WO2025206091A1 - Pharmaceutical composition containing l-menthol and loxoprofen - Google Patents

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

The present invention relates to a pharmaceutical composition comprising l-menthol, a lower alcohol, at least one member selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and a specific surfactant.

l-Menthol is extremely poorly soluble in water, and is known to reduce the stability of formulations and cause precipitation and cloudiness. Precipitation and cloudiness are particularly likely to occur in pharmaceutical compositions containing high concentrations of l-menthol.

Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (hereafter referred to as "NSAIDs"), exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs, but is known to have strong antipyretic, analgesic, and anti-inflammatory effects. After oral administration, loxoprofen is absorbed from the gastrointestinal tract as an unchanged form with little irritation to the gastric mucosa, and is a prodrug that becomes active in the body. As such, it is known to cause less gastric mucosal damage than other NSAIDs.

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 with an HLB of 10 or more; at least one polyhydric alcohol and/or poly(oxyalkylene) glycol having three or more hydroxyl groups in the molecule 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, carboxyvinyl polymer, ethanol, and at least one nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polysorbate.

Japanese Patent Application Laid-Open No. 2020-158501 Patent No. 7300995 Japanese Patent Application Laid-Open No. 2022-111098

l-Menthol is extremely poorly soluble in water, which can reduce the stability of the formulation, cause precipitation and cloudiness, and cause precipitates to adhere to the container. Improving the solubility of l-menthol is a challenge when developing a formulation that prevents l-menthol from precipitating during repeated use and has transparency that makes it inconspicuous even when it adheres to clothing. Increasing the amount of active agent can be considered to dissolve high concentrations of l-menthol in low-ethanol formulations, but it is known that incorporating a large amount of active agent can cause issues such as increased skin irritation. Formulations combining loxoprofen sodium and l-menthol are known, but it is not known that incorporating loxoprofen sodium into a pharmaceutical composition containing a high concentration of l-menthol improves the storage stability and transparency of l-menthol.

The objective of the present invention is to provide a pharmaceutical composition that contains 6% by mass or more of l-menthol and 20% by mass or less of a lower alcohol relative to the total composition, and that improves the solubility of l-menthol.

As a result of extensive research into resolving the above-mentioned problems, the inventors discovered that the solubility of l-menthol can be improved by using loxoprofen sodium hydrate in combination with a specific nonionic surfactant, leading to the completion of the present invention.

That is, the aspects of the present invention are as follows.
<1> (A) 6% by mass or more of 1-menthol based on the entire composition;
(B) 20% by mass or less of a lower alcohol based on the entire composition;
(C) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof;
(D) polyoxyethylene hydrogenated castor oil,
(E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters,
A pharmaceutical composition comprising:
<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 relative to the total mass of the 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 mass of the 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 agent.

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. The unexpected effect of improving the solubility of l-menthol is achieved 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.

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

<l-Menthol>
The l-menthol used in the present invention is listed in the 18th revised Japanese Pharmacopoeia and the Pharmaceutical Additives Dictionary 2021.
The content of 1-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.

<Lower alcohol>
Examples of lower alcohols in the present invention include ethanol and isopropanol. Ethanol (also known as ethyl alcohol or alcohol) is listed in the Pharmaceutical Additives Dictionary 2021 (Yakuji Nipposha, 2021), and examples thereof include ethanol, ethanol 95, and absolute ethanol.
The content of the lower alcohol (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.

<Loxoprofen, its salts, and hydrates thereof>
The pharmaceutical composition of the present invention comprises at least one member selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof.
In the present invention, "at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof" may also be referred to as "loxoprofen or its salts," and refers to loxoprofen or its salts (including hydrated salts) (the salts are preferably pharmacologically acceptable salts), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.
At least one member selected from the group consisting of loxoprofen, its salts, and hydrates thereof used in the present invention is listed in the 18th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

The content of at least one compound 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 total mass of the pharmaceutical composition.

<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.

<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 ester used in the present invention include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc., with polysorbate 80 being preferred.
Examples of the polyethylene glycol fatty acid ester used in the present invention include polyethylene glycol monostearate (10 EO), polyethylene glycol monostearate (25 EO), polyethylene glycol monostearate (40 EO), polyethylene glycol monostearate (45 EO), and polyethylene glycol monostearate (55 EO), with polyethylene glycol monostearate (25 EO) 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.

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, and more preferably 5 to 15% by mass, based on the total mass of the pharmaceutical composition.

The pharmaceutical composition of the present invention may preferably further comprise a gelling agent.
The gelling agent is not particularly limited, but examples thereof include carboxyvinyl polymers, acrylic copolymers, such as acrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides, etc. Carboxyvinyl polymers are particularly preferred as the gelling agent. The gelling agents may be used alone or in combination of two or more.
When a gelling agent is used, the content of the gelling agent in the pharmaceutical composition is not particularly limited, but is 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 mass of the entire pharmaceutical composition.

Furthermore, 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.

<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 salt;

(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). Tocopherols may be α-tocopherol, β-tocopherol, γ-tocopherol, or δ-tocopherol, with α-tocopherol being preferred. Tocotrienols may be α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol, with α-tocotrienol being preferred. Tocopherol acetate is particularly preferred.

(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. There are no particular limitations on their structure, and examples include monoterpenes, sesquiterpenes, and derivatives thereof. They may also be cyclic or chain-chain. Examples of terpenes include isoborneol, irone, ocimene, carveol, carbotanacetone, carvomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, thymol, isothujol, 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.

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, 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.

(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 (liquorice root) or extracts thereof, which contain glycyrrhizinic acids.

(A-4) Examples of herbal medicines include licorice, arnica tincture, Mallotus japonicus, Acacia japonica, Columbine, 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, kaempferia chinensis, Magnolia officinalis, Bezoar, Gomoku berry, Chinese rhizome, Chinese holly, Chinese pepper, Aster rhizome, Juglans chinensis, Lithospermum root, peony, musk, Chinese rhizome, and Chinese rhizome. Examples of herbal medicines include jasmine, rhododendron bark, animal gall (including bear gall), ginger, sage, radix ginseng, senega, cnidium rhizome, rhododendron bark, swertia bristlecone, atractylodes rhizome, mulberry bark, perilla serrata, tang, ginseng root, tangerine peel, angelica tree, ipecac, nandina fruit, carrot, fritillary root, rhododendron bark, rhododendron rhizome, rhododendron bark, angelica tree, rhododendron rhizome, poria rhizome, moutan peel, columbine, and rokujo, as well as extracts (extracts, tinctures, dried extracts, etc.) of these. Licorice may be used as a glycyrrhizic acid compound, as a herbal medicine, or may serve as both a glycyrrhizic acid compound and a herbal medicine.

(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, and specific examples thereof include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; metal salts such as aluminum, iron and zinc salts; basic amino acid salts such as lysine, arginine, histidine and ornithine salts; and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine and stearylamine salts. Furthermore, tranexamic acid derivatives or salts thereof may be used, and specific examples thereof include ester derivatives such as tranexamic acid cetyl ester and amide derivatives such as tranexamic acid methylamide.

(A-6) Vanilloids is a general term for compounds containing a vanillyl group. The vanilloids of the present invention are not particularly limited as long as they are compounds containing a vanillyl group, and examples thereof include vanillin, vanillic acid, capsaicin, vanillylmandelic acid (VMA), and vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol).
Furthermore, the vanilloids of the present invention may include natural products containing compounds containing a vanillyl group, derivatives of compounds having a vanillyl group, and synthetic compounds in which a functional group has been added to the vanillyl group.
Furthermore, as the vanilloids in the present invention, capsicums containing a compound containing a vanillyl group may be used, or may be contained as part of the vanilloids.
Suitable examples of chili peppers include the fruit of Capsicum annuum Linne (Solanaceae) listed in the 18th Revised Japanese Pharmacopoeia. The chili pepper can be adjusted in shape as needed, by cutting or crushing it into small pieces or chunks, or by pulverizing it into powder. For example, "chili pepper powder," which is a powder of chili pepper, can also be used as the "chili pepper" of the present invention. Chili peppers that have undergone 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 undergone processing such as heating, drying, or 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 are preferably used as chili peppers.

(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 ester.

(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. Of the chlorpheniramines, chlorpheniramine maleate is preferred.

(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. Diphenhydramine or diphenhydramine hydrochloride is preferred as a diphenhydramine.

(A-10) Examples of pyrrolidones include dl-pyrrolidonecarboxylic acid or its salts, with sodium pyrrolidonecarboxylate being preferred.

(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.

In addition to the above-mentioned ingredients, pharmaceutical additives 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 or the feel when used. Examples include humectants, moisturizers, thickeners, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, softeners, preservatives, transdermal absorption enhancers, stabilizers, solubilizers, pH adjusters, antioxidants, and cooling agents. The pharmaceutical composition of the present invention may also contain other optional ingredients.

As the wetting agent, for example, hyaluronic acid, sodium dl-pyrrolidone carboxylate or a salt thereof (for example, sodium dl-pyrrolidone carboxylate), etc. can be used.
Examples of the moisturizing agent that can be used 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 thickening agents that can be used include hypromellose, hydroxypropyl cellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose (carmellose sodium), methyl cellulose, carrageenan, locust bean gum, and propylene glycol alginate.

Adhesives include, for example, acrylic acid/octyl acrylate copolymer, acrylic 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, acrylic acid Butyl/2-ethylhexyl methacrylate/diacetoneacrylamide copolymer, Butyl acrylate/2-hydroxyethyl methacrylate/diacetoneacrylamide copolymer, Butyl acrylate/ethyl acrylate/2-hydroxyethyl methacrylate/diacetoneacrylamide copolymer, Butyl acrylate/2-ethylhexyl acrylate/2-hydroxyethyl methacrylate/diacetoneacrylamide copolymer, Isononyl acrylate/2-hydroxyethyl methacrylate/diacetoneacrylamide copolymer, 2-ethylhexyl acrylate/2-hydroxyethyl methacrylate/diacetoneacrylamide copolymer, Butyl acrylate Acrylic pressure-sensitive adhesives such as ethyl acrylate, 3-hydroxypropyl methacrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, butyl acrylate, ethyl acrylate, 3-hydroxypropyl methacrylate, diacetone acrylamide copolymer; 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 Examples of adhesives that can be used include synthetic rubber adhesives such as cellulose gum and SBR synthetic latex; silicone adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane; as well as 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 adhesives crosslinked with metal salts such as aluminum, zinc, magnesium, and calcium.

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 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).
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.

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; glycerin, etc.

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, azone or derivatives thereof, and the like.
As the stabilizer, for example, oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, UV absorbers (for example, dibenzoylmethane derivatives), etc. can be used.

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 adjusters 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.), phosphoric acid, etc.
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, and propyl gallate.
Examples of the cooling agent include l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, and thymol.

Specific dosage forms of topical preparations include, for example, topical liquids, ointments, creams, sprays (topical aerosols, pump sprays), gels, patches (tapes, poultices), and topical solids. These can be manufactured using appropriate additives and bases suitable for each dosage form, according to standard methods described in the 18th Edition of the Japanese Pharmacopoeia, etc. Gels are particularly preferred as a dosage form for topical preparations.

In addition, topical preparation formulations can be contained and sealed in, for example, glass containers or packaging, or containers or packaging made of metal such as aluminum, or containers or packaging made of olefin resins such as polyethylene or polypropylene, and can further be contained in moisture-proof bags containing metal such as aluminum. The containers and packaging may also be made from environmentally friendly raw materials such as recycled plastics or biomass materials, and as 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 or packaging, such as heat or light in high-temperature environments, and that properly maintains the quality of the topical skin preparation. In one embodiment of the present invention, the topical skin preparation formulation or composition may be contained in an appropriate container or packaging to form a pharmaceutical product.

<About usage>
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.

The active ingredient, l-menthol, has analgesic and antipruritic effects, as well as bactericidal and antiseptic properties.
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 can be 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 the patient once to several times a day.

The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples in any way.

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

Carboxyvinyl polymer and purified water are mixed and dissolved the day before the preparation process. A mixture containing l-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 above composition can then be mixed with water to dissolve each component. The mixture can be further stirred to thicken and obtain a gel.

<Sample preparation>
(1) On the day before preparation, a portion of purified water was weighed out in a beaker in advance, and while stirring with a disperser, the carboxyvinyl polymer was gradually added and mixed uniformly to obtain composition A.
(2) Loxoprofen sodium hydrate and a portion of purified water were weighed in advance into a beaker and stirred to completely dissolve, yielding composition B. For the comparative example, step (2) was omitted.
(3) Triethanolamine and a portion of purified water were weighed out in advance into a beaker, and the mixture was stirred to completely dissolve, thereby obtaining composition C.
(4) 1-Menthol, ethanol 95 or isopropanol, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, or polyethylene glycol monostearate (the components and amounts shown in Tables 1 and 2 were used) were weighed out in advance into a beaker, stirred with a stirring rod to make the mixture uniform, and dissolution was confirmed.
(5) Composition B, Composition C, and the remainder of the purified water were added to (4), stirred with a stirring rod to make the mixture homogeneous, 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.

<Appearance evaluation>
Each gel 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 immediately after spreading B: Changes in appearance such as cloudiness or precipitation over less than 50% of the surface area immediately after spreading C: Changes in appearance such as cloudiness or precipitation over 50% or more of the surface area to the entire surface immediately after spreading

*1: 20.0% by mass of ethanol

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.

The above describes preferred embodiments and examples of the present invention, but 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.

The pharmaceutical composition of the present invention is used as an anti-inflammatory and analgesic, particularly for the relief of pain from lower back pain, joint pain, muscle pain, stiff shoulders, ear pain, bruises, fractures, sprains, and trauma.

Claims (7)

(A) 6% by mass or more of 1-menthol based on the total mass of the composition;
(B) 20% by mass or less of a lower alcohol based on the entire composition;
(C) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof;
(D) polyoxyethylene hydrogenated castor oil,
(E) at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters,
A pharmaceutical composition comprising: (C) The pharmaceutical composition according to claim 1, wherein the content of 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. The pharmaceutical composition of 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. The pharmaceutical composition of claim 1, further comprising a gelling agent. The pharmaceutical composition of claim 4, wherein the gelling agent is a carboxyvinyl polymer. The pharmaceutical composition of claim 4, which is a gel. The pharmaceutical composition according to any one of claims 1 to 6, which is used as an anti-inflammatory agent or an analgesic agent.