Topical pharmaceutical composition containing loxoprofen and diclofenac

Abstract

To provide a topical pharmaceutical composition containing diclofenac in which crystal precipitation is suppressed. [Solution] A topical pharmaceutical composition comprising (A) one or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (B) one or more selected from the group consisting of diclofenac, its salts and hydrates thereof, and (C) a lower alcohol, wherein the content of the lower alcohol of (C) is 35% by mass or more and 60% by mass or less based on the total mass of the topical pharmaceutical composition, and the pH of the topical pharmaceutical composition is 5.0 to 7.5.

Description

Technical Field

[0001] The present invention relates to an external pharmaceutical composition containing loxoprofen and diclofenac, in which crystal precipitation is suppressed.

Background Art

[0002] Non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs) are widely used as antipyretic, analgesic and anti-inflammatory agents. Loxoprofen, which is a propionic acid-based NSAID (hereinafter also referred to as LOX), is known to have a strong antipyretic, analgesic and anti-inflammatory effect, although it exhibits an inhibitory effect on prostaglandin biosynthesis similar to other NSAIDs. Diclofenac, which is a phenylacetic acid-based NSAID, also exhibits an inhibitory effect on prostaglandin biosynthesis and has analgesic and anti-inflammatory effects.

[0003] Patent Document 1 describes an external pharmaceutical composition characterized by containing (A) diclofenac and / or its pharmaceutically acceptable salt, (B) tocopherol and / or its derivative, (C) menthol, and (D) water. In Patent Document 1, in an external preparation containing diclofenac and / or its salt, tocopherol and / or its derivative, and water, menthol is blended to suppress the formation of turbidity or precipitate because it cannot be solubilized and turbidity or precipitate is generated.

[0004] ​​[Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. WO2015 / 151990 [Patent Document 2] Patent No. 6060742 [Overview of the project] [Problems that the invention aims to solve]

[0006] The inventors of the present invention have found that in a pharmaceutical composition containing diclofenac or a salt thereof and a lower alcohol, when the lower alcohol content is 35% by mass or more and 60% by mass or less, crystalline precipitates originating from diclofenac and its salts occur. The problem to be solved by the present invention is to provide a topical pharmaceutical composition containing diclofenac or a salt thereof in which crystal precipitation is suppressed. [Means for solving the problem]

[0007] The present inventors, after diligent research to solve the above problems, have found that crystal precipitation can be suppressed by adding one or more substances selected from the group consisting of diclofenac, its salts, and hydrates thereof, and a lower alcohol, wherein the lower alcohol content is 35% by mass or more and 60% by mass or less, and by adjusting the pH of the pharmaceutical composition to 5.0 to 7.5. The present invention was completed based on the above findings.

[0008] In other words, embodiments of the present invention are as follows. <1> (A) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (B) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (C) Lower alcohol A topical pharmaceutical composition comprising (C), wherein the content of the lower alcohol (C) is 35% by mass or more and 60% by mass or less relative to the total mass of the topical pharmaceutical composition, and the pH of the topical pharmaceutical composition is 5.0 to 7.5. <2> (A) Contains 1-10% by mass of loxoprofen sodium as an ingredient. <1> The topical pharmaceutical composition described above. <3> (B) contains 1 to 10% by mass of diclofenac sodium as component, <1> The topical pharmaceutical composition described above. <4> pH adjusters containing ingredients other than malic acid, <1> from <3> A topical pharmaceutical composition as described in any one of the following. <5> The pH adjuster further comprises one or more selected from the group consisting of hydrochloric acid, lactic acid, and diisopropanolamine. <1> from <3> A topical pharmaceutical composition as described in any one of the following. <6> The topical pharmaceutical composition contains water. <1> from <3> A topical pharmaceutical composition as described in any one of the following. <7> The topical pharmaceutical composition is one selected from the group consisting of liquids, gels, creams, sprays, ointments, hard gels, poultices, and tapes. <1> from <3> A topical pharmaceutical composition as described in any one of the following. <8> (A) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (B) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (C) Lower alcohol A method for stabilizing an external pharmaceutical composition, comprising: blending (C) such that the content of the lower alcohol is 35% by mass or more and 60% by mass or less relative to the total mass of the external pharmaceutical composition; and adjusting the pH of the resulting composition to 5.0 to 7.5. [Effects of the Invention]

[0009] According to the present invention, crystal precipitation can be suppressed in a topical pharmaceutical composition containing diclofenac. [Modes for carrying out the invention]

[0010] The topical pharmaceutical composition of the present invention is (A) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (B) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (C) Lower alcohol The topical pharmaceutical composition contains (C) a lower alcohol content of 35% to 60% by mass relative to the total mass of the topical pharmaceutical composition, and has a pH of 5.0 to 7.5.

[0011] The method for stabilizing the topical pharmaceutical composition of the present invention is: (A) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (B) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (C) Lower alcohol The method involves blending (C) such that the lower alcohol content is 35% by mass or more and 60% by mass or less relative to the total mass of the topical pharmaceutical composition, and adjusting the pH of the resulting composition to 5.0 to 7.5.

[0012] <Loxoprofen, its salts, and their hydrates> In the present invention, "one selected from the group consisting of loxoprofen, its salts, and their hydrates" may also be referred to as "loxoprofen or its salt," and is loxoprofen or its salt (including hydrated salts) (the salt is preferably a pharmaceutically acceptable salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate. At least one substance selected from the group consisting of loxoprofen, its salts, and their hydrates used in this invention is listed in the 18th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0013] The content of at least one selected from the group consisting of loxoprofen, its salts and their hydrates in the external pharmaceutical composition is not particularly limited, but based on the mass of the entire external pharmaceutical composition, it is preferably 0.1 to 10% by mass, more preferably 0.2 to 10% by mass, still more preferably 0.5 to 10% by mass, and particularly preferably 1 to 10% by mass. As an example, the external pharmaceutical composition of the present invention preferably contains 1 to 10% by mass of loxoprofen sodium as the component (A).

[0014] <One selected from the group consisting of diclofenac, its salts and their hydrates> Diclofenac sodium is included in the 18th revised Japanese Pharmacopoeia. Examples of the salts of diclofenac include diclofenac sodium which is a sodium salt and diclofenac potassium which is a potassium salt.

[0015] The content of one or more selected from the group consisting of diclofenac, its salts and their hydrates contained in the external pharmaceutical composition is not particularly limited, but based on the mass of the entire external pharmaceutical composition, it is preferably 0.3 to 20% by mass, more preferably 0.3 to 10% by mass, still more preferably 0.5 to 10% by mass, and particularly preferably 1 to 10% by mass. As an example, the external pharmaceutical composition of the present invention preferably contains 1 to 10% by mass of diclofenac sodium as the component (B).

[0016] The mass ratio of one or more selected from the group consisting of diclofenac, its salts and their hydrates to one or more selected from the group consisting of loxoprofen, its salts and their hydrates (one or more selected from the group consisting of diclofenac, its salts and their hydrates / one or more selected from the group consisting of loxoprofen, its salts and their hydrates) is preferably 1.0×10 -4 ~200, more preferably 1.0×10 -2 ~100, still more preferably 1.0×10 -2 ~50, and particularly preferably 1.0×10-1 It is ~10.

[0017] <Lower alcohol> The topical pharmaceutical composition of the present invention contains a lower alcohol. The lower alcohol in the present invention refers to aliphatic alcohols having 1 to 4 carbon atoms used in topical preparations for purposes such as solubilizers, bases, preservatives, solvents, and solubilizers. Examples include methanol, ethanol (also called ethyl alcohol), propanol, isopropanol (also called isopropyl alcohol), and butyl alcohol. Preferably, it is ethanol or isopropanol, and more preferably ethanol. Ethanol with an ethanol content of 99.5% by volume or more is also called anhydrous ethanol, and this is also included in the ethanol of the present invention. Ethanol is listed in the Pharmaceutical Additives Dictionary 2021 (Yakuji Nippo Co., Ltd., 2021), and examples include ethanol, ethanol 95, and anhydrous ethanol.

[0018] The lower alcohol content in the topical pharmaceutical composition of the present invention is 35% by mass or more and 60% by mass or less based on the total mass of the topical pharmaceutical composition. The lower alcohol content may be 35% by mass or more and 45% by mass or less, 45% by mass or more and 50% by mass or less, or 50% by mass or more and 60% by mass or less based on the total mass of the topical pharmaceutical composition. The lower alcohol content may be 38% by mass or more and 45% by mass or less, 45% by mass or more and 50% by mass or less, or 50% by mass or more and 57% by mass or less based on the total mass of the topical pharmaceutical composition.

[0019] The pH of the topical pharmaceutical composition of the present invention is 5.0 to 7.5, preferably 5.0 to 7.0, more preferably 5.5 to 7.0, and particularly preferably 5.5 to 6.5.

[0020] The topical pharmaceutical composition of the present invention may be a composition containing water or a composition that does not contain water, but it is preferably a composition that contains water.

[0021] The topical pharmaceutical composition of the present invention can be manufactured by combining component (A), component (B), and component (C). For example, the topical pharmaceutical composition of the present invention may be manufactured by a process in which component (A), component (B), and component (C) are combined, completely dissolved, and then a pH adjuster and water are added.

[0022] <About topical medicinal compositions> The topical pharmaceutical composition of the present invention may contain drugs or pharmaceutical additives. The topical pharmaceutical composition of the present invention may contain one or more components selected from the group consisting of the following components (X-1) to (X-11). Ingredients (X-1): Tocopherols Components (X-2): Terpenes Ingredients (X-3): Glycyrrhizic acid derivatives Ingredients (X-4): Herbal medicines Ingredients (X-5): Tranexamic acid derivatives Ingredients (X-6): Vanilloids Ingredients (X-7): Nicotinic acid Ingredients (X-8): Chlorpheniramines Ingredients (X-9): Diphenhydramines Ingredients (X-10): Pyrrolidones Ingredients (X-11): Inorganic salts

[0023] (X-1) Examples of tocopherols include tocopherol, tocotrienol and their derivatives (e.g., esterified derivatives such as acetate, succinate, and nicotinate), and their salts (e.g., alkaline earth metal salts such as calcium and magnesium salts). The tocopherol may be α-tocopherol, β-tocopherol, γ-tocopherol, or δ-tocopherol, but α-tocopherol is preferred. The tocotrienol may be α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol, but α-tocotrienol is preferred. Among the tocopherols, tocopherol acetate is particularly preferred.

[0024] (X-2) Terpenes are a general term (terpenoids) that includes terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and their structure is not particularly limited, and examples include monoterpenes, sesquiterpenes, or their derivatives. They may also be cyclic or chain-like. Examples of terpenes include isoborneol, ylone, ocimene, carveol, carbotanacetone, carbomenthone, carvone, carene, carone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, thymol, isothujole, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampeol, pinol, piperitenon, phellandral, phellandrene, fenthen, phenthyl alcohol, periryl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene.

[0025] As terpenes, essential oils containing terpenes may be used. Examples of essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, cajapto oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, sansho oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, gingergrass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, tere Examples include bottle oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, beniroyal oil, henopodium oil, bergamot oil, bois de rose oil, pine oil, marjoram oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil, which may be used individually or in combination of two or more.

[0026] (X-3) Examples of glycyrrhizic acid derivatives include glycyrrhizic acid or its salts, and glycyrrhetinic acid or its salts. Examples of salts include alkali metal salts such as potassium salts and sodium salts; and ammonium salts. In addition, licorice (Glycyrrhiza uralensis) or extracts thereof containing glycyrrhizic acid derivatives may be used as glycyrrhizic acid derivatives.

[0027] (X-4) Examples of crude drugs include licorice, arnica tincture, Japanese red oak, catechu, edamame, fennel, turmeric, Corydalis, scutellaria, aster, Phellodendron bark, parsley, Coptis japonica, Polygala tenuifolia, Curcuma longa, Valerian, chamomile, caronine, balloon flower, apricot kernel, goji berry, goji leucocephala, schizonepeta, cinnamon bark, Cassia seed, gentian, geranium, safflower, cypress, bezoar, schisandra, asarum, gardenia, sansho pepper, aster, peony, musk, dandelion, scutellaria, cypress Examples include crude drugs such as Shazenshi, Shazensou, animal bile (including bear bile), ginger, Ziziphus, Magnolia, horse chestnut, Sekisan, Senega, Cnidium, Zenko, Swertia, Atractylodes, Mulberry bark, Perilla, Southern laurel, Chikusetsuninjin, Citrus unshiu peel, Angelica, Tokon, Nandina, Ginseng, Fritillaria, Ophiopogon, Pinellia, Bankouka, Deer vine, Angelica, Atractylodes, Poria, Paeonia, Bamboo bark, and Deer antler, as well as extracts (extracts, tinctures, dried extracts, etc.) of these. Licorice may be used as glycyrrhizic acid derivatives, as well as as crude drugs, or may be used to fulfill both roles.

[0028] (X-5) Tranexamic acid derivatives may include, for example, tranexamic acid or its salts, tranexamic acid derivatives or their salts. There are no particular restrictions on the salts of tranexamic acid, but specific examples include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; metal salts such as aluminum, iron, and zinc; basic amino acid salts such as lysine, arginine, histidine, and ornithine; and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine, and stearylamine. In addition, tranexamic acid derivatives or salts thereof may also be used, and specific examples include ester derivatives such as tranexamic acid cetyl ester and amide derivatives such as tranexamic acid methylamide.

[0029] (X-6) Vanilloids are a general term for compounds containing a vanillyl group. In the present invention, vanilloids are not particularly limited as long as they contain a vanillyl group, and examples include vanillin, vanillic acid, capsaicin, vanillylmandelic acid (VMA), and vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol). Furthermore, the vanilloids in the present invention may include natural products containing compounds with a vanillyl group, derivatives of compounds having a vanillyl group, or synthetic compounds in which a functional group has been added to the vanillyl group. Furthermore, the vanilloids used in this invention may include peppers containing a compound with a vanillyl group, or they may be included as part of the vanilloids. As for the chili peppers, for example, the chili pepper (fruit of Capsicum annuum Linne (Solanaceae)) listed in the 18th edition of the Japanese Pharmacopoeia can be suitably used. The form of the chili peppers can be adjusted as needed, and they can be cut or crushed into small pieces or lumps, or ground into powder. For example, "chili pepper powder" made from powdered chili peppers can also be used as the "chili peppers" of this invention. Alternatively, chili peppers that have undergone some kind of extraction treatment (such as chili pepper extract or chili pepper tincture) may be used. In addition to extraction, the chili pepper extract may also be processed by heating, drying, or grinding. Furthermore, as the chili peppers, capsaicinoids, which are the main components of chili peppers, may be used. Capsaicin and vanillylamide nonanoate are preferred as capsaicinoids. Preferably, chili pepper extract, chili pepper tincture, vanillylamide nonylate, or capsaicin can be used as the chili peppers.

[0030] (X-7) Nicotinic acid derivatives include nicotinic acid and its derivatives, as well as salts thereof. Examples of nicotinic acid derivatives include nicotinic acid esters (specifically methyl nicotinate, β-butoxyethyl nicotinate, benzyl nicotinate, inositol hexanicotinate, hepronicate, etc.), nicotinic acid amide, nicotinic acid amide adenine dinucleotide, nicotinic acid amide adenine dinucleotide phosphate, etc.). As nicotinic acid esters, monoesters of nicotinic acid are preferred. As nicotinic acid derivatives, benzyl nicotinate is preferred.

[0031] (X-8) Chlorpheniramines include chlorpheniramines and their salts. Specifically, chlorpheniramine salts include organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; and various salts such as metal salts. Chlorpheniramine maleate is preferred among the chlorpheniramines.

[0032] (X-9) Examples of diphenhydramines include diphenhydramine or its salts. Examples of diphenhydramine salts include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyl disulfonate, tannate, lauryl sulfate, and sulfate. Diphenhydramine or diphenhydramine hydrochloride are preferred as diphenhydramines.

[0033] (X-10) Examples of pyrrolidones include dl-pyrrolidone carboxylic acid or its salts, with sodium pyrrolidone carboxylate being preferred, for example.

[0034] (X-11) Inorganic salts include salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium or potassium, or ammonium salts. For example, sodium chloride, potassium chloride, and ammonium chloride are preferred.

[0035] The topical pharmaceutical composition of the present invention may contain pharmaceutical additives other than the above-mentioned components, as necessary, for purposes such as further improving content stability over time or the feel of use. Examples include humectants, moisturizers, thickeners, adhesives, tackifying resins, surfactants, crosslinking agents, fillers, oils and fats, softeners, preservatives, transdermal absorption enhancers, stabilizers, solubilizers, pH adjusters, antioxidants, and cooling agents. Furthermore, the topical pharmaceutical composition of the present invention may contain any other components.

[0036] Examples of humectants that can be used include hyaluronic acid, dl-pyrrolidone carboxylic acid or its salts (e.g., sodium dl-pyrrolidone carboxylate). Examples of humectants that can be used include sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol, which are polyhydric alcohols.

[0037] Examples of thickening agents (viscosity enhancers / gelling agents) that can be used include hypromellose, hydroxypropylcellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose (carmellose sodium), methylcellulose, carrageenan, locust bean gum, propylene glycol alginate, and acrylic copolymer.

[0038] Examples of adhesives include acrylic acid / octyl acrylate copolymer, acrylic acid ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer solution, ethyl acrylate / methyl methacrylate copolymer dispersion, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution, methacrylic acid / n-butyl acrylate copolymer, silk fibroin acrylate copolymer resin, 300 acrylate starch, 1000 acrylate starch, butyl acrylate / 2-ethylhexyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / 2-ethylhexyl methacrylate / methacrylamide Acrylic adhesives such as 2-hydroxyethyl acrylate / diacetone acrylamide copolymer, isononyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, and butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / diacetone acrylamide copolymer; synthetic rubber adhesives such as cis-isoprene rubber, styrene-isoprene rubber, cis-polyisoprene rubber, high-cis-polyisoprene rubber, styrene-butadiene rubber (SBR), styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), polyisoprene, polyisobutylene (PIB), chloroprene rubber, polybutene, natural rubber latex, and SBR synthetic latex;In addition to silicone-based adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane, polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, N-vinylacetamide / sodium acrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, sodium carboxymethylcellulose, alginic acid, sodium alginate, gelatin, guar gum, tragacanth gum, and gum arabic, as well as those crosslinked with metal salts such as aluminum, zinc, magnesium, and calcium, can be used.

[0039] Examples of tackifying resins that can be used include rosin, hydrogenated rosin glycerol ester, ester gum, maleic acid resin, maleated rosin glycerol ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and the like.

[0040] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 100, etc.), polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, and polyoxyethylene (160) polyoxypropylene (30) glycol. Polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, and polyethylene glycol fatty acid esters (e.g., polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (40 E.O.), polyethylene glycol monostearate (45 E.O.), polyethylene glycol monostearate (55 E.O.), etc.) can be used.

[0041] Examples of crosslinking agents that can be used include dried aluminum hydroxide gel, magnesium aluminum hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosaltite, and dihydroxyaluminum aminoacetate. Examples of fillers that can be used include alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, and silica (silicon dioxide).

[0042] Examples of oils and fats that can be used include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum, and gelling hydrocarbons; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, hexyldecanol, isostearyl alcohol, and octyldodecanol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; waxes such as carnauba wax, whale wax, shellac, jojoba oil, beeswax, bleached beeswax, montan wax, lanolin, refined lanolin, and reduced lanolin; and silicone oils.

[0043] Examples of softening agents that can be used include petroleum oils such as paraffinic process oils, naphthenic process oils, and aromatic process oils; squalane; squalene; vegetable oils such as cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, olive oil, camellia oil, castor oil, tall oil, and peanut oil; silicone oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, and diisopropyl sebacate; diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton; glycerin, etc.

[0044] Examples of preservatives that can be used include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid, etc. Examples of transdermal absorption enhancers include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactic acid esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbide, azeon, or derivatives thereof. Examples of stabilizers that can be used include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (e.g., dibenzoylmethane derivatives).

[0045] Examples of solubilizers that can be used include benzyl alcohol; pyrrothiodecane; isopropyl myristate; crotamiton; pyrrolidones such as N-methyl-2-pyrrolidone; higher alcohols; polybasic acids such as diethyl adipate, isopropyl adipate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, di(2-heptylundecyl) adipate, diisopropyl sebacate, and diethyl sebacate; polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol; and oxyalkylene fatty acid esters such as polyethylene glycol monostearate.

[0046] Examples of pH adjusting agents that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), and phosphoric acid. It is preferable to use a pH adjusting agent other than malic acid. That is, it is preferable that the topical pharmaceutical composition of the present invention does not contain malic acid as a pH adjusting agent. It is more preferable to use one or more pH adjusting agents selected from the group consisting of hydrochloric acid, lactic acid, and diisopropanolamine. Examples of antioxidants that can be used include ascorbic acid, ascorbic palmitate, sodium bisulfite, anhydrous sodium sulfite, sodium pyrosulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, tocopherol acetate, dI-α-tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, butylhydroxyanisole, soy lecithin, pentaerythritol-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, and propyl gallate. Examples of cooling agents include l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, and thymol.

[0047] Specific dosage forms of topical pharmaceutical compositions include, for example, any of the following selected from the group consisting of liquids, gels, creams, sprays (topical aerosols, pump sprays), ointments, hard gels, poultices, and tapes. Each dosage form can be manufactured using appropriate additives and bases, following the usual methods described in the 18th edition of the Japanese Pharmacopoeia. Preferred dosage forms for topical preparations are liquids, gels, creams, sprays, hard gels, and poultices, with liquids, gels, or sprays being particularly preferred.

[0048] Furthermore, the preparation of the topical agent can be contained and sealed in, for example, a glass container or packaging, a metal container or packaging such as aluminum, or a container or packaging made of olefin resin such as polyethylene or polypropylene, and can be further contained in a moisture-proof bag containing metal such as aluminum. In addition, the container or packaging may contain environmentally friendly raw materials such as recycled plastic or biomass raw materials, and if necessary, any material that prevents deterioration of the topical agent due to external factors, elements, or environmental changes to the pharmaceutical container or packaging, such as heat and light in high-temperature environments, and that appropriately maintains the quality of the topical agent may be used. In one embodiment of the present invention, the pharmaceutical product may be a preparation or composition of the topical agent contained in an appropriate container or packaging.

[0049] <Regarding Uses> The topical pharmaceutical composition of the present invention can preferably be used for anti-inflammatory or analgesic purposes. The topical pharmaceutical composition of the present invention is preferably used as an anti-inflammatory agent, an analgesic agent, an oral / pharyngeal agent, or a hemorrhoid agent.

[0050] At least one selected from the group consisting of the active ingredient loxoprofen, its salts, and their hydrates has antipyretic, analgesic, and anti-inflammatory effects. Therefore, the topical pharmaceutical composition of the present invention is used as an analgesic, particularly for the relief of pain from lower back pain, joint pain, muscle pain, stiff shoulders, earaches, bruises, fractures, sprains, trauma, and eye pain. It is also used as an anti-inflammatory agent for muscle fatigue and chilblains. Furthermore, it is used as an oral and pharyngeal drug for pharyngitis, tonsillitis, stomatitis, swelling of the mouth and pharynx, sterilization and disinfection of the mouth and throat, and removal of bad breath. It is also used as a hemorrhoid drug to relieve pain, bleeding, swelling, and itching from hemorrhoids and anal fissures. The topical pharmaceutical composition of the present invention can be applied, sprayed, or patched to the affected area in an appropriate amount to the patient one to several times a day.

[0051] The application site for the topical pharmaceutical composition of the present invention may be any surface of the body, specifically the skin, mucous membranes, oral mucosa, pharyngeal mucosa, surface of the eyeball, nasal cavity, outer ear, anus, etc.

[0052] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way to these examples. [Examples]

[0053] The sources for the ingredients used are listed below. Loxoprofen sodium hydrate (LOX): KOLONLIFE SCIENCE INC. Diclofenac sodium: Tokyo Chemical Industry Co., Ltd. Japanese Pharmacopoeia Ethanol (95% Ethanol): Kaneichi Kogyo Co., Ltd. Diisopropanolamine: Fujifilm Wako Pure Chemical Corporation Hydrochloric acid: Kosakai Pharmaceutical Co., Ltd. Lactic acid: Fujifilm Wako Pure Chemical Corporation

[0054] (1) Preparation of pharmaceutical compositions In a beaker, the components shown in the table below were added to lower alcohol, stirred, and their dissolution was confirmed. Then, a pH adjuster (diisopropanolamine) and water were added, and diluted hydrochloric acid or lactic acid was added while adjusting the pH to the level shown in the table below. Finally, the total mass of the pharmaceutical composition was made up to 100 g to prepare the pharmaceutical composition. The prepared pharmaceutical composition was filled into a clear glass bottle and sealed tightly.

[0055] (2) Evaluation of the presence or absence of crystals The table below shows the results of evaluating crystal precipitation for each pharmaceutical composition immediately after manufacturing and one day after the start of storage at 5°C following manufacturing. ○: No crystal precipitation △: Slight crystal precipitation (not enough to cover the bottom of the glass bottle) ×: Crystals precipitate (covering the bottom of the glass bottle)

[0056] [Table 1]

[0057] [Table 2]

[0058] [Table 3]

[0059] <Explanation of Results> From a comparison between Comparative Example 1 and Example 1, Comparative Example 2 and Example 2, Comparative Example 3 and Example 3, and Comparative Example 4 and Example 4, it was found that in the topical pharmaceutical compositions of Comparative Examples 1 to 4, which contained diclofenac sodium and ethanol, with an ethanol content of 35% to 60% by mass relative to the total mass of the topical pharmaceutical composition, and a pH of 5.0 to 7.5, crystal precipitation (including slight crystal precipitation) occurred immediately after manufacturing or after 1 day of storage at 5°C. However, no crystal precipitation occurred in the topical pharmaceutical compositions of Examples 1 to 4, which contained loxoprofen sodium hydrate. In other words, it was demonstrated that by incorporating loxoprofen sodium hydrate, the topical pharmaceutical composition can be stabilized, and a topical pharmaceutical composition with suppressed crystal precipitation can be provided.

[0060] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention. [Industrial applicability]

[0061] The topical pharmaceutical composition of the present invention is used as an anti-inflammatory and analgesic agent, particularly for the pain relief of lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, traumatic pain, and eye pain. It is also used as an anti-inflammatory agent for muscle fatigue and chilblains. Furthermore, as an oral and pharyngeal agent, it is used for pharyngitis, tonsillitis, stomatitis, swelling of the mouth and throat, sterilization and disinfection of the mouth and throat, and removal of bad breath. It is also used as a hemorrhoid agent to relieve pain, bleeding, swelling, and itching associated with hemorrhoids and anal fissures.

Claims

1. (A) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (B) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (C) Lower alcohol A topical pharmaceutical composition comprising (C), wherein the content of the lower alcohol (C) is 35% by mass or more and 60% by mass or less relative to the total mass of the topical pharmaceutical composition, and the pH of the topical pharmaceutical composition is 5.0 to 7.

5.

2. (A) The topical pharmaceutical composition according to claim 1, comprising 1 to 10% by mass of loxoprofen sodium as an ingredient.

3. (B) The topical pharmaceutical composition according to claim 1, comprising 1 to 10% by mass of diclofenac sodium as component (B).

4. A topical pharmaceutical composition according to any one of claims 1 to 3, comprising a pH adjusting agent other than malic acid.

5. The topical pharmaceutical composition according to any one of claims 1 to 3, further comprising one or more selected from the group consisting of hydrochloric acid, lactic acid, and diisopropanolamine as a pH adjusting agent.

6. The topical pharmaceutical composition according to any one of claims 1 to 3, wherein the topical pharmaceutical composition contains water.

7. The topical pharmaceutical composition according to any one of claims 1 to 3, wherein the topical pharmaceutical composition is selected from the group consisting of liquids, gels, creams, sprays, ointments, hard gels, poultices, and tapes.

8. (A) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (B) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (C) Lower alcohol A method for stabilizing an external pharmaceutical composition, comprising: blending (C) such that the content of the lower alcohol is 35% by mass or more and 60% by mass or less relative to the total mass of the external pharmaceutical composition; and adjusting the pH of the resulting composition to 5.0 to 7.5.

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