Ketoprofen-containing patches

Abstract

The present invention provides a patch that prevents ketoprofen from forming menthol ester, suppresses crystal deposition and yet shows excellent skin permeability. More particularly, the present invention provides a patch that contains ketoprofen, L-menthol, zinc oxide and a fatty acid ester in a plaster.

Description

[Technical Field]

[0001] The present invention relates to a patch containing ketoprofen, L-menthol, zinc oxide, and a fatty acid ester. [Background technology]

[0002] Ketoprofen is a nonsteroidal anti-inflammatory analgesic that exhibits excellent anti-inflammatory and analgesic effects and has long been used as an external preparation. Patches often contain L-menthol as a cooling agent, but it has long been known that nonsteroidal anti-inflammatory analgesics, such as ketoprofen, that have a carboxylic acid group in their molecules react with menthol to form menthol esters, which can cause problems with drug stability. Regarding the stability issue caused by the formation of menthol esters in nonsteroidal anti-inflammatory analgesics that have a carboxylic acid group in their molecules, techniques for improving stability by adding metal compounds such as metal oxides, metal hydroxides, and metal carbonates have already been disclosed (Patent Documents 1-3). However, the inclusion of these metal compounds has been shown to inhibit drug release from patches, so further improvements are desired. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2002-226366 [Patent Document 2] Japanese Patent Application Laid-Open No. 2005-314328 [Patent Document 3] Japanese Patent Application Laid-Open No. 2010-90098 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a patch that suppresses the production of a menthol ester of ketoprofen, suppresses crystal precipitation, and also has excellent skin permeability. [Means for solving the problem]

[0005] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that in a patch containing ketoprofen and L-menthol, by incorporating a fatty acid ester together with zinc oxide, not only can the production of menthol ester of ketoprofen be suppressed, but also excellent skin permeability can be achieved, thereby completing the present invention. Furthermore, unexpectedly, it has been found that the present invention can also suppress the crystallization of ketoprofen over time. The present invention provides a patch for external use, which comprises ketoprofen, L-menthol, zinc oxide, and a fatty acid ester.

[0006] That is, the present invention relates to the following. [1] A patch comprising ketoprofen, L-menthol, zinc oxide, and a fatty acid ester in a paste base (hereinafter also referred to as the patch of the present invention). [2] The patch according to [1], wherein the fatty acid ester is one or more selected from isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate. [3] The patch according to [1] or [2], wherein the fatty acid ester is one or two selected from isopropyl myristate and diisopropyl adipate. [4] The patch according to any one of [1] to [3], wherein the fatty acid ester is a combination of a fatty acid diester and a fatty acid monoester. [5] The patch according to any one of [1] to [4], wherein the content of ketoprofen is 0.1 to 10% by weight, the content of L-menthol is 0.1 to 10% by weight, the content of zinc oxide is 0.03 to 0.5% by weight, and the content of fatty acid ester is 0.1 to 20% by weight, relative to the weight of the plaster. [6] The patch according to any one of [1] to [5], wherein the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.03 to 1:0.1. [7] The patch according to any one of [1] to [6], further comprising one or more components selected from a base polymer, a tackifying resin, and a softener in the paste base. [8] The base polymer is a styrene-isoprene-styrene block copolymer; the tackifying resin is one or more selected from hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, and terpene resin; The softener is one or two selected from polybutene and liquid paraffin. [7] The patch described in [7]. [9] The patch according to [7] or [8], wherein the tackifier resin is one or two selected from hydrogenated rosin glycerin ester and alicyclic saturated hydrocarbon resin.

[10] The patch according to any one of [7] to [9], wherein the content of the base polymer is 5 to 50% by weight, the content of the tackifier resin is 10 to 60% by weight, and the content of the softener is 10 to 60% by weight, relative to the weight of the paste.

[11] The patch according to any one of [1] to

[10] , further comprising an antioxidant in the paste.

[12] The patch according to

[11] , wherein the antioxidant is dibutylhydroxytoluene.

[13] The patch according to

[11] or

[12] , wherein the content of the antioxidant is 0.05 to 5% by weight relative to the weight of the plaster.

[14] The patch according to any one of [1] to

[13] , for use in the prevention or treatment of inflammation or pain. [Effects of the Invention]

[0007] The present invention makes it possible to provide a patch that suppresses the production of menthol esters of ketoprofen, inhibits crystal precipitation, and exhibits excellent skin permeability. DETAILED DESCRIPTION OF THE INVENTION

[0008] In this specification, the terms "contain" and "include" may be used interchangeably with "blended." Furthermore, in this specification, the term "content" may be used interchangeably with "blended amount."

[0009] The adhesive patch of the present invention contains ketoprofen, L-menthol, zinc oxide, and a fatty acid ester in a paste base. The paste is usually a paste-like composition containing an adhesive base mainly composed of an adhesive and a drug, and may also be referred to as an adhesive composition.

[0010] The content of ketoprofen incorporated as an active ingredient in the patch of the present invention is not particularly limited as long as it can be formulated, but is usually in the range of 0.1 to 10 wt.%, preferably 0.5 to 8 wt.%, and more preferably 1 to 5 wt.% relative to the weight of the plaster. If the content of ketoprofen in the plaster is less than 0.1 wt.%, transdermal absorbability will be insufficient, while if it exceeds 10 wt.%, not only will the physical properties of the patch be impaired but it will also be economically disadvantageous and undesirable.

[0011] The L-menthol contained in the patch of the present invention functions as a transdermal absorption enhancer and a cooling agent. The content of L-menthol incorporated into the patch of the present invention is not particularly limited as long as it can be formulated, but is usually in the range of 0.1 to 10% by weight, preferably 0.5 to 8% by weight, and more preferably 1 to 5% by weight, relative to the weight of the paste. If the content of L-menthol in the paste is less than 0.1% by weight, transdermal absorbability will be insufficient, and if it exceeds 10% by weight, the physical properties of the patch will be impaired, which is undesirable.

[0012] The zinc oxide contained in the patch of the present invention has the function of suppressing the esterification reaction of ketoprofen and the function of inhibiting crystallization. The content of zinc oxide contained in the patch of the present invention is usually in the range of 0.03 to 0.5% by weight, preferably 0.06 to 0.3% by weight, more preferably 0.1 to 0.2% by weight, based on the weight of the plaster. The content of zinc oxide incorporated into the patch of the present invention is preferably varied depending on the content of ketoprofen in order to inhibit the esterification reaction and crystallization of ketoprofen, and the weight ratio of the content of zinc oxide to the content of ketoprofen is preferably in the range of 0.03 to 0.1, more preferably in the range of 0.04 to 0.1, and even more preferably in the range of 0.05 to 0.1, when the content of ketoprofen is taken as 1. If the weight ratio of the content of zinc oxide to ketoprofen is less than 0.03, the effect of inhibiting crystal precipitation and esterification reaction will be insufficient, and if it exceeds 0.1, the skin permeability of the drug will be inhibited, which is undesirable.

[0013] Furthermore, zinc oxide does not dissolve in the preparation and exists in a dispersed state. The zinc oxide incorporated in the patch of the present invention preferably has a particle size of 1 to 100 nm, taking into consideration dispersibility during production.

[0014] The fatty acid ester incorporated into the patch of the present invention has the function of increasing the dispersibility of zinc oxide during production and the function of suppressing a decrease in drug permeability due to the incorporation of zinc oxide. The fatty acid ester used in the patch of the present invention is preferably a fatty acid ester that is liquid at room temperature. Furthermore, in consideration of the dispersibility of zinc oxide, it is preferable that the fatty acid ester has an appropriate viscosity when mixed with zinc oxide. The viscosity of the fatty acid ester used is preferably 100 mPa·s or less, more preferably 5 to 50 mPa·s. Fatty acid esters that can be used in the patch of the present invention include, for example, hexyl laurate, isopropyl myristate, methyl myristate, myristyl myristate, cetyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isopropyl isostearate, diisobutyl adipate, diisopropyl adipate, dioctyl adipate, diisopropyl sebacate, diethyl sebacate, ethyl oleate, decyl oleate, oleyl oleate, ethyl linoleate, isopropyl linoleate, cetyl lactate, and ethyl lactate, and these may be used alone or in combination of two or more. One or more selected from isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate are preferred, and one or two selected from isopropyl myristate and diisopropyl adipate are more preferred. Furthermore, when two or more fatty acid esters are used in combination, it is preferable to use a fatty acid diester (e.g., diisobutyl adipate, diisopropyl adipate, dioctyl adipate, diisopropyl sebacate, diethyl sebacate, etc.) in combination with a fatty acid monoester (e.g., hexyl laurate, isopropyl myristate, methyl myristate, myristyl myristate, cetyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isopropyl isostearate, ethyl oleate, decyl oleate, oleyl oleate, ethyl linoleate, isopropyl linoleate, cetyl lactate, etc.). The content of fatty acid ester incorporated into the patch of the present invention is generally in the range of 0.1 to 20% by weight, preferably 0.5 to 15% by weight, and more preferably 1 to 10% by weight, relative to the weight of the plaster. If the content of fatty acid ester in the plaster is less than 0.1% by weight, the effect of increasing the dispersibility of zinc oxide and the effect of promoting drug permeation will be insufficient, while if it exceeds 20% by weight, the physical properties of the preparation will deteriorate, which is undesirable.

[0015] In one embodiment, the adhesive base of the patch of the present invention further contains one or more components selected from a base polymer, a tackifying resin, and a softener, and other components may also be appropriately added.

[0016] The base polymer used in the patch of the present invention can be, for example, an acrylic adhesive, a rubber adhesive, or a silicone adhesive, but it is preferable to use a rubber adhesive. Examples of rubber adhesives include natural rubber, polyisobutylene, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer (hereinafter also referred to as SIS), styrene-butadiene rubber, and styrene-isoprene rubber, and these may be used alone or in combination of two or more, but it is preferable to use a styrene-isoprene-styrene block copolymer (SIS). The content of the base polymer incorporated into the patch of the present invention is determined taking into consideration the contents of other ingredients, but is usually in the range of 5 to 50 wt.%, preferably 10 to 40 wt.%, and more preferably 10 to 30 wt.%, of the paste weight. If the content of the base polymer in the paste is less than 5 wt.%, the cohesive strength and shape retention of the paste will decrease, while if it exceeds 50 wt.%, the adhesive strength will decrease, the paste will become non-uniform, and workability in the manufacturing process will decrease.

[0017] The tackifying resin is not particularly limited as long as it is one that is generally incorporated into patches, and examples thereof include rosin-based resins such as rosin esters and hydrogenated rosin glycerin esters; petroleum-based resins such as alicyclic saturated hydrocarbon resins; and terpene resins, and the like. These may be used alone or in combination of two or more. One or more selected from rosin-based resins, petroleum-based resins, and terpene resins are preferred, for example, one or more selected from hydrogenated rosin glycerin esters, alicyclic saturated hydrocarbon resins, and terpene resins, more preferably one or more selected from rosin-based resins and petroleum-based resins, and even more preferably one or two selected from hydrogenated rosin glycerin esters and alicyclic saturated hydrocarbon resins. The content of the tackifying resin incorporated into the patch of the present invention is not particularly limited as long as it allows formulation, but is usually in the range of 10 to 60 wt. % of the paste weight, preferably 15 to 50 wt. % and more preferably 20 to 40 wt. If the content of the tackifying resin in the paste is less than 10 wt. %, the physical properties of the preparation will deteriorate and undesirable phenomena such as adhesive residue will occur, while if it exceeds 60 wt. %, it will undesirably cause skin irritation.

[0018] The softener used in the patch of the present invention is not particularly limited as long as it is compatible with other base components and provides flexibility to the plaster.Softeners that can be used include, for example, polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin, and these may be used alone or in combination of two or more.Preferably, one or two selected from polybutene and liquid paraffin. The content of the softener to be incorporated into the patch of the present invention is determined taking into consideration the content of other liquid components to be incorporated into the paste, and is usually in the range of 10 to 60% by weight, preferably 20 to 50% by weight, and more preferably 30 to 45% by weight, relative to the weight of the paste.

[0019] Furthermore, the adhesive patch of the present invention can use various base components used in conventional adhesive patches, as long as they do not adversely affect other components. Such base components are not particularly limited, but include, for example, water-soluble polymers such as polyvinylpyrrolidone and polyvinyl alcohol; cellulose derivatives such as hydroxypropylmethylcellulose; silicon compounds such as silicic anhydride and light silicic anhydride; antioxidants such as dibutylhydroxytoluene (also known as BHT), pentaerythrityl-tetrakis-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], tocopherol acetate, and ascorbic acid; and inorganic fillers such as silicas and zinc stearate. The adhesive patch of the present invention can further contain, if necessary, preservatives such as parahydroxybenzoic acid esters (e.g., methyl parahydroxybenzoate); disinfectants such as ethanol and isopropyl alcohol; flavoring agents such as peppermint oil; and colorants such as yellow ferric oxide, and these can be added in appropriate amounts.

[0020] In one embodiment, the adhesive base of the patch of the present invention further contains an antioxidant, preferably dibutylhydroxytoluene. The content of the antioxidant contained in the patch of the present invention is usually 0.05 to 5% by weight, preferably 0.1 to 1% by weight, more preferably 0.2 to 0.5% by weight, based on the weight of the plaster.

[0021] The patch of the present invention generally comprises a backing, a paste, and a release liner, and the paste is spread or coated between the backing and the release liner.

[0022] Examples of the backing used in the patch of the present invention include films, nonwoven fabrics, woven fabrics, knitted fabrics, and laminated composites of nonwoven fabrics and films. Materials for these backings include polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate.

[0023] The release liner used in the patch of the present invention may be made of, for example, polyethylene terephthalate, polypropylene, or paper, with polyethylene terephthalate being particularly preferred. The release liner may be siliconized as needed to optimize the release force.

[0024] Methods for producing the patch of the present invention include, but are not limited to, a solvent method characterized by dissolving the pressure-sensitive adhesive composition in an organic solvent such as toluene or hexane, and then removing the organic solvent through coating and drying processes, and a hot melt method characterized by carrying out a coating process in a state in which the pressure-sensitive adhesive composition is melted at a high temperature of 100° C. or higher. In one embodiment, the patch of the present invention is produced by the hot melt method.

[0025] In one embodiment, the method for producing the patch of the present invention includes the steps of: Mixing ketoprofen, zinc oxide, and a fatty acid ester to obtain a main drug solution; and A step of mixing the main chemical solution, L-menthol, and other components as needed to obtain a pressure-sensitive adhesive composition. Includes.

[0026] In another embodiment, the method for producing the patch of the present invention includes the steps of: a step of dissolving the base polymer, the tackifying resin, the softener, and the antioxidant under heating to obtain a pressure-sensitive adhesive solution; mixing ketoprofen, zinc oxide, and fatty acid ester to obtain a main drug solution; a step of adding L-menthol and a main chemical solution to the adhesive solution and mixing them to obtain an adhesive composition; applying the pressure-sensitive adhesive composition onto a release liner to form a pressure-sensitive adhesive layer; and A step of laminating the adhesive layer onto the support Includes.

[0027] The patch of the present invention contains ketoprofen as an active ingredient and is therefore useful for the prevention or treatment of diseases or symptoms that are expected to be improved by the administration of ketoprofen. Examples of such diseases or symptoms include inflammation and pain. Examples of inflammation and pain include lower back pain (myofascial lower back pain, spondylosis osteoarthritis, discopathy, lumbar sprain, etc.), osteoarthritis, scapulohumeral periarthritis, tendonitis, peritendinitis, epicondylitis (tennis elbow, etc.), muscle pain, swelling and pain after trauma, and local joint pain in rheumatoid arthritis.

[0028] In the present invention, "prevention" refers to the act of administering the patch of the present invention to an individual who has not yet developed a disease or symptom. "Treatment" refers to the act of administering the patch of the present invention to an individual who has already developed a disease or symptom. Therefore, administering the patch to an individual who has already developed a disease or symptom to prevent the worsening of symptoms, attacks, or recurrence is one aspect of "treatment."

[0029] The patch of the present invention is usually applied to a patient, such as a human or animal, suffering from or at risk of suffering from the above-mentioned disease or condition, preferably a human. The number of times it is applied may vary depending on conditions such as the severity of the disease or condition, the patient's age, weight, and sex, and the amount of ketoprofen contained in the patch. When administered to a human, the patch of the present invention is usually replaced once or multiple times a day, for example, 1 to 3 times, 1 to 2 times, or once a day, or every few days, for example, once every 2 to 3 days.

[0030] The following are embodiments of the present invention. The present invention also encompasses any combination of the following embodiments, and any combination of the following embodiments with any of the embodiments or modes described herein.

[0031] 1. Patches [Aspect 1] The patch of the present invention, wherein the fatty acid ester is one or more selected from hexyl laurate, isopropyl myristate, methyl myristate, myristyl myristate, cetyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isopropyl isostearate, diisobutyl adipate, diisopropyl adipate, dioctyl adipate, diisopropyl sebacate, diethyl sebacate, ethyl oleate, decyl oleate, oleyl oleate, ethyl linoleate, isopropyl linoleate, cetyl lactate, and ethyl lactate. [Aspect 2] The patch of the present invention, wherein the fatty acid ester is one or more selected from isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate. [Aspect 3] The patch of the present invention, wherein the fatty acid ester is one or two selected from isopropyl myristate and diisopropyl adipate. [Aspect 4] The patch of the present invention according to any one of Aspects 1 to 3, wherein the fatty acid ester is a combination of a fatty acid diester and a fatty acid monoester. [Aspect 5] The patch of the present invention according to any one of Aspects 1 to 4, wherein the content of ketoprofen is 0.1 to 10% by weight, the content of L-menthol is 0.1 to 10% by weight, the content of zinc oxide is 0.03 to 0.5% by weight, and the content of fatty acid ester is 0.1 to 20% by weight, relative to the weight of the paste. [Aspect 6] The patch of the present invention according to any one of Aspects 1 to 4, wherein the content of ketoprofen is 0.5 to 8 wt %, the content of L-menthol is 0.5 to 8 wt %, the content of zinc oxide is 0.06 to 0.3 wt %, and the content of fatty acid ester is 0.5 to 15 wt %, relative to the weight of the paste. [Aspect 7] The patch of the present invention according to any one of Aspects 1 to 4, wherein the content of ketoprofen is 1 to 5 wt %, the content of L-menthol is 1 to 5 wt %, the content of zinc oxide is 0.1 to 0.2 wt %, and the content of fatty acid ester is 1 to 10 wt %, relative to the weight of the plaster. [Aspect 8] A patch according to any one of Aspects 1 to 7, wherein the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.03 to 1:0.1. [Aspect 9-1] The patch of the present invention contains, relative to the weight of the plaster, a ketoprofen content of 0.1 to 10% by weight, an L-menthol content of 0.1 to 10% by weight, a zinc oxide content of 0.03 to 0.5% by weight, and a fatty acid ester content of 0.1 to 20% by weight, the fatty acid ester being one or more selected from isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate, and the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.03 to 1:0.1. [Aspect 9] The patch of the present invention contains, relative to the weight of the plaster, a ketoprofen content of 0.1 to 10% by weight, an L-menthol content of 0.1 to 10% by weight, a zinc oxide content of 0.03 to 0.5% by weight, and a fatty acid ester content of 0.1 to 20% by weight, the fatty acid ester being one or two selected from isopropyl myristate and diisopropyl adipate, and the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.03 to 1:0.1. [Aspect 10] The patch of the present invention according to any one of Aspects 1 to 9, wherein the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.04 to 1:0.1. [Aspect 11] The patch of the present invention according to any one of Aspects 1 to 9, wherein the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.05 to 1:0.1. [Aspect 12] The patch of the present invention according to any one of Aspects 1 to 11, wherein the particle size of the zinc oxide is 1 to 100 nm. [Aspect 13] A patch of the present invention according to any one of Aspects 1 to 12, wherein the viscosity of the fatty acid ester is 100 mPa·s or less. [Aspect 14] A patch of the present invention according to any one of Aspects 1 to 12, wherein the viscosity of the fatty acid ester is 5 to 50 mPa·s. [Aspect 15] The patch of the present invention according to any one of Aspects 1 to 14, further comprising one or more components selected from a base polymer, a tackifying resin, and a softener in the paste base. [Aspect 16] A patch of the present invention according to Aspect 15, wherein the base polymer is a rubber-based adhesive. [Aspect 17] A patch of the present invention according to Aspect 16, wherein the rubber-based adhesive is one or more selected from natural rubber, polyisobutylene, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, and styrene-isoprene rubber. [Aspect 18] Aspect 17. The patch of the present invention according to aspect 16, wherein the rubber-based adhesive is a styrene-isoprene-styrene block copolymer. [Aspect 19-1] A patch according to any one of Aspects 15 to 18, wherein the tackifier resin is one or more resins selected from rosin-based resins, petroleum-based resins, and terpene resins. [Aspect 19] A patch according to any one of Aspects 15 to 18, wherein the tackifier resin is one or more resins selected from rosin-based resins and petroleum-based resins. [Aspect 20-1] A patch according to any one of Aspects 15 to 18, wherein the tackifier resin is one or more selected from hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, and terpene resin. [Aspect 20] A patch according to any one of Aspects 15 to 18, wherein the tackifier resin is one or two selected from hydrogenated rosin glycerin ester and alicyclic saturated hydrocarbon resin. [Aspect 21] A patch of the present invention according to any one of Aspects 15 to 20, wherein the softener is one or more selected from polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin. [Aspect 22] A patch of the present invention according to any one of Aspects 15 to 20, wherein the softener is one or two selected from polybutene and liquid paraffin. [Aspect 23-1] The base polymer is a styrene-isoprene-styrene block copolymer; the tackifying resin is one or more selected from hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, and terpene resin; The softener is one or two selected from polybutene and liquid paraffin. A patch of the present invention according to aspect 15. [Aspect 23] The base polymer is a styrene-isoprene-styrene block copolymer; the tackifying resin is one or two selected from hydrogenated rosin glycerin ester and alicyclic saturated hydrocarbon resin; The softener is one or two selected from polybutene and liquid paraffin. A patch of the present invention according to aspect 15. [Aspect 24] A patch of the present invention according to any one of Aspects 15 to 23, wherein the content of the base polymer is 5 to 50% by weight, the content of the tackifier resin is 10 to 60% by weight, and the content of the softener is 10 to 60% by weight, relative to the weight of the paste. [Aspect 25] A patch of the present invention according to any one of Aspects 15 to 23, wherein the base polymer content is 10 to 40% by weight, the tackifier resin content is 15 to 50% by weight, and the softener content is 20 to 50% by weight, relative to the weight of the paste. [Aspect 26] A patch of the present invention according to any one of Aspects 15 to 23, wherein the base polymer content is 10 to 30% by weight, the tackifier resin content is 20 to 40% by weight, and the softener content is 30 to 45% by weight, relative to the weight of the paste. [Aspect 27] The patch of the present invention according to any one of Aspects 1 to 26, further comprising an antioxidant in the paste base. [Aspect 28] Aspect 27. The patch of the present invention according to aspect 27, wherein the antioxidant is one or more selected from dibutylhydroxytoluene, pentaerythrityl tetrakis-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], tocopherol acetate, and ascorbic acid. [Aspect 29] The patch of the present invention according to Aspect 27, wherein the antioxidant is dibutylhydroxytoluene. [Aspect 30] A patch according to any one of Aspects 27 to 29, wherein the content of the antioxidant is 0.05 to 5% by weight relative to the weight of the patch. [Aspect 31] A patch according to any one of Aspects 27 to 29, wherein the content of the antioxidant is 0.1 to 1% by weight based on the weight of the patch. [Aspect 32] A patch according to any one of Aspects 27 to 29, wherein the content of the antioxidant is 0.2 to 0.5% by weight relative to the weight of the patch. [Aspect 33] The patch of the present invention according to any one of Aspects 1 to 32, further comprising in the paste base one or more components selected from water-soluble polymers, cellulose derivatives, silicon compounds, inorganic fillers, preservatives, bactericides, flavoring agents, and colorants. [Aspect 34] the water-soluble polymer is one or two selected from polyvinylpyrrolidone and polyvinyl alcohol; The cellulose derivative is hydroxypropyl methylcellulose; the silicon compound is one or two selected from silicic anhydride and light silicic anhydride; the inorganic filler is one or more selected from silicas and zinc stearate; The preservative is parahydroxybenzoic acid ester; The disinfectant is one or two selected from ethanol and isopropyl alcohol; The flavoring agent is peppermint oil; The coloring agent is yellow ferric oxide A patch of the present invention according to aspect 33. [Aspect 35-1] In relation to the weight of the plaster, 0.1 to 10% by weight of ketoprofen; 0.1 to 10% by weight of L-menthol; 0.03-0.5% by weight of zinc oxide; 0.1 to 20% by weight of one or more fatty acid esters selected from isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate; 5 to 50% by weight of a styrene-isoprene-styrene block copolymer; 10 to 60% by weight of one or more tackifying resins selected from hydrogenated rosin glycerin esters, alicyclic saturated hydrocarbon resins, and terpene resins; 10 to 60% by weight of one or two softeners selected from polybutene and liquid paraffin; and 0.05 to 5% by weight of dibutylhydroxytoluene Including, The adhesive patch of the present invention, wherein the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.03 to 1:0.1. [Aspect 35] In relation to the weight of the plaster, 0.1 to 10% by weight of ketoprofen; 0.1 to 10% by weight of L-menthol; 0.03-0.5% by weight of zinc oxide; 0.1 to 20% by weight of one or two fatty acid esters selected from isopropyl myristate and diisopropyl adipate; 5 to 50% by weight of a styrene-isoprene-styrene block copolymer; 10 to 60% by weight of one or two tackifying resins selected from hydrogenated rosin glycerin esters and alicyclic saturated hydrocarbon resins; 10 to 60% by weight of one or two softeners selected from polybutene and liquid paraffin; and 0.05 to 5% by weight of dibutylhydroxytoluene Including, The adhesive patch of the present invention, wherein the weight ratio of the ketoprofen content to the zinc oxide content is 1:0.03 to 1:0.1.

[0032] 2. Manufacturing method and uses of patches [Aspect 36] Mixing ketoprofen, zinc oxide, and a fatty acid ester to obtain a main drug solution; and A step of mixing the main chemical solution, L-menthol, and other components as needed to obtain a pressure-sensitive adhesive composition. A method for producing the patch of the present invention according to any one of Aspects 1 to 35, comprising: [Aspect 37] A patch of the present invention according to any one of Aspects 1 to 35, for use in the prevention or treatment of inflammation or pain. [Aspect 38] Use of the patch of the present invention according to any one of Aspects 1 to 35 in the manufacture of a medicament for preventing or treating inflammation or pain. [Aspect 39] A method for preventing or treating inflammation or pain, comprising administering the patch of the present invention according to any one of Aspects 1 to 35 to a patient. [Aspect 40] Use of the patch of the present invention according to any one of Aspects 1 to 35 in the prevention or treatment of inflammation or pain. [Example]

[0033] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples. Note that numerical values ​​in the examples and comparative examples are in "% by weight" unless otherwise specified.

[0034] Example 1 SIS (SIS5002; manufactured by JSR Corporation), alicyclic saturated hydrocarbon resin (Arcon P100; manufactured by Arakawa Chemical Industries, Ltd.), polybutene (HV-300F; manufactured by JXTG Nippon Oil & Energy Corporation), liquid paraffin (Hicol M-352; manufactured by Kaneda Co., Ltd.), and BHT were dissolved under heating and stirring under a nitrogen atmosphere to obtain an adhesive solution. Ketoprofen, zinc oxide, diisopropyl adipate, and isopropyl myristate were mixed to obtain a main chemical solution. L-menthol and the main chemical solution were added to the adhesive solution, and the mixture was further stirred and mixed to prepare an adhesive composition. The prepared adhesive composition was coated on a siliconized polyethylene terephthalate film to form an adhesive layer approximately 150 μm thick. The obtained adhesive layer was laminated on a polyester woven fabric support to obtain the adhesive patch of the present invention. The content of each component is shown in Table 1.

[0035] Examples 2 to 9 Using the compositions shown in Tables 1 to 3 and according to the manufacturing method of Example 1, patches of Examples 2 to 9 were obtained.

[0036] Examples 10 to 18 The patches of Examples 10 to 18 were obtained using the compositions shown in Tables 5 to 7 and in accordance with the manufacturing method of Example 1. The terpene resin used in Examples 10 and 11 was PX1150N (manufactured by Yasuhara Chemical Co., Ltd.), the SIS used in Examples 11 and 12 was D1161JS (manufactured by Kraton Polymer Japan Co., Ltd.), and the alicyclic saturated hydrocarbon resin used in Example 13 was Alcon P115 (manufactured by Arakawa Chemical Industries, Ltd.), but the other components were the same as those used in Example 1.

[0037] [Comparative Examples 1, 2, 4, and 5] Using the compositions shown in Table 3 or Table 4 and according to the manufacturing method of Example 1, patches of Comparative Examples 1, 2, 4, and 5 were obtained.

[0038] Comparative Example 3 SIS (SIS5002; manufactured by JSR Corporation), alicyclic saturated hydrocarbon resin (Arcon P100; manufactured by Arakawa Chemical Industries, Ltd.), polybutene (HV-300F; manufactured by JXTG Nippon Oil & Energy Corporation), 2 / 3 of the liquid paraffin (Hicol M-352; manufactured by Kaneda Co., Ltd.), and BHT were dissolved under a nitrogen atmosphere with heating and stirring to obtain an adhesive solution. Ketoprofen, zinc oxide, and 1 / 3 of the liquid paraffin were mixed to obtain a main chemical solution. L-menthol and the main chemical solution were added to the adhesive solution, and the mixture was further stirred and mixed to prepare an adhesive composition. The prepared adhesive composition was coated on a siliconized polyethylene terephthalate film to form an adhesive layer approximately 150 μm thick. The obtained adhesive layer was laminated on a polyester woven fabric support to obtain a patch of Comparative Example 3. The content of each component is shown in Table 3.

[0039] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0040] [Test example] [Test Example 1] In vitro skin permeation test An in vitro hairless rat skin permeation test was conducted for each of the patches of Examples 1 to 18 and Comparative Examples 1 to 5. The abdominal skin of a male hairless rat (HWY strain, 7 weeks old) was excised and placed in a Franz diffusion cell, with the dermis side serving as the receptor side. The inside of the cell was filled with phosphate buffered saline, and 37°C warm water was circulated through the water jacket. Each patch was placed in a circular shape (1.54 cm 2 ) and attached to the excised skin. Receptor fluid was sampled 24 hours after the start of the test, and the amount of drug permeated through the skin was measured by high performance liquid chromatography. The test results are shown in Tables 1 to 7 above.

[0041] [Test Example 2] Quantitative test of menthol esters Each of the patches of Examples 1 to 18 and Comparative Examples 1 to 5, which had been stored at 40°C for one month, was placed in a 7 x 10 cm 2 The resulting extract was punched out and placed in a 50 mL centrifuge tube, to which tetrahydrofuran (hereafter referred to as THF) was added, followed by ultrasonic extraction and extraction using a shaker. The resulting extract was placed in a 50 mL measuring flask and made up to 50 mL with THF. Five mL of this extract was taken and made up to 50 mL with a 40% acetonitrile-water mixture, then filtered using a membrane filter (0.45 μm), and the amount of menthol ester of ketoprofen produced was measured using HPLC under the following measurement conditions. The test results are shown in the above Tables 1 to 7. The amount of menthol ester produced is shown as the ratio (%) of the peak area of ​​each decomposition product to the peak area of ​​the main drug ingredient (ketoprofen).

[0042] [HPLC measurement conditions] Column: ACQUITY C18 (2.1 x 100 mm) Mobile phase: A acetonitrile:water:phosphoric acid = 100:900:1 B Acetonitrile:water:phosphoric acid=900:100:1 ·Wavelength: 254nm ·Flow rate: 0.4mL / min Concentration gradient control [Table 8]

[0043] As can be seen from the results of Examples 1 to 5 and 9, and Comparative Example 1, and Example 6, and Comparative Examples 4 and 5, it was confirmed that increasing the amount of zinc oxide added suppresses the production of menthol esters, but at the same time, the skin permeability of the drug also decreases. Furthermore, when Example 2 and Comparative Example 3 are compared, it is found that the addition of a fatty acid ester in the presence of zinc oxide results in excellent drug permeability while suppressing the production of menthol esters.

[0044] [Test Example 3] Presence or absence of crystal precipitation The presence or absence of crystal precipitation was visually confirmed for the initial products immediately after production and for each of the formulations of Examples 1 to 9 and Comparative Examples 1 to 5 after storage at room temperature for 3 months, 6 months, and 12 months, as well as for the initial products immediately after production and for each of the formulations of Examples 10 to 18 after storage at room temperature for 3 months. The test results are shown in Tables 1 to 7 above.

[0045] As can be seen from the results in Tables 1 to 7, no crystal precipitation was observed initially in any of the formulations, but in Comparative Example 2, which did not contain zinc oxide, crystals precipitated after 3 months of storage, and in Comparative Example 1, which contained 0.05% zinc oxide, crystals precipitated after 6 months of storage. On the other hand, no crystal precipitation was observed in any of the patches of Examples 1 to 18 of the present invention even after 3 months of storage, and in particular, no crystal precipitation was observed in any of the patches of Examples 1 to 9 even after 12 months of storage. [Industrial Applicability]

[0046] The present invention can provide a patch that inhibits the formation of menthol esters of ketoprofen in the preparation during storage and production, inhibits crystal precipitation even during long-term storage, and exhibits excellent drug release properties.

Claims

1. A patch containing ketoprofen, L-menthol, zinc oxide, and a fatty acid ester in a paste base, the fatty acid ester is one or more selected from isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate; A patch, wherein the weight ratio of the content of ketoprofen to the content of zinc oxide is 1:0.03 to 1:0.

1.

2. 2. The patch according to claim 1, wherein the fatty acid ester is one or two selected from isopropyl myristate and diisopropyl adipate.

3. The patch according to any one of claims 1 to 2, wherein the fatty acid ester is a combination of a fatty acid diester and a fatty acid monoester.

4. 4. The patch according to claim 1, wherein the content of ketoprofen is 0.1 to 10% by weight, the content of L-menthol is 0.1 to 10% by weight, the content of zinc oxide is 0.03 to 0.5% by weight, and the content of fatty acid ester is 0.1 to 20% by weight, relative to the weight of the plaster.

5. The patch according to any one of claims 1 to 4, further comprising one or more components selected from a base polymer, a tackifying resin, and a softener in the paste base.

6. The base polymer is a styrene-isoprene-styrene block copolymer; the tackifying resin is one or more selected from hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, and terpene resin; The softener is one or two selected from polybutene and liquid paraffin. The patch according to claim 5.

7. 7. The patch according to claim 5, wherein the tackifier resin is one or two resins selected from the group consisting of hydrogenated rosin glycerin ester and alicyclic saturated hydrocarbon resin.

8. The patch according to any one of claims 5 to 7, wherein the content of the base polymer is 5 to 50% by weight, the content of the tackifier resin is 10 to 60% by weight, and the content of the softener is 10 to 60% by weight, relative to the weight of the paste.

9. The patch according to any one of claims 1 to 8, further comprising an antioxidant in the paste.

10. The patch according to claim 9, wherein the antioxidant is dibutylhydroxytoluene.

11. The patch according to claim 9 or 10, wherein the content of the antioxidant is 0.05 to 5% by weight relative to the weight of the plaster.

12. The patch according to any one of claims 1 to 11, for use in the prevention or treatment of inflammation or pain.

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