Loxoprofen-containing patch and method for producing same

Abstract

This invention provides a patch that inhibits the formation of loxoprofen decomposition products and has excellent skin penetration, as well as a method for manufacturing the same. Specifically, this invention provides a patch comprising, in a paste form, loxoprofen or a salt thereof or a hydrate of any of these; a C2-C6 hydroxy acid; and a metal oxide, and a method for manufacturing the patch.

Description

[Technical Field]

[0001] This invention relates to patches containing loxoprofen or its salts or any of the above hydrates, C2-C6 hydroxy acids and metal oxides, and a method for manufacturing the same. [Previous Technology]

[0002] Loxoprofen is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits excellent anti-inflammatory and analgesic effects. It has been used topically in the past, and various studies have been conducted to improve its stability and skin penetration. For example, techniques have been disclosed to inhibit the esterification reaction between NSAIDs with carboxyl groups and L-menthol by containing metal oxides (Patent Document 1); or techniques have been disclosed to inhibit the formation of similar substances and improve the drug release rate into the skin by including carboxyl-containing anti-inflammatory components, C12-C18 fatty acids, metal oxides, and flowing paraffin in the ointment and using monovalent lower alcohols during manufacturing (Patent Document 2). However, these documents do not specifically disclose patches containing loxoprofen. Furthermore, as patches containing loxoprofen sodium, techniques have been disclosed to improve the inhibition of breakdown product formation and penetration by incorporating lactic acid and higher fatty acids in a specific ratio (Patent Document 3). However, there is no record or suggestion regarding the patch of this invention or its manufacturing method. [Prior Art Documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 2002-226366 [Patent Document 2] International Publication No. 2019 / 160067 [Patent Document 3] International Publication No. 2013 / 008909 [Summary of the Invention]

[0004] [The problem that the invention aims to solve]

[0005] The object of the present invention is to provide a patch that inhibits the degradation products of loxoprofen and has excellent skin penetration, and a method for manufacturing the same. [Means for Solving the Problem]

[0006] Through repeated research efforts to solve the aforementioned problems, the inventors were surprised to discover that in patches containing loxoprofen or its salts or hydrates of any of these (hereinafter also referred to as "loxoprofen components"), C2-C6 hydroxy acids, and metal oxides, not only was the formation of menthol esters inhibited when L-menthol was added, but the formation of the ring-opening form (hereinafter referred to as "loxoprofen ring-opening form") obtained by opening the 5-membered ring (cyclopentyl ring) of loxoprofen, which is an oxidative decomposition product, was also inhibited, thus completing the present invention. Furthermore, it was found that in this patch, by setting the order of addition of additives during the preparation of the main drug solution to a specific order, the stability and skin penetration of the drug were improved. More specifically, it has been found that by first mixing the C2-C6 hydroxy acid and loxoprofen, followed by mixing the metal oxide, when preparing the main drug solution containing loxoprofen, C2-C6 hydroxy acid, and metal oxide, the workability of the main drug solution is improved. Furthermore, a patch that not only inhibits the formation of similar substances but also exhibits excellent skin penetration can be obtained. This invention provides a patch characterized by containing loxoprofen, C2-C6 hydroxy acid, and metal oxide in a paste, as well as a method for its manufacture.

[0007] That is, the present invention relates to the following. [1] A patch comprising, in the form of a paste, a hydrate of loxoprofen or a salt thereof or any of the above; a C2-C6 hydroxy acid; and a metal oxide (hereinafter also referred to as the patch of the present invention). [2] In the patch described in [1], the hydrate of loxoprofen or a salt thereof or any of the above is loxoprofen sodium or a hydrate thereof; the C2-C6 hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitric acid, mevalonic acid and pantoic acid; and the metal oxide is one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, calcium oxide, titanium oxide and iron oxide. [3] The patch as described in [1] or [2], wherein the hydrate of loxoprofen or its salt or any of the thereof is loxoprofen sodium dihydrate; the C2-C6 hydroxy acid is lactic acid; and the metal oxide is zinc oxide. [4] The patch as described in any one of [1] to [3], wherein the content of the hydrate of loxoprofen or its salt or any of the thereof is 0.1 to 10% by weight, the content of the C2-C6 hydroxy acid is 0.1 to 2.0% by weight, and the content of the metal oxide is 0.03 to 1.5% by weight, relative to the weight of the ointment. [5] The patch as described in any one of [1] to [4], wherein the weight ratio of the content of the hydrate of loxoprofen or its salt or any of the thereof to the content of the C2-C6 hydroxy acid is 1:0.01 to 1:0.4. [6] The patch described in any one of [1] to [5], wherein the weight ratio of the content of loxoprofen or its salt or any of the hydrates to the content of the metal oxide is 1:0.03 to 1:0.3. [7] The patch described in any one of [1] to [6], wherein the paste further comprises one or more components selected from the group consisting of a matrix polymer, an adhesive resin and a softener. [8] The patch described in [7], wherein the matrix polymer is a styrene-isoprene-styrene block copolymer; the adhesive resin is an alicyclic saturated hydrocarbon resin; and the softener is one or more components selected from the group consisting of polybutene and flowing paraffin. [9] The patch described in [7] or [8], wherein the content of the matrix polymer is 5 to 50% by weight, the content of the adhesive 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.

[10] The patch described in any of [1] to [9] further comprises one or more ingredients selected from the group consisting of L-menthol, higher fatty acids, fatty acid esters and antioxidants.

[11] The patch described in

[10] contains, wherein, the higher fatty acid is isostearic acid; the fatty acid ester is diethyl sebacate; and the antioxidant is butylated hydroxytoluene.

[12] The patch described in

[10] or

[11] contains, relative to the weight of the paste, 0.1 to 10% by weight of L-menthol, 0.1 to 20% by weight of higher fatty acids, 0.1 to 20% by weight of fatty acid esters, and 0.05 to 5% by weight of antioxidant.

[13] The patch described in any one of [1] to

[10] contains, in the paste, loxoprofen sodium dihydrate, lactic acid, zinc oxide, styrene-isoprene-styrene block copolymer, alicyclic saturated hydrocarbon resin, polybutene, flowing paraffin, L-menthol, isostearic acid, and butylated hydroxytoluene.

[14] A method for manufacturing a patch as described in any one of [1] to

[13] , comprising step 1: dissolving loxoprofen or its salt or a hydrate of any of them in a solution containing a C2-C6 hydroxy acid to obtain a solution containing loxoprofen; and step 2: mixing the solution containing loxoprofen obtained in step 1 with a metal oxide to obtain a main drug solution (hereinafter also referred to as the manufacturing method of the present invention).

[15] In the manufacturing method described in

[14] , the solution containing a C2-C6 hydroxy acid comprises a C2-C6 hydroxy acid and one or more components selected from the group consisting of L-menthol, higher fatty acids and fatty acid esters. [Effects of the Invention].

[0008] The present invention provides a patch that inhibits the formation of loxoprofen decomposition products and exhibits excellent skin penetration, as well as a manufacturing method thereof that improves workability in manufacturing.

Implementation Method

[0009] In this specification, the terms "containing" or "comprising" may be used interchangeably with "blending". In addition, in this specification, the term "content" may be used interchangeably with "blending amount".

[0010] The patch of the present invention contains loxoprofen, C2-C6 hydroxy acids, and metal oxides in its paste. The paste is usually a paste-like composition containing an adhesive base with an adhesive as the main component and the drug, also known as an adhesive composition.

[0011] Examples of loxoprofen components incorporated into the patch of the present invention as active ingredients include free loxoprofen, base addition salts of loxoprofen (e.g., loxoprofen sodium), and hydrates of free loxoprofen or base addition salts of loxoprofen (e.g., loxoprofen sodium dihydrate). Loxoprofen sodium or its hydrate is preferred, and loxoprofen sodium dihydrate is more preferred. The content of the loxoprofen component is not particularly limited provided that it can be formulated, and is generally 0.1 to 10% by weight relative to the weight of the patch, preferably 0.5 to 8% by weight, and more preferably 1 to 6% by weight. If the content of the loxoprofen component in the patch is less than 0.1% by weight, transdermal absorption will be insufficient; if it exceeds 10% by weight, it will not only impair the physical properties of the patch but is also economically disadvantageous.

[0012] The C2-C6 hydroxy acid incorporated into the patch of the present invention is an excellent solvent for loxoprofen, which enables the loxoprofen to dissolve stably in the adhesive base and exhibits excellent transdermal absorption enhancement effects. The C2-C6 hydroxy acid incorporated into the patch of the present invention is not particularly limited as long as it is an acid with 2 to 6 carbon atoms having hydroxyl and carboxyl groups in its molecule. Examples of C2-C6 hydroxy acids include, for example, one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitrate, mevalonic acid, and pantothenic acid; more preferably, one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, and tartaric acid; and even more preferably, lactic acid. C2-C6 hydroxy acids are additives that react with loxoprofen to produce decomposition products, thus reducing the stability of the formulation. Therefore, the content of C2-C6 hydroxy acids in the patch of the present invention is typically 0.1-2.0% by weight, preferably 0.1-1.7% by weight, and more preferably 0.1-1.5% by weight, relative to the weight of the patch. If the amount of C2-C6 hydroxy acids is less than 0.1% by weight, the loxoprofen cannot be sufficiently dissolved in the adhesive base, resulting in reduced transdermal absorption of the formulation or crystallization of the active pharmaceutical ingredient during storage. Conversely, when the content of C2-C6 hydroxy acids exceeds 4.0% by weight, the decomposition products derived from C2-C6 hydroxy acids increase, reducing the stability of the formulation. In addition, the ratio of loxoprofen content to C2-C6 hydroxy acid content by weight is preferably 1:0.01 to 1:0.4, more preferably 1:0.05 to 1:0.35, and even more preferably 1:0.07 to 1:0.3.

[0013] The metal oxide incorporated into the patch of the present invention has the function of inhibiting the formation of loxoprofen decomposition products. Examples of metal oxides incorporated into the patch of the present invention include one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, calcium oxide, titanium oxide, and iron oxide, preferably one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, and calcium oxide, and more preferably zinc oxide. The content of the metal oxide in the patch of the present invention is generally 0.03 to 1.5% by weight relative to the weight of the paste, preferably 0.06 to 1.2% by weight, and more preferably 0.1 to 1.0% by weight. The content of metal oxides incorporated into the patch of the present invention is preferably adjusted according to the content of loxoprofen to inhibit the formation of decomposition products of loxoprofen. The weight ratio of loxoprofen content to metal oxide content is preferably in the range of 1:0.03 to 1:0.3, more preferably in the range of 1:0.04 to 1:0.3, and even more preferably in the range of 1:0.05 to 1:0.3. If the weight ratio of metal oxide content to loxoprofen content is less than 0.03, the inhibition effect on decomposition product formation will be insufficient; if it exceeds 0.3, the skin penetration of the drug will be inhibited, which is less effective. Furthermore, the metal oxides are not dissolved in the formulation and exist in a dispersed state. The metal oxides incorporated into the patch of the present invention are selected with consideration for dispersibility during manufacturing, and the particle size is preferably 1 to 100 nm.

[0014] In one embodiment, the paste of the patch of the present invention is further incorporated with one or more components selected from the group consisting of a matrix polymer, an adhesive resin and a softener, and may be further suitably incorporated with other components.

[0015] Regarding the base polymer used in the patch of the present invention, acrylic adhesives, rubber adhesives, and silicone adhesives can be used, with rubber adhesives being preferred. Examples of rubber adhesives include natural rubber, polyisobutylene, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymers (hereinafter also referred to as "SIS"), styrene-butadiene rubber, and styrene-isoprene rubber. Only one of these can be used, or two or more can be used in combination. Styrene-isoprene-styrene block copolymers (SIS) are preferred. The content of the base polymer incorporated into the patch of the present invention is determined by taking into account the content of other components, and is typically 5-50% by weight relative to the weight of the paste, preferably 10-40% by weight, and more preferably 10-30% by weight. If the content of the matrix polymer in the paste is less than 5% by weight, the cohesiveness or shape retention of the paste will decrease. If it exceeds 50% by weight, it will lead to a decrease in adhesion, unevenness of the paste, and reduced workability in the manufacturing process.

[0016] As the adhesive resin used in the patch of the present invention, there is no particular limitation as long as it can generally be incorporated into the patch. Examples include rosin-based resins such as rosin esters and hydrogenated rosin glycerol esters; petroleum-based resins such as alicyclic saturated hydrocarbon resins; and terpene-based resins. Only one of these may be used, or two or more may be used in combination. Preferably, it is selected from one or more of the group consisting of rosin-based resins and petroleum-based resins, more preferably from one or more of the group consisting of hydrogenated rosin glycerol esters and alicyclic saturated hydrocarbon resins, and even more preferably from alicyclic saturated hydrocarbon resins. The content of the adhesive resin incorporated into the patch of the present invention is not particularly limited, provided that it can be formulated. It is generally 10 to 60% by weight relative to the weight of the paste, preferably 15 to 50% by weight, and more preferably in the range of 20 to 40% by weight. If the content of adhesive resin in the ointment is less than 10% by weight, the physical properties of the formulation will deteriorate, and adverse phenomena such as ointment residue during peeling will occur. If it exceeds 60% by weight, it will become a cause of skin irritation and is less desirable.

[0017] The softening agent used in the patch of the present invention is not particularly limited as long as it has good miscibility with other base ingredients and imparts softness to the paste. Examples of usable softening agents include polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, peach kernel oil, peanut oil, process oil, extender oil, and flowing paraffin wax. Only one of these may be used, or two or more may be used in combination. Preferably, one or more are selected from the group consisting of polybutene and flowing paraffin wax. The content of the softening agent incorporated into the patch of the present invention is also determined by taking into account the content of other liquid components incorporated into the paste, and is generally 10 to 60% by weight relative to the weight of the paste, preferably 20 to 50% by weight, and more preferably 30 to 45% by weight.

[0018] In one embodiment, L-menthol is further incorporated into the ointment of the patch of the present invention. The L-menthol incorporated into 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, provided that it can be formulated, and is generally 0.1 to 10% by weight relative to the weight of the ointment, preferably 0.5 to 8% by weight, and more preferably 1 to 5% by weight. If the content of L-menthol in the ointment is less than 0.1% by weight, the transdermal absorption will be insufficient; if it exceeds 10% by weight, the physical properties of the patch will be impaired, and the results will be undesirable.

[0019] In one embodiment, a liquid component is further incorporated into the ointment of the patch of the present invention. Furthermore, the term "liquid component" does not necessarily mean that it is liquid at room temperature; it also includes components that become liquid due to heating during manufacturing. The liquid component incorporated into the patch of the present invention serves to adjust the viscosity of the main medicinal solution, thereby improving manufacturing suitability. Examples of such liquid components include higher fatty acids and fatty acid esters.

[0020] Examples of higher fatty acids include isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linolenic acid, alpha-linolenic acid, capric acid, lauric acid, and hexanoic acid. One or more of these can be used in combination, preferably one or more selected from the group consisting of isostearic acid and oleic acid, and more preferably isostearic acid. The content of higher fatty acids incorporated into the patch of the present invention is generally 0.1 to 20% by weight relative to the weight of the patch, preferably 0.5 to 15% by weight, and more preferably 1 to 10% by weight.

[0021] Examples of fatty acid esters include hexyl laurate, isopropyl myristate, methyl myristate, myristyl myristate, cetyl myristate, octyl dodecyl myristate, isopropyl palmitate, cetyl palmitate, isopropyl isostearate, diisobutyl adipate, diisopropyl adipate, dioctyl adipate, diisopropyl sebacate, diethyl sebacate, ethyl oleate, decyl oleate, oleic acid ester, ethyl linoleate, isopropyl linoleate, cetyl lactate, and ethyl lactate. One or more of these esters may be used in combination. It is preferred that one or more of the following groups are selected: isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate. Diethyl sebacate is even more preferred. The content of fatty acid esters incorporated into the patch of the present invention is adjusted appropriately according to the viscosity of the main drug solution within a range that will not affect the physical properties of the preparation. It is usually 0.1 to 20% by weight relative to the weight of the patch, preferably 0.5 to 15% by weight, and more preferably 1 to 10% by weight.

[0022] Furthermore, in the patch of the present invention, various base ingredients commonly used in patches can be used, as long as they do not affect other components. There are no particular limitations on such base ingredients; examples include, for instance, cellulose derivatives such as polyvinylpyrrolidone, polyvinyl alcohol, and hydroxypropyl methylcellulose; silicone compounds such as silicic anhydride and light silicic anhydride; antioxidants such as butylated hydroxytoluene (BHT), neopentyl tert-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], tocopheryl acetate, and ascorbic acid; and inorganic fillers such as silicates and zinc stearate. In the patch of the present invention, preservatives such as p-hydroxybenzoic acid esters (e.g., methyl p-hydroxybenzoate); bactericides such as ethanol and isopropanol; fragrances such as peppermint oil; and colorants such as yellow ferric oxide can be appropriately incorporated as needed.

[0023] In one embodiment, an antioxidant is further incorporated into the paste of the patch of the present invention. Preferred antioxidant is butylated hydroxytoluene. The content of the antioxidant incorporated into the patch of the present invention is generally 0.05 to 5% by weight relative to the weight of the paste, preferably 0.1 to 1% by weight, and more preferably 0.2 to 0.5% by weight.

[0024] The patch of the present invention is generally composed of a support, an ointment and a release liner, wherein the ointment is spread or coated between the support and the release liner.

[0025] Examples of supports for the patches used in this invention include films, nonwoven fabrics, woven fabrics, knitted fabrics, and laminated composites of nonwoven fabrics and films. Examples of materials used for such supports include polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate.

[0026] The release liner used in the patch of the present invention may be, for example, polyethylene terephthalate, polypropylene, or paper, and more particularly, polyethylene terephthalate is preferred. To optimize the peel force, the release liner may also be silicone treated as needed.

[0027] The manufacturing method of the patch of the present invention is not limited, and examples include the solvent method, characterized by dissolving the active ingredient and each base ingredient in an organic solvent such as toluene or hexane, and removing the organic solvent by coating and drying steps; and the hot melt method, characterized by coating the adhesive composition in a molten state at a high temperature of 100°C or higher. In one embodiment, the patch of the present invention is manufactured by the hot melt method.

[0028] In this specification, "solution containing C2-C6 hydroxy acids" may be a solution containing only C2-C6 hydroxy acids, or a solution containing C2-C6 hydroxy acids and other components (e.g., one or more components selected from the group consisting of L-menthol, higher fatty acids, and fatty acid esters). Examples of solutions containing C2-C6 hydroxy acids include lactic acid solutions and solutions composed of lactic acid and one or more components selected from the group consisting of L-menthol, higher fatty acids, and fatty acid esters. In this specification, "solution containing loxoprofen" means a solution obtained by dissolving loxoprofen in a solution containing C2-C6 hydroxy acids. In this specification, "main drug solution" means a solution obtained by mixing a solution containing loxoprofen with a metal oxide. In this specification, "adhesive solution" means a solution obtained by mixing components other than the main drug solution that include an adhesive.

[0029] The method for manufacturing the patch of the present invention includes step 1: dissolving loxoprofen in a solution containing C2-C6 hydroxy acids to obtain a solution containing loxoprofen; and step 2: mixing the solution containing loxoprofen obtained in step 1 with a metal oxide to obtain a main drug solution.

[0030] In one embodiment of the manufacturing method of the present invention, the solution containing C2-C6 hydroxy acid comprises C2-C6 hydroxy acid and one or more components selected from the group consisting of L-menthol, higher fatty acids, and fatty acid esters. In another embodiment of the manufacturing method of the present invention, the method further comprises step 3: mixing one or more other components selected from the group consisting of matrix polymer, adhesive-improving resin, softener, and antioxidant to obtain an adhesive solution; step 4: mixing the main pharmaceutical solution obtained in step 2 with the adhesive solution obtained in step 3 to obtain an adhesive composition; step 5: applying the adhesive composition obtained in step 4 onto a release liner to form an adhesive layer; and step 6: laminating the adhesive layer obtained in step 5 onto a support.

[0031] The patch of the present invention contains loxoprofen as an active ingredient, and is therefore used for the prevention or treatment of diseases or symptoms that are expected to be improved by administration of loxoprofen. Such diseases or symptoms include inflammation or pain. In addition, examples of inflammation or pain include myalgia, osteoarthritis, and swelling / pain after trauma.

[0032] In this invention, "prevention" means the act of applying the patch of this invention to an individual who has not yet developed a disease or symptoms. Furthermore, "treatment" means the act of applying the patch of this invention to an individual who has already developed a disease or symptoms. Therefore, the act of applying the patch to an individual who has already developed a disease or symptoms in order to prevent the worsening of symptoms, prevent the onset of symptoms, or prevent recurrence is considered a form of "treatment."

[0033] The patch of the present invention is generally applied to patients suffering from the aforementioned disease or symptoms or having such concerns, such as humans or animals, preferably humans. The number of applications may vary depending on the severity of the disease or symptoms, the patient's age, weight, sex, the amount of loxoprofen in the patch, etc. When administered to humans, the patch of the present invention is generally changed once a day or several times, for example, once to three times, once to two times, or once a day, or every few days, for example, once every two to three days.

[0034] Hereinafter, embodiments of the present invention will be described. In addition, embodiments obtained by arbitrarily selecting and combining the following embodiments, as well as embodiments obtained by arbitrarily combining the following embodiments with any embodiment or implementation described in this specification, are also included in the present invention.

[0035] 1. Patch [Sample 1] A patch of the present invention, comprising loxoprofen, C2-C6 hydroxy acid and metal oxide in a paste. [Sample 2] The patch of the present invention as described in Sample 1, wherein the loxoprofen is loxoprofen sodium or its hydrate. [Sample 3] The patch of the present invention as described in Sample 1, wherein the loxoprofen is loxoprofen sodium dihydrate. [Sample 4] The patch of the present invention as described in any one of Samples 1 to 3, wherein the C2-C6 hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitric acid, mevalonic acid and pantothenic acid. [Sample 5] The patch of the present invention as described in any one of Samples 1 to 3, wherein the C2-C6 hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, and tartaric acid. [Sample 6] The patch of the present invention as described in any one of Samples 1 to 3, wherein the C2-C6 hydroxy acid is lactic acid. [Sample 7] The patch of the present invention as described in any one of Samples 1 to 6, wherein the metal oxide is one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, calcium oxide, titanium oxide, and iron oxide. [Sample 8] The patch of the present invention as described in any one of Samples 1 to 6, wherein the metal oxide is one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, and calcium oxide. [Sample 9] The patch of the present invention as described in any one of Samples 1 to 6, wherein the metal oxide is zinc oxide. [Sample 10] The patch of the present invention as described in Sample 1, wherein loxoprofen or its salt or any of the hydrates thereof is loxoprofen sodium or its hydrate; the C2-C6 hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitrate, mevalonic acid, and pantothenic acid; and the metal oxide is one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, calcium oxide, titanium oxide, and iron oxide. [Sample 11] The patch of the present invention as described in Sample 1, wherein loxoprofen or its salt or any of the hydrates thereof is loxoprofen sodium dihydrate; the C2-C6 hydroxy acid is lactic acid; and the metal oxide is zinc oxide. [Sample 12] The patch of the present invention as described in any one of Samples 1 to 11, wherein, relative to the weight of the patch, the content of loxoprofen is 0.1 to 10% by weight, the content of C2-C6 hydroxy acid is 0.1 to 2.0% by weight, and the content of metal oxide is 0.03 to 1.5% by weight.[Sample 13] The patch of the present invention as described in any one of Samples 1 to 11, wherein, relative to the weight of the paste, the content of loxoprofen is 0.5 to 8% by weight, the content of C2-C6 hydroxy acid is 0.1 to 1.7% by weight, and the content of metal oxide is 0.06 to 1.2% by weight. [Sample 14] The patch of the present invention as described in any one of Samples 1 to 11, wherein, relative to the weight of the paste, the content of loxoprofen is 1 to 6% by weight, the content of C2-C6 hydroxy acid is 0.1 to 1.5% by weight, and the content of metal oxide is 0.1 to 1.0% by weight. [Sample 15] The patch of the present invention as described in any one of Samples 1 to 14, wherein the weight ratio of the content of loxoprofen to the content of C2-C6 hydroxy acid is 1:0.01 to 1:0.4. [Sample 16] The patch of the present invention as described in any one of Samples 1 to 14, wherein the weight ratio of the loxoprofen content to the C2-C6 hydroxy acid content is 1:0.05 to 1:0.35. [Sample 17] The patch of the present invention as described in any one of Samples 1 to 14, wherein the weight ratio of the loxoprofen content to the C2-C6 hydroxy acid content is 1:0.07 to 1:0.3. [Sample 18] The patch of the present invention as described in any one of Samples 1 to 17, wherein the weight ratio of the loxoprofen content to the metal oxide content is 1:0.03 to 1:0.3. [Sample 19] The patch of the present invention as described in any one of Samples 1 to 17, wherein the weight ratio of the loxoprofen content to the metal oxide content is 1:0.04 to 1:0.3. [Sample 20] The patch of the present invention as described in any one of Samples 1 to 17, wherein the weight ratio of the loxoprofen component to the metal oxide component is 1:0.05 to 1:0.3. [Sample 21] The patch of the present invention as described in any one of Samples 1 to 20, wherein the particle size of the metal oxide is 1 to 100 nm. [Sample 22] The patch of the present invention as described in any one of Samples 1 to 21, wherein the paste further comprises one or more components selected from the group consisting of a matrix polymer, an adhesive-improving resin, and a softener. [Sample 23] The patch of the present invention as described in Sample 22, wherein the matrix polymer is a rubber-based adhesive. [Sample 24] In the patch of the present invention as described in Sample 23, the rubber adhesive is selected from one or more of the group consisting of natural rubber, polyisobutylene, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, and styrene-isoprene rubber. [Sample 25] In the patch of the present invention as described in Sample 23, the rubber adhesive is a styrene-isoprene-styrene block copolymer.[Sample 26] The patch of the present invention as described in any one of Samples 22 to 25, wherein the adhesive-imparting resin is one or more selected from the group consisting of rosin-based resins and petroleum-based resins. [Sample 27] The patch of the present invention as described in any one of Samples 22 to 25, wherein the adhesive-imparting resin is one or more selected from the group consisting of hydrogenated rosin glycerol esters and alicyclic saturated hydrocarbon resins. [Sample 28] The patch of the present invention as described in any one of Samples 22 to 25, wherein the adhesive-imparting resin is an alicyclic saturated hydrocarbon resin. [Sample 29] The patch of the present invention as described in any one of Samples 22 to 28, wherein the softener is one or more selected from the group consisting of polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, peach kernel oil, peanut oil, processed oil, bulking oil, and flowing paraffin. [Sample 30] The patch of the present invention as described in any one of Samples 22 to 28, wherein the softener is one or more selected from the group consisting of polybutene and flowing paraffin. [Sample 31] The patch of the present invention as described in Sample 22, wherein the matrix polymer is a styrene-isoprene-styrene block copolymer; the adhesive-imparting resin is an alicyclic saturated hydrocarbon resin; and the softener is one or more selected from the group consisting of polybutene and flowing paraffin. [Sample 32] The patch of the present invention as described in any one of Samples 22 to 31, wherein, relative to the weight of the paste, the content of the matrix polymer is 5 to 50% by weight, the content of the adhesive-imparting resin is 10 to 60% by weight, and the content of the softener is 10 to 60% by weight. [Sample 33] The patch of the present invention as described in any one of Samples 22 to 31, wherein, relative to the weight of the paste, the content of the matrix polymer is 10 to 40% by weight, the content of the adhesive resin is 15 to 50% by weight, and the content of the softener is 20 to 50% by weight. [Sample 34] The patch of the present invention as described in any one of Samples 22 to 31, wherein, relative to the weight of the paste, the content of the matrix polymer is 10 to 30% by weight, the content of the adhesive resin is 20 to 40% by weight, and the content of the softener is 30 to 45% by weight. [Sample 35] The patch of the present invention as described in any one of Samples 1 to 34, wherein the paste further comprises one or more ingredients selected from the group consisting of L-menthol, higher fatty acids, fatty acid esters, and antioxidants. [Sample 36] In the patch of the present invention as described in Sample 35, the higher fatty acid is one or more selected from the group consisting of isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linolenic acid, alpha-linolenic acid, capric acid, lauric acid, and hexanoic acid. [Sample 37] In the patch of the present invention as described in Sample 35, the higher fatty acid is one or more selected from the group consisting of isostearic acid and oleic acid.[Sample 38] The patch of the present invention as described in Sample 35, wherein the higher fatty acid is isostearic acid. [Sample 39] The patch of the present invention as described in any one of Samples 35 to 38, wherein the fatty acid ester is selected from one or more of the group consisting of hexyl laurate, isopropyl myristate, methyl myristate, myristyl myristate, cetyl myristate, octyl dodecyl myristate, isopropyl palmitate, cetyl palmitate, isopropyl isostearate, diisobutyl adipate, diisopropyl adipate, dioctyl adipate, diisopropyl sebacate, diethyl sebacate, ethyl oleate, decyl oleate, oleic acid ester, ethyl linoleate, isopropyl linoleate, cetyl lactate, and ethyl lactate. [Sample 40] The patch of the present invention as described in any one of Samples 35 to 38, wherein the fatty acid ester is one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate. [Sample 41] The patch of the present invention as described in any one of Samples 35 to 38, wherein the fatty acid ester is diethyl sebacate. [Sample 42] The patch of the present invention as described in any one of Samples 35 to 41, wherein the antioxidant is one or more selected from the group consisting of butylated hydroxytoluene, neopentyl tert-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], tocopheryl acetate, and ascorbic acid. [Sample 43] The patch of the present invention as described in any one of Samples 35 to 41, wherein the antioxidant is butylated hydroxytoluene. [Sample 44] The patch of the present invention as described in Sample 35, wherein the higher fatty acid is isostearic acid; the fatty acid ester is diethyl sebacate; and the antioxidant is butylated hydroxytoluene. [Sample 45] The patch of the present invention as described in any one of Samples 35 to 44, wherein, relative to the weight of the paste, the content of L-menthol is 0.1 to 10% by weight, the content of higher fatty acids is 0.1 to 20% by weight, the content of fatty acid esters is 0.1 to 20% by weight, and the content of antioxidants is 0.05 to 5% by weight. [Sample 46] The patch of the present invention as described in any one of Samples 35 to 44, wherein, relative to the weight of the paste, the content of L-menthol is 0.5 to 8% by weight, the content of higher fatty acids is 0.5 to 15% by weight, the content of fatty acid esters is 0.5 to 15% by weight, and the content of antioxidants is 0.1 to 1% by weight. [Sample 47] The patch of the present invention as described in any one of Samples 35 to 44, wherein, relative to the weight of the patch, the content of L-menthol is 1 to 5% by weight, the content of higher fatty acids is 1 to 10% by weight, the content of fatty acid esters is 1 to 10% by weight, and the content of antioxidants is 0.2 to 0.5% by weight.[Sample 48] The patch of the present invention as described in any one of Samples 1 to 47, wherein the paste further comprises one or more ingredients selected from the group consisting of cellulose derivatives, silicone compounds, inorganic fillers, preservatives, bactericides, fragrances, and colorants. [Sample 49] The patch of the present invention as described in Sample 48, wherein the cellulose derivative is one or more ingredients selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, and hydroxypropyl methylcellulose; the silicone compound is one or more ingredients selected from the group consisting of silicic anhydride and light silicic anhydride; the inorganic filler is one or more ingredients selected from the group consisting of silicates and zinc stearate; the preservative is p-hydroxybenzoic acid ester; the bactericide is one or more ingredients selected from the group consisting of ethanol and isopropanol; the fragrance is peppermint oil; and the colorant is yellow ferric oxide. [Sample 50] A patch of the present invention, comprising loxoprofen sodium dihydrate, lactic acid, zinc oxide, styrene-isoprene-styrene block copolymer, alicyclic saturated hydrocarbon resin, polybutene, flowing paraffin, L-menthol, isostearic acid, and butylated hydroxytoluene in the ointment. [Sample 51] A patch of the present invention, wherein the ointment system is composed of loxoprofen sodium dihydrate, lactic acid, zinc oxide, styrene-isoprene-styrene block copolymer, alicyclic saturated hydrocarbon resin, polybutene, flowing paraffin, L-menthol, isostearic acid, and butylated hydroxytoluene. [Sample 52] The patch of the present invention as described in Sample 50 or 51 comprises, relative to the weight of the paste, 0.1 to 10% by weight of loxoprofen sodium dihydrate; 0.1 to 2.0% by weight of lactic acid; 0.03 to 1.5% by weight of zinc oxide; 5 to 50% by weight of styrene-isoprene-styrene block copolymer; 10 to 60% by weight of alicyclic saturated hydrocarbon resin; 10 to 60% by weight of one or more softeners selected from the group consisting of polybutene and flowing paraffin; 0.1 to 10% by weight of L-menthol; 0.1 to 20% by weight of isostearic acid; and 0.05 to 5% by weight of dibutylhydroxytoluene. [Sample 53] The patch of the present invention as described in Sample 50 or 51 comprises, relative to the weight of the paste, 0.5 to 8 wt% of loxoprofen sodium dihydrate; 0.1 to 1.7 wt% of lactic acid; 0.06 to 1.2 wt% of zinc oxide; 10 to 40 wt% of styrene-isoprene-styrene block copolymer; 15 to 50 wt% of alicyclic saturated hydrocarbon resin; 20 to 50 wt% of one or more softeners selected from the group consisting of polybutene and flowing paraffin; 0.5 to 8 wt% of L-menthol; 0.5 to 15 wt% of isostearic acid; and 0.1 to 1 wt% of butylated hydroxytoluene.[Sample 54] The patch of the present invention as described in Samples 50 or 51 comprises, relative to the weight of the ointment, 1 to 6 wt% of loxoprofen sodium dihydrate; 0.1 to 1.5 wt% of lactic acid; 0.1 to 1.0 wt% of zinc oxide; 10 to 30 wt% of styrene-isoprene-styrene block copolymer; 20 to 40 wt% of alicyclic saturated hydrocarbon resin; 30 to 45 wt% of one or more softeners selected from the group consisting of polybutene and flowing paraffin; 1 to 5 wt% of L-menthol; 1 to 10 wt% of isostearic acid; and 0.2 to 0.5 wt% of butylated hydroxytoluene. [Sample 55] The patch of the present invention as described in any one of Samples 52 to 54, wherein the weight ratio of the content of loxoprofen sodium dihydrate to the content of lactic acid is 1:0.01 to 1:0.4. [Sample 56] The patch of the present invention as described in any one of Samples 52-54, wherein the weight ratio of loxoprofen sodium dihydrate to lactic acid is 1:0.05 to 1:0.35. [Sample 57] The patch of the present invention as described in any one of Samples 52-54, wherein the weight ratio of loxoprofen sodium dihydrate to lactic acid is 1:0.07 to 1:0.3. [Sample 58] The patch of the present invention as described in any one of Samples 52-57, wherein the weight ratio of loxoprofen sodium dihydrate to zinc oxide is 1:0.03 to 1:0.3. [Sample 59] The patch of the present invention as described in any one of Samples 52-57, wherein the weight ratio of loxoprofen sodium dihydrate to zinc oxide is 1:0.04 to 1:0.3. [Sample 60] The patch of the present invention as described in any one of Samples 52 to 57, wherein the weight ratio of the content of loxoprofen sodium dihydrate to the content of zinc oxide is 1:0.05 to 1:0.3.

[0036] 2. Method for manufacturing a patch [Sample 61] A method for manufacturing a patch as described in any one of Samples 1 to 60, comprising step 1: dissolving a loxoprofen component in a solution containing a C2-C6 hydroxy acid to obtain a solution containing loxoprofen; and step 2: mixing the solution containing loxoprofen obtained in step 1 with a metal oxide to obtain a main drug solution. [Sample 62] In the manufacturing method described in Sample 61, the solution containing a C2-C6 hydroxy acid comprises a C2-C6 hydroxy acid and one or more components selected from the group consisting of L-menthol, higher fatty acids, and fatty acid esters. [Sample 63] The manufacturing method described in Sample 61 or 62 further includes step 3: mixing one or more other components selected from the group consisting of a matrix polymer, an adhesive-improving resin, a softener, and an antioxidant to obtain an adhesive solution; step 4: mixing the main pharmaceutical solution obtained in step 2 with the adhesive solution obtained in step 3 to obtain an adhesive composition; step 5: applying the adhesive composition obtained in step 4 onto a release liner to form an adhesive layer; and step 6: laminating the adhesive layer obtained in step 5 onto a support. [Sample 64] The manufacturing method described in any one of Samples 61 to 63 comprises: Step 1: mixing loxoprofen sodium dihydrate, lactic acid, and one or more components suitable for selection from the group consisting of L-menthol, isostearic acid, and diethyl sebacate to obtain a solution containing loxoprofen; Step 2: mixing the loxoprofen-containing solution obtained in Step 1 with zinc oxide to obtain a main pharmaceutical solution; Step 3: heating and dissolving styrene-isoprene-styrene block copolymer, alicyclic saturated hydrocarbon resin, polybutene and / or flowing paraffin and butylated hydroxytoluene to obtain an adhesive solution; Step 4: mixing the main pharmaceutical solution obtained in Step 2 with the adhesive solution obtained in Step 3 to obtain an adhesive composition; Step 5: applying the adhesive composition obtained in step 4 onto the release liner to form an adhesive layer; and Step 6: laminating the adhesive layer obtained in step 5 onto the support. [Sample 65] A patch of the present invention is manufactured by the manufacturing method described in any one of Samples 61 to 64.

[0037] 3. Use of the Patch [Sample 66] The patch of the present invention as described in any one of Samples 1 to 60 or 65 is used for the prevention or treatment of inflammation or pain. [Sample 67] Use of the patch of the present invention as described in any one of Samples 1 to 60 or 65 in the manufacture of a medicine for the prevention or treatment of inflammation or pain. [Sample 68] A method for the prevention or treatment of inflammation or pain comprising administering the patch of the present invention as described in any one of Samples 1 to 60 or 65 to a patient. [Sample 69] Use of the patch of the present invention as described in any one of Samples 1 to 60 or 65 in the prevention or treatment of inflammation or pain. [Example]

[0038] Hereinafter, embodiments are provided to illustrate the present invention in more detail, but the present invention is not limited to the following embodiments. In addition, unless otherwise specified, the values ​​in the embodiments and comparative examples are "weight %".

[0039] [Example 1S] Loxoprofen sodium dihydrate (also referred to as loxoprofen Na·2H2O), lactic acid, and isostearic acid were mixed. After visually confirming that the loxoprofen sodium had dissolved, zinc oxide was mixed in to prepare the main drug solution. The content of each component is shown in Table 1.

[0040] [Examples 2S-7S] According to the compositions shown in Tables 1 and 2, loxoprofen sodium dihydrate, lactic acid, isostearic acid and L-menthol were mixed. After visually confirming that loxoprofen sodium was dissolved, zinc oxide was mixed in to obtain the main drug solutions of Examples 2S-7S.

[0041] [Example 8S] Loxoprofen sodium dihydrate and lactic acid were mixed. After visually confirming that the loxoprofen sodium had dissolved, zinc oxide was mixed in to prepare the main drug solution. The content of each component is shown in Table 2.

[0042] [Comparative Example 1S] Lactic acid, isostearic acid, and zinc oxide were mixed, and then loxoprofen sodium dihydrate was mixed to prepare the main drug solution. The content of each component is shown in Table 3.

[0043] [Comparative Examples 2S to 7S] According to the compositions shown in Tables 3 and 4, lactic acid, isostearic acid, zinc oxide and L-menthol were mixed and then mixed with loxoprofen sodium dihydrate to obtain the main drug solutions of Comparative Examples 2S to 7S.

[0044] [Comparative Examples 8S-10S] Except that Comparative Example 8S did not contain lactic acid and Comparative Example 10S did not contain isostearic acid, loxoprofen sodium dihydrate, lactic acid, and isostearic acid were mixed in the same manner as in Example 1S. After visually confirming that loxoprofen sodium was dissolved, zinc oxide was mixed in to prepare the main drug solutions of Comparative Examples 8S-10S. The content of each component is shown in Table 4.

[0045] [Example 9] Loxoprofen sodium dihydrate, lactic acid, and isostearic acid were mixed. After visual confirmation that the loxoprofen sodium was dissolved, zinc oxide was mixed in to prepare the main drug solution. All components except the main drug solution of SIS (SIS5002; manufactured by JSR Corporation), alicyclic saturated hydrocarbon resin (Alcon P100; manufactured by Arakawa Chemical Industry Co., Ltd.), flowing paraffin (Hycol M-352; manufactured by Kaneda Corporation), and BHT were heated and stirred under nitrogen to obtain an adhesive solution. The main drug solution was added to the adhesive solution, and the mixture was further stirred to prepare the adhesive composition. The prepared adhesive composition was coated onto a silicone-treated polyethylene terephthalate film to form an adhesive layer with a thickness of approximately 150 μm. The obtained adhesive layer was laminated onto a polyester fabric as a support to obtain the patch of Example 9. The content of each component is shown in Table 5.

[0046] [Comparative Example 11] Lactic acid, isostearic acid, and zinc oxide were mixed, and then loxoprofen sodium dihydrate was mixed to prepare the main drug solution. The components of SIS (SIS5002; manufactured by JSR Corporation), alicyclic saturated hydrocarbon resin (Alcon P100; manufactured by Arakawa Chemical Industry Co., Ltd.), flowing paraffin (Hycol M-352; manufactured by Kaneda Corporation), and BHT were heated and stirred under nitrogen to obtain an adhesive solution. The main drug solution was added to the adhesive solution, and the mixture was further stirred to prepare an adhesive composition. The prepared adhesive composition was coated onto a silicone-treated polyethylene terephthalate film to form an adhesive layer with a thickness of approximately 150 μm. The obtained adhesive layer was laminated onto a polyester fabric as a support to obtain the patch of Comparative Example 11. The content of each component is shown in Table 5.

[0047]

[0048] [Examples 10 and 11] Except for the addition of polybutene to the adhesive solution and L-menthol to the main drug solution, the patches of Examples 10 and 11 were obtained by means of the same method as in Example 9, with the blending amounts in Table 6.

[0049] [Example 12] Except that diethyl sebacate was used instead of isostearic acid, the patch of Example 12 was obtained by the same method as in Example 9, with the amount of admixture in Table 6.

[0050] [Comparative Example 12] Except that polybutene was added to the adhesive solution, L-menthol was added to the main drug solution, and zinc oxide was not added, the patch of Comparative Example 12 was obtained by means of the same method as in Example 9, with the amount of addition shown in Table 6.

[0051]

[0052] [Test Examples] [Test Example 1] The dissolution state of the main drug solution was assessed by visually confirming the dissolution state of the main drug solutions in Examples 1S-8S, Examples 9-12, Comparative Examples 1S-10S, and Comparative Examples 11-12. A state of complete dissolution (clear state) was recorded as 0, and a state of undissolved matter (turbid state) was recorded as ×. The test results are shown in Tables 1-6.

[0053] [Experimental Example 2] Quantitative Test of Loxoprofen Open Ring Form: Patches from Examples 9 and Comparative Example 11, stored at 60°C for 2 weeks, and Examples 10-12 and Comparative Example 12, stored at 40°C for 6 months, were cut into 5×7 cm² pieces and placed in 50 mL centrifuge tubes. Internal standard substances and tetrahydrofuran (THF) were added, and ultrasonic extraction and extraction via a shaker were performed. 0.5 mL of this extract was diluted to 5 mL with a 40% acetonitrile / water mixture and filtered using a 0.45 μm membrane filter. The amount of loxoprofen open ring formed was determined by HPLC under the following conditions. The test results are shown in Tables 5 and 6. Furthermore, the amount of loxoprofen open ring formed is expressed as the ratio (%) of the peak area of ​​the loxoprofen open ring to the peak area of ​​the active pharmaceutical ingredient (loxoprofen sodium).

[0054] [HPLC Determination Conditions] • Column: ACQUITY UPLC BEH C8 (2.1×100mm) • Mobile phase: Acetonitrile:Water:Phosphoric acid = 280:720:1 • Wavelength: 222nm • Flow rate: 0.4mL / min

[0055] [Experimental Example 3] In vitro skin penetration test: In vitro skin penetration tests were performed on each patch of Example 9 and Comparative Example 11 using hairless rats. Abdominal skin was removed from male hairless rats (HWY strain, 7 weeks old) and placed in a Franz diffusion chamber, with the dermal side as the receiving side. The chamber was filled with phosphate-buffered saline and refluxed with warm water at 37°C in a water jacket. Each patch was cut into a circle (1.54 cm²) and applied to the removed skin. Samples of the receiving fluid were taken 12 hours after the start of the test. The skin penetration amount of the drug was determined by HPLC under the following conditions. The test results are shown in Table 5.

[0056] [HPLC Determination Conditions] • Column: ACQUITY UPLC BEH C18 (2.1×50mm) • Mobile phase: Acetonitrile:Water:Phosphoric acid = 420:580:1 • Wavelength: 222nm • Flow rate: 0.4mL / min

[0057] As seen in the results of Examples 1S-8S and 9, and Comparative Examples 1S-7S and 11, it was found that if loxoprofen sodium dihydrate is mixed with lactic acid first and then zinc oxide is mixed, it will be in a dissolved state. However, if lactic acid and zinc oxide are mixed first and then loxoprofen sodium dihydrate is mixed, undissolved matter is found, and a uniform main drug solution cannot be prepared. Furthermore, when comparing Example 9 with Comparative Example 11, it was found that when loxoprofen sodium dihydrate is mixed with lactic acid first and then zinc oxide is mixed, compared to when lactic acid and zinc oxide are mixed first and then loxoprofen sodium dihydrate is mixed, the amount of loxoprofen open ring, a decomposition product of loxoprofen, is suppressed to about 90%. The cumulative penetration of the drug also showed a result of about 146% within 12 hours. The patch of the present invention is a formulation in which drug decomposition is suppressed and skin penetration is also excellent. As observed in Comparative Examples 8S-10S, it was also understood that even when loxoprofen sodium dihydrate was mixed with lactic acid before adding zinc oxide, undissolved matter was detected in the main drug solution if the amount of lactic acid added was insufficient or excessive, making it impossible to prepare a homogeneous main drug solution. Furthermore, as seen in the results of Examples 10-12 and Comparative Example 12, it was understood that the formation of the loxoprofen open ring was significantly suppressed in Examples 10-12 with added zinc oxide compared to Comparative Example 12 without added zinc oxide. [Industrial Applicability]

[0058] By means of the present invention, a patch with excellent drug release properties and inhibition of the formation of the open ring of loxoprofen, which is a decomposition product of loxoprofen, generated in the formulation during storage or between manufacturing steps, can be provided, as well as a manufacturing method with good manufacturing properties such as improving workability when making the main drug solution because no undissolved substances are generated during manufacturing, or easily and uniformly blending the drug into the ointment.

Claims

1. A patch comprising, in the form of a paste, hydrates of loxoprofen or its salts or any of the thereof; lactic acid; and zinc oxide; wherein, relative to the weight of the paste, the content of the hydrates of loxoprofen or its salts or any of the thereof is 0.1 to 10% by weight, the content of lactic acid is 0.1 to 2.0% by weight, and the content of zinc oxide is 0.03 to 1.5% by weight.

2. As in request item 1, the patch, wherein, Loxoprofen or its salts or hydrates thereof are loxoprofen sodium or their hydrates.

3. The patch as requested in item 1 or 2, wherein, The hydrate of loxoprofen or its salts or any of the above is loxoprofen sodium dihydrate.

4. For patches as requested in item 1 or 2, wherein, The weight ratio of the hydrate of loxoprofen or its salt or any of the above to the lactic acid content is 1:0.01 to 1:0.

4.

5. The patch as requested in item 1 or 2, wherein, The weight ratio of the hydrate content of loxoprofen or its salt or any of the above to the content of zinc oxide is 1:0.03 to 1:0.

3.

6. The patch as requested in item 1 or 2, wherein, The paste further comprises one or more components selected from the group consisting of matrix polymers, adhesive resins and softeners.

7. The patch as requested in item 6, wherein, The matrix polymer is a styrene-isoprene-styrene block copolymer; the adhesive-imparting resin is an alicyclic saturated hydrocarbon resin; and the softener is one or more selected from the group consisting of polybutene and flowing paraffin.

8. The patch as requested in item 6, wherein, The content of the matrix polymer is 5-50% by weight relative to the weight of the paste, the content of the adhesive resin is 10-60% by weight, and the content of the softener is 10-60% by weight.

9. The patch as requested in item 1 or 2, wherein, The cream further contains one or more ingredients selected from the group consisting of L-menthol, higher fatty acids, fatty acid esters, and antioxidants.

10. The patch as requested in item 9, wherein, The higher fatty acid is isostearic acid; the fatty acid ester is diethyl sebacate; and the antioxidant is butylated hydroxytoluene.

11. The patch as requested in item 9, wherein, The content of L-menthol is 0.1 to 10% by weight relative to the weight of the paste, the content of higher fatty acids is 0.1 to 20% by weight, the content of fatty acid esters is 0.1 to 20% by weight, and the content of antioxidants is 0.05 to 5% by weight.

12. The patch as requested in item 1 or 2, wherein, The ointment contains loxoprofen sodium dihydrate, lactic acid, zinc oxide, styrene-isoprene-styrene block copolymer, alicyclic saturated hydrocarbon resin, polybutene, fluidized paraffin, L-menthol, isostearic acid, and butylated hydroxytoluene.

13. A method for manufacturing a patch as claimed in any one of claims 1 to 12, comprising step 1: dissolving loxoprofen or its salt or a hydrate of any of them in a solution containing lactic acid to obtain a solution containing loxoprofen; and step 2: mixing the solution containing loxoprofen obtained in step 1 with zinc oxide to obtain a main drug solution.

14. The manufacturing method as described in claim 13, wherein, A solution containing lactic acid includes lactic acid and one or more components selected from the group consisting of L-menthol, higher fatty acids and fatty acid esters.