JP7595418B2 - Poultice - Google Patents

Description

The present invention relates to a poultice and a method for producing the same.

A cataplasm is a type of patch produced by spreading a medicinal paste layer on a support such as cloth, and is generally characterized by a high moisture content, a thick paste layer, and low skin irritation. In addition, the adhesive strength of a cataplasm often decreases over time after application, and efforts are being made to develop a cataplasm that is less likely to lose adhesive strength even when applied for long periods of time (Patent Documents 1 to 4).

Patent Document 1 discloses that by blending poly(methyl acrylate/2-ethylhexyl acrylate) with a cataplasm containing partially neutralized polyacrylic acid, it is possible to suppress a decrease in adhesive strength. In particular, Patent Document 2 discloses that by further blending polyacrylic acid in the paste layer, a cataplasm with excellent moldability and shape retention can be obtained. In addition, since the drug is contained in the hydrous paste layer, poultices tend to have lower skin permeability of the drug compared to tapes (for example, Patent Document 3).

International Publication No. 2006/090782 International Publication No. 2015/025935 International Publication No. 2015/129808 Japanese Patent Application Publication No. 10-95728

While investigating the development of a cataplasm containing ketoprofen as an active ingredient, the present inventors discovered that a portion of ketoprofen is easily converted to its ester analogue by transesterification or the like during storage of the cataplasm. Thus, the present invention aims to provide a cataplasm that has excellent storage stability of ketoprofen.

[1] A poultice comprising a paste layer on a support, the paste layer containing ketoprofen or a pharma- ceutically acceptable salt thereof, propylene glycol, 1-menthol, and water, the mass of propylene glycol in the paste layer being 3 times or less the mass of ketoprofen, and the content of 1-menthol being 0.1 to 0.5 mass% based on the total mass of the paste layer.
[2] The poultice according to [1], wherein the paste layer further contains a fatty acid alkyl ester.
[3] A method for stabilizing ketoprofen in a poultice comprising a support and a paste layer containing ketoprofen or a pharma- ceutically acceptable salt thereof, comprising adding propylene glycol to the paste layer in an amount three times or less by mass of ketoprofen.

According to the present invention, a cataplasm with excellent storage stability of ketoprofen can be provided. By improving the storage stability of ketoprofen, the shelf life of the cataplasm as a medicine can be extended, which can be beneficial from the standpoint of stable supply of medicines, reduction of the economic burden on users, and reduction of environmental burden, etc.

In this specification, "excellent storage stability of ketoprofen" means that the amount of ketoprofen esters produced is small. For example, when the content of ketoprofen ester analogues in the paste layer after storage at 60°C for 2 weeks is 2.1% or less, preferably 1.9% or less based on the ketoprofen content immediately after the preparation of the poultice, the storage stability of ketoprofen can be determined to be excellent. When the content of ketoprofen ester analogues is 2.1% or less, the therapeutic effect of ketoprofen as a pharmaceutical product can be exhibited sufficiently even 2 years after production.

A preferred embodiment of the present invention is described in detail below.

The poultice according to one embodiment of the present invention is a poultice comprising a paste layer on a support, the paste layer containing ketoprofen or a pharma- ceutically acceptable salt thereof, propylene glycol, l-menthol, and water, the mass of propylene glycol in the paste layer being 3 times or less the mass of ketoprofen, and the content of l-menthol being 0.1 to 0.5% by mass based on the total mass of the paste layer.

The support may be any support capable of supporting a water-containing paste, and those well known to those skilled in the art may be used. Examples of the support include woven fabric (including knitted fabric), nonwoven fabric, resin film, foam sheet, and paper. When woven fabric, nonwoven fabric, or resin film is used as the support, examples of the material include polyolefins such as polyethylene, polypropylene, and polybutylene, polyesters such as polyethylene terephthalate, rayon, polyurethane, and cotton, and these may be used alone or in combination of two or more. Polyester is more preferable as the material for the support.

The support is preferably a nonwoven fabric or a woven fabric, and particularly preferably a nonwoven fabric or a woven fabric having a predetermined elongation recovery rate (elongation elasticity). In this specification, "elongation recovery rate" is a value measured according to the description in JIS L1096:2010, and means "elongation elasticity at constant load" or "elongation elasticity at constant rate elongation". For example, "50% elongation recovery rate" is the elongation elasticity when elongated to an elongation rate of 50% (constant rate elongation), and "load at 50% elongation" is the load (constant load) required to elongate to an elongation rate of 50%. By using a nonwoven fabric or a woven fabric having a predetermined elongation recovery rate, the support expands and contracts in response to the movement of the application site when applied to a movable part such as a joint, and is therefore preferable.

When the support is a nonwoven fabric, for example, the 50% elongation recovery rate of the nonwoven fabric is 60 to 99%, preferably 65 to 95%, and more preferably 70 to 90%. In addition, the load at 50% elongation of the nonwoven fabric is, for example, 1 to 5 N/2.5 cm in the longitudinal direction (long axis direction) and 0.1 to 3 N/2.5 cm in the transverse direction (short axis direction). The basis weight of the suitable support is, for example, 80 to 120 g/ ^m2 , and preferably 90 to 110 g/ ^m2 . The thickness of the suitable support is, for example, 0.5 to 2 mm. The bending resistance of the support (the bending resistance is measured by JIS L1096:2010, Method A (45° cantilever method)) can be, for example, 20 to 40 mm in the longitudinal direction (long axis direction) and 10 to 35 mm in the transverse direction (short axis direction), and is preferably 25 to 35 mm in the longitudinal direction (long axis direction) and 15 to 30 mm in the transverse direction (short axis direction). The thickness of the nonwoven fabric is preferably 0.5 to 2 mm. The basis weight of the nonwoven fabric is preferably 80 to 150 g/ ^m2 .

The knitted fabric used as the support includes knitted fabrics that have been processed into a cloth shape by assembling stitches, for example, by circular knitting, warp knitting, weft knitting, etc. Knitted fabrics made of one or a combination of two or more materials such as polyester, nylon, polypropylene, rayon, etc. are preferred, and among these, knitted fabrics made of polyethylene terephthalate, which has little interaction with drugs, are more preferred.

In particular, when the support 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%. The load at 50% elongation is, for example, 1 to 5 N/2.5 cm in the longitudinal direction (long axis direction) and 0.1 to 3 N/2.5 cm in the transverse direction (short axis direction). The bending resistance of the support can be, for example, 10 to 30 mm in the longitudinal direction (long axis direction) and 10 to 30 mm in the transverse direction (short axis direction), and is preferably 15 to 25 mm in the longitudinal direction (long axis direction) and 15 to 25 mm in the transverse direction (short axis direction). The thickness of the woven fabric is preferably 0.5 to 2 mm.

In particular, when a polyethylene terephthalate woven fabric having a basis weight of 80 to 150 g/ ^m2 is used, the water contained in the paste is less likely to seep out through the meshes of the woven fabric when it is spread, and the anchoring property between the woven fabric and the paste is superior.

The polyethylene terephthalate woven fabric preferably has a longitudinal (long axis) modulus of 2 to 12 N/5 cm and a transverse (short axis) modulus of 2 to 8 N/5 cm (the modulus is measured in accordance with JIS L1018:1999). If the modulus is lower than 2 N/5 cm, the woven fabric may stretch when the paste is spread, causing the adhesive to soak into the mesh, reducing its functionality as a poultice. If the modulus is higher than 12 N/5 cm (longitudinal) or 8 N/5 cm (transverse), the fabric may have poor elasticity and may have difficulty following the expansion of the skin when applied to a moving part.

The plaster layer contains ketoprofen or a pharma- ceutically acceptable salt thereof, propylene glycol, and water.

Ketoprofen is a compound represented by the chemical formula (1) and exists as two optical isomers, R- and S-. In the present embodiment, ketoprofen of either one of the optical isomers may be used, or the two optical isomers may be mixed in any ratio and used.

Pharmaceutically acceptable salts of ketoprofen include inorganic salts such as sodium salts, potassium salts, and calcium salts; and amine salts such as monoethanolamine and diethanolamine salts.

The content of ketoprofen in the paste layer is 1.5 to 2.5% by mass, and preferably 1.8 to 2.2% by mass, based on the mass of the entire paste layer. If the paste layer contains a pharma- ceutically acceptable salt of ketoprofen, the mass of the salt is converted to the mass of ketoprofen.

Propylene glycol is particularly effective in improving the skin permeability of ketoprofen. The content of propylene glycol in the paste layer is 3 times or less, by mass, the content of ketoprofen, and may be 0.5 to 3 times, 0.7 to 3 times, 1 to 3 times, 0.5 to 2.5 times, 0.7 to 2.5 times, 1 to 2.5 times, or 1.5 to 2.5 times.

The content of propylene glycol in the paste layer may be 1.5 to 6.5% by mass, 2.5 to 6.5% by mass, or 3 to 6% by mass, based on the total mass of the paste layer.

The fatty acid alkyl ester may be an ester synthesized from a fatty acid and an alkyl alcohol. The alkyl alcohol may be, for example, an alkyl alcohol having 1 to 10 carbon atoms. In this specification, the term "fatty acid" refers to a saturated or unsaturated alkyl carboxylic acid having 8 to 18 carbon atoms. Examples of the fatty acid alkyl ester include caprylic acid alkyl ester, capric acid alkyl ester, lauric acid alkyl ester, myristate acid alkyl ester, palmitic acid alkyl ester, palmitoleic acid alkyl ester, stearate alkyl ester, and oleic acid alkyl ester. A preferred fatty acid alkyl ester is hexyl laurate or isopropyl myristate. The fatty acid alkyl ester may be used alone or in combination of two or more. The inclusion of a fatty acid alkyl ester may improve the skin permeability of ketoprofen.

The content of fatty acid alkyl ester in the paste layer may be 1 to 20% by mass, and preferably 1 to 15% by mass or 2 to 13% by mass, based on the total mass of the paste layer. In particular, the content of hexyl laurate or isopropyl myristate may be 0.5 to 15% by mass or 0.5 to 10% by mass, and preferably 0.5 to 5.0% by mass or 1.0 to 3.5% by mass, based on the total mass of the paste layer. When the content of hexyl laurate or isopropyl myristate is 0.5 to 5.0% by mass, the skin permeability of ketoprofen is particularly excellent.

The water content in the paste layer may be 30 to 60% by mass, or 35 to 50% by mass, based on the total mass of the paste layer.

The paste layer may further contain a neutralized polyacrylic acid. The neutralized polyacrylic acid may be a completely neutralized polyacrylic acid, a partially neutralized polyacrylic acid, or a mixture of these. Examples of the neutralized polyacrylic acid include polyacrylic acid salts, such as sodium salts, potassium salts, calcium salts, and ammonium salts.

As the neutralized polyacrylic acid, partially neutralized polyacrylic acid is preferred because it has high initial adhesion and adhesion over time. Partially neutralized polyacrylic acid is a polymer chain in which structural units derived from acrylic acid and structural units derived from acrylate salts are present in any ratio. As the partially neutralized polyacrylic acid, it is preferable to use one in which 50 mol % of the carboxyl groups in one polymer chain are neutralized.

The content of the neutralized polyacrylic acid in the plaster layer is preferably 1 to 6% by mass, and more preferably 2 to 6% by mass, based on the total mass of the plaster layer. If the content of the neutralized polyacrylic acid is 1% by mass or more, the adhesive strength of the plaster layer is sufficiently high and it is less likely to fall off. If the content of the neutralized polyacrylic acid is 6% by mass or less, the moldability and shape retention of the plaster layer are improved.

The paste layer may further contain polyacrylic acid. By containing polyacrylic acid, the adhesive force is maintained at a high level and the shape retention of the poultice is improved. The content of polyacrylic acid is preferably 1 to 5% by mass based on the mass of the paste layer. When the content of polyacrylic acid is 1% by mass or more, the moldability and shape retention of the paste layer are improved. When the content of polyacrylic acid is 5% by mass or less, the hardness of the paste layer is unlikely to increase and adhesion to the skin is improved. By containing both neutralized polyacrylic acid and polyacrylic acid, the adhesiveness, moldability, shape retention, and hardness of the poultice are improved in a well-balanced manner.

The paste layer may further contain poly(methyl acrylate/2-ethylhexyl acrylate) or poly(methacrylic acid/n-butyl acrylate). Poly(methyl acrylate/2-ethylhexyl acrylate) is a copolymer of methyl acrylate and 2-ethylhexyl acrylate. Poly(methacrylic acid/n-butyl acrylate) is a copolymer of methacrylic acid and n-butyl acrylate. There are no particular limitations on the content ratio of each monomer.

Poly(methyl acrylate/2-ethylhexyl acrylate) or poly(methacrylic acid/n-butyl acrylate) may be in the form of an emulsion (aqueous emulsion) dispersed in any solvent such as water or a water-containing organic solvent. An example of an aqueous emulsion of poly(methyl acrylate/2-ethylhexyl acrylate) is Nicasol TS-620 (trade name, manufactured by Nippon Carbide Industries Co., Ltd.). An example of an aqueous emulsion of poly(methacrylic acid/n-butyl acrylate) is Primal N-580NF (trade name, manufactured by Rohm and Haas Co., Ltd.) or Ultrasol W-50 (trade name, manufactured by Aica Kogyo Co., Ltd.). When preparing a plaster fluid for a cataplasm, these copolymers are mixed with other components in the form of an aqueous emulsion, which makes it easier for these polymers to disperse throughout the plaster fluid. By dispersing these copolymers throughout the plaster layer, a more significant effect of suppressing the decrease in adhesive strength can be obtained, and sufficient adhesive strength can be exhibited even after a longer application period.

The content of poly(methyl acrylate/2-ethylhexyl acrylate) or poly(methacrylic acid/n-butyl acrylate) may be 2.75 to 15.75% by mass as solids based on the total mass of the paste layer, and is preferably 3.3 to 13.86% by mass, 5.5 to 12.6% by mass, or 5.5 to 11.34% by mass.

The content of the aqueous emulsion of poly(methyl acrylate/2-ethylhexyl acrylate) or poly(methacrylic acid/n-butyl acrylate) may be 5-25% by mass (2.75-15.75% by mass as solids) based on the total mass of the paste layer, and is preferably 6-22% by mass (3.3-13.86% by mass as solids), 10-20% by mass (5.5-12.6% by mass as solids), or 10-18% by mass (5.5-11.34% by mass as solids). For example, in Nikasol TS-620, the aqueous emulsion contains 55-63% poly(methyl acrylate/2-ethylhexyl acrylate) as solids. When a poultice is produced using an aqueous emulsion of the above polymer, the water content in the paste layer described above also includes the amount of water added as a medium for the aqueous emulsion.

Other ingredients may be added to the paste layer, such as other drugs, plant-derived ingredients, animal-derived ingredients, water-soluble polymers, solubilizers, crosslinking agents, moisturizers, cooling agents, stabilizers, inorganic powders, colorants, flavoring agents, and pH adjusters.

The other drug may be a physiologically active substance other than ketoprofen that is absorbable through the skin. Other drugs include, for example, nonsteroidal anti-inflammatory drugs such as felbinac, flurbiprofen, diclofenac, diclofenac sodium, methyl salicylate, glycol salicylate, indomethacin, and ketoprofen, or esters thereof, antihistamines such as diphenhydramine, analgesics such as aspirin, acetaminophen, ibuprofen, and loxoprofen sodium, local anesthetics such as lidocaine, muscle relaxants such as suxamethonium chloride, antifungal agents such as clotrimazole, antihypertensives such as clonidine, vasodilators such as nitroglycerin and isosorbide dinitrate, vitamins such as vitamin A, vitamin E (tocopherol), tocopherol acetate, vitamin K, octothiacin, and riboflavin butyrate, prostaglandins, scopolamine, fentanyl, l-menthol, capsicum extract, and vanillylamide nonylate.

The plant-derived ingredient may be any ingredient extracted from at least a part of a plant (e.g., leaves, roots, skin, fruit) or a hydrolysate thereof, and examples thereof include fruit-derived ingredients such as apple extract, orange extract, orange juice, raspberry extract, kiwi extract, cucumber extract, gardenia extract, grapefruit extract, hawthorn extract, Japanese pepper extract, hawthorn extract, juniper extract, oak extract, duke extract, tomato extract, grape extract, loofah extract, lime juice, apple extract, apple juice, lemon extract, and lemon juice, as well as allantoin, lecithin, amino acids, kojic acid, and ingredients extracted from various herbal medicines such as aloe vera and licorice. In addition, the plant-derived ingredients include Angelica extract, Avocado extract, Hydrangea extract, Althea extract, Arnica extract, Ginkgo extract, Fennel extract, Turmeric extract, Oolong tea extract, Scutellaria extract, Phellodendron bark extract, Barley extract, Dutch mustard extract, Seaweed extract, Hydrolyzed elastin, Hydrolyzed wheat powder, Chamomilla extract, Artemisia capillaris extract, Licorice extract, Karkade extract, Guanosine, Sasa kumazasa extract, Walnut extract, Clematis extract, Burdock extract, Comfrey extract, Cowberry extract, Bupleurum extract, Salvia extract, Soapwort extract, Bamboo grass extract, Crataegus crenata extract, Shiitake mushroom extract, Rehmannia extract, Lithospermum root extract, Tilia extract, Spiraea extract, Calamus root extract, Birch extract, Horsetail extract, Honeysuckle extract, Ivy extract, Crataegus monogyna extract, Sambucus nigra extract The extracts may be yarrow extract, peppermint extract, mallow extract, swertia japonica extract, tsarium extract, thyme extract, clove extract, Imperata cylindrica extract, chinpi extract, spruce extract, dokudami extract, natto extract, carrot extract, wild rose extract, hibiscus extract, burdock extract, parsley extract, parietaria extract, scutellaria extract, bisabolol, coltsfoot extract, butterbur bud extract, bupleurum extract, butcher's broom extract, propolis, peppermint extract, linden extract, hop extract, pine extract, horse chestnut extract, skunk cabbage extract, soapberry extract, peach leaf extract, cornflower extract, eucalyptus extract, yuzu extract, mugwort extract, lavender extract, lettuce extract, astragalus extract, rose extract, rosemary extract, Roman chamomile extract, etc.

The animal-derived component may be a component extracted from at least a part of an animal (e.g., placenta, umbilical cord) or a hydrolysate thereof, or a component produced by an animal, and examples of such components include placenta extract, umbilical cord extract, water-soluble placenta extract, hydrolyzed silk, honey, royal jelly extract, and yeast extract.

There are no particular limitations on the water-soluble polymer, so long as it can retain moisture in the poultice, and any polymer generally known to those skilled in the art can be used. Examples of water-soluble polymers include gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, sodium carboxymethylcellulose (carmellose sodium), methylcellulose, and carrageenan. One type may be used alone, or two or more types may be used in combination. Preferred water-soluble polymers are carmellose sodium, gelatin, or polyvinyl alcohol. The content of the water-soluble polymer is preferably 3 to 20% by mass, or 3 to 10% by mass, based on the mass of the plaster layer.

The solubilizing agent is not particularly limited as long as it can dissolve the drug, and examples thereof 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; and surfactants such as polyoxyethylene hydrogenated castor oil. These solubilizing agents may be used alone or in combination of two or more. The content of the solubilizing agent is preferably 0.1 to 10% by mass based on the mass of the plaster layer.

The crosslinking agent is a component for adjusting the progress of the crosslinking reaction between neutralized polyacrylic acid and between the neutralized polyacrylic acid and optionally added polyacrylic acid, and may be any of those commonly used in the industry. Examples of crosslinking agents include aluminum compounds. The content of the crosslinking agent is preferably 0.01 to 6% by mass based on the mass of the paste layer. If the content of the crosslinking agent is within this range, a poultice with better skin conformability can be obtained.

There are no particular limitations on the moisturizing agent, so long as it can suppress the evaporation of water from the paste layer over time. Examples of moisturizing agents include polyhydric alcohols such as concentrated glycerin, sorbitol, ethylene glycol, 1,4-butanediol, polyethylene glycol, and liquid paraffin. These moisturizing agents may be used alone or in combination of two or more. Concentrated glycerin is preferred as the moisturizing agent. The content of the moisturizing agent is preferably 20 to 40% by mass based on the mass of the paste layer.

Examples of cooling agents include thymol, l-menthol, dl-menthol, l-isopulegol, and peppermint oil. A preferred cooling agent is l-menthol. The content of the cooling agent is preferably 0.1 to 3 mass% or 0.5 to 3 mass% based on the total mass of the paste layer. The content of l-menthol is preferably 0.1 to 0.5 mass% and more preferably 0.2 to 0.4 mass% based on the total mass of the paste layer. If the content of l-menthol is 0.1 mass% or more, a sufficient cooling sensation can be imparted to the user of the poultice. If the content of l-menthol is 0.5 mass% or less, the storage stability of ketoprofen is superior.

Examples of stabilizers include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (e.g., dibenzoylmethane derivatives). The content of the stabilizer is preferably 0.5 to 3% by mass based on the mass of the paste layer.

The mass of the paste layer may be 214 to 1000 g/ ^m2 , 400 to 1000 g/ ^m2 , or 400 to 650 g/ ^m2 . Preferably, a mass of 400 to 650 g/ ^m2 improves the fit and improves adhesion for a longer period of time. If the mass of the paste layer is within the above range, the overall thickness of the poultice can be reduced, making it easier to conform to the skin, and furthermore, since the difference in level with the peripheral edge is reduced when applied, it tends to be less likely to peel off.

The pH of the plaster layer is preferably 4 to 8, and more preferably 4.5 to 6. A pH of 4 or higher reduces irritation to the skin, while a pH of 8 or lower improves the moldability and shape retention of the poultice. In particular, when the support is a woven fabric, particularly a knitted fabric, bleeding may occur when the plaster layer is formed, but bleeding tends to be suppressed when the pH is 5 to 6.5. The pH can be measured, for example, according to the pH measurement method in the general test method of the Japanese Pharmacopoeia, using a glass composite electrode and diluting the sample 20 times with purified water.

The poultice may be provided with a release liner. The release liner is laminated on the surface of the paste layer opposite the support. The provision of a release liner tends to inhibit a decrease in the water content of the paste layer during storage, and to reduce adhesion of dirt and the like to the paste layer.

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, examples of the material of the release liner include polyethylene, polypropylene, polybutylene, polyethylene terephthalate, rayon, and polyurethane, and one type may be used alone or two or more types may be used in combination. Polypropylene film is preferred as the material of the release liner.

The poultice may be stored inside a pouch. By storing it inside a pouch, it is possible to suppress a decrease in the water content of the paste layer, and to reduce adhesion of dirt and the like to the paste layer.

The poultice can be produced, for example, by mixing ketoprofen, propylene glycol, and water, adding the optional ingredients described above to obtain a paste liquid, spreading this paste liquid evenly on a release liner, and laminating a support on top of it.

The present invention also has an aspect of being a method for stabilizing ketoprofen in a poultice having a plaster layer containing ketoprofen or a pharma- ceutically acceptable salt thereof on a support, the plaster layer containing propylene glycol in an amount three times or less by mass of ketoprofen.

The present invention will be described in detail below using examples and test examples, but the present invention is not limited to these examples. Furthermore, the numbers in Tables 1, 3, and 5 represent mass % unless otherwise specified.

Examples 1 to 4 and Comparative Examples 1 to 6
(1) Production of cataplasms A plaster liquid was obtained by mixing the components shown in Table 1 for a certain period of time. The obtained plaster liquid was evenly spread on a release liner so that the plaster mass per cataplasm (140 mm x 100 mm) was 6 g, and then a knitted fabric (support) was immediately laminated thereon to produce a cataplasm.

(2) Evaluation of storage stability The obtained cataplasm was stored at 60°C for 2 weeks. After storage, the cataplasm was cut to an application area of 35 ^cm2 (5 cm x 7 cm), the release liner was removed, and the paste layer was extracted with 30 mL of methanol to obtain a sample solution. The content of ketoprofen and the total content of ketoprofen esters (glycerin, propylene glycol, menthol, or ethylhexyl esters of ketoprofen) in the sample solution were calculated based on the peak area by high performance liquid chromatography (HPLC).

The results are shown in Table 2. The total amount of ketoprofen esters was calculated as a relative value (mol %) when the amount of ketoprofen at the time of production of the cataplasm was taken as 100. The amount of ketoprofen in each Example was 95% or more based on the content of ketoprofen at the time of production of the cataplasm. Meanwhile, the amount of ketoprofen esters was 2.2% or more in Comparative Examples 1 to 6, but less than 2.1% in Examples 1 to 4. The total amount of esters was even lower in the cataplasms of Examples 3 and 4, which contained hexyl laurate.

Examples 5 to 10 and Comparative Examples 7 to 13
(1) Production of cataplasms A plaster liquid was obtained by mixing the components shown in Table 3 for a certain period of time. The obtained plaster liquid was evenly spread on a release liner so that the plaster mass per cataplasm (140 mm x 100 mm) was 6 g, and then a knitted fabric (support) was immediately laminated thereon to produce a cataplasm.

(2) Evaluation of storage stability According to the above-mentioned method, the content of ketoprofen and the total content of ketoprofen esters in the sample solution were calculated based on the peak area by high performance liquid chromatography (HPLC).

The results are shown in Table 4. The amount of ketoprofen in each Example was 95% or more based on the ketoprofen content at the time of manufacturing the poultice. Meanwhile, the amount of ketoprofen ester was 2.29% or more in Comparative Examples 7 to 13, but less than 2.1% in Examples 5 to 10.

Example 11 and Comparative Examples 14 to 15
(1) Production of cataplasms A plaster liquid was obtained by mixing the components shown in Table 5 for a certain period of time. The obtained plaster liquid was evenly spread on a release liner so that the plaster mass per cataplasm (140 mm x 100 mm) was 6 g, and then a knitted fabric (support) was immediately laminated thereon to produce a cataplasm.

(2) Evaluation of storage stability According to the above-mentioned method, the content of ketoprofen and the total content of ketoprofen esters in the sample solution were calculated based on the peak area by high performance liquid chromatography (HPLC).

The results are shown in Table 6. In Comparative Examples 14 and 15, the total amount of ketoprofen esters was 2.5% or more, and in Example 11, it was 2% or less.

Claims (1)

A poultice comprising a paste layer on a support,
the paste layer contains ketoprofen or a pharma- ceutically acceptable salt thereof, propylene glycol, 1-menthol, and water;
The paste layer further contains a fatty acid alkyl ester,
the fatty acid alkyl ester is hexyl laurate or isopropyl myristate;
the content of ketoprofen in the paste layer is 1.8 to 2.2% by mass based on the total mass of the paste layer;
the mass of propylene glycol in the paste layer is 3 times or less the mass of ketoprofen;
The poultice has an 1-menthol content of 0.1 to 0.5% by mass based on the total mass of the paste layer.