Adhesive patch

Abstract

To provide a transdermal patch using a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, which has skin permeability, skin adhesion, skin irritation, and long-term stability of the active ingredient comparable to a transdermal patch using a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion listed in the 2018 Japanese Pharmaceutical Additives Standards. [Solution] A patch comprising a support and an ointment layer on the support, The ointment layer contains a pharmaceutically active ingredient, an adhesive, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, and water. Adhesive patch.

Description

Technical Field

[0001] The present invention relates to an adhesive. Specifically, the present invention relates to an adhesive using a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonyl phenyl ether.

Background Art

[0002] Among adhesives, an adhesive using a base containing water is called a poultice, and an adhesive using a base containing almost no water is called a tape.

[0003] Since the poultice contains water, it has a drawback of lower adhesiveness compared to the tape. Therefore, in a poultice having a support layer and an adhesive layer in order to improve the adhesion to the skin, a methyl acrylate / 2-ethylhexyl acrylate copolymer is used in the adhesive layer (Patent Document 1).

[0004] The above-mentioned methyl acrylate / 2-ethylhexyl acrylate copolymer is a pharmaceutical additive and is generally used in the state of an emulsion. The methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion (hereinafter also referred to as "conventional methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion") described in the Pharmaceutical Additive Standards 2018 is an emulsion of a copolymer resin obtained by polymerizing methyl acrylate and 2-ethylhexyl acrylate in an aqueous solution using polyoxyethylene nonyl phenyl ether (30 E.O.) as an emulsifier and contains polyoxyethylene nonyl phenyl ether.

[0005] However, when the above-mentioned polyoxyethylene nonyl phenyl ether is decomposed by microorganisms or the like in the environment, nonyl phenyl ether, which is an environmental harmful substance, is generated. Therefore, in recent years, the use of polyoxyethylene nonyl phenyl ether has been regulated.

[0006] On the other hand, changing the emulsifier used during the polymerization of methyl acrylate and 2-ethylhexyl acrylate may affect the composition of the resulting methyl acrylate / 2-ethylhexyl acrylate copolymer resin, and it is unclear whether the performance as a pharmaceutical additive will be maintained. Furthermore, to the best of the inventors' knowledge, no methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether and has performance comparable to conventional methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsions has been proposed. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Patent No. 7292560 [Overview of the project] [Problems that the invention aims to solve]

[0008] The present invention aims to solve the above-mentioned problems, and specifically aims to provide a patch using a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, which has skin permeability, skin adhesion, skin irritation, and long-term stability of the pharmacoactive ingredient comparable to conventional patches using methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsions. [Means for solving the problem]

[0009] As a result of diligent research to solve the above problems, the present inventors have found that a patch using a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether has the same level of skin permeability, skin adhesion, skin irritation, and long-term stability of the active ingredient as a patch using a conventional methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and have completed the present invention.

[0010] In other words, the present invention relates to the following [1] to [6] adhesive patches. [1] A patch comprising a support and an ointment layer on the support, The ointment layer contains a pharmaceutically active ingredient, an adhesive, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, and water. Adhesive patch. [2] The patch according to [1], wherein the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion contains at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyrylphenyl ether. [3] The patch according to [1] or [2], wherein the pharmacoactive ingredient is loxoprofen sodium hydrate or flurbiprofen. [4] The patch according to [3], wherein the content (on a solid content basis) of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.1% to 9.2% by mass, based on the total mass of the ointment layer. [5] The patch according to [4], wherein the patch further comprises a liner layer on the ointment layer. [6] The support is a polyethylene terephthalate nonwoven fabric. The liner layer is a polypropylene film. The patch described in [5]. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide a patch using a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, which has skin permeability, skin adhesion, skin irritation, and long-term stability of the pharmacoactive ingredient comparable to conventional patches using methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsions. [Modes for carrying out the invention]

[0012] [Patch] A patch comprising a support and an ointment layer on the support, The ointment layer contains a pharmaceutically active ingredient, an adhesive, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, and water. Adhesive patch Regarding.

[0013] <Paste layer> The ointment layer of the patch of the present invention contains a pharmaceutically active ingredient, an adhesive, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, and water.

[0014] In the present invention, the pharmacoactive ingredient is not particularly limited, but loxoprofen sodium hydrate and flurbiprofen are preferred. Loxoprofen sodium hydrate and flurbiprofen are ingredients that exert analgesic and anti-inflammatory effects. When using loxoprofen sodium hydrate as the medicinal ingredient, its content is not particularly limited as long as it can exert analgesic and anti-inflammatory effects. However, based on the total mass of the paste layer, it is preferably 0.8% by mass to 1.4% by mass (0.7% by mass to 1.2% by mass in terms of anhydrous loxoprofen sodium), and more preferably 1.0% by mass to 1.2% by mass (0.8% by mass to 1.1% by mass in terms of anhydrous loxoprofen sodium). When using flurbiprofen as the medicinal ingredient, its content is not particularly limited as long as it can exert analgesic and anti-inflammatory effects. However, based on the total mass of the paste layer, it is preferably 0.1% by mass to 0.5% by mass, and more preferably 0.2% by mass to 0.4% by mass.

[0015] The adhesive is a component that imparts adhesiveness to the paste layer. The adhesive is not particularly limited, and examples include partially neutralized polyacrylic acid, sodium polyacrylate, acrylate starch 300, sodium carboxymethylcellulose (carboxymethylcellulose sodium), and hydroxypropylcellulose. The adhesive can be used alone or in combination of two or more. In the present invention, as the adhesive, at least one selected from partially neutralized polyacrylic acid and sodium carboxymethylcellulose is preferable, and a combination of partially neutralized polyacrylic acid and sodium carboxymethylcellulose is more preferable. The partially neutralized polyacrylic acid is one in which a part of the acid groups of polyacrylic acid is neutralized with an alkali metal such as sodium or potassium or an ammonium ion. The partially neutralized polyacrylic acid can be used alone or in combination of two or more. In the present invention, as the partially neutralized polyacrylic acid, one in which a part of the acid groups of polyacrylic acid is neutralized with sodium is preferable. The content of the adhesive (the total content when using two or more adhesives) is preferably 4.1% by mass to 20.0% by mass based on the total mass of the paste layer, and more preferably 5.5% by mass to 13.0% by mass. When using a combination of a partially neutralized polyacrylic acid and sodium carboxymethylcellulose, based on the total mass of the paste layer, the content of the partially neutralized polyacrylic acid is preferably 4.0% to 10.0% by mass, and the content of sodium carboxymethylcellulose is preferably 0.1% to 10.0% by mass. More preferably, the content of the partially neutralized polyacrylic acid is 5.0% to 8.0% by mass, and the content of sodium carboxymethylcellulose is 0.5% to 5.0% by mass.

[0016] The methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonyl phenyl ether is a component that improves the adhesiveness of the paste layer. The methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonyl phenyl ether does not contain polyoxyethylene nonyl phenyl ether and contains at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyryl phenyl ether and is preferably a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and more preferably a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that contains one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyryl phenyl ether. If a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether contains at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyrylphenyl ether, the content of at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyrylphenyl ether (the total content if two or more are contained) is, for example, 0.1% to 10.0% by mass, based on the total mass of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion. According to the 2018 Pharmaceutical Additives Standards, when a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is evaporated to dryness on a water bath and then dried at 105°C for 3 hours, the amount of evaporation residue (solid content) is 57% to 61%.

[0017] The content of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, which does not contain polyoxyethylene nonylphenyl ether, is preferably 2.0% to 15.0% by mass (1.1% to 9.2% by mass in terms of solid content), and more preferably 3.0% to 11.0% by mass (1.7% to 6.7% by mass in terms of solid content), based on the total mass of the ointment layer. When loxoprofen sodium hydrate is used as the active ingredient, the content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is preferably 5.0% to 15.0% by mass (2.9% to 9.2% by mass in terms of solids) based on the total mass of the ointment layer, and more preferably 7.0% to 11.0% by mass (4.0% to 6.7% by mass in terms of solids). Furthermore, when flurbiprofen is used as the active ingredient, the content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is preferably 2.0% to 10.0% by mass (1.1% to 6.1% by mass in terms of solids) based on the total mass of the ointment layer, and more preferably 3.0% to 6.0% by mass (1.7% to 3.7% by mass in terms of solids).

[0018] The methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion used in the present invention is not particularly limited and can be produced by known methods. For example, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether can be produced by uniformly dispersing methyl acrylate, 2-ethylhexyl acrylate and an emulsifier other than polyoxyethylene nonylphenyl ether in water, micellizing the methyl acrylate and 2-ethylhexyl acrylate with the emulsifier, adding a polymerization initiator (such as hydrogen peroxide, peracetic acid, t-butyl hydroperoxide, and perbenzoic acid), and heating to carry out emulsion polymerization. Examples of the emulsifiers mentioned above include nonionic emulsifiers such as polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyrylphenyl ether. One or more emulsifiers can be used in combination. In the present invention, the emulsifier is preferably at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyrylphenyl ether, and preferably one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyrylphenyl ether.

[0019] While there are no particular restrictions on the type of water, it is preferable that the water has been purified by methods such as ion exchange, distillation, or filtration, and more preferably that it is "purified water" as defined in the Japanese Pharmacopoeia. The water in the ointment layer includes not only water added as part of the additive, but also water contained in other components such as the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion. The water content can be adjusted as appropriate, for example, from 35% to 65% by mass, or from 40% to 60% by mass.

[0020] The ointment layer of the patch of the present invention may further contain additives such as pH adjusters, wetting agents, solvents, bases, and crosslinking agents, to the extent that they do not impair the effects of the present invention.

[0021] Examples of pH adjusting agents include tartaric acid, citric acid, oxalic acid, lactic acid, and acetic acid. pH adjusting agents can be used individually or in combination of two or more. In the present invention, tartaric acid is preferred as the pH adjusting agent. The content of pH adjusters (or the total content if two or more pH adjusters are used) is preferably 0.3% to 0.9% by mass, and more preferably 0.5% to 0.7% by mass, based on the total mass of the ointment layer.

[0022] Examples of wetting agents include concentrated glycerin, sorbitol solution, ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol. One or more wetting agents can be used in combination. In the present invention, concentrated glycerin is preferred as the wetting agent. The content of the wetting agent (or the total content if two or more wetting agents are used) is preferably 20.0% to 35.0% by mass, and more preferably 24.0% to 30.0% by mass, based on the total mass of the ointment layer.

[0023] Examples of solvents include crotamiton, isopropyl myristate, peppermint oil, l-menthol, and diethylene glycol monoethyl ether. One or more solvents can be used in combination. In the present invention, the solvent is preferably at least one selected from the group consisting of crotamiton, isopropyl myristate, and peppermint oil, and more preferably a combination of crotamiton and peppermint oil, and a combination of isopropyl myristate and peppermint oil. The content of the solvent (or the total content if two or more solvents are used) is preferably 1.1% to 6.3% by mass, and more preferably 1.5% to 4.1% by mass, based on the total mass of the ointment layer. When using a combination of crotamiton and peppermint oil, based on the total mass of the ointment layer, the crotamiton content is preferably 0.8% to 5.0% by mass, and the peppermint oil content is preferably 0.3% to 1.3% by mass, and more preferably the crotamiton content is 1.0% to 3.0% by mass, and the peppermint oil content is 0.5% to 1.1% by mass. Furthermore, when using a combination of isopropyl myristate and peppermint oil, based on the total mass of the ointment layer, the isopropyl myristate content is preferably 0.8% to 5.0% by mass, the peppermint oil content is preferably 0.3% to 1.3% by mass, and more preferably the isopropyl myristate content is 1.0% to 3.0% by mass, and the peppermint oil content is preferably 0.5% to 1.1% by mass.

[0024] Examples of base materials include kaolin, talc, hydrated silicon dioxide, and soft anhydrous silicic acid. One or more base materials can be used in combination. In the present invention, kaolin is preferred as the base material. The base content (total content if two or more bases are used) is based on the total mass of the ointment layer. Therefore, it is preferably 0.7% to 12.0% by mass, and more preferably 1.5% to 9.0% by mass.

[0025] Examples of crosslinking agents include dried aluminum hydroxide gel, dihydroxyaluminum aminoacetate, and aluminum magnesium hydroxide. One or more crosslinking agents can be used in combination. In the present invention, dried aluminum hydroxide gel is preferred as the crosslinking agent. The crosslinking agent content (or the total content if two or more crosslinking agents are used) is preferably 0.02% to 0.08% by mass, and more preferably 0.03% to 0.06% by mass, based on the total mass of the ointment layer.

[0026] <Support> Nonwoven fabrics, woven fabrics, knitted fabrics, films, sheets, and laminates thereof can be used as the support for the adhesive patch of the present invention. Examples of materials for the support include polyesters such as polyethylene terephthalate and polybutylene terephthalate; and polyolefins such as polyethylene and polypropylene. In the present invention, polyethylene terephthalate nonwoven fabric is preferred as the support material.

[0027] <Liner layer (release layer)> The patch of the present invention may have a liner layer laminated on the ointment layer. By laminating the liner layer, the ointment layer can be protected until the patch is used. Examples of liner layers include films and laminates made of polyolefins such as polyethylene and polypropylene, and polyesters such as polyethylene terephthalate and polybutylene terephthalate. In the present invention, a polypropylene film is preferred as the liner layer. Furthermore, the surface of the liner layer that comes into contact with the ointment layer may be treated with silicone or fluorine. This makes it easier to peel the liner layer from the ointment layer when using the patch.

[0028] [Manufacturing method for adhesive patches] The adhesive patch of the present invention can be manufactured by conventionally known methods. An example of a method for manufacturing the adhesive patch of the present invention (for example, an adhesive patch comprising a support, an ointment layer laminated on the support, and a liner layer laminated on the ointment layer) is a manufacturing method including the following steps (a) to (c). (a) A step of preparing an ointment layer-forming composition by mixing a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain a pharmacoactive ingredient, an adhesive, polyoxyethylene nonylphenyl ether, water, and additives as needed. (b) A step of spreading the plaster layer-forming composition prepared in step (a) onto the surface of a film or the like that constituting the liner layer to form a plaster layer on the liner layer, or a step of spreading the plaster layer-forming composition prepared in step (a) onto the surface of a support to form a plaster layer on the support, and (c) A step of bonding the plaster layer formed on the liner layer in step (b) to the support, or a step of bonding the plaster layer formed on the support in step (b) to the film or the like that constituting the liner layer. [Examples]

[0029] The present invention will be described in detail below based on examples, but the present invention is not limited in any way to those examples.

[0030] [Synthesis Example 1] Except for using polyoxyethylene lauryl ether as an emulsifier, methyl acrylate and 2-ethylhexyl acrylate were polymerized in an aqueous solution by conventionally known methods to obtain a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether (a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether but contains polyoxyethylene lauryl ether) [evaporation residue (solids) 60%].

[0031] [Synthesis Example 2] Except for using polyoxyethylene distyrylphenyl ether as an emulsifier, methyl acrylate and 2-ethylhexyl acrylate were polymerized in an aqueous solution by conventionally known methods to obtain a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether (a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether but contains polyoxyethylene distyrylphenyl ether) [evaporation residue (solids) 60%].

[0032] [Synthesis Example 3] Except for using polyoxyethylene oleyl ether as an emulsifier, methyl acrylate and 2-ethylhexyl acrylate were polymerized in an aqueous solution by conventionally known methods to obtain a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether (a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether but contains polyoxyethylene oleyl ether) [evaporation residue (solids) 60%].

[0033] [Example 1] A plaster layer-forming composition was prepared by mixing loxoprofen sodium hydrate, tartaric acid, partially neutralized polyacrylic acid, carmellose sodium, concentrated glycerin, crotamiton, peppermint oil, kaolin, dried aluminum hydroxide gel, the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion from Synthesis Example 1, and water in the proportions shown in Table 1. The obtained ointment layer-forming composition was uniformly spread on the release-treated surface of a 30 μm thick polypropylene film (release liner) so that 10 g of the composition was used per patch (10 cm x 14 cm), forming an ointment layer. Next, a polyethylene terephthalate nonwoven fabric was laminated onto the ointment layer to obtain a patch (poultice).

[0034] [Comparative Example 1] Except for using Nikazol® TS-620 (methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion containing polyoxyethylene nonylphenyl ether) [evaporation residue (solids) 60%] (manufactured by Nippon Carbide Industries, Ltd.) instead of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion used in Synthesis Example 1, a patch (poultice) with the composition shown in Table 1 was obtained using the same procedure as in Example 1.

[0035] [Example 2] Except for using flurbiprofen instead of loxoprofen sodium hydrate, using isopropyl myristate instead of crotamiton, and spreading the resulting ointment layer-forming composition to 12 g per patch (10 cm × 14 cm), a patch (poultice) with the composition shown in Table 1 was obtained using the same procedure as in Example 1.

[0036] [Comparative Example 2] This is the same as Example 2, except that Nikazol® TS-620 was used instead of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion used in Synthesis Example 1. Following the operating procedure, a patch (poultice) with the composition shown in Table 1 was obtained.

[0037] [Example 3] Except for using the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion from Synthesis Example 2 instead of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion from Synthesis Example 1, a patch (poultice) with the composition shown in Table 1 was obtained using the same procedure as in Example 2.

[0038] [Example 4] Except for using the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion from Synthesis Example 3 instead of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion from Synthesis Example 1, a patch (poultice) with the composition shown in Table 1 was obtained using the same procedure as in Example 2.

[0039]

Table 1

[0040] [Test Example 1: In Vitro Skin Permeation Test] (1) Loxoprofen Sodium-containing Patch (Patches of Example 1 and Comparative Example 1) The abdominal skin of male hairless rats (7 weeks old) was excised, and the excised skin was set in a Franz-type diffusion cell with the dermal side of the excised skin facing the receptor side. The receptor side was filled with phosphate isotonic buffer (pH 7.4) (4.3 mL), and warm water at 37 °C was refluxed in the water jacket. The patch produced in Example 1 or Comparative Example 1 was cut into a circle with a diameter of 1 cm (effective area 0.785 cm 2 ) to obtain test pieces. The polypropylene film (liner layer) was peeled off from the test pieces to expose the paste layer, and the paste layer was applied to the stratum corneum of the skin. At 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after the start of the test, receptor fluid (0.5 mL) was collected, and the same amount of phosphate isotonic buffer (pH 7.4) as the collected volume was replenished. Using the collected receptor fluid, the skin permeation amount of the drug efficacy component was measured by high performance liquid chromatography (HPLC). The results are shown in Table 2 and Table 3. The measurement conditions of the HPLC method are as follows. <HPLC Measurement Conditions> · Column: CAPCELL PAK C18 UG120 (particle size: 5 μm, inner diameter: 4.6 mm, length: 150 mm) (manufactured by Shiseido Company, Limited) · Mobile phase: Acetonitrile:Water:Phosphoric acid = 650:350:1 · Wavelength: 222 nm · Flow rate: 1.0 mL / min · Column temperature: 50 °C

[0041]

Table 2

[0042] [Table 3]

[0043] (2) Flurbiprofen-containing patch (patches of Example 2 and Comparative Example 2) The abdominal skin of male hairless rats (7 weeks old) was excised, and the excised skin was set in a Franz-type diffusion cell with the dermal side facing the receptor side. The receptor side was filled with phosphate isotonic buffer (pH 7.4) (4.3 mL), and warm water at 37 °C was refluxed in the water jacket. The patch produced in Example 2 or Comparative Example 2 was cut into a circle with a diameter of 1 cm (effective area 0.785 cm ) to obtain test pieces. The polypropylene film (liner layer) was peeled off from the test pieces to expose the paste layer, and the paste layer was applied to the stratum corneum of the skin. 2 At 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after the start of the test, receptor fluid (0.5 mL) was collected, and the same amount of phosphate isotonic buffer (pH 7.4) as the collected volume was replenished. Using the collected receptor fluid, the skin permeation amount of the drug efficacy component was measured by high performance liquid chromatography (HPLC). The results are shown in Table 4 and Table 5. The measurement conditions of the HPLC method are as follows. <HPLC measurement conditions> · Column: CAPCELL PAK C18 MG (particle size: 3 μm, inner diameter: 4.6 mm, length: 75 mm) (manufactured by Shiseido Co., Ltd.) · Mobile phase: Acetonitrile: 0.1% phosphoric acid = 1:1 · Wavelength: 248 nm · Flow rate: 1.0 mL / min · Column temperature: 45 °C

[0044] [Table 4]

[0045] [Table 5]

[0046] The results shown in Tables 2 to 5 clearly demonstrate that the patch of the present invention has skin permeability comparable to that of conventional patches using methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion.

[0047] [Test Example 2: Stability Test] The residual rate of flurbiprofen, the active ingredient in the patches after storage, was calculated using the following method, with the patches prepared in Examples 2 to 4 and Comparative Example 2, and the patches that were sealed in aluminum packaging and stored in a constant temperature bath at 60°C for 3 weeks. The remaining percentage of flurbiprofen after storage (s2 / s1 × 100) was calculated from the peak area of ​​flurbiprofen in the patch before storage (s1) and the peak area of ​​flurbiprofen in the patch after storage (s2). The results are shown in Table 6. <Method> As the adhesive patches, we used the patches from Examples 2 to 4 and Comparative Example 2, as well as the patches from Examples 2 to 4 and Comparative Example 2 that were sealed in aluminum packaging and stored in a constant temperature bath at 60°C for 3 weeks. One patch (10 cm × 14 cm) and 100 mL of methanol were added to a 200 mL round-bottom flask, heated under reflux for 1 hour, and then cooled to obtain the sample. The obtained sample was subjected to high-performance liquid chromatography under the following analytical conditions, and the remaining percentage of flurbiprofen was calculated from the resulting chromatogram. <Analysis conditions> • Column: Resolve C18 column, 5μm, 3.9×150mm (Waters Corporation) Mobile phase: Acetonitrile:Acetic acid:Water = 350:25:625 ·Flow rate: 1.0mL / min ·Wavelength: 280nm ·Injection volume: 10μL • Column temperature: 35℃

[0048] [Table 6]

[0049] The results shown in Table 6 clearly demonstrate that the patch of the present invention has a similar level of long-term stability of the active ingredient as conventional patches using methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion.

[0050] [Test Example 3: Patch Test] A patch test was conducted with 6 subjects. (1) Adhesives of Example 1 and Comparative Example 1 For the patches (10cm x 14cm) of Example 1 and Comparative Example 1, subjects 1, 3 through 6 applied them simultaneously to the same location on both upper arms for 24 hours, while subject 2 applied them simultaneously to the same location on both thighs for 24 hours for evaluation. The results are shown in Tables 7 through 11. (2) Adhesives of Example 2 and Comparative Example 2 For the patches (10cm x 14cm) of Example 2 and Comparative Example 2, subjects 1, 3 through 6 applied them simultaneously to the same location on both upper arms for 12 hours, while subject 2 applied them simultaneously to the same location on both thighs for 12 hours for evaluation. The results are shown in Tables 7 through 11.

[0051] The evaluation criteria were as follows: (1) Initial adhesion The strength of the adhesive immediately after application was evaluated using the following scale. [Table 7]

[0052] (2) Irritation feeling (feeling of use) The intensity of skin irritation one hour after application was evaluated using the following scale. [Table 8]

[0053] (3) Peeling off The degree of peeling of the patch at the end of the patch test was evaluated using the following scale. [Table 9]

[0054] (4) Pain during peeling After the patch application test, the pain experienced when removing the patch was evaluated using the following scale. [Table 10]

[0055] (5) Skin condition 1 hour after peeling The condition of the skin one hour after removal of the patch was evaluated using the following scale. [Table 11]

[0056] [Table 12]

[0057] [Table 13]

[0058] [Table 14]

[0059] [Table 15]

[0060] [Table 16]

[0061] The adhesive patch of the present invention has been shown to cause less pain upon removal (Table 10) and to have comparable skin adhesion and skin irritation (Tables 7 to 9 and 11) compared to conventional adhesive patches using methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion.

Claims

1. A patch comprising a support and an ointment layer on the support, The ointment layer contains a pharmaceutically active ingredient, an adhesive, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion that does not contain polyoxyethylene nonylphenyl ether, and water. Adhesive patch.

2. The patch according to claim 1, wherein the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion contains at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene distyrylphenyl ether.

3. The patch according to claim 1 or claim 2, wherein the pharmacoactive ingredient is loxoprofen sodium hydrate or flurbiprofen.

4. The patch according to claim 3, wherein the content (on a solid content basis) of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.1% by mass to 9.2% by mass, based on the total mass of the ointment layer.

5. The patch according to claim 4, wherein the patch further comprises a liner layer on the ointment layer.

6. The support is a polyethylene terephthalate nonwoven fabric. The liner layer is a polypropylene film. The adhesive patch according to claim 5.

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