Skin external preparation comprising heparinoid, salicylic acid and surfactant

Abstract

To provide an external preparation for skin comprising a heparinoid, salicylic acid and surfactant having a polyoxyethylene group, with improved storage stability.SOLUTION: Disclosed is an external preparation for skin comprising at least one selected from the group consisting of heparinoids and salts thereof, at least one selected from the group consisting of salicylic acid and salts thereof, a surfactant having a polyoxyethylene group and a compound having a quaternary ammonium group.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an external preparation for skin containing a heparinoid, salicylic acid, and a surfactant. More specifically, the present invention relates to an external preparation for skin containing a heparinoid, salicylic acid, and a surfactant, and having improved storage stability. [Background technology]

[0002] Heparinoids are polysulfated mucopolysaccharides such as chondroitin polysulfate extracted from the lungs, including tracheal cartilage, of healthy animals, mainly cattle. They are called heparinoids because they have a structure similar to that of heparin, which is a sulfate ester of mucopolysaccharides with alternating 1,4 bonds between uronic acid and glucosamine. Heparinoids are known to have moisturizing, anti-inflammatory, and blood circulation promoting effects. The efficacy of skin preparations containing heparinoids is said to be the treatment and prevention of thrombophlebitis (including hemorrhoids), pain and inflammatory diseases due to blood circulation disorders (induration and pain after injection), frostbite, hypertrophic scars and keloids, progressive keratoderma tylodes palmaris, cortical deficiency, swelling, hematoma, tendonitis, muscle pain, arthritis after trauma (bruises, sprains, contusions), and muscular torticollis (infancy). Heparinoid-containing topical skin preparations are available in the form of creams, soft ointments, lotions, and sprays.

[0003] When a heparinoid is mixed with other active ingredients in a composition for external use, the storage stability of each active ingredient and the maintenance of the quality of the composition become issues. For example, Patent Document 1 discloses that in a composition for external use containing a heparinoid, the stability of the heparinoid, lidocaine and vitamin A palmitate can be improved by mixing lidocaine with an amino alcohol or by mixing pyrrolidone carboxylate. In addition, Patent Document 2 discloses that in a composition for external use containing a heparinoid and vitamin B6, the stability of the heparinoid and vitamin B6 can be improved by adjusting the pH to 4 or higher.

[0004] However, based on the diverse actions of heparinoids, the development of further skin topical compositions is anticipated. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2004-307491 [Patent Document 2] WO2020 / 138403 Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, in developing a topical skin preparation containing a heparinoid, the inventors investigated the storage stability of the topical skin preparation and found a problem that when a heparinoid, salicylic acid, and a surfactant having a polyoxyethylene group are mixed in water, insoluble matter appears and the preparation becomes cloudy after storage at 5°C for one week.

[0007] That is, an object of the present invention is to provide an external skin preparation containing a heparinoid, salicylic acid, and a surfactant having a polyoxyethylene group, and having improved storage stability. [Means for solving the problem]

[0008] As a result of extensive research into solving the above problems, the inventors discovered that the storage stability of a topical skin preparation containing a heparinoid, salicylic acid, and a surfactant having a polyoxyethylene group can be improved by adding a compound having a quaternary ammonium group, and thus completed the present invention.

[0009] That is, according to the present invention, the following inventions are provided. (1) at least one selected from the group consisting of heparinoids and salts thereof; At least one member selected from the group consisting of salicylic acid and salts thereof; A surfactant having a polyoxyethylene group; A compound having a quaternary ammonium group; A skin topical preparation comprising: (2) The topical skin preparation described in (1), wherein the surfactant having a polyoxyethylene group is at least one of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyethylene glycol monostearate. (3) The topical skin preparation according to (1), further comprising a polyhydric alcohol. (4) The topical skin preparation according to (3), wherein the polyhydric alcohol is 1,3-butylene glycol. (5) A skin topical preparation according to any one of (1) to (4), which contains water. (6) The topical skin preparation according to any one of (1) to (4), wherein the content of the heparinoid and its salt is 0.1 to 1.0% by mass relative to the total mass of the topical skin preparation. (7) The topical skin preparation according to any one of (1) to (4), wherein the content of salicylic acid and its salts relative to the total mass of the topical skin preparation is 0.1 to 3.0% by mass. (8) The topical skin preparation according to any one of (1) to (4), wherein the content of the surfactant having a polyoxyethylene group is 0.5 to 10.0% by mass relative to the total mass of the topical skin preparation. (9) The topical skin preparation according to any one of (1) to (4), wherein the content of the compound having a quaternary ammonium group is 0.05 to 1.0% by mass relative to the total mass of the topical skin preparation. (10) A skin topical preparation according to any one of (1) to (4), in which the ratio of the content of the compound having a quaternary ammonium group to the total content of the heparinoid and its salt and the salicylic acid and its salt is 0.1 or more. (11) The external skin preparation according to any one of (1) to (4), wherein the compound having a quaternary ammonium group is at least one selected from the group consisting of benzethonium, benzalkonium, cetylpyridinium, and salts thereof. (12) The topical skin preparation according to any one of (1) to (4), which is a liquid, cream, gel, ointment, spray, foam, or patch. Effect of the Invention

[0010] According to the topical skin preparation of the present invention, the storage stability of the topical skin preparation is improved, and therefore the medicinal effect can be effectively exhibited even after storage. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The skin topical preparation of the present invention comprises At least one selected from the group consisting of heparinoids and salts thereof; At least one member selected from the group consisting of salicylic acid and salts thereof; A surfactant having a polyoxyethylene group; A compound having a quaternary ammonium group; It is a skin topical preparation comprising:

[0012] The heparinoid in the present invention is a substance also called mucopolysaccharide polysulfate or heparinoid, which is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have moisturizing, anti-inflammatory, and blood circulation promoting effects. Examples of heparinoids include heparin; chondroitin polysulfates such as chondroitin sulfate D and chondroitin sulfate E. The origin of the heparinoid used in the present invention is not particularly limited, and examples thereof include those obtained by polysulfating mucopolysaccharides and those extracted from the tissues of edible animals (e.g., lungs containing tracheal cartilage of cows, pigs, etc.). As the heparinoid, heparinoids listed in the Japanese Pharmacopoeia Non-Drug Standards 2002 are preferred.

[0013] The heparinoid may be in the form of a physiologically acceptable salt obtained by a salt-forming reaction using a hydroxide or carbonate of an alkali metal such as sodium or potassium, or an amine, if necessary. The proportion (%) of organic sulfate groups in the heparinoid of the present invention is not particularly limited, but is preferably 20 to 40% (mass%), particularly preferably 25 to 38% (mass%), from the viewpoints of improving the anti-inflammatory and analgesic effect and reducing skin irritation, etc. The amount of organic sulfate groups is measured by the method described in the section on "heparinoids" in the Japanese Pharmacopoeia Extra Pharmaceutical Standards 2002. The average molecular weight of the heparinoid in the present invention is not particularly limited, but is preferably, for example, 1,000 to 1,000,000, and particularly preferably 5,000 to 100,000, in weight average molecular weight (MW).

[0014] The skin topical preparation of the present invention may also contain an analogue of a heparinoid as an optional ingredient. The analogue of a heparinoid may be, for example, another acidic mucopolysaccharide. Examples of acidic mucopolysaccharides as analogs of heparin-like substances include chondroitin sulfates such as chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, and chondroitin sulfate K, heparin, heparan sulfate, and keratan sulfate. That is, in the skin external preparation of the present invention, in addition to the heparinoid, acidic mucopolysaccharides may be further added as analogues of the above-mentioned heparinoid, if necessary, within the range that does not impair the effects of the present invention. These heparinoid analogs may be in the form of pharma- ceutically acceptable salts and / or solvates, such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., magnesium salt, calcium salt, etc.). Additionally, solvates include hydrates.

[0015] The salicylic acid and its salts in the present invention include, for example, salicylic acid, and if desired, pharma- ceutically acceptable salts such as alkali metal salts of salicylic acid, such as sodium salt and potassium salt, and alkaline earth metal salts, such as magnesium salt and calcium salt, may be used. The salicylic acid and its salts that can be used in the present invention include, for example, "salicylic acid" listed in the 18th Edition of the Japanese Pharmacopoeia.

[0016] The compound having a quaternary ammonium group in the present invention may be at least one selected from the group consisting of benzethonium, benzalkonium, cetylpyridinium and their salts.The compound having a quaternary ammonium group that can be used in the present invention may, for example, be "benzethonium chloride", "benzalkonium chloride" and "cetylpyridinium chloride" listed in the 18th revised Japanese Pharmacopoeia.

[0017] In the present invention, a surfactant having a polyoxyethylene structure is used as the surfactant.

[0018] The surfactant is preferably at least one of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyethylene glycol monostearate.

[0019] The external skin preparation of the present invention may further contain a polyhydric alcohol.

[0020] The polyhydric alcohol in the present invention is an alcohol having two or more hydroxyl groups in the molecule, which is used in skin external preparations for purposes such as solubilizers, bases, moisturizers, thickeners, solvents, and dissolution aids, and is, for example, propylene glycol, 1,3-butylene glycol, macrogol (also called polyethylene glycol), glycerin, D-sorbitol, and dipropylene glycol, which are listed in the Pharmaceutical Additives Encyclopedia 2021. The molecular weight of macrogol is not particularly limited, and may be, for example, 200 to 20,000 in number average molecular weight. In addition, the molecular weight of the alcohols in the present invention is not particularly limited, but may be, for example, 400 or less, preferably less than 400, more preferably 300 or less, even more preferably 250 or less, particularly preferably 200 or less, and may be 100 or less.

[0021] The skin external preparation of the present invention may contain a lower alcohol other than the polyhydric alcohol. The lower alcohol in the present invention refers to an aliphatic alcohol having 1 to 4 carbon atoms that is used in external skin preparations for purposes such as a solubilizer, base, preservative, solvent, and dissolution aid, and is, for example, one or more selected from the group consisting of methanol, ethanol (also called ethyl alcohol), propanol, isopropanol (also called isopropyl alcohol), and butyl alcohol, and is preferably ethanol.

[0022] The content of heparinoids and their salts in the topical skin preparation of the present invention is not particularly limited, but is preferably 0.1 to 10 mass% relative to the total amount of the topical skin preparation, more preferably 0.1 to 1.0 mass%, and even more preferably 0.1 to 0.5 mass%.

[0023] The content of salicylic acid and its salts in the topical skin preparation of the present invention is not particularly limited, but is preferably 0.05 to 10 mass% relative to the total amount of the topical skin preparation, more preferably 0.1 to 3.0 mass%, and even more preferably 0.1 to 0.7 mass%.

[0024] The content of the surfactant having a polyoxyethylene group in the topical skin preparation of the present invention is not particularly limited, but is preferably 0.5 to 10.0 mass% relative to the total amount of the topical skin preparation, more preferably 1.0 to 10.0 mass%, and even more preferably 1.0 to 5.0 mass%.

[0025] The content of the compound having a quaternary ammonium group in the topical skin preparation of the present invention is not particularly limited, but is preferably 0.05 to 10 mass% relative to the total amount of the topical skin preparation, more preferably 0.05 to 1.0 mass%, and even more preferably 0.05 to 0.7 mass%.

[0026] In the topical skin preparation of the present invention, the ratio of the compound having a quaternary ammonium group to the total content of the heparinoid and its salt and the salicylic acid and its salt is not particularly limited, but is preferably 0.1 or more, more preferably 0.1 to 1.0, and even more preferably 0.1 to 0.5.

[0027] When the skin external preparation of the present invention contains a polyhydric alcohol, the ratio of the content of the heparinoid to the mass of the polyhydric alcohol (heparinoid / polyhydric alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 -3 ~100, more preferably 1.4 × 10 -3 ~10, and more preferably 2.0 × 10 -3 ~5.0.

[0028] When the skin external preparation of the present invention contains a lower alcohol, the ratio of the content of the heparinoid to the mass of the lower alcohol (heparinoid / lower alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 -3 ~100, more preferably 1.4 × 10 -3 ~10, and more preferably 1.4 × 10 -3 ~5.0.

[0029] When the topical skin preparation of the present invention contains a polyhydric alcohol, the range of the content of the polyhydric alcohol in the topical skin preparation is not particularly limited, but may be selected depending on the dosage form, and is preferably 0.1 to 70 mass% relative to the total amount of the topical skin preparation, more preferably 0.1 to 20 mass%, more preferably 0.5 to 20 mass%, and even more preferably 1.0 to 15 mass%. For example, when the topical skin preparation of the present invention is a liquid or gel for topical use, the range of the content of the polyhydric alcohol added is not particularly limited, but is, for example, preferably 0.5 to 20 mass %, and more preferably 1.0 to 15 mass %, based on the total amount of the liquid or gel for topical use. For example, when the topical skin preparation of the present invention is a cream, the range of the amount of polyhydric alcohol added is not particularly limited, but is, for example, preferably 0.5 to 20 mass %, and more preferably 1.0 to 15 mass %, relative to the total amount of the cream.

[0030] When the topical skin preparation of the present invention contains a lower alcohol, the range of the content of the lower alcohol in the topical skin preparation is not particularly limited, but may be selected depending on the dosage form, and is preferably 0.1 to 70.0 mass% and more preferably 0.1 to 50.0 mass% relative to the total amount of the topical skin preparation.

[0031] For example, when the topical skin preparation of the present invention is a liquid or gel for topical use, the range of the content of the lower alcohol added is, for example, not particularly limited to, 1.0 to 70.0% by mass, and more preferably 5.0 to 60.0% by mass, based on the total amount of the liquid or gel for topical use. For example, when the topical skin preparation of the present invention is a cataplasm, the range of the content of the lower alcohol added is, for example, preferably 0.1 to 50 mass%, more preferably 0.1% to 30 mass%, based on the total amount of the cataplasm.

[0032] The external skin preparation of the present invention may further contain water. When the topical skin preparation of the present invention contains water, the range of the water content is not particularly limited and may be selected depending on the dosage form, and is preferably 20 to 99% by mass, more preferably 25 to 98% by mass, and even more preferably 30 to 98% by mass, based on the total amount of the topical skin preparation.

[0033] The pH range of the external skin preparation is not particularly limited, but is preferably 4.0 to 7.5, more preferably 4.5 to 7.5, and even more preferably 4.5 to 7.0.

[0034] The skin external preparation of the present invention may contain drugs and pharmaceutical additives that are generally used in skin external preparations for analgesia, anti-inflammatory purposes, and suppurative diseases, other than the above-mentioned components.

[0035] Examples of drugs (active ingredients) other than the above-mentioned ingredients include sulfur, ibuprofen piconol, dipotassium glycyrrhizinate, glycyrrhetinic acid, allantoin, d-camphor, homosulfamine, tocopherol acetate, ethanol, isopropylmethylphenol, chlorhexygluconate, sulfazine, zinc oxide, pyridoxine hydrochloride, pyridoxine dipalmitate, vitamin A oil, chlorpheniramine maleate, diphenhydramine, and resorcinol.

[0036] Pharmaceutical additives are added as necessary for the purpose of, for example, further improving the stability of content over time and the feeling of use, and examples thereof include wetting agents, moisturizing agents, thickening agents, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, softeners, preservatives, percutaneous absorption promoters, stabilizers, solubilizing agents, pH regulators, antioxidants, refreshing agents, emulsifiers, etc. Furthermore, the topical skin preparation of the present invention may contain other optional components.

[0037] As the wetting agent, for example, hyaluronic acid, sodium dl-pyrrolidone carboxylate or a salt thereof (eg, sodium dl-pyrrolidone carboxylate), etc. can be used. As the moisturizing agent, for example, polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol can be used. Examples of thickening agents (thickening agents / gelling 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.

[0038] 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 / diacetone acrylamide copolymer, butyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / 2-ethylhexyl acrylate / methacryl ... 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; 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 be used.

[0039] 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.

[0040] As the crosslinking agent, for example, dried aluminum hydroxide gel, aluminum magnesium hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosaltite, dihydroxyaluminum aminoacetate, etc. can be used. Examples of the filler 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).

[0041] Examples of fats and oils that can be used include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum, medium-chain fatty acid triglycerides, 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, and oleyl alcohol; 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, refined lanolin, and reduced lanolin; and silicone oils.

[0042] 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, and the like.

[0043] 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 the percutaneous absorption enhancer 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), dimethylpolysiloxane, etc. can be used.

[0044] Examples of solubilizing agents 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. Examples of pH adjusters that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, sodium citrate hydrate, trisodium citrate dihydrate, sodium hydrogen phosphate hydrate, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), phosphoric acid, and the like. Examples of antioxidants that can be used include ascorbic acid, ascorbic acid palmitate, sodium bisulfite, dried 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, soybean lecithin, pentaerythritol-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.

[0045] As the emulsifier in the present invention, for example, any of the above-mentioned various surfactants, the above-mentioned higher alcohols, cetostearyl alcohol, and glycerin monostearate may be used.

[0046] Other optional components in the present invention may include, for example, nonsteroidal anti-inflammatory drugs (NSAIDs). As the NSAIDs, those other than diclofenac and / or its salts and felbinac may be used. More specifically, the skin external preparation of the present invention may further include an NSAID, for example, loxoprofen or its salts.

[0047] Specific examples of the dosage form of the skin external preparation of the present invention include liquid, cream, gel, ointment, spray (external aerosol, pump spray), foam, or cataplasm, and each dosage form can be produced by appropriately using additives and bases suitable for the respective dosage forms, according to the usual methods described in the 17th Edition of the Japanese Pharmacopoeia, etc. The dosage form of the skin external preparation of the present invention is preferably a liquid (particularly a liquid for external use).

[0048] The preparation of the topical skin preparation of the present invention can be, for example, stored and sealed in a glass container or package, or a container or package made of a metal such as aluminum, or a container or package made of an olefin resin such as polyethylene or polypropylene, and can further be stored in a moisture-proof bag containing a metal such as aluminum. In addition, the container or package may be a container or package containing environmentally friendly raw materials such as recycled plastics or biomass raw materials, and if necessary, any material that prevents deterioration of the topical skin preparation due to factors, elements, and environmental changes from outside the container or package of the pharmaceutical product, such as laminated materials, gas barrier materials, heat and light in a high-temperature environment, and appropriately maintains the quality of the topical skin preparation may be used. In one embodiment of the present invention, the topical skin preparation may be a pharmaceutical product in which the preparation or composition of the topical skin preparation is stored in a suitable container or package.

[0049] In one embodiment of the present invention, a compound having a quaternary ammonium group may be used as a stabilizer for an external preparation for skin, which contains at least one selected from the group consisting of heparinoids and their salts, at least one selected from the group consisting of salicylic acid and its salts, and a surfactant having a polyoxyethylene group.Specifically, a stabilizer for an external preparation for skin is provided, which contains a compound having a quaternary ammonium group, at least one selected from the group consisting of heparinoids and their salts, at least one selected from the group consisting of salicylic acid and its salts, and a surfactant having a polyoxyethylene group.

[0050] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples in any way. EXAMPLES

[0051] (Test Example 1) Examination of the appearance stability of a composition containing a heparinoid, salicylic acid, and a compound having a quaternary ammonium group (benzethonium chloride) Components that improve the appearance stability of compositions containing heparinoids, salicylic acid, and benzethonium chloride were investigated. (1) Preparation of test materials and specimens The ingredients listed in each sample in Table 1 below were mixed and dissolved, and the pH was adjusted to 4.5 with a solution of citric acid diluted 2-fold or a solution of trisodium citrate dihydrate diluted 4-fold (pH adjuster) to obtain liquid preparations for samples 1 to 8. The following reagents were used: Heparinoid (manufactured by API Co., Ltd.) (ratio of organic sulfate groups to the total heparinoid is 35.2% (mass%)) Salicylic acid (API Corporation) Benzethonium chloride (Lonza Co., Ltd.) 1,3-Butylene glycol (Kanto Chemical Co., Ltd.) Macrogol 400 (NOF Corporation) Polyoxyethylene cetyl ether (NIKKOL BC-20, Nikko Chemicals Co., Ltd.) Polyoxyethylene stearyl ether (NIKKOL BS-20, Nikko Chemicals Co., Ltd.) Polyethylene glycol monostearate (NIKKOL MYS-40V, Nikko Chemicals Co., Ltd.) Citric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) Sodium citrate hydrate (Fujifilm Wako Pure Chemical Industries, Ltd.)

[0052] (2) Manufacturing method The obtained preparation was dispensed into transparent glass vials with a body diameter of 35 mm and sealed. The transparent glass vials used were Mighty Vials (transparent, No. 7) manufactured by Maruemu Co., Ltd. The dispensed samples were stored at 5°C for one week. The appearance of the samples at room temperature before storage and at 5°C after one week of storage was observed. Samples that were clear and free of precipitate were marked with an ◯, and those that were not clear or had precipitate were marked with an ×.

[0053] (3) Test results The results for each sample are shown in Table 1.

[0054] [Table 1]

[0055] From the results in Table 1, it is clear that salicylic acid can be dissolved without producing insoluble matter by using macrogol 400 and polyoxyethylene stearyl ether, as in sample 1. However, in sample 2, which is sample 1 mixed with a heparinoid, insoluble matter appeared and the sample became cloudy after one week of storage at 5°C. On the other hand, no insoluble matter was produced in sample 3, which is sample 2 further mixed with benzethonium chloride. In addition, in sample 4, which contained a combination of salicylic acid and a heparinoid, insoluble matter appeared and the sample became cloudy after storage at 5°C for one week, but in sample 5, which contained benzethonium chloride, no insoluble matter appeared. Furthermore, in samples 6 to 8, which contained combinations of salicylic acid, a heparinoid, and benzethonium chloride, no insoluble matter appeared.

[0056] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Addition, omission, substitution, and other modifications of the configuration are possible without departing from the spirit of the present invention.

[0057] (Formulation example) After dissolving the ingredients shown in the following Tables 2 to 5 by stirring and mixing, the skin topical preparation of each formulation example can be obtained. The preparation can be produced by taking the above-mentioned ingredients and amounts and following the procedures prescribed in the General Provisions for Preparations in the Japanese Pharmacopoeia, Sections on "External Solutions" and "Creams". For example, when a liquid or semi-solid composition is formulated as a specific dosage form, a known means may be applied for each dosage form, such as placing the liquid or semi-solid composition in a container (e.g., a bottle-shaped container, a tube-shaped container, a sheet-shaped container, a spray container, etc.) as appropriate for the dosage form, spreading the liquid or semi-solid composition on a support to form a shape, or mixing with a propellant and then placing it in an aerosol can.

[0058] [Table 2] JPEG2025020501000003.jpg180170

[0059] [Table 3] JPEG2025020501000005.jpg150170

[0060] [Table 4] JPEG2025020501000007.jpg234170JPEG2025020501000008.jpg141170

[0061] [Table 5] JPEG2025020501000010.jpg247170JPEG2025020501000011.jpg157170

[0062] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Addition, omission, substitution, and other modifications of the configuration are possible without departing from the spirit of the present invention. [Industrial Applicability]

[0063] The skin external preparation of the present invention has excellent storage stability and is extremely useful.

Claims

1. At least one selected from the group consisting of heparinoids and salts thereof; At least one member selected from the group consisting of salicylic acid and salts thereof; A surfactant having a polyoxyethylene group; A compound having a quaternary ammonium group; A skin topical preparation comprising:

2. 2. The skin topical preparation according to claim 1, wherein the surfactant having a polyoxyethylene group is at least one of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyethylene glycol monostearate.

3. The external skin preparation according to claim 1 , further comprising a polyhydric alcohol.

4. 4. The skin topical preparation according to claim 3, wherein the polyhydric alcohol is 1,3-butylene glycol.

5. The skin topical preparation according to any one of claims 1 to 4, which contains water.

6. The external skin preparation according to any one of claims 1 to 4, wherein the content of the heparinoid and its salt relative to the total mass of the external skin preparation is 0.1 to 1.0 mass%.

7. The external preparation for skin according to any one of claims 1 to 4, wherein the content of salicylic acid and its salts relative to the total mass of the external preparation for skin is 0.1 to 3.0% by mass.

8. The external skin preparation according to any one of claims 1 to 4, wherein the content of the surfactant having a polyoxyethylene group is 0.5 to 10.0% by mass relative to the total mass of the external skin preparation.

9. The external preparation for skin according to any one of claims 1 to 4, wherein the content of the compound having a quaternary ammonium group is 0.05 to 1.0% by mass based on the total mass of the external preparation for skin.

10. The skin topical preparation according to any one of claims 1 to 4, wherein the ratio of the content of the compound having a quaternary ammonium group to the total content of the heparinoid and its salt and the salicylic acid and its salt is 0.1 or more.

11. The skin external preparation according to any one of claims 1 to 4, wherein the compound having a quaternary ammonium group is at least one selected from the group consisting of benzethonium, benzalkonium, cetylpyridinium, and salts thereof.

12. The skin topical preparation according to any one of claims 1 to 4, which is a liquid, cream, gel, ointment, spray, foam, or cataplasm.

Images