Method for manufacturing poultices and method for suppressing the precipitation of l-menthol crystals in poultices
A poultice with controlled ratios of methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, magnesium aluminometasilicate, and gelatin addresses l-menthol crystal precipitation issues, ensuring uniform spreading, adhesion, and pain-free peeling.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- HISAMITSU PHARM CO INC
- Filing Date
- 2025-07-10
- Publication Date
- 2026-05-22
AI Technical Summary
Poultices containing l-menthol face issues such as uneven spreading, leakage of adhesive components, insufficient adhesion, liner release properties, and pain during peeling due to l-menthol crystal precipitation.
A poultice composition comprising a support layer, adhesive layer, and release liner, with specific ratios of methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, magnesium aluminometasilicate, and gelatin in the adhesive layer to suppress l-menthol crystal precipitation and improve adhesion and peelability.
The poultice effectively suppresses l-menthol crystal precipitation, ensures uniform spreading, prevents leakage, enhances adhesion, and reduces peeling pain.
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Abstract
Description
[Technical Field]
[0001] The present invention relates to a method for producing a poultice and a method for suppressing the crystal precipitation of l-menthol in a poultice. [Background technology]
[0002] Poultices are a type of adhesive patch manufactured by spreading a drug-containing adhesive layer on a support layer such as cloth, and generally, the adhesive layer has a high water content. To achieve a high water content in the adhesive layer and ensure excellent shape retention and cohesiveness, the adhesive layer contains water-soluble polymers such as gelatin, polyacrylic acid, polyacrylic acid neutralized product, and polyvinyl alcohol. Furthermore, poultices containing cooling agents such as l-menthol can provide a cooling sensation upon use and exhibit pain-relieving and cooling effects (for example, Patent Documents 1 and 2).
[0003] In poultices containing l-menthol, it is known that l-menthol crystals may precipitate in the adhesive layer. To solve this problem, for example, Patent Document 3 describes how the menthol content in the aqueous gel composition is set to a specific amount, and one or more substances selected from silica and talc are added to the aqueous gel composition to suppress menthol precipitation. [Prior art documents] [Patent Documents]
[0004] [Patent Document 1] Japanese Patent Publication No. 2020-132637 [Patent Document 2] Japanese Patent Publication No. 2019-81755 [Patent Document 3] Japanese Patent Publication No. 2022-75038 [Overview of the Initiative] [Problems that the invention aims to solve]
[0005] In the process of developing a poultice in which the precipitation of l-menthol crystals is suppressed, the inventors found that in addition to the precipitation of l-menthol crystals, problems such as uneven spreading during application, leakage of adhesive layer components from the support layer after application, insufficient adhesion and liner release properties, and pain when removing the poultice after application to the skin may occur.
[0006] This invention has been made in view of the problems of the prior art described above, and aims to provide a poultice that suppresses the precipitation of l-menthol crystals, has no unevenness in spread, has excellent adhesion and liner peelability, suppresses seepage, and suppresses pain during peeling. [Means for solving the problem]
[0007] As a result of diligent research to achieve the above objective, the present inventors have found that in an adhesive layer containing water, gelatin, l-menthol, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate, a poultice can be obtained in which the precipitation of l-menthol crystals is suppressed by setting the content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion within a predetermined range.
[0008] However, even when the content of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion was kept within a specified range, new problems arose, such as unevenness during the spreading of the adhesive layer, leakage of components from the adhesive layer into the support layer after spreading, insufficient adhesion and liner release properties, and pain when removing the poultice.
[0009] As a result of diligent research by the inventors of the present invention, they discovered that the above problems can be solved by setting the amounts of magnesium aluminometasilicate and gelatin, which are components of the poultice of the present invention, within a predetermined range, and thus completed the present invention.
[0010] In other words, the present invention relates to the following [1] to [6]. [1] A poultice comprising a support layer, an adhesive layer laminated on the support layer, and a release liner provided on the side of the adhesive layer opposite to the support layer, wherein the adhesive layer contains a drug, water, gelatin, l-menthol, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate, and based on the total mass of the adhesive layer, the content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.5% to 20% by mass, the content of magnesium aluminometasilicate is 0.25% to 0.45% by mass, and the content of gelatin is 1% to 3% by mass. [2] The poultice according to [1], wherein the adhesive layer further contains at least one selected from the group consisting of polyacrylic acid and polyacrylic acid neutralized products. [3] A method for producing a poultice, comprising a support layer, an adhesive layer laminated on the support layer, and a release liner provided on the side of the adhesive layer opposite to the support layer, comprising the steps of: obtaining an adhesive composition containing a drug, water, gelatin, l-menthol, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate; and spreading the adhesive composition on a release liner or support layer, and laminating the support layer or release liner thereon, wherein, based on the total mass of the adhesive layer, the content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.5% to 20% by mass, the content of magnesium aluminometasilicate is 0.25% to 0.45% by mass, and the content of gelatin is 1% to 3% by mass. [4] The method according to [3], wherein the adhesive composition further contains at least one selected from the group consisting of polyacrylic acid and polyacrylic acid neutralized products. [5] A method for suppressing the crystal precipitation of l-menthol in a poultice comprising a support layer, an adhesive layer laminated on the support layer, and a release liner provided on the side of the adhesive layer opposite to the support layer, comprising the steps of: obtaining an adhesive composition containing a drug, water, gelatin, l-menthol, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate; and spreading the adhesive composition on a release liner or support layer, and laminating the support layer or release liner thereon, wherein, based on the total mass of the adhesive layer, the content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.5% to 20% by mass, the content of magnesium aluminometasilicate is 0.25% to 0.45% by mass, and the content of gelatin is 1% to 3% by mass. [6] The method according to [5], wherein the adhesive composition further contains at least one selected from the group consisting of polyacrylic acid and polyacrylic acid neutralized products. [Effects of the Invention]
[0011] According to the present invention, it is possible to provide a poultice in which the precipitation of l-menthol crystals is suppressed, there is no unevenness in spreading, there are excellent adhesion and liner peelability, leakage is suppressed, and pain during peeling is suppressed. [Modes for carrying out the invention]
[0012] Preferred embodiments of the present invention will be described in detail below.
[0013] The transdermal patch according to the first embodiment of the present invention includes a support layer, an adhesive layer laminated on the support layer, and a release liner provided on the surface of the adhesive layer opposite to the support layer. The adhesive layer contains a drug, water, gelatin, l-menthol, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate. Based on the total mass of the adhesive layer, the content of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.5% to 20% by mass, the content of magnesium aluminometasilicate is 0.25% to 0.45% by mass, and the content of gelatin is 1% to 3% by mass.
[0014] The support layer only needs to be capable of supporting the adhesive layer containing water, and those well-known to those skilled in the art can be used. Examples of the support layer include woven fabrics (including knitted fabrics), non-woven fabrics, resin films, foamed sheets, and paper. When using a woven fabric, non-woven fabric, or resin film as the support layer, the material thereof includes, for example, polyolefins such as polyethylene, polypropylene, and polybutylene, polyesters such as polyethylene terephthalate, rayon, polyurethane, and cotton. These may be used alone, in combination of two or more, and may be single-layer or laminated. The material of the support layer is more preferably polyester.
[0015] The support layer is preferably a non-woven fabric or a woven fabric, and particularly preferably a non-woven fabric or a woven fabric having a predetermined elongation recovery rate (elongation elastic modulus). In the present specification, the "elongation recovery rate" is a value measured according to the description in JIS L1096:2010, and means the "elongation elastic modulus at constant load" or the "elongation elastic modulus at constant rate elongation". For example, the "50% elongation recovery rate" is the elongation elastic modulus when elongated (constant rate elongation) so that the elongation rate becomes 50%, and the "load at 50% elongation" is the load (constant load) required to elongate so that the elongation rate becomes 50%. By using a non-woven fabric or a woven fabric having a predetermined elongation recovery rate, when attached to a movable part such as a joint, the support layer expands and contracts according to the movement of the attachment site, which is preferable.
[0016] When the support layer is a non-woven fabric, for example, the 50% elongation recovery rate of the non-woven fabric is 60 to 99%, preferably 65 to 95%, and more preferably 70 to 90%. Also, the load at 50% elongation of the non-woven fabric is, for example, 1 to 6 N / 50 mm in the longitudinal direction (major axis direction) and preferably 0.1 to 3 N / 50 mm in the transverse direction (minor axis direction). The basis weight of a suitable support layer is, for example, 80 to 150 g / m 2 and preferably 90 to 120 g / m 2 . The thickness of a suitable support layer is, for example, 0.5 to 2 mm. The basis weight and thickness of the support layer are measured in accordance with the standards of JIS L1906:2000. Also, the stiffness-flexibility of the support layer (the method for measuring stiffness-flexibility is by Method A (45° cantilever method) of JIS L1096:2010.) can be, for example, 20 to 40 mm in the longitudinal direction (major axis direction) and 10 to 35 mm in the transverse direction (minor axis direction), and preferably 25 to 35 mm in the longitudinal direction (major axis direction) and 15 to 30 mm in the transverse direction (minor axis direction).
[0017] The knitted fabrics used as the support layer include, for example, knitted fabrics formed by gathering stitches by circular knitting, warp knitting, weft knitting, etc. and processed into a cloth shape. Knitted fabrics made by combining one or more materials such as polyester-based, nylon-based, polypropylene-based, and rayon-based materials are preferred, and among them, knitted fabrics made of polyethylene terephthalate with less interaction with drugs are more preferred.
[0018] In particular, when the support layer is a woven fabric, the 50% elongation recovery rate of the woven fabric is, for example, 60 to 99%, preferably 65 to 95%, and more preferably 70 to 90%. Also, the load at 50% elongation is, for example, 1 to 5 N / 25 mm in the longitudinal direction (major axis direction) and preferably 0.1 to 3 N / 25 mm in the transverse direction (minor axis direction). The stiffness-flexibility of the support layer can be, for example, 10 to 30 mm in the longitudinal direction (major axis direction) and 10 to 30 mm in the transverse direction (minor axis direction), and preferably 15 to 25 mm in the longitudinal direction (major axis direction) and 15 to 25 mm in the transverse direction (minor axis direction).
[0019] The thickness of the woven fabric used as the support layer is preferably 0.5 to 2 mm.
[0020] In particular, the basis weight is 80-150g / m 2 With polyethylene terephthalate woven fabric, when spread, water contained in the adhesive is less likely to seep through the mesh of the fabric, and the anchoring properties between the fabric and the adhesive are superior.
[0021] Furthermore, polyethylene terephthalate woven fabrics preferably have a modulus of 2-12 N / 50 mm in the longitudinal direction (long axis direction) and 2-8 N / 50 mm in the transverse direction (short axis direction) (the modulus is measured according to JIS L1018:1999). If the modulus is lower than 2 N / 50 mm, the woven fabric may stretch when the adhesive is spread, causing the adhesive to seep into the mesh and reducing its function as a poultice. Also, if the modulus is higher than 12 N / 50 mm (longitudinal direction) or 8 N / 50 mm (transverse direction), the elasticity will be poor, and when the poultice is applied to a movable part, it may not be able to follow the stretching of the skin.
[0022] The material of the release liner is not particularly limited, and liners made of materials generally known to those skilled in the art can be used. When a woven fabric, nonwoven fabric, knitted fabric, or resin film is used as the support layer, examples of release liner materials include polyethylene, polypropylene, polybutylene, polyethylene terephthalate, rayon, polyurethane, and paper. These materials may be used individually or in combination of two or more. A polypropylene film is preferred as the material for the release liner.
[0023] The adhesive layer contains drugs, water, gelatin, l-menthol, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate.
[0024] The drugs are not particularly limited as long as they are drugs that can be absorbed through the skin. Examples of drugs include nonsteroidal anti-inflammatory drugs or their esters such as indomethacin, felbinac, flurbiprofen, diclofenac, diclofenac sodium, methyl salicylate, glycol salicylate, and ketoprofen; antihistamines such as diphenhydramine; analgesics such as aspirin, acetaminophen, ibuprofen, and loxoprofen sodium; local anesthetics such as lidocaine; muscle relaxants such as succinylcholine chloride; antifungal agents such as clotrimazole; antihypertensive agents such as clonidine; vasodilators such as nitroglycerin and isosorbide dinitrate; vitamins such as vitamin A, vitamin E (tocopherol), tocopherol acetate, vitamin K, octotiamine, and riboflavin butyrate; prostaglandins; scopolamine, fentanyl, capsicum extract, and nonyl vanillylamide. Some drugs have two optical isomers, R-isomers and S-isomers. The drug used in this embodiment may be either one optical isomer or a mixture of the two optical isomers in any proportion. The drug may also be in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include inorganic base salts such as sodium salts, potassium salts, and calcium salts; organic base salts such as amine salts such as monoethanolamine and diethanolamine; inorganic acid salts such as hydrochloride, nitrate, and phosphate; and organic acid salts such as acetate, lactate, benzenesulfonate, and citrate.
[0025] The amount of drug in the adhesive layer should be sufficient to allow the drug to exert its therapeutic effect, and this varies depending on the type of drug. For example, the amount can be 0.5% to 1.5% by mass for indomethacin, 0.5% to 1.5% by mass for diclofenac sodium, 0.1% to 1% by mass for ketoprofen, 0.5% to 1.5% by mass for felbinac, and 0.1% to 1% by mass for flurbiprofen.
[0026] The water content in the adhesive layer can be 30% to 70% by mass, based on the total mass of the adhesive layer, and may be 30% to 60% by mass, or 35% to 52% by mass.
[0027] The gelatin content in the adhesive layer is 1% to 3% by mass, preferably 1.25% to 3% by mass, and more preferably 1.5% to 3% by mass, based on the total mass of the adhesive layer.
[0028] The l-menthol content in the adhesive layer can be 0.5% to 3% by mass, preferably 1% to 2% by mass, and more preferably 1% to 1.5% by mass, based on the total mass of the adhesive layer.
[0029] Methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is an emulsion (aqueous emulsion) in which methyl acrylate / 2-ethylhexyl acrylate copolymer resin is dispersed in water. The content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin in the emulsion can be 55% to 65% by mass based on the total mass of the emulsion. The emulsion may also contain an emulsifier, such as polyoxyethylene nonylphenyl ether. The content of the emulsifier can be 1% to 5% by mass based on the total mass of the emulsion. The content of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion in the adhesive layer is 1.5% to 20% by mass (corresponding to 0.825% to 13% by mass as methyl acrylate / 2-ethylhexyl acrylate copolymer resin) based on the total mass of the adhesive layer, preferably 2% to 19% by mass (corresponding to 1.1% to 12.35% by mass as methyl acrylate / 2-ethylhexyl acrylate copolymer resin) or 3% to 20% by mass (corresponding to 1.65% to 13% by mass as methyl acrylate / 2-ethylhexyl acrylate copolymer resin), and more preferably 3% to 18% by mass (corresponding to 1.65% to 11.7% by mass as methyl acrylate / 2-ethylhexyl acrylate copolymer resin). Examples of commercially available methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsions include Nikazol TS-620 (trade name, manufactured by Nippon Carbide Industries, Ltd.) and BPW HW-2 (trade name, manufactured by Toyo Chem Co., Ltd.).
[0030] The magnesium aluminometasilicate content in the adhesive layer is 0.25% to 0.45% by mass, preferably 0.25% to 0.43% by mass, and more preferably 0.28% to 0.4% by mass, based on the total mass of the adhesive layer.
[0031] The ratio of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion content to magnesium aluminometasilicate content in the adhesive layer is preferably 3.3:1 to 80:1 (corresponding to 1.815:1 to 52:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin), more preferably 5.4:1 to 76:1 (corresponding to 2.97:1 to 49.4:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin) or 6.6:1 to 80:1 (corresponding to 3.63:1 to 52:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin), and even more preferably 7.5:1 to 72:1 (corresponding to 4.125:1 to 46.8:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin). The ratio of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion content to gelatin content in the adhesive layer is preferably 0.5:1 to 20:1 (corresponding to 0.275:1 to 13:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin), more preferably 0.75:1 to 16:1 (corresponding to 0.4125:1 to 10.4:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin) or 1:1 to 20:1 (corresponding to 0.55:1 to 13:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin), and even more preferably 1:1 to 12:1 (corresponding to 0.55:1 to 7.8:1 as methyl acrylate / 2-ethylhexyl acrylate copolymer resin).
[0032] The adhesive layer may also contain other components such as water-soluble polymers (excluding gelatin; the same applies hereinafter), cooling agents (excluding l-menthol; the same applies hereinafter), tack enhancers (excluding methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion; the same applies hereinafter), solubilizers, crosslinking agents (excluding magnesium aluminometasilicate; the same applies hereinafter), fillers, humectants, stabilizers, preservatives, chelating agents, colorants, fragrances, pH adjusters, etc. In one embodiment of the present invention, it is preferable that the adhesive layer does not contain propylene glycol.
[0033] Examples of tack enhancers include acrylic acid ester copolymers such as aminoalkyl methacrylate copolymer E. When the adhesive layer contains a tack enhancer, its content is preferably 0.1% to 1.0% by mass, based on the total mass of the adhesive layer. It is preferable that the adhesive layer does not contain any tack enhancers other than methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion.
[0034] The water-soluble polymer is not particularly limited as long as it can retain moisture in the adhesive layer, and those generally known to those skilled in the art can be used. Examples of water-soluble polymers include polyacrylic acid, neutralized polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, sodium carboxymethylcellulose (carmellose sodium), methylcellulose, and carrageenan. The water-soluble polymer may be used alone or in combination of two or more. The neutralized polyacrylic acid may be fully neutralized polyacrylic acid, partially neutralized polyacrylic acid, or a mixture thereof. Examples of neutralized polyacrylic acid include polyacrylate salts, such as sodium salts, potassium salts, calcium salts, and ammonium salts. Partially neutralized polyacrylic acid has structural units derived from acrylic acid and structural units derived from acrylate salts in any proportion within a single polymer chain. It is preferable to use partially neutralized polyacrylic acid in which 50 mol% of the carboxyl groups in a single polymer chain have been neutralized. The water-soluble polymer preferably contains at least one selected from the group consisting of polyacrylic acid and polyacrylic acid neutralized product, and more preferably contains both polyacrylic acid and polyacrylic acid neutralized product. When the adhesive layer contains a water-soluble polymer, its content is preferably 3% to 15% by mass, more preferably 5% to 13% by mass, and even more preferably 7% to 11% by mass, based on the total mass of the adhesive layer. When the adhesive layer contains polyacrylic acid, its content is preferably 1% to 5% by mass, more preferably 2% to 5% by mass, and even more preferably 2.5% to 4.5% by mass, based on the total mass of the adhesive layer. When the adhesive layer contains polyacrylic acid neutralized product, its content is preferably 1% to 5% by mass, more preferably 1.5% to 4.5% by mass, and even more preferably 2% to 4% by mass, based on the total mass of the adhesive layer.If the adhesive layer contains polyvinyl alcohol, its content is preferably 1% to 5% by mass, more preferably 1% to 4% by mass, and even more preferably 1.5% to 3.5% by mass, based on the total mass of the adhesive layer.
[0035] Examples of cooling agents include thymol, l-isopulegol, and peppermint oil. Cooling agents may be used individually or in combination of two or more. If the adhesive layer contains a cooling agent, its content is preferably 1% to 1.5% by mass based on the total mass of the adhesive layer.
[0036] The solubilizer is not particularly limited as long as it can dissolve the drug, and examples include crotamiton; N-methylpyrrolidone; polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol; oxyalkylene fatty acid esters such as polyethylene glycol monostearate; polyoxyalkylene sorbitan fatty acid esters such as polysorbate 80; sorbitan fatty acid esters such as sorbitan monooleate; and surfactants such as polyoxyethylene hydrogenated castor oil. These solubilizers may be used individually or in combination of two or more. If the adhesive layer contains a solubilizer, its content is preferably 0.1% to 3% by mass, more preferably 0.2% to 1% by mass, and even more preferably 0.3% to 0.7% by mass, based on the total mass of the adhesive layer.
[0037] The crosslinking agent is a component used to adjust the progress of the crosslinking reaction between polyacrylic acid neutralized products and the crosslinking reaction between polyacrylic acid neutralized products and optionally added polyacrylic acid. Crosslinking agents commonly used in poultices can be used. Examples of crosslinking agents include aluminum compounds. If the adhesive layer contains a crosslinking agent, its content is preferably 0.05% to 1% by mass, more preferably 0.1% to 0.7% by mass, and even more preferably 0.2% to 0.5% by mass, based on the total mass of the adhesive layer. When the crosslinking agent content is within this range, a poultice with better conformability to the skin can be obtained. It is preferable that the adhesive layer does not contain any crosslinking agents other than magnesium aluminometasilicate.
[0038] Examples of fillers include inorganic fillers such as anhydrous silicic acid, titanium dioxide, synthetic aluminum silicate, kaolin, talc, bentonite, and magnesium aluminometasilicate, and may be one of these or a combination of two or more. If the adhesive layer contains a filler, its content is preferably 0.1% to 1.5% by mass, more preferably 0.2% to 1% by mass, and even more preferably 0.3% to 0.7% by mass, based on the total mass of the adhesive layer.
[0039] The humectant is not particularly limited as long as it can suppress the evaporation of moisture from the adhesive layer over time. Examples of humectants include polyhydric alcohols such as glycerin, sorbitol, ethylene glycol, 1,4-butanediol, polyethylene glycol, and liquid paraffin. These humectants may be used individually or in combination of two or more. It is preferable that the humectant contains at least one selected from the group consisting of glycerin and sorbitol, and more preferably contains both glycerin and sorbitol. When the adhesive layer contains a humectant, its content is preferably 15% to 45% by mass, more preferably 20% to 40% by mass, and even more preferably 25% to 35% by mass, based on the total mass of the adhesive layer.
[0040] Examples of stabilizers include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (e.g., dibenzoylmethane derivatives). When the adhesive layer contains a stabilizer, its content is preferably 0.05% to 1% by mass, more preferably 0.1% to 0.6% by mass, and even more preferably 0.2% to 0.6% by mass, based on the total mass of the adhesive layer.
[0041] Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, 1,2-pentanediol, benzoic acid and its salts, salicylic acid and its salts, sorbic acid and its salts, dehydroacetic acid and its salts, 4-isopropyl-3-methylphenol, 2-isopropyl-5-methylphenol, phenol, hinokitiol, cresol, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanilide, chlorobutanol, benzalkonium chloride, and benzethonium chloride. These preservatives may be used individually or in combination of two or more. If the adhesive layer contains a preservative, its content is preferably 0.01% to 1% by mass, more preferably 0.05% to 0.5% by mass, and even more preferably 0.1% to 0.2% by mass, based on the total mass of the adhesive layer.
[0042] Examples of chelating agents include EDTA (also known as ethylenediaminetetraacetic acid) or its salts, ascorbic acid, pyrophosphates, hexametaphosphates, glucons, etc. These chelating agents may be used individually or in combination of two or more. More specifically, sodium edetate is an example of an EDTA salt. When the adhesive layer contains a chelating agent, its content is preferably 0.05% to 1% by mass, more preferably 0.1% to 0.6% by mass, and even more preferably 0.2% to 0.6% by mass, based on the total mass of the adhesive layer.
[0043] The total mass of the adhesive layer is 200 g / m 2 ~1000 g / m 2 and can be 400 g / m 2 ~1000 g / m 2 or can be 400 g / m 2 ~650 g / m 2 or can be. Preferably, by setting it to 400 g / m 2 ~650 g / m 2 the fit feeling can be improved, and the adhesiveness for a longer period can be enhanced. If the total mass of the adhesive layer is within the above range, the thickness of the entire patch can be reduced, making it easier to follow the skin, and furthermore, the step difference from the peripheral part when pasted becomes smaller, so it tends to be difficult to peel off.
[0044] The pH of the adhesive layer is preferably 4 to 8, and more preferably 4.5 to 6. By setting the pH to 4 or higher, the irritation to the skin is reduced, and by setting the pH to 8 or lower, the moldability and shape retention of the patch can be improved. In particular, when the support layer is a woven fabric, especially a knitted fabric, bleeding may occur when forming the adhesive layer, but when the pH is 5 to 6.5, bleeding tends to be suppressed. The pH can be measured, for example, in accordance with the pH measurement method in the General Test Methods of the Japanese Pharmacopoeia, using a glass composite electrode and diluting the sample 20 times with purified water.
[0045] The patch can be manufactured, for example, by mixing a drug, water, gelatin, l-menthol, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, magnesium aluminometasilicate, and, if necessary, any of the above-mentioned optional components to obtain an adhesive composition, uniformly spreading this adhesive composition on a release liner, and laminating a support layer thereon. Also, the patch may be manufactured by uniformly spreading the adhesive composition on the support layer and laminating a release liner thereon.
Example
[0046] The components of the compositions shown in Examples and Comparative Examples in Tables 1 to 4 (the numerical values of each component in the table represent mass %) were mixed to prepare an adhesive composition. Next, the obtained adhesive composition was uniformly spread on a release liner (a polypropylene film) so that the mass of the adhesive layer per unit area was 500 g / m 2 2 and a support layer (a non-woven fabric made of polyethylene terephthalate, basis weight: 100 g / m) was laminated thereon, and then cut into a size of 140 cm 2 (10 cm × 14 cm) to obtain a patch. A methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion was Nikkazol TS-620 (trade name, manufactured by Nippon Carbide Industries Co., Ltd.). Also, concentrated glycerin and D-sorbitol solution were those listed in the Japanese Pharmacopoeia (The Eighteenth Revised Japanese Pharmacopoeia). For each patch, l-menthol precipitation, unevenness during spreading, bleeding, liner blush, liner peelability, initial adhesiveness, adhesiveness over time, pain during peeling, and remaining adhesive layer were evaluated by the following methods, respectively.
[0047] <Unevenness during spreading> The adhesive layer during spreading was observed and evaluated according to the following evaluation scores. A score of 2 or more was judged as acceptable. 2. The surface and thickness are uniform over the entire surface of the adhesive layer (area: 90% or more) and there is no unevenness in spreading 1. In a part of the adhesive layer (area: exceeding 10%), the surface and / or thickness are not uniform and unevenness in spreading is confirmed
[0048] [[ID= / / ]] All of the following evaluations were performed on the patches that were sealed in an aluminum packaging bag, allowed to stand at 25°C for 10 days or more, up to 15 days at most, and then taken out of the packaging bag.
[0049] <l-menthol precipitation> The surface of the adhesive layer of the patch was visually observed, and the presence or absence of crystal precipitation of l-menthol was evaluated according to the following criteria. Ten patches were evaluated, and the average value of the scores was taken as the evaluation result. A score (average value) of 2.0 or more was judged as acceptable. 2. No precipitation 1. Precipitation present
[0050] <Staining> The area where components of the adhesive layer had seeped into the support layer was measured and evaluated according to the following evaluation score. Evaluations were performed on 5 to 20 patches, and the average score was used as the evaluation result. A score (average) of 5.0 or higher was judged to be acceptable. 5. No staining. 4. Slight bleeding (area: less than 10%) 3. Slight bleeding (area: 10% to less than 20%) 2. Significant staining (area: 20% to less than 30%) 1. Significant bleeding (area: 30% or more)
[0051] <Liner misalignment> The degree of misalignment between the adhesive layer and the release liner of the poultice was scored according to the following criteria. Evaluations were performed on 5 to 20 poultices, and the average score was used as the evaluation result. A score (average) of 4.0 or higher was deemed acceptable. 4. No liner misalignment (misalignment of less than 0.5 mm) 3. Almost no liner misalignment (misalignment of 0.5mm to less than 1.5mm) 2. Clear liner misalignment (misalignment of 1.5 mm or more) 1. Measurement impossible (liner layer detached during testing)
[0052] <Liner release properties> The ease of removing the release liner from the poultice was scored according to the following criteria. Evaluations were conducted for 5 to 20 poultices, and the average score was used as the evaluation result. A score (average) of 3.0 or higher was considered acceptable. 5. Very easy to peel off 4. Relatively easy to peel off 3. Acceptable peelability 2. Somewhat difficult to peel off 1. Very difficult to remove
[0053] <Initial adhesion> The release liner was peeled off the poultice and applied to the elbows of 5 to 20 subjects. After the subjects flexed their elbows 40 times, the adhesion of the adhesive layer to the skin was scored according to the following criteria. The average score of the 5 to 20 subjects was used as the evaluation result, and a score (average) of 5.0 or higher was considered acceptable. 6. No peeling 5. Peeling off the edges (less than 1 / 4) 4. Peeling of more than 1 / 4 but less than 1 / 3 3. Peeling of more than 1 / 3 but less than 1 / 2 2.5% or more of the skin is peeled off. 1. Falling off
[0054] <Adhesion over time> The release liner was peeled off the poultice and applied to the elbows of 5 to 20 subjects. The adhesion of the adhesive layer to the skin was scored according to the following criteria after 4 hours and 6 hours. The average score of the 5 to 20 subjects was used as the evaluation result, and a score (average) of 5.0 or higher was judged as acceptable. 6. No peeling 5. Peeling off the edges (less than 1 / 4) 4. Peeling of more than 1 / 4 but less than 1 / 3 3. Peeling of more than 1 / 3 but less than 1 / 2 2.5% or more of the skin is peeled off. 1. Falling off
[0055] <Pain during peeling> In the above-mentioned adhesion test over time, the poultice was removed from the subject's elbow after 6 hours of application, and the pain experienced during removal was scored according to the following criteria. The average score of 5 to 20 subjects was used as the evaluation result, and a score (average) of 3.0 or higher was considered acceptable. 4. None 3. Slightly present (not noticeable) 2. Somewhat present 1. Quite likely
[0056] <Remaining adhesive layer> In the above-mentioned pain test during peeling, the percentage of the adhesive layer remaining on the skin after peeling off the poultice (based on area) was scored according to the following criteria. The average score of 5 to 20 subjects was used as the evaluation result, and a score (average) of 3.0 or higher was considered acceptable. 4. None 3. A small amount remains (less than 1 / 10) 2. Some remain (1 / 10 or more but less than 1 / 5) 1. A considerable amount remains (more than 1 / 5)
[0057] The results are summarized in Tables 1 to 4. In the tables, A indicates that the acceptable conditions in the above evaluation are met, and B indicates that the acceptable conditions are not met. [Table 1]
[0058] As is clear from the results shown in Table 1, in the poultice with a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion content of less than 1.5% by mass (Comparative Example 1), it was confirmed that l-menthol crystals precipitated and that the liner peelability was insufficient. On the other hand, in the poultices with a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion content of 3.0% to 25% by mass (Comparative Examples 2 to 6), although the precipitation of l-menthol crystals was suppressed, it was confirmed that other problems arose, such as insufficient liner peelability, adhesion, seepage, and pain during peeling.
[0059] [Table 2]
[0060] As is clear from the results shown in Table 2, poultices containing less than 0.25% by mass or more than 0.45% by mass of magnesium aluminometasilicate (Comparative Examples 7, 8, 11, 12, and 15) and poultices containing less than 1% by mass or more than 3% by mass of gelatin (Comparative Examples 7-15) were found to be insufficient in at least one respect: unevenness during spreading, adhesion, bleeding, and liner peelability.
[0061] [Table 3]
[0062] [Table 4]
[0063] As is clear from the results shown in Tables 3-4, the poultices of the present invention (Examples 1-8 and 14-18) were confirmed to be superior in all evaluation items.
[0064] Furthermore, poultices (Examples 9-12) were prepared in the same manner as in Example 4, except that diclofenac sodium (1.0% by mass), ketoprofen (0.3% by mass), felbinac (0.7% by mass), or flurbiprofen (0.33% by mass) were used instead of indomethacin, and the poultices were evaluated. All of the poultices in Examples 9-12 showed good results in all evaluation items.
[0065] Furthermore, a poultice (Example 13) was prepared in the same manner as in Example 4, except that BPW HW-2 (product name, manufactured by Toyo Chem Co., Ltd.) was used as the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion instead of Nikazol TS-620 (product name, manufactured by Nippon Carbide Industries, Ltd.), and the poultice was evaluated. The poultice of Example 13 showed good results in all evaluation items.
Claims
1. Support layer and An adhesive layer laminated on the support layer, A release liner is provided on the side of the adhesive layer opposite to the support layer, A method for manufacturing a poultice comprising: A step to obtain an adhesive composition containing a drug, water, gelatin, l-menthol, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate, The process includes spreading the adhesive composition onto a release liner or support layer, and then laminating the support layer or release liner thereon, Based on the total mass of the adhesive layer, the content of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.5% to 20% by mass, the content of the magnesium aluminometasilicate is 0.25% to 0.45% by mass, and the content of the gelatin is 1% to 3% by mass. A method for manufacturing poultices.
2. The method according to claim 1, wherein the adhesive composition further contains at least one selected from the group consisting of polyacrylic acid and polyacrylic acid neutralized products.
3. Support layer and An adhesive layer laminated on the support layer, A release liner is provided on the side of the adhesive layer opposite to the support layer, A method for suppressing the crystal precipitation of l-menthol in a poultice comprising: A step to obtain an adhesive composition containing a drug, water, gelatin, l-menthol, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and magnesium aluminometasilicate, The process includes spreading the adhesive composition onto a release liner or support layer, and then laminating the support layer or release liner thereon, Based on the total mass of the adhesive layer, the content of the methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion is 1.5% to 20% by mass, the content of the magnesium aluminometasilicate is 0.25% to 0.45% by mass, and the content of the gelatin is 1% to 3% by mass. method.
4. The method according to claim 3, wherein the adhesive composition further contains at least one selected from the group consisting of polyacrylic acid and polyacrylic acid neutralized products.