hydroxyl group) may be affected by bisoprolol, causing changes in adhesive properties such as increased retention during storage.

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1: Japanese Patent Application Laid-Open No. 2003-313122

[0011] Patent Document 2: Japanese Patent Application Laid-Open No. 4-150865 Summary of the Invention

[0012] Problems to be solved by the invention

[0013] The present invention has been discovered in view of the above-mentioned actual situation. In one embodiment of the present invention, an object of the present invention is to provide a bisoprolol-containing patch that can maintain good adhesive properties and has high bisoprolol skin permeability.

[0014] Means used to solve problems

[0015] The present inventors have conducted intensive studies to solve the above-mentioned problems and have found that by including in a bisoprolol-containing adhesive layer a polymer obtained by copolymerizing a monomer component comprising a hydroxyl group-containing monomer and an alkyl (meth)acrylate monomer, and a polymer obtained by copolymerizing a monomer component comprising a methyl methacrylate monomer and a butyl methacrylate monomer, good adhesive properties can be maintained (particularly, good adhesive properties can be maintained even when a large amount of an organic liquid component is contained), thereby completing the present invention.

[0016] That is, one embodiment of the present invention is as follows.

[0017] [1] A patch containing bisoprolol, comprising a support and an adhesive layer formed on one surface of the support, wherein the adhesive layer contains the following components (A) to (C):

[0018] (A) component: a polymer obtained by copolymerizing a monomer component comprising a hydroxyl group-containing monomer and an alkyl (meth)acrylate monomer;

[0019] (B) component: a polymer obtained by copolymerizing monomer components including a methyl methacrylate monomer and a butyl methacrylate monomer;

[0020] (C) Ingredient: Bisoprolol.

[0021] [2] The bisoprolol-containing patch according to [1] above, wherein the adhesive layer further contains an organic liquid component.

[0022] [3] The bisoprolol-containing patch according to [1] or [2] above, wherein the content ratio of component (A) to component (B) contained in the adhesive layer (component (A) : component (B)) is 1:0.05 to 1:1 by weight.

[0023] Effects of the Invention

[0024] The bisoprolol-containing patch according to one embodiment of the present invention can maintain good adhesive properties (especially, can maintain good adhesive properties even when containing a large amount of organic liquid components) and has high bisoprolol skin permeability. DETAILED DESCRIPTION

[0025] Hereinafter, one embodiment of the present invention will be described in more detail based on its preferred embodiments.

[0026] The bisoprolol-containing patch according to one embodiment of the present invention is provided as a transdermal absorption preparation, specifically, as a matrix-type patch, a reservoir-type patch, or the like.

[0027] As the supporter in the patch (hereinafter, also referred to as " patch " of a mode of the present invention) containing bisoprolol of a mode of the present invention, it is not particularly limited, as long as can form and keep adhesive layer on one side.Specifically, can use polyester (for example, polyethylene terephthalate etc.), polyamide (for example, nylon etc.), polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride (trade name: Saran etc.), ionomer resin (trade name: Surlyn etc.), polytetrafluoroethylene, ethylene-ethyl acrylate copolymer, ethylene-vinyl alcohol copolymer (trade name: Eval etc.) etc. various plastic films or the monolayer body of various metal foil etc. or their laminated body.It should be noted that, in order to improve with the anchoring force of the adhesive layer formed on the supporter, the process of primer layer, corona discharge treatment or plasma irradiation treatment, primer treatment etc. can be carried out to supporter surface, preferably use the supporter that further forms the face side laminated with porous sheet at the adhesive layer of supporter. In this case, practical examples of the porous sheet include paper, nonwoven fabrics, woven fabrics, knitted fabrics, and perforated plastic sheets. Among these, paper, nonwoven fabrics, and woven fabrics are preferably used from the perspectives of feel during application and ease of application.

[0028] The thickness of the support in the patch containing bisoprolol is preferably 10 μm to 200 μm from the aspects of improving the anchoring force, the flexibility of the percutaneous absorption preparation as a whole and the pasting operability. In the case of a thin patch, a support having a thickness of 10 μm to 100 μm is adopted. In addition, when using woven fabrics or nonwoven fabrics as porous sheets, their weight per unit area can be set to 5 g / m 2 ~30g / m 2 , preferably set to 6g / m 2 ~15g / m 2As the most preferred support in one embodiment of the present invention, a polyester film with a thickness of 1.5 μm to 6 μm and a unit area weight of 6 g / m 2 ~12g / m 2 A laminated film of a polyester nonwoven fabric or an ethylene-vinyl alcohol copolymer film having a thickness of 10 μm to 80 μm.

[0029] When forming a primer layer on the surface of the support, the primer layer preferably contains porous inorganic particles. In addition, the primer layer preferably further contains a binder resin for attaching the porous inorganic particles to the support.

[0030] Examples of the porous inorganic particles include porous silica particles, porous alumina particles, and porous titanium oxide particles. Porous silica particles are preferred because they are difficult to destroy even in the manufacturing process or dispersion. It should be noted that the porous inorganic particles may be used alone or in combination of two or more.

[0031] As the binder resin, any appropriate resin can be used as long as it can adhere the porous inorganic particles to the support, and examples thereof include polyurethane resins, ethyleneimine resins, aminoethyl resins, polyester resins, polyolefin resins, and ethylene-vinyl alcohol copolymer resins.

[0032] Prepare the primer solution by making the above-mentioned porous inorganic particles and the above-mentioned binder resin disperse or be dissolved in any suitable solvent.As this solvent, the excellent dispersibility of the porous inorganic particles and the excellent solvent with the miscibility of the binder resin can be appropriately selected.As the specific example of this solvent, can enumerate: water, methanol, ethanol, 1-propyl alcohol, 2-propyl alcohol, ethyl acetate, methyl ethyl ketone, toluene etc. Solvent can be used alone, and also can be used in combination of two or more.About the solid content concentration of the primer solution, from the viewpoints such as workability, can be set to any appropriate value.

[0033] The undercoat layer can be formed by applying the above-mentioned undercoat layer solution on the surface of the support and drying and / or curing the solution.

[0034] The basis weight of the primer layer can be appropriately set according to the type, use, and purpose of the support or adhesive layer. The basis weight is preferably 0.1 g / m 2 ~10g / m 2 , more preferably 0.1 g / m 2 ~8g / m 2 , more preferably 0.2g / m 2 ~5g / m 2If the weight per unit area is such, a uniform primer layer can be obtained and good anchoring force can be imparted.

[0035] For the patch of one embodiment of the present invention, in order to protect the adhesive surface of its adhesive layer until use, a release liner is preferably stacked on the adhesive surface. As the release liner, as long as it is possible to ensure sufficient light peelability, it is not particularly limited. As a specific example, it is possible to list: by applying silicone resin, fluororesin, etc. on the surface in contact with the adhesive layer and implementing a plastic film, high-quality paper (high-quality paper), glassine, etc. of polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, etc., or high-quality paper, glassine, etc., and a laminated film (the side in contact with the adhesive layer is paper) of polyolefins. The thickness of the release liner is generally 10 μm ~ 200 μm, preferably 25 μm ~ 100 μm.

[0036] The polymer obtained by copolymerizing a monomer component comprising a hydroxyl group-containing monomer and an alkyl (meth)acrylate monomer, which is the component (A) contained in the adhesive layer, is not particularly limited as long as the alkyl (meth)acrylate unit is copolymerized at a ratio of 40% by weight or more, preferably 40% to 99% by weight, more preferably 40% to 90% by weight, and even more preferably 50% to 90% by weight, relative to the entire polymer of the component (A) and the polymer has a hydroxyl group in the molecule.

[0037] In addition, in this specification, "(meth)acrylic acid" means both "acrylic acid" and "methacrylic acid".

[0038] The alkyl (meth)acrylate monomer is not particularly limited. However, from the perspective of adhesiveness, an alkyl (meth)acrylate monomer having an alkyl group with 4 or more carbon atoms is preferred. Specific examples include alkyl (meth)acrylate monomers having an alkyl group that is a linear or branched alkyl group with 4 to 13 carbon atoms, such as n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, or tridecyl. Among these, 2-ethylhexyl acrylate is preferred. Alkyl (meth)acrylate monomers may be used alone or in combination.

[0039] The hydroxyl group-containing monomer is not particularly limited, and any hydroxyl group-containing monomer having at least one unsaturated double bond in the molecule that participates in the copolymerization reaction can be used. Examples thereof include N-hydroxyalkyl (meth)acrylamide, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, and the like, preferably N-hydroxyalkyl acrylamide, hydroxyethyl acrylate, and hydroxypropyl acrylate. Here, N-hydroxyalkyl (meth)acrylamide is preferably an N-hydroxyalkyl (C) acrylamide having an alkyl group with 1 to 4 carbon atoms. 1-4 (Meth)acrylamide, more preferably N-hydroxyalkyl (C 2-4 ) acrylamide. The alkyl group in the hydroxyalkyl group may be a straight chain or a branched chain. Examples of N-hydroxyalkyl (meth) acrylamide include N-(2-hydroxyethyl) acrylamide, N-(2-hydroxyethyl) methacrylamide, N-(2-hydroxypropyl) acrylamide, N-(2-hydroxypropyl) methacrylamide, N-(1-hydroxypropyl) acrylamide, N-(1-hydroxypropyl) methacrylamide, N-(3-hydroxypropyl) acrylamide, N-(3-hydroxypropyl) methacrylamide, N-(2-hydroxybutyl) acrylamide, N-(2-hydroxybutyl) methacrylamide, N-(3-hydroxybutyl) acrylamide, N-(3-hydroxybutyl) methacrylamide, N-(4-hydroxybutyl) acrylamide, and N-(4-hydroxybutyl) methacrylamide.

[0040] Among these, the hydroxyl group-containing monomer is preferably N-(2-hydroxyethyl)acrylamide or N-(2-hydroxyethyl)methacrylamide, and most preferably N-(2-hydroxyethyl)acrylamide.

[0041] The hydroxyl group-containing monomers may be used alone or in combination of two or more.

[0042] The hydroxyl group-containing monomer is preferably contained in the polymer of component (A) in an amount of 1 to 20% by weight, more preferably 1 to 15% by weight, and even more preferably 5 to 10% by weight, relative to the total weight of the polymer. If the content does not meet the lower limit, compatibility with additives such as organic liquid components may be poor, and these additives may not be retained. If the content exceeds the upper limit, the polymer may be susceptible to the effects of bisoprolol, resulting in significant changes in physical properties over time.

[0043] The polymer of (A) component can be the polymer obtained by copolymerizing the monomer (hereinafter, sometimes referred to as " the 3rd monomer ") except (meth) alkyl acrylate monomer and hydroxyl-containing monomer. When containing the 3rd monomer as the monomer component of the polymer constituting (A) component, its content is preferably below 50 weight % in the polymer of (A) component, more preferably 1 weight %~50 weight %, further preferably 5 weight %~45 weight %, particularly preferably 10 weight %~45 weight %, most preferably 20 weight %~45 weight %. By making the 3rd monomer be copolymerized, the adhesive force and the cohesive force of the patch can be regulated, in addition, the solubility and the release of the drug can be regulated. If the content of the 3rd monomer in the polymer is greater than 50 weight %, the viscosity or the adhesive force of the patch obtained sometimes reduce.

[0044] As the third monomer, a monomer containing nitrogen (N) as a constituent atom can be used (however, excluding the monomer containing nitrogen (N) as a constituent atom among the above-mentioned hydroxyl-containing monomers). Examples of such nitrogen-containing monomers include N-vinyl-2-pyrrolidone, N-vinyl-2-piperidone, N-vinyl-3-morpholinone, N-vinyl-2-caprolactam, N-vinyl-1,3- N-vinyl cyclic amides such as oxazine-2-one and N-vinyl-3,5-morpholinedione are preferred. Among them, N-vinyl-2-pyrrolidone is most preferred.

[0045] The weight average molecular weight (Mw) of the polymer of component (A) is preferably in the range of 1,400,000 to 2,400,000, and more preferably in the range of 1,600,000 to 2,200,000. When the weight average molecular weight (Mw) is within this preferred range, the ability to retain the organic liquid component in the adhesive layer, the cohesive force of the adhesive layer, etc. are improved, and good adhesive properties can be obtained.

[0046] In one embodiment of the present invention, the weight-average molecular weight (Mw) is measured using a multi-angle light scattering detector (MALS). Specifically, the weight-average molecular weight measured using MALS can be obtained as follows: a DAWN DSP manufactured by Wyatt Technology is used as a detector, a polymer dissolved in tetrahydrofuran and ethanol is continuously injected using a syringe pump, and the weight-average molecular weight is calculated using a calibration curve of standard polystyrene.

[0047] Component (B) contained in the adhesive layer is a polymer obtained by copolymerizing monomer components comprising methyl methacrylate monomer and butyl methacrylate monomer. The weight ratio of methyl methacrylate monomer to butyl methacrylate monomer in the polymer is preferably 1:1 to 1:4, more preferably 1:3. The side chains of this polymer are neutral groups. Therefore, compared to polymers containing basic or acidic groups in their side chains, the content of bisoprolol in the adhesive layer is more stable over time.

[0048] The weight average molecular weight (Mw) of the polymer of component (B) is preferably in the range of 100,000 to 200,000, more preferably in the range of 130,000 to 170,000. When the weight average molecular weight (Mw) is within this preferred range, good compatibility with component (A) is achieved, resulting in good adhesive properties.

[0049] The weight ratio of component (A) to component (B) in the adhesive layer (component (A) : component (B)) is preferably 1:0.05 to 1:1, more preferably 1:0.05 to 1:0.8. If the weight ratio of component (B) to component (A) (component (B) / component (A)) is less than 0.05, good adhesive properties may not be achieved. If the weight ratio (component (B) / component (A)) is greater than 1, components (A) and (B) may be unevenly mixed during patch preparation or may tend to separate over time.

[0050] The "bisoprolol" as the (C) component contained in the adhesive layer not only contains the free form of bisoprolol, but also contains its hydrochloride or organic acid salt. For bisoprolol, two or more salts can be used as needed. As for the content of bisoprolol in the adhesive layer, as long as it satisfies the pharmaceutical effect of bisoprolol and does not damage the adhesive properties of the adhesive, it is sufficient. From the perspective of the interaction with the polymer containing hydroxyl-containing monomers and (meth)acrylates and the effect of the drug, based on the gross weight of the adhesive layer, it is preferably contained in an amount of 0.1% by weight to 40% by weight of bisoprolol, more preferably in an amount of 1% by weight to 30% by weight of bisoprolol.

[0051] In the above-mentioned adhesive layer, there is no particular limitation as long as it is a component that has the effect of improving the adhesive feeling. For example, it can contain an organic liquid component. Examples of the organic liquid component include: glycols such as ethylene glycol, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, and polypropylene glycol; oils such as olive oil, castor oil, squalane, and lanolin; hydrocarbons such as liquid paraffin; various surfactants; ethoxylated stearyl alcohol; glycerides (monoglycerides, diglycerides, triglycerides, or mixtures thereof) of long-chain or medium-chain fatty acids such as oleic acid, caprylic acid, and lauric acid; monohydric alcohol fatty acid esters (including ethyl laurate, isopropyl myristate, isotridecyl myristate, octyl palmitate, isopropyl palmitate, ethyl oleate, and diisopropyl adipate) Monohydric alcohol fatty acid esters of fatty acids having 6 to 22 carbon atoms, more preferably 12 to 16 carbon atoms, and alcohols having 1 to 20 carbon atoms are preferred; higher fatty acids such as oleic acid and caprylic acid (preferably higher fatty acids having 8 to 22 carbon atoms); higher alcohols such as oleyl alcohol (preferably higher alcohols having 6 to 22 carbon atoms); polyhydric alcohol fatty acid esters such as propylene glycol monolaurate, propylene glycol monooleate, and propylene glycol monostearate; citric acid esters such as triethyl citrate, acetyl triethyl citrate, tributyl citrate, and acetyl tributyl citrate; N-methylpyrrolidone; 1,3-butanediol, etc. Among these, higher alcohols, monohydric alcohol fatty acid esters, glycerides of long-chain or medium-chain fatty acids (preferably monoglycerides), and citric acid esters are preferred; higher alcohols and monohydric alcohol fatty acid esters are particularly preferred; and isopropyl myristate, diisopropyl adipate, and oleyl alcohol are most preferred.

[0052] The content of the organic liquid component in the adhesive layer is preferably 0.1 to 2.5 parts by weight, more preferably 0.2 to 2.0 parts by weight, and particularly preferably 0.3 to 1.5 parts by weight, relative to 1 part by weight of the combined content of components (A) and (B). When the content of the organic liquid component falls within this range, better skin adhesion and reduced skin irritation can be achieved, and the adhesive feel can be improved.

[0053] It should be noted that the adhesive layer may contain not only the above-mentioned organic liquid components but also other optional components within the scope that does not impair the effects of the present invention. Optional components include, for example: antioxidants such as ascorbic acid, tocopheryl acetate, natural vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, etc.; amine-ketone antioxidants such as 2,6-tert-butyl-4-methylphenol; aromatic secondary amine antioxidants such as N,N'-di-2-naphthyl-p-phenylenediamine; monophenol antioxidants such as 2,2,4-trimethyl-1,2-dihydroquinoline polymer; bisphenol antioxidants such as 2,2'-methylenebis(4-ethyl-6-tert-butylphenol); polyphenol antioxidants such as 2,5-tert-butylhydroquinone; kaolin, hydrated silica, zinc oxide, acrylic starch 1000. Fillers such as denpone 1000 (Acrylic Acid); softeners such as polybutene and polyethylene glycol 1500; preservatives such as benzoic acid, sodium benzoate, chlorhexidine hydrochloride, sorbic acid, methylparaben, and butylparaben; colorants such as yellow iron oxide, yellow ferric oxide, ferric oxide, black iron oxide, carbon black, magenta, β-carotene, copper chlorophyll, food blue No. 1, food yellow No. 4, food red No. 2, and licorice extract; cooling agents such as fennel oil, d-camphor, dl-camphor, peppermint oil, d-borneol, and l-menthol; flavors such as spearmint oil, clove oil, vanillin, bergamot oil, and lavender oil.

[0054] The thickness of the adhesive layer in one embodiment of the present invention is not particularly limited. For example, the thickness of the adhesive layer is preferably 5 μm to 400 μm, more preferably 7 μm to 200 μm, and even more preferably 10 μm to 100 μm. If the thickness is above, good adhesive properties (e.g., adhesive strength) can be achieved.

[0055] The adhesive layer can be formed by applying (typically coating) a coating solution for forming the adhesive layer to a support or a release liner and drying it to remove the solvent. It should be noted that the coating solution for forming the adhesive layer comprises the adhesive layer composition of one embodiment of the present invention and a suitable solvent capable of dissolving the composition.

[0056] Example

[0057] Hereinafter, one embodiment of the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to the description of the examples.

[0058] [Preparation of component (A)]

[0059] Preparation of polymer (A1)

[0060] To a reaction vessel equipped with a condenser, nitrogen inlet tube, thermometer, dropping funnel, and stirrer, 70 parts by weight of 2-ethylhexyl acrylate (hereinafter sometimes referred to as "2-EHA"), 5 parts by weight of N-(2-hydroxyethyl)acrylamide (hereinafter sometimes referred to as "HEAA"), 25 parts by weight of N-vinyl-2-pyrrolidone (hereinafter sometimes referred to as "N-VP"), and 333.3 parts by weight of ethyl acetate as a solvent were added. The mixture was stirred at room temperature for 1 hour while bubbling nitrogen (100 mL / min). The contents of the reaction vessel were then heated, and 0.2 parts of 2,2'-azobisisobutyronitrile (AIBN) as a polymerization initiator was added when the temperature reached 60°C. The temperature of the contents was controlled to maintain at 60°C, and polymerization was carried out in a nitrogen stream for 6 hours, followed by 15 hours at 76°C. By solution polymerization in the above manner, an adhesive composition was obtained as a solution of an acrylic copolymer (2-EHA / HEAA / N-VP = 70 / 5 / 25 (weight ratio), Mw: 2,200,000) (substantially, the coating liquid for forming the adhesive layer was the same in Examples 2 to 3 and Comparative Examples 1 to 3).

[0061] Preparation of polymer (A2)

[0062] The same method as for polymer (A1) was followed except that 2-EHA was used in an amount of 55 parts by weight, HEAA was used in an amount of 5 parts by weight, and N-VP was used in an amount of 40 parts by weight.

[0063] As the component (A), a polymer (A1) and a polymer (A2) are used.

[0064] As component (B), a copolymer (Plastoid B (trade name), manufactured by Rohm Pharma, weight average molecular weight 150,000) (polymer (B1)) containing methyl methacrylate monomer and butyl methacrylate monomer at a weight ratio of 1:3 was used.

[0065] Isopropyl myristate (IPM), diisopropyl adipate (DIPA), and oleyl alcohol (OA) were used as organic liquid components.

[0066] The free form of bisoprolol was used as the component (C).

[0067] (Example 1)

[0068] 55 parts by weight (in terms of solid content) of polymer (A1) as component (A), 10 parts by weight of polymer (B1) as component (B), 5 parts by weight of free form of bisoprolol as component (C), and 30 parts by weight of isopropyl myristate as an organic liquid component are mixed, and an appropriate amount of ethyl acetate for concentration adjustment is added and stirred to obtain a uniform adhesive solution. The obtained adhesive solution is applied to the release-treated surface of a polyester release sheet with a thickness of 75 μm so that the thickness after drying is 45 μm, and dried at 80°C for 5 minutes to form an adhesive layer. Next, a polyester film with a thickness of 4 μm and a unit area weight of 12 g / m 2 A laminate of a polyester nonwoven fabric of is used as a support, and the nonwoven fabric surface is pressed against the adhesive layer to obtain a bisoprolol-containing patch according to one embodiment of the present invention.

[0069] (Examples 2, 3, Comparative Example 1)

[0070] Bisoprolol-containing patches of Examples 2 and 3 and Comparative Example 1 were prepared using the compositions shown in Table 1 by the same procedure as in Example 1.

[0071] (Example 4)

[0072] 52 parts by weight (solids basis) of polymer (A2) as component (A), 5 parts by weight of polymer (B1) as component (B), 13 parts by weight of bisoprolol as component (C), and 30 parts by weight of isopropyl myristate as an organic liquid component were mixed, and an appropriate amount of ethyl acetate was added for concentration adjustment, followed by stirring to obtain a uniform adhesive solution. The resulting adhesive solution was applied to the release-treated surface of a 75 μm thick polyester release sheet to a dried thickness of 17 μm, and dried at 80°C for 5 minutes to form an adhesive layer.

[0073] Separately, an ethylene-vinyl alcohol copolymer resin and porous silica particles (Sylysia 350 manufactured by Fuji Silysia) were dissolved and dispersed in a mixed solvent of n-propanol and water (n-propanol / water = 7 / 3 (volume basis)) at a mixing ratio of 1:1 (weight basis) to prepare a primer. The resulting primer was applied to one side of a 15 μm thick ethylene-vinyl alcohol copolymer film as a support so that the dried coating (primer layer) had a weight per unit area of 0.7 g / m. 2 , and drying is performed to form a primer layer, thereby obtaining a support.

[0074] The surface of the primer layer of the support is pressed against the adhesive layer and bonded together to obtain the bisoprolol-containing patch of one embodiment of the present invention.

[0075] (Examples 5 to 13, Comparative Examples 2 to 5)

[0076] Bisoprolol-containing patches of Examples 5 to 13 and Comparative Examples 2 to 5 were prepared using the compositions shown in Table 1 by the same procedure as in Example 4.

[0077] Table 1 [Parts by weight]

[0078]

[0079] 1. <Cohesion> (Functional evaluation)

[0080] After peeling off the release liner of the patch, the cohesiveness of the adhesive layer was visually evaluated by touching the exposed surface of the adhesive layer with a finger according to the following indices.

[0081] ○: No stringing, no adhesive residue on fingers.

[0082] ×: Severe stringing, with adhesive residue on fingers.

[0083] 2. Adhesion

[0084] Each patch is cut into the article obtained by more than 12mm of width × 40mm of length as a test piece. The peeling liner of the test piece is removed, and according to JISZ0237:2009, a 2kg rubber roller is pressed onto the test plate (bakelite) by going back and forth once, and placed under 23°C for 30 minutes. Afterwards, it is installed in a tensile testing machine, the guide portion of the test piece is folded back 180 degrees, and peeled off at a speed of 300mm per minute. The load at 3 points is read at roughly equal intervals, and the average value is set to adhesive force (N / 12mm width). In addition, visual evaluation is performed on the bakelite after the test to determine whether there is glue residue or not, thereby judging the quality of cohesion.

[0085] 3. Holding power

[0086] Each patch was cut into an article of 10 mm in width and 50 mm in length as a test piece. The peeling liner of the test piece was removed and, according to JIS Z 0237: 2009, one end (10 mm in width and 20 mm in length) of a test plate (bakelite) was pressed against the test piece by moving a rubber roller weighing 2 kg back and forth once, and the opposite end was reinforced with auxiliary paper. The test piece was mounted on a hook in a stable device at a temperature of 40 ± 5 ° C and placed for 30 minutes. Afterwards, a load of 100 g was applied, and the time until the test piece fell was set to the holding force (minutes). Regarding the number of tests, n = 3 was used, and the measured values for a total of 3 times were averaged.

[0087] 4. <Skin penetration test>

[0088] The patches obtained in Example 5, Example 9, Comparative Example 3, and Comparative Example 5 were cut into approximate circles with a diameter of 8 mm. The release liner was peeled off and then pasted onto the horny surface of the excised skin of hairless mice that had been punched into approximate circles with a diameter of 20 mm.

[0089] The excised skin of hairless mice was mounted on a skin permeation test unit (application area: 6 mmφ) with the stratum corneum side as the donor phase and the dermis side as the receptor phase. Physiological saline was added to the receptor phase, and a 12-hour skin permeation test was carried out at 32°C. The receptor fluid after 24 hours was taken, and the drug concentration therein was measured by high performance liquid chromatography (HPLC). Regarding the number of tests, n = 3 was used, and the measured values for a total of 3 times were averaged.

[0090] <HPLC measurement conditions>

[0091] Column: YMC-Pack C8 (particle size 5 μm, inner diameter 4.6 mm × length 150 mm), manufactured by YMC Company. Mobile phase: phosphate buffer with a pH of 2.5 / acetonitrile = 7 / 3

[0092] Detection wavelength: 225 nm

[0093] Flow rate: 0.75 mL / minute [[ID=X]]

[0094] Column temperature: 40°C

[0095] As shown in Table 2, the cohesiveness of the patches containing bisoprolol in Examples 1 to 3 of one embodiment of the present invention was ○. In contrast, in Comparative Example 1, the cohesiveness was ×, and it was evaluated that the adhesive paste was more likely to remain on the fingers compared to Examples 1 to 3.

[0096] As shown in Table 2, the cohesiveness of the patches containing bisoprolol in Examples 4 to 13 of one embodiment of the present invention was ○, indicating good adhesive properties with both adhesive force and holding force. In addition, good results were also obtained in the skin permeation tests of Examples 5 and 9.

[0097] In contrast, in Comparative Examples 2 to 5, the cohesiveness was ×, indicating cohesive failure, and it was evaluated that the adhesive paste was more likely to remain on the fingers compared to the examples. Regarding Comparative Examples 3 and 5, although good results were obtained in the skin permeation tests, cohesive failure occurred in terms of adhesive properties, so they were not suitable as patches.

[0098] Table 2

[0099]

[0100] *Cohesive failure occurred

[0101] “-” in the table indicates not measured

[0102] While the present application has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the present invention.

[0103] This application is based on Japanese Patent Application No. 2015-122405 filed on June 17, 2015, the contents of which are incorporated herein by reference.

[0104] Industrial Applicability

[0105] The bisoprolol-containing patch according to one embodiment of the present invention can maintain good adhesive properties (especially, can maintain good adhesive properties even when containing a large amount of organic liquid components) and has high bisoprolol skin permeability.

Claims

1. A patch containing bisoprolol, comprising a support and an adhesive layer formed on one side of the support, wherein: The adhesive layer contains the following components (A) to (C): (A) component: a polymer obtained by copolymerizing monomer components including a hydroxyl group-containing monomer, an alkyl (meth)acrylate monomer, and an N-vinyl cyclic amide monomer; Component (B): a polymer having a neutral group as a side chain obtained by copolymerizing a monomer component comprising a methyl methacrylate monomer and a butyl methacrylate monomer; (C) Ingredients: Bisoprolol, The adhesive layer further comprises an organic liquid component, wherein the organic liquid component comprises isopropyl myristate. The content ratio of the component (A) to the component (B) contained in the adhesive layer (component (A) : component (B)) is 1: 0.05～1：1， The adhesive layer contains 0.1 wt% to 40 wt% of bisoprolol based on the total weight of the adhesive layer.

2. The bisoprolol-containing patch according to claim 1, wherein (A) The hydroxyl group-containing monomer in the component contains N-hydroxyalkyl (meth)acrylamide.

3. The bisoprolol-containing patch according to claim 1 or 2, wherein The weight average molecular weight (Mw) of the polymer of the component (A) is within the range of 1,400,000 to 2,400,000, and the weight average molecular weight (Mw) of the polymer of the component (B) is within the range of 100,000 to 200,000.

4. The bisoprolol-containing patch according to claim 1 or 2, wherein The hydroxyl group-containing monomer is contained in an amount within a range of 1% by weight to 20% by weight based on the entire polymer of the component (A).

5. The bisoprolol-containing patch according to claim 1 or 2, wherein The content ratio of the methyl methacrylate monomer to the butyl methacrylate monomer in the polymer of the component (B) is 1:1 to 1:4 by weight.

6. The bisoprolol-containing patch according to claim 1 or 2, wherein The organic liquid component is contained in an amount of 0.1 to 2.5 parts by weight relative to 1 part by weight of the total content of the components (A) and (B).

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