Pharmaceutical composition containing l-menthol and loxoprofen

Abstract

The present invention addresses the problem of providing a pharmaceutical composition comprising l-menthol at 6 mass% or more and a lower alcohol at 20 mass% or less, the pharmaceutical composition demonstrating improved solubility of l-menthol. The present invention provides a pharmaceutical composition containing: (A) l-menthol at 6 mass% or more; (B) a lower alcohol at 20 mass% or less; (C) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; (D) a polyoxyethylene hydrogenated castor oil; and (E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters.

Description

Pharmaceutical composition containing l-menthol and loxoprofen

[0001] The present invention relates to a pharmaceutical composition comprising 1-menthol, a lower alcohol, at least one member selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and a specific surfactant.

[0002] L-menthol is extremely poorly soluble in water, which is known to cause a decrease in the stability of formulations and the occurrence of precipitation and cloudiness. In particular, pharmaceutical compositions containing high concentrations of l-menthol are prone to the problems of precipitation and cloudiness.

[0003] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (hereinafter referred to as NSAIDs), is known to have strong antipyretic, analgesic, and anti-inflammatory effects, although it exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with weak gastric mucosal irritation after oral administration and becomes an active form in the body, and is therefore known to have the characteristic of causing less gastric mucosal damage than other NSAIDs.

[0004] Patent Document 1 describes a topical skin preparation containing loxoprofen or a salt thereof, l-menthol, ethanol, tocopherol or a derivative thereof, and polysorbate. Patent Document 2 describes a pharmaceutical composition containing l-menthol; at least one selected from the group consisting of medium-chain fatty acid triglycerides, medium-chain fatty acids, and salts of medium-chain fatty acids; a nonionic surfactant having an HLB of 10 or more; a polyhydric alcohol and / or poly(oxyalkylene) glycol having three or more hydroxyl groups in the molecule, which is at least one selected from the group consisting of glycerin, D-sorbitol, D-mannitol, and macrogol 400; and water. Patent Document 3 describes a topical skin preparation containing loxoprofen or a salt thereof, l-menthol, a carboxyvinyl polymer, ethanol, and at least one nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polysorbate.

[0005] Japanese Patent Application Publication No. 2020-158501 Japanese Patent Application Publication No. 7300995 Japanese Patent Application Publication No. 2022-111098

[0006] L-menthol is extremely poorly soluble in water, which can lead to reduced formulation stability, precipitation, cloudiness, and deposition on containers. Improving the solubility of l-menthol is a key challenge in developing a formulation that prevents l-menthol precipitation during repeated use and has transparency that makes it inconspicuous even when deposited on clothing. Increasing the amount of active agent can be considered to dissolve high concentrations of l-menthol in low-ethanol formulations, but incorporating a large amount of active agent is known to cause issues such as increased skin irritation. While formulations combining loxoprofen sodium and l-menthol are known, it is not known that incorporating loxoprofen sodium into a pharmaceutical composition containing high concentrations of l-menthol improves the storage stability and transparency of l-menthol.

[0007] An object of the present invention is to provide a pharmaceutical composition containing 6% by mass or more of 1-menthol and 20% by mass or less of a lower alcohol relative to the total amount of the composition, in which the solubility of 1-menthol is improved.

[0008] As a result of extensive research into solving the above problems, the present inventors have found that the solubility of 1-menthol can be improved by using loxoprofen sodium hydrate in combination with a specific nonionic surfactant, and have thus completed the present invention.

[0009] That is, aspects of the present invention are as follows. <1> A pharmaceutical composition comprising (A) 6% by mass or more of l-menthol based on the total composition, (B) 20% by mass or less of a lower alcohol based on the total composition, (C) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, (D) polyoxyethylene hydrogenated castor oil, and (E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters. <2> The pharmaceutical composition according to <1>, wherein the content of (C) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof is 0.1 to 10% by mass based on the total composition. <3> The pharmaceutical composition according to <1> or <2>, wherein the total content of (D) polyoxyethylene hydrogenated castor oil and (E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters is 5 to 20% by mass based on the total composition. <4> The pharmaceutical composition according to any one of <1> to <3>, further comprising a gelling agent. <5> The pharmaceutical composition according to <4>, wherein the gelling agent is a carboxyvinyl polymer. <6> The pharmaceutical composition according to <4> or <5>, which is a gel. <7> The pharmaceutical composition according to any one of <1> to <6>, which is used as an anti-inflammatory agent or an analgesic.

[0010] The pharmaceutical composition of the present invention can improve the solubility of l-menthol in a pharmaceutical composition containing 6% by mass or more of l-menthol and 20% by mass or less of a lower alcohol relative to the total composition. It is an unexpected effect that the solubility of l-menthol can be improved by using at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof in combination with at least one nonionic surfactant selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, and polyethylene glycol fatty acid esters.

[0011] The pharmaceutical composition of the present invention contains: (A) 1-menthol in an amount of 6% by mass or more based on the total composition; (B) a lower alcohol in an amount of 20% by mass or less based on the total composition; (C) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (D) polyoxyethylene hydrogenated castor oil; and (E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters.

[0012] <l-Menthol> The l-menthol used in the present invention is listed in the 18th Edition of the Japanese Pharmacopoeia and the Pharmaceutical Additives Dictionary 2021. The content of l-menthol in the pharmaceutical composition is not particularly limited as long as it is 6% by mass or more based on the mass of the entire pharmaceutical composition, but is preferably 6 to 20% by mass, more preferably 6 to 15% by mass, and even more preferably 6 to 10% by mass.

[0013] <Lower Alcohol> Examples of lower alcohols in the present invention include ethanol and isopropanol. Ethanol (also referred to as ethyl alcohol or alcohol) is listed in the Pharmaceutical Additives Dictionary 2021 (Yakuji Nipposha, 2021), and examples include ethanol, ethanol 95, and absolute ethanol. The content of lower alcohols (such as ethanol or isopropanol) in the pharmaceutical composition is not particularly limited as long as it is 20% by mass or less based on the mass of the entire pharmaceutical composition, but is preferably 5 to 20% by mass, more preferably 10 to 20% by mass, and even more preferably 12 to 18% by mass.

[0014] <Loxoprofen, its salts, and hydrates thereof> The pharmaceutical composition of the present invention contains at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof. In the present invention, "at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof" is sometimes referred to as "loxoprofen or its salt," and refers to loxoprofen or a salt thereof (including a hydrate salt) (the salt is preferably a pharmacologically acceptable salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate. The at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof used in the present invention is listed as loxoprofen sodium hydrate in the 18th Edition of the Japanese Pharmacopoeia.

[0015] The content of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof in the pharmaceutical composition is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.5 to 10% by mass, and even more preferably 0.5 to 5% by mass, based on the mass of the entire pharmaceutical composition.

[0016] <Polyoxyethylene hydrogenated castor oil> Examples of the polyoxyethylene hydrogenated castor oil used in the present invention include polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene hydrogenated castor oil 100, with polyoxyethylene hydrogenated castor oil 60 being preferred. The content of polyoxyethylene hydrogenated castor oil in the pharmaceutical composition is not particularly limited, but is preferably 1 to 20% by mass, more preferably 2 to 15% by mass, and even more preferably 3 to 10% by mass, based on the mass of the entire pharmaceutical composition.

[0017] <At least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters> Examples of the polyoxyethylene sorbitan fatty acid esters used in the present invention include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, and polysorbate 80, with polysorbate 80 being preferred. Examples of the polyethylene glycol fatty acid esters used in the present invention include polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (40 E.O.), polyethylene glycol monostearate (45 E.O.), and polyethylene glycol monostearate (55 E.O.), with polyethylene glycol monostearate (25 E.O.) being preferred. The content of at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters in the pharmaceutical composition is not particularly limited, but is preferably 1 to 20% by mass, more preferably 1 to 15% by mass, and even more preferably 1 to 10% by mass, based on the mass of the entire pharmaceutical composition.

[0018] The total content of (D) polyoxyethylene hydrogenated castor oil and (E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters in the pharmaceutical composition is preferably 5 to 20% by mass, more preferably 5 to 15% by mass, based on the mass of the entire pharmaceutical composition.

[0019] The pharmaceutical composition of the present invention may preferably further contain a gelling agent. Examples of gelling agents include, but are not limited to, carboxyvinyl polymers, acrylic copolymers (e.g., acrylate / alkyl acrylate copolymers), polyacrylamides, polysaccharides, and the like. Carboxyvinyl polymers are particularly preferred. Gelling agents may be used singly or in combination of two or more. When a gelling agent is used, the content of the gelling agent in the pharmaceutical composition is, but is not limited to, preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, and even more preferably 0.2 to 2% by mass, based on the total mass of the pharmaceutical composition.

[0020] The pH range of the pharmaceutical composition is preferably 4.0 to 12.0, more preferably 4.0 to 8.0, and even more preferably 5.0 to 8.0.

[0021] <Regarding the Pharmaceutical Composition> Drugs and pharmaceutical additives can be added to the pharmaceutical composition of the present invention. The pharmaceutical composition of the present invention may contain one or more components selected from the group consisting of the following components (A-1) to (A-11): (A-1) tocopherols; (A-2) terpenes; (A-3) glycyrrhizic acids; (A-4) herbal medicines; (A-5) tranexamic acids; (A-6) vanilloids; (A-7) nicotinic acids; (A-8) chlorpheniramines; (A-9) diphenhydramines; (A-10) pyrrolidones; (A-11) inorganic salts;

[0022] (A-1) Examples of tocopherols include tocopherol, tocotrienol, and derivatives thereof (e.g., esterified derivatives such as acetate ester, succinate ester, and nicotinate ester), as well as salts thereof (e.g., alkaline earth metal salts such as calcium salt and magnesium salt). The tocopherol may be any of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, with α-tocopherol being preferred. The tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, with α-tocotrienol being preferred. The tocopherol is particularly preferably tocopherol acetate.

[0023] (A-2) Terpenes are a general term (terpenoids) that includes terpene hydrocarbons as well as terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc. The structure is not particularly limited, and examples include monoterpenes, sesquiterpenes, and derivatives thereof. In addition, they may be cyclic or chain. Examples of terpenes include isoborneol, irone, ocimene, carveol, carbotanacetone, carbomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, thymol, isothujole, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene.

[0024] Terpenes may be used in the form of essential oils containing terpenes. Examples of essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaputo oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, Japanese pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, and terephthalate. Examples of oils that can be used include bottle oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, chenopodium oil, bergamot oil, bois de rose oil, hosho oil, marjolan 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, and these may be used alone or in combination of two or more.

[0025] (A-3) Examples of glycyrrhizic acids 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. Furthermore, glycyrrhetinic acids may be used in the form of licorice or extracts thereof, which contain glycyrrhizinic acids.

[0026] (A-4) Examples of crude drugs include licorice, arnica tincture, Mallotus japonicus, Acacia japonica, Coriaceae, fennel, turmeric, Corydalis chinensis, Scutellaria baicalensis, Phellodendron amurense, Phellodendron bark, Coptis chinensis, Onion, Zedoary, valerian, chamomile, calonin, platycodon, apricot kernel, lycium bark, wolfberry, cinnamon bark, Cassia japonica, gentian, Geranium herb, Kouka, Magnolia officinalis, Bezoar, Gomoku berry, Chinese rhizome, Chinese holly, Chinese pepper, Aster rhizome, Juglans chinensis, Lithospermum root, Peony root, Musk, Shajin, and Shi. Examples of herbal medicines that can be used include: jasmine, rhododendron, animal gall (including bear gall), ginger, jiru, shino, horse chestnut, sekisan, senega, cnidium, zenko, swertia bristlecone, soju, mulberry bark, perilla, tang, tang, ginseng, tangerine peel, angelica, ipecac, nandina, carrot, fritillary, chinese ginseng, pinecone, asiatic ginseng, angelica, peony, angelica tree, white berry, atractylodes rhizome, poria, moutan peel, columbine, and rokujo, as well as extracts thereof (extract, tincture, dried extract, etc.). Licorice may be used as a glycyrrhizic acid compound, as a herbal medicine, or may serve both the roles of a glycyrrhizic acid compound and a herbal medicine.

[0027] (A-5) Tranexamic acids may include, for example, tranexamic acid or a salt thereof, or a tranexamic acid derivative or a salt thereof. The salt of tranexamic acid is not particularly limited, 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. 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.

[0028] (A-6) Vanilloids is a general term for compounds containing a vanillyl group. Vanilloids in the present invention 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, vanilloids in the present invention may include natural products containing compounds containing a vanillyl group, derivatives of compounds containing a vanillyl group, and synthetic compounds in which a functional group has been added to the vanillyl group. Furthermore, as vanilloids in the present invention, chili peppers containing compounds containing a vanillyl group may be used, or may be included as part of the vanilloids. Suitable chili peppers include, for example, the fruit of Capsicum annuum Linne (Solanaceae), listed in the 18th Edition of the Japanese Pharmacopoeia. The form of chili peppers can be adjusted as needed, and they can be cut or crushed into small pieces or chunks, or pulverized into powder. For example, "chili pepper powder" obtained by powdering chili peppers can also be used as the "chili pepper" of the present invention. Chili peppers that have been subjected to some kind of extraction process (chili pepper extract, chili pepper tincture, etc.) can also be used. Chili pepper extracts may also be those that have been subjected to processing processes such as heating, drying, and pulverization in addition to the extraction process. Furthermore, capsaicinoids, which are the main components of chili peppers, can also be used as chili peppers. Capsaicin and nonanoic acid vanillylamide are preferred capsaicinoids. Chili pepper extracts, chili pepper tincture, nonanoic acid vanillylamide, or capsaicin can preferably be used as chili peppers.

[0029] (A-7) Examples of nicotinic acids include nicotinic acid and its derivatives, as well as salts thereof. Examples of nicotinic acid derivatives include nicotinic acid esters (specifically, nicotinic acid methyl ester, nicotinic acid β-butoxyethyl ester, nicotinic acid benzyl ester, inositol hexanicotinate, hepronicate, etc.), nicotinamide, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, etc.). Preferred nicotinic acid esters are monoesters of nicotinic acid. Preferred nicotinic acids are nicotinic acid benzyl esters.

[0030] (A-8) Examples of chlorpheniramines include chlorpheniramines and their salts. Specific examples of 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. Preferred chlorpheniramines are chlorpheniramine maleate.

[0031] (A-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, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate. Preferred diphenhydramines are diphenhydramine or diphenhydramine hydrochloride.

[0032] (A-10) Pyrrolidones include dl-pyrrolidonecarboxylic acid and salts thereof, and for example, sodium pyrrolidonecarboxylate is preferred.

[0033] (A-11) Examples of inorganic salts include salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium or ammonium salts, and preferred examples include sodium chloride, potassium chloride, and ammonium chloride.

[0034] Pharmaceutical additives other than the above-mentioned components may be added to the pharmaceutical composition of the present invention as needed, for example, to further improve the stability of the content over time and the feel when used. Examples of such additives include humectants, moisturizers, thickeners, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, softeners, preservatives, transdermal absorption enhancers, stabilizers, solubilizers, pH adjusters, antioxidants, and refreshing agents. The pharmaceutical composition of the present invention may also contain other optional components.

[0035] Examples of usable humectants include hyaluronic acid, sodium dl-pyrrolidone carboxylate, or a salt thereof (e.g., sodium dl-pyrrolidone carboxylate). Examples of usable moisturizers include polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol. Examples of usable thickeners include hypromellose, hydroxypropyl cellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose (carmellose sodium), methylcellulose, carrageenan, locust bean gum, and propylene glycol alginate.

[0036] Examples of the adhesive 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, acrylic acid silk fibroin copolymer resin, starch acrylate 300, starch acrylate 1000, butyl acrylate-2-ethylhexyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-2-hydroxyethyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-ethyl acrylate-2-hydroxyethyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-ethyl acrylate-2-hydroxyethyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-2-ethylhexyl ... Acrylic pressure-sensitive 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 pressure-sensitive 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, gum arabic, and the like, as well as those crosslinked with metal salts such as aluminum, zinc, magnesium, and calcium can also be used;

[0037] Examples of tackifying resins that can be used include rosin, hydrogenated rosin glycerin ester, ester gum, maleic acid resin, maleated rosin glycerin ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, and aliphatic hydrocarbon resin. Examples of crosslinking agents that can be used include dried aluminum hydroxide gel, aluminum magnesium hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosultite, 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). Examples of fats and oils that can be used include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum, and gelled 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, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, purified lanolin, and reduced lanolin; and silicone oils.

[0038] Examples of softeners that can be used include petroleum-based oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil; 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; and glycerin.

[0039] 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, and aminoethylsulfonic acid. Examples of percutaneous absorption enhancers that can be used include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactate esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbonate, and azone or derivatives thereof. Examples of stabilizers that can be used include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (e.g., dibenzoylmethane derivatives).

[0040] Examples of solubilizing agents that can be used include benzyl alcohol, pyrothiodecane, 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. Examples of pH adjusting agents that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), and phosphoric acid. Examples of antioxidants that can be used include ascorbic acid, ascorbic acid palmitate, sodium bisulfite, dried sodium sulfite, sodium metabisulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, tocopherol acetate, dI-α-tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, butylhydroxyanisole, soybean lecithin, pentaerythryl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, propyl gallate, etc. Examples of freshening agents that can be used include 1-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, thymol, etc.

[0041] Specific dosage forms of topical preparations include, for example, topical liquid preparations, ointments, creams, sprays (topical aerosols, pump sprays), gels, patches (tapes, poultices), and topical solid preparations, and these can be produced by appropriately using additives and bases suitable for each dosage form, according to the usual methods described in the 18th Edition of the Japanese Pharmacopoeia, etc. Gels are particularly preferred as the dosage form of topical preparations.

[0042] Furthermore, the topical preparation can be housed and sealed in, for example, a glass container / packaging, a metal container / packaging such as aluminum, or an olefin resin container / packaging such as polyethylene or polypropylene, and further housed in a moisture-proof bag containing a metal such as aluminum. Furthermore, the container / packaging may be made from environmentally friendly raw materials such as recycled plastic or biomass raw materials, and, if necessary, any material may be used that prevents deterioration of the topical skin preparation due to factors, elements, or environmental changes from outside the pharmaceutical container / packaging, such as heat or light in a high-temperature environment, and that properly maintains the quality of the topical skin preparation. In one embodiment of the present invention, the topical skin preparation formulation / composition may be housed in a suitable container / packaging to provide a pharmaceutical product.

[0043] <Use> The pharmaceutical composition of the present invention can be suitably used for anti-inflammatory or analgesic purposes. The pharmaceutical composition of the present invention is preferably used as an anti-inflammatory agent or an analgesic agent.

[0044] The active ingredient, l-menthol, has analgesic and antipruritic effects, as well as bactericidal and antiseptic effects. At least one active ingredient selected from the group consisting of loxoprofen, its salts, and hydrates thereof has antipyretic, analgesic, and anti-inflammatory effects. Therefore, the pharmaceutical composition of the present invention is used as an analgesic, particularly for relieving pain from lower back pain, joint pain, muscle pain, stiff shoulder pain, ear pain, bruise pain, fracture pain, sprain pain, trauma pain, and the like. The pharmaceutical composition of the present invention can be applied, sprayed, or pasted in an appropriate amount to the affected area of ​​a patient once to several times a day.

[0045] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples in any way.

[0046] <Test Materials> 1-Menthol manufactured by Suzuki Mint Co., Ltd., loxoprofen sodium dihydrate manufactured by KOLON LIFE SCIENCE Co., Ltd., polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyethylene glycol monostearate manufactured by Nikko Chemicals Co., Ltd., ethanol 95 manufactured by Fuji Film Wako Co., Ltd., isopropanol manufactured by Kosakai Pharmaceutical Co., Ltd., carboxyvinyl polymer manufactured by Lubrizol Co., Ltd., and triethanolamine manufactured by Fuji Film Wako Pure Chemical Industries, Ltd. were used.

[0047] The carboxyvinyl polymer and purified water are mixed and dissolved at least one day before the preparation process. A mixture containing 1-menthol, ethanol 95 or isopropanol, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, or polyethylene glycol monostearate can be stirred to obtain a uniform composition. The composition can then be mixed with water to dissolve each component. The mixture can then be further stirred to thicken, resulting in a gel.

[0048] <Sample Preparation> (1) A portion of purified water was weighed into a beaker the day before preparation, and carboxyvinyl polymer was gradually added while stirring with a disperser. The mixture was mixed uniformly to obtain Composition A. (2) Loxoprofen sodium hydrate and a portion of purified water were weighed into a beaker and stirred until completely dissolved, obtaining Composition B. Step (2) was omitted for the comparative example. (3) Triethanolamine and a portion of purified water were weighed into a beaker and stirred until completely dissolved, obtaining Composition C. (4) 1-Menthol, ethanol 95 or isopropanol, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, or polyethylene glycol monostearate (the ingredients and amounts listed in Tables 1 and 2 were used) were weighed into a beaker and stirred with a stirrer until homogenous, and dissolution was confirmed. (5) Compositions B, C, and the remaining purified water were added to (4), stirred with a stirrer until homogenous, and dissolution was confirmed. (6) Composition A was added and mixed until homogenous. The pH of the sample was adjusted to be within the range of 6.0 to 7.0.

[0049] <Appearance evaluation> Each gel obtained was spread on a black acrylic plate to a uniform thickness and size, and then left at room temperature for 30, 60, and 90 minutes before visually inspecting the appearance. The results are shown in Tables 1 and 2. A: No change from immediately after spreading B: Changes in appearance such as cloudiness or precipitation over less than 50% of the surface area were observed immediately after spreading C: Changes in appearance such as cloudiness or precipitation were observed over 50% or more of the surface area or over the entire surface immediately after spreading

[0050]

[0051] *1: 20.0% by mass of ethanol

[0052] As shown in Table 1, the appearance evaluations of Examples 1 to 3 were all better than those of Comparative Examples 1 to 3. As shown in Table 2, the appearance evaluations of Examples 4 to 6 were all better than those of Comparative Examples 4 and 5.

[0053] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

[0054] The pharmaceutical composition of the present invention is used as an anti-inflammatory and analgesic, particularly for relieving pain from lower back pain, joint pain, muscle pain, stiff shoulder pain, ear pain, bruise pain, fracture pain, sprain pain, trauma pain, and the like.

Claims

1. A pharmaceutical composition containing: (A) 6% by mass or more of l-menthol based on the total composition; (B) 20% by mass or less of a lower alcohol based on the total composition; (C) at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof; (D) polyoxyethylene hydrogenated castor oil; and (E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters.

2. The pharmaceutical composition according to claim 1, wherein the content of (C) at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof is 0.1 to 10% by mass of the total composition.

3. The pharmaceutical composition according to claim 1, wherein the total content of (D) polyoxyethylene hydrogenated castor oil and (E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters is 5 to 20% by mass of the total composition.

4. The pharmaceutical composition of claim 1, further comprising a gelling agent.

5. The pharmaceutical composition of claim 4, wherein the gelling agent is a carboxyvinyl polymer.

6. The pharmaceutical composition according to claim 4, which is a gel.

7. The pharmaceutical composition according to any one of claims 1 to 6, which is used as an anti-inflammatory agent or an analgesic agent.

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