Skin topical composition

Abstract

Provided is a composition for an external preparation for skin, the composition including (A) vitamin A and (B) a quaternary ammonium salt-type antimicrobial agent. The composition exhibits high stability of vitamin A and excellent antimicrobial effect.

Description

[Technical Field]

[0001] The present invention relates to a vitamin A-containing composition for external use on the skin. [Background technology]

[0002] Vitamin A, such as retinol palmitate, is an active ingredient in topical skin preparations. Specifically, it is known to inhibit keratinization and promote collagen production, making it a useful ingredient for treating acne caused by clogged pores due to keratinization of the hair follicle infundibulum, as well as the atrophic acne scars that result from these scars. In particular, its analogue, retinol (retinoic acid) preparations, are also used as acne treatments.

[0003] On the other hand, since acne is caused by acne bacteria and the like, acne treatment drugs contain isopropylmethylphenol (IPMP), ibuprofen piconol, salicylic acid (Patent Document 1: JP 2011-11993 A), and allantoin (Patent Document 2: JP 2008-88127 A). Of these, IPMP is widely used in acne treatment drugs because it has a wide antibacterial spectrum.

[0004] However, when vitamin A and IPMP are combined, the stability of vitamin A is significantly reduced, and the bactericidal activity of IPMP is also reduced, making it extremely difficult to simultaneously combine the two. For these reasons, there has been a demand for a skin external preparation composition that has good vitamin A stability and excellent bactericidal effect. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-11993 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-88127 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention has been made in view of the above circumstances, and aims to provide a skin external preparation composition which has good stability of vitamin A and excellent bactericidal effect. [Means for solving the problem]

[0007] As a result of intensive research into achieving the above-mentioned object, the present inventors discovered that by combining (A) vitamin A with (B) a quaternary ammonium salt type disinfectant as a disinfectant, a skin topical composition having good stability of vitamin A and excellent disinfecting effect can be obtained, and this led to the creation of the present invention.

[0008] Therefore, the present invention provides the following external skin preparation composition. 1. A skin topical composition containing (A) vitamin A and (B) a quaternary ammonium salt type disinfectant. 2. The external skin preparation composition according to 1, having a pH of 4 to 8. 3. The topical skin composition according to 1 or 2, further comprising (C) one or more selected from esters (C-1) consisting of fatty acids having 4 to 18 carbon atoms and alcohols having 2 to 18 carbon atoms and hydrocarbons (C-2). 4. The topical skin preparation composition according to any one of 1 to 3, further comprising (D) an antioxidant and (E) one or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol. 5. The external skin preparation composition according to any one of 1 to 4, further comprising (F) ibuprofen piconol. 6. The topical skin composition according to any one of 1 to 5, wherein component (A) is retinol palmitate. 7. The external skin preparation composition according to any one of 1 to 6, wherein component (B) is benzethonium chloride. 8. The external skin preparation composition according to any one of 1 to 7, which is an O / W cream. 9. The skin external preparation composition described in any one of 1 to 8, which is for treating acne. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a skin external preparation composition in which vitamin A is highly stable and which has an excellent bactericidal effect. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will be described in detail below. [Component (A)] Examples of vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. These can be used alone or in combination of two or more. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among these, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitate is typically commercially available with a concentration of 1,000,000 to 1,800,000 international units / g (hereinafter abbreviated as IU / g). Specific examples include retinol palmitate [1.74 million IU / g] manufactured by DSM and retinol palmitate manufactured by Sigma-Aldrich.

[0011] The content of component (A) in the topical skin composition is preferably 0.01% by mass or more from the viewpoint of improving stability, and is preferably 1% by mass or less, more preferably 0.1 to 0.6% by mass, from the viewpoint of bactericidal effect. The content of component (A) in 15 g of the topical skin composition is preferably 15,000 to 1,500,000 units, more preferably 150,000 to 1,000,000 units.

[0012] [(B) Component] As the quaternary ammonium salt type disinfectant, known disinfectants can be used, and one type can be used alone or two or more types can be used in combination. Examples of component (B) include benzethonium chloride, cetylpyridinium chloride, benzalkonium chloride, etc., and among these, benzethonium chloride is preferred. As component (B), commercially available products can be used, such as benzethonium chloride: Hyamine Crystal, manufactured by Mitsubishi Chemical Foods Corporation, and benzalkonium chloride: Nissan Cation M2-100R, manufactured by NOF Corporation.

[0013] The content of component (B) in the skin external preparation composition is preferably 0.01% by mass or more from the viewpoint of bactericidal effect, and is preferably 0.5% by mass or less, more preferably 0.01 to 0.3% by mass from the viewpoint of skin irritation.

[0014] The content mass ratio represented by (A) / (B) is preferably 0.1 to 100, more preferably 1 to 100, from the viewpoint of ensuring the stability of vitamin A and maximizing the bactericidal effect.

[0015] [(C) component] From the viewpoint of the stability of vitamin A, it is preferable to blend (C) one or more selected from esters (C-1) composed of fatty acids having 4 to 18 carbon atoms and alcohols having 2 to 18 carbon atoms and hydrocarbons (C-2) in the topical skin preparation composition of the present invention. Component (C) can be used alone or in combination of two or more. Component (C-1) does not include component (E) or nonionic surfactants, which will be described later.

[0016] The ester (C-1) composed of a fatty acid having 4 to 18 carbon atoms and an alcohol having 2 to 18 carbon atoms is preferably an ester composed of a fatty acid having 4 to 18 carbon atoms, more preferably an ester composed of a fatty acid having 6 to 18 carbon atoms, and an alcohol having 2 to 18 carbon atoms.

[0017] Examples of fatty acids include, but are not limited to, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and elaidic acid. Of these, palmitic acid, stearic acid, oleic acid, and elaidic acid are preferred. Examples of alcohols include lower alcohols such as ethanol and isopropyl alcohol, and tri- to hexahydric polyalcohols such as glycerin, pentaerythritol, sorbitol, and triethanolamine. Examples of fatty acid esters include isopropyl palmitate and isopropyl myristate, with isopropyl palmitate and isopropyl myristate being preferred. Component (C-1) can be a commercially available product, such as isopropyl palmitate (NIKKOL IPP-EX, manufactured by Nikko Chemicals Co., Ltd., IPP-R, manufactured by NOF Corporation).

[0018] The hydrocarbon (C-2) is preferably a saturated hydrocarbon, and examples thereof include squalane, synthetic squalane, vegetable squalane, liquid paraffin, light liquid paraffin, petrolatum, and squalene. Among these, squalane and liquid paraffin are preferred. As the (C-2) component, commercially available products can be used, such as squalane (manufactured by Nikko Chemicals Co., Ltd.), olive squalane (manufactured by Kokyu Alcohol Kogyo Co., Ltd.), and liquid paraffin (manufactured by Sanko Chemical Industry Co., Ltd.).

[0019] The content of component (C) in the skin external preparation composition is preferably 3% by mass or more from the viewpoint of vitamin A stability, and is preferably 10% by mass or less, more preferably 5 to 8% by mass from the viewpoint of non-stickiness.

[0020] [(D) component] The topical skin preparation composition of the present invention preferably contains a fat-soluble or water-soluble antioxidant (D) from the viewpoint of the stability of vitamin A. Component (D) can be used alone or in combination of two or more. Examples of component (D) include fat-soluble stabilizers such as dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and vitamin E (e.g., tocopherol acetate, tocopherol nicotinate, tocopherol succinate, etc.), with dibutylhydroxytoluene being preferred.

[0021] Examples of water-soluble stabilizers (antioxidants) include sulfites such as sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium bisulfite, and potassium bisulfite, ascorbic acid, sodium ascorbate, glycine, and trimethylglycine. Commercially available products can be used as component (D). For example, dibutylhydroxytoluene (Fujifilm Wako Pure Chemical Industries, Ltd.) and Uvinal MC80 (BASF Japan Ltd.) are examples. Sodium pyrosulfite and ascorbic acid are preferred. Among these, sodium pyrosulfite and ascorbic acid are preferably added after cooling to 40°C or below following the emulsification step. Sodium pyrosulfite and ascorbic acid are also effective in stabilizing (F) ibuprofen piconol.

[0022] Vitamin E is used as a general term to refer to, for example, tocopherol, tocotrienol, and their salts and derivatives (esters). Specific examples include d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, mixed tocopherol, etc. Derivatives thereof include, for example, vitamin E acetate (tocopherol acetate), vitamin E nicotinate, vitamin E succinate, vitamin E linolenate, etc. These may be used alone or in appropriate combinations of two or more. Among these, tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) is preferred. Commercially available products include d-α-tocopherol acetate: Riken E Acetate α, manufactured by Riken Vitamin Co., Ltd., and dl-α-tocopherol acetate: Tocopherol Acetate, manufactured by Mitsubishi Chemical Corporation.

[0023] The content of component (D) in the topical skin preparation composition is preferably 0.05% by mass or more from the viewpoint of the stability of vitamin A, and is preferably 5% by mass or less, more preferably 0.1 to 3% by mass from the viewpoint of non-stickiness. When vitamin E is added, the content thereof in the topical skin preparation composition is preferably 0.1 to 1% by mass.

[0024] [(E) component] From the viewpoint of the stability of vitamin A, the topical skin composition of the present invention preferably contains (E) one or more nonionic surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol, and component (E) can be used alone or in combination of two or more. As component (E), polyoxyethylene hydrogenated castor oil is preferred.

[0025] Polyoxyethylene hydrogenated castor oil is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types are known with different average number of moles of ethylene oxide added. The average number of moles of ethylene oxide added in polyoxyethylene hydrogenated castor oil is not particularly limited, but is preferably 5 to 100 moles. Specific examples include polyoxyethylene hydrogenated castor oil 5 (average number of moles of EO added: 5), polyoxyethylene hydrogenated castor oil 10 (average number of moles of EO added: 10), polyoxyethylene hydrogenated castor oil 20 (average number of moles of EO added: 20), polyoxyethylene hydrogenated castor oil 30 (average number of moles of EO added: 30), polyoxyethylene hydrogenated castor oil 40 (average number of moles of EO added: 40), polyoxyethylene hydrogenated castor oil 50 (average number of moles of EO added: 50), polyoxyethylene hydrogenated castor oil 60 (average number of moles of EO added: 60), polyoxyethylene hydrogenated castor oil 80 (average number of moles of EO added: 80), and polyoxyethylene hydrogenated castor oil 100 (average number of moles of EO added: 100). Among these, polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 are preferred.

[0026] Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) with castor oil, and several types with different average moles of ethylene oxide are known. The average moles of ethylene oxide added in polyoxyethylene castor oil is not particularly limited, but is preferably 3 to 60 moles. Specific examples include polyoxyethylene castor oil 3 (average moles of EO added: 3), polyoxyethylene castor oil 10 (average moles of EO added: 10), polyoxyethylene castor oil 20 (average moles of EO added: 20), polyoxyethylene castor oil 35 (average moles of EO added: 35), polyoxyethylene castor oil 40 (average moles of EO added: 40), polyoxyethylene castor oil 50 (average moles of EO added: 50), and polyoxyethylene castor oil 60 (average moles of EO added: 60).

[0027] Examples of sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.

[0028] Specific examples of polyethylene glycol fatty acid esters include polyethylene glycol-25 stearate and polyethylene glycol-40 stearate.

[0029] In polyoxyethylene polyoxypropylene glycol, the average degree of polymerization of ethylene oxide is preferably 4 to 220, more preferably 20 to 220. The average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 5 to 80, and may be a block copolymer or a random polymer. Specific examples include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol.

[0030] Commercially available products can be used as component (E). Examples of commercially available products include polyoxyethylene hydrogenated castor oil 5 (average number of EO added moles: 5): NIKKOL HCO-5, manufactured by Nikko Chemicals Co., Ltd.; polyoxyethylene hydrogenated castor oil 10 (average number of EO added moles: 10): NIKKOL HCO-10, manufactured by Nikko Chemicals Co., Ltd.; polyoxyethylene hydrogenated castor oil 20 (average number of EO added moles: 20): NIKKOL HCO-20, manufactured by Nikko Chemicals Co., Ltd.; polyoxyethylene hydrogenated castor oil 30 (average number of EO added moles: 30): NIKKOL HCO-30, manufactured by Nikko Chemicals Co., Ltd.; polyoxyethylene hydrogenated castor oil 40 (average number of EO added moles: 40): NIKKOL HCO-40, manufactured by Nikko Chemicals Co., Ltd.; and polyoxyethylene hydrogenated castor oil 50 (average number of EO added moles: 50): NIKKOL HCO-50, manufactured by Nikko Chemicals Co., Ltd.; polyoxyethylene hydrogenated castor oil 60 (average EO addition mole number 60): NIKKOL HCO-60, manufactured by Nikko Chemicals Co., Ltd.; EMALEX HC-60, manufactured by Nippon Emulsion Co., Ltd.; sorbitan monostearate: Rheodol AS-10V, manufactured by Kao Corporation.

[0031] The content of component (E) in the skin external preparation composition is preferably 0.1% by mass or more from the viewpoint of vitamin A stability, and is preferably 3% by mass or less, more preferably 0.3 to 2% by mass from the viewpoint of non-stickiness.

[0032] [Component (F)] From the viewpoint of anti-inflammatory activity, it is preferable to incorporate (F) ibuprofen piconol into the topical skin composition of the present invention. The content of component (F) in the topical skin composition is preferably 1% by mass or more from the viewpoint of anti-inflammatory activity, and is preferably 5% by mass or less, more preferably 3 to 5% by mass from the viewpoint of side effects.

[0033] [Optional ingredients] In addition to the above-mentioned components, the topical skin preparation composition of the present invention may contain various optional components that can be incorporated into topical skin preparation compositions, such as alcohol, water, vitamin E, thickeners, pH adjusters, chelating agents, preservatives, colorants, fragrances, oily bases, surfactants other than component (E), active ingredients, etc., within a range that does not impair the effects of the present invention. These may be used alone or in appropriate amounts in appropriate combinations of two or more.

[0034] Examples of alcohols include lower alcohols having 2 to 5 carbon atoms, higher alcohols having 6 to 25 carbon atoms, polyhydric alcohols, sugar alcohols, and sterols. Examples of lower alcohols having 2 to 5 carbon atoms include ethanol and isopropanol. Examples of polyhydric alcohols having 2 to 10 carbon atoms include butylene glycol, propylene glycol, dibutylene glycol, and pentylene glycol. Examples of higher alcohols having 6 to 25 carbon atoms include lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, behenyl alcohol, hexadecyl alcohol, oleyl alcohol, isostearyl alcohol, hexyldodecanol, octyldodecanol, cetostearyl alcohol, 2-decyltetradecynol, cholesterol, phytosterol, POE cholesterol ether, monostearyl glycerin ether (batyl alcohol), and monooleyl glyceryl ether (selachyl alcohol). Examples of sugar alcohols include sorbitol and maltose. Examples of sterols include cholesterol, sitosterol, phytosterol, lanosterol, etc. When a higher alcohol is added, the content thereof is preferably 0.1 to 10% by mass in the external skin preparation composition in order to improve skin compatibility and provide a moist feeling.

[0035] Among these, from the viewpoint of composition stability (particularly prevention of separation from oily components), it is preferable to use polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, butylene glycol, and polyethylene glycol (specifically, Macrogol 200, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, and Macrogol 20000).When a polyhydric alcohol is incorporated, its content in the topical skin composition is preferably 0.05 to 20% by mass, and more preferably 1 to 15% by mass.

[0036] When water is added, the content is appropriately selected from the range of 50 to 90% by mass in the skin external preparation composition.

[0037] The thickener is preferably a polymer compound soluble in water or a mixed solvent system of lower alcohol / water, and examples thereof include cellulose derivatives such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carmellose, croscarmellose, ethyl cellulose, and methyl cellulose, processed starches such as partially pregelatinized starch, polyvinyl alcohol, polyvinyl methyl ether, polyvinylpyrrolidone, crospovidone, polyethylene glycol, xanthan gum, carrageenan, sodium alginate, guar gum, tamarind gum, gum arabic, karaya gum, tragacanth gum, and lactic acid bacteria. Examples of thickeners include carob gum, pullulan, gelatin, carboxyvinyl polymer, acrylic acid / alkyl methacrylate copolymer, sodium polyacrylate, hydroxyethyl acrylate / acryloyldimethyl taurate crosslinked polymer, quince seed, casein, dextrin, sodium pectinate, dimethylacrylamide / acryloyldimethyl taurate crosslinked polymer, dialkyldimethylammonium cellulose sulfate, magnesium aluminum silicate, bentonite, hectorite, magnesium aluminum silicate (veegum), laponite, and silicic anhydride. When a thickener is added, its content is selected appropriately depending on the desired viscosity of the topical skin composition, but is preferably 0.01 to 5% by mass, and more preferably 0.05 to 3% by mass, of the topical skin composition.

[0038] Examples of the acid pH adjuster include inorganic acids such as hydrochloric acid, phosphoric acid, and boric acid, and organic acids such as lactic acid, tartaric acid, and citric acid. Examples of alkaline agents include sodium hydroxide, potassium hydroxide, various amines such as monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, and tromethamine. Examples of organic salts include phosphates such as potassium hydrogen phosphate and sodium hydrogen phosphate, sodium citrate, and sodium lactate. The amount of pH adjuster can be appropriately selected depending on the desired pH. When a pH adjuster is contained, its amount is an amount that results in a suitable pH of the topical skin preparation composition, as described below. For example, the amount is preferably 0.01 to 5% by mass, and more preferably 0.05 to 1% by mass, of the topical skin preparation composition. By keeping the amount within the above range, the content stability of component (A) is further improved, and the content stability of any active ingredient is also improved.

[0039] In addition, from the viewpoint of pH stability, sodium hydroxide, diisopropanolamine, triisopropanolamine, and triethanolamine are preferred as alkaline agents when vitamin A or a nonionic surfactant is used. This is because the content of easily oxidizable substances such as vitamin A and nonionic surfactants decreases due to oxidative decomposition in the cream, and the oxidation can be prevented to suppress the decrease in content.

[0040] Examples of chelating agents that can be added to stabilize the composition include disodium edetate, ethylenediaminetetraacetate, edetate, pyrophosphate, hexametaphosphate, citric acid, tartaric acid, gluconic acid, etc. When a chelating agent is added, the content thereof in the external skin preparation composition is preferably 0.001 to 5% by mass, and more preferably 0.01 to 1% by mass.

[0041] Examples of preservatives include benzoic acids, parabens (methylparaben, ethylparaben, butylparaben), phenoxyethanol, sorbic acid and its salts, boric acid, borax, etc. When a preservative is added, the content thereof in the external skin preparation composition is preferably 1% by mass or less, and more preferably 0.08 to 0.5% by mass.

[0042] Any dye that can be used in topical preparations (cosmetics, pharmaceuticals), such as acid dyes, basic dyes, oxidative dyes, and pigments, can be used as the colorant. Natural and synthetic flavors can be used as the fragrance without any particular restrictions. For example, fragrances described in literature such as "Perfume and Flavor Chemicals" Vol. I and II (Steffen Arctander, Allured Pub. Co. (1994)), "Synthetic Fragrances: Chemistry and Product Knowledge" (by Genichi Indo, Chemical Daily Co. (1996)), "Perfume and Flavor Materials of Natural Origin" (Steffen Arctander, Allured Pub. Co. (1994)), "Encyclopedia of Fragrances" (edited by the Japan Fragrance Manufacturers Association, Asakura Shoten (1989)), and "Flower Oils and Floral Compounds in Perfumery" (Danute Lajaujis Anonis, Allured Pub. Co. (1993)) can be used. For example, natural fragrances include plant-based fragrances such as peppermint oil, spearmint oil, jasmine oil, lemon oil, orange oil, lime oil, mandarin oil, rose oil, and rosemary oil. Synthetic fragrances include monoterpenes, diterpenes, and sesquiterpenes, specifically geraniol, linalool, citronellol, nerol, limonene, pinene, camphene, citral, citronellal, cineole, curcumene, hinoki acid, hinokiol, and phytol. When a colorant and a fragrance are incorporated, their content in the external skin preparation composition is preferably 0.0001 to 5% by mass, and more preferably 0.0001 to 1% by mass.

[0043] Examples of oily bases for aiding in the dissolution of oil-soluble ingredients such as vitamin A include vegetable oils such as olive oil, cacao oil, camellia oil, palm oil, Japan wax, jojoba oil, grapeseed oil, and avocado oil; natural and synthetic fatty acids such as lauric acid, myristic acid, stearic acid, oleic acid, isostearic acid, and behenic acid; natural and synthetic higher alcohols such as cetanol, stearyl alcohol, hexyldecanol, octyldodecanol, and lauryl alcohol; linear silicones such as dimethylpolysiloxane, methylphenylpolysiloxane, and methylhydrogenpolysiloxane; decamethylcyclopentasiloxane; and octamethylcyclopentasiloxane. Examples of suitable oily bases include cyclic silicones such as cyclotetrasiloxane, crosslinked silicones such as crosslinked methylpolysiloxane and crosslinked methylphenylpolysiloxane, silicone oils such as modified silicones modified with polyoxyethylene or polyoxypropylene, and silicone polymer compounds in which linear or cyclic silicone chains are copolymerized with polymers such as polyacrylic acid. More preferred are natural and synthetic fatty acids such as lauric acid, myristic acid, stearic acid, oleic acid, isostearic acid, and behenic acid; and natural and synthetic higher alcohols such as cetanol, stearyl alcohol, hexyldecanol, octyldodecanol, and lauryl alcohol. When an oily base is incorporated, its content in the topical skin preparation composition is preferably 10% by mass or less.

[0044] As surfactants other than component (E), any of nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants other than component (E) can be used to maintain the physical stability of the topical skin preparation composition and disperse insoluble components. Examples of nonionic surfactants other than component (E) include polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene (20) sorbitan monooleate (polysorbate 80) and polyoxyethylene (20) sorbitan monostearate (polysorbate 60). Other surfactants that can be used include glycerin fatty acid esters such as glyceryl monostearate, polyglycerin fatty acid esters such as polyglyceryl monostearate, polyoxyethylene sorbit fatty acid esters such as polyoxyethylene (60) sorbit tetraoleate, and polyoxyethylene alkyl ethers such as polyoxyethylene (25) lauryl ether. When surfactants other than component (E) are incorporated, their content in the topical skin preparation composition is preferably 5% by mass or less, more preferably 3% by mass or less.

[0045] The active ingredient is not particularly limited as long as it can be incorporated into an external preparation, and examples thereof include prednisolone valerate acetate, ufenamate, crotamiton, glycyrrhetinic acid, glycyrrhizinic acid and its derivatives and pharmaceutically acceptable salts, allantoin, methyl salicylate, lidocaine, l-menthol, panthenol, heparinoids, urea, etc.

[0046] [Manufacturing method] The method for producing the topical skin preparation composition of the present invention is not particularly limited, and examples thereof include the following method. An aqueous phase containing water-soluble components is prepared by heating and dissolving at 60 to 70°C. Separately, an oil phase containing components (A) and (B), and optionally components (C) and (D), is prepared by heating and dissolving at 60 to 70°C. The oil phase dissolved by heating at 60 to 70°C is added to the stirred aqueous phase heated to 60 to 70°C to obtain an O / W emulsion. The obtained O / W emulsion is cooled to 40°C or below, and a fragrance dissolved in a polyhydric alcohol is prepared and added, if necessary. The mixture is then cooled to 30°C or below, and the pH is adjusted to obtain the topical skin preparation composition.

[0047] [External skin preparations] The viscosity of the topical skin composition of the present invention is not particularly limited and can be selected appropriately depending on the purpose, but the viscosity at 25° C. is preferably 1 to 100 Pa·s, more preferably 15 to 75 Pa·s. The viscosity is measured using a BH-type viscometer (manufactured by Tokyo Keiki Co., Ltd.) with a No. 7 rotor at 25° C., at a rotation speed of 20 rpm, for 1 minute.

[0048] The pH (20°C) of the topical skin composition of the present invention is not particularly limited, but from the viewpoints of skin irritation and stabilization of the content of component (A), it is preferably 4 to 8, more preferably 6 to 8. The pH is measured according to the General Testing Methods of the Japanese Pharmacopoeia, 17th Edition (measurement temperature: 20°C).

[0049] The formulation of the topical skin preparation composition is not particularly limited, and examples include emulsions, gels, liquids, and the like. Among these, emulsions are preferred, more preferably O / W emulsions, and even more preferably O / W creams. Furthermore, the topical skin preparation composition of the present invention has excellent bactericidal activity against acne-related bacteria, and when used in combination with vitamin A, it has an inhibitory effect on keratinization in hair follicles and enhances the metabolism of mucopolysaccharides, resulting in excellent acne treatment effects. Therefore, it is suitable as a treatment (medicine) for acne and eczema, and is particularly suitable as a treatment (medicine) for acne.

[0050] [Stabilization method] The present invention provides a method for stabilizing component (A) in a skin external preparation composition containing vitamin A, by blending (B) a quaternary ammonium salt-type disinfectant. As shown in the examples below, the stability of component (A) over time is achieved. The preferred components, amounts, etc. are the same as those described above. [Example]

[0051] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, unless otherwise specified, "%" in the composition indicates % by mass, and the ratio indicates the mass ratio.

[0052] [Examples and Comparative Examples] Skin topical compositions having the compositions shown in the table below were obtained by the method described below. The obtained skin topical compositions were evaluated as follows. The results are also shown in the table. (1) Preparation of Preliminary Solution I (Aqueous Phase) A portion of 1,3-butylene glycol was added to purified water, and sodium edetate and carboxyvinyl polymer were added to swell the mixture, which was then heated to 60°C to dissolve (aqueous phase). (2) Preparation of Preliminary Solution II (Oil Phase) The oil-soluble ingredients (components (A) to (D), etc., excluding sodium pyrosulfite and ascorbic acid) were added in order and dissolved by heating at 60°C. (3) Emulsification The aqueous phase prepared in (1) was stirred with a homogenizer while the oil phase prepared in (2) was added. After the addition was complete, the mixture was stirred for about 5 minutes to obtain an O / W emulsion. (4) Fragrance blending and pH adjustment The O / W emulsion was then cooled, and when the temperature reached 40°C or below, a fragrance was added, and the emulsion was further cooled to 30°C or below, after which the pH was adjusted to 7.0 with sodium hydroxide to obtain a skin topical preparation composition. In Examples 16, 19, 20, and 21, sodium pyrosulfite and / or ascorbic acid were added immediately before the fragrance was added (when the emulsion reached 40°C or below).

[0053] <Vitamin A stability> 15 g of the obtained skin external preparation composition was stored in an aluminum tube for 6 weeks at 50° C. After storage, the remaining amount of vitamin A (retinol palmitate) was measured using liquid chromatography, and the remaining vitamin A rate (%) was calculated, assuming the initial content as 100%.

[0054] <Bactericidal activity: MIC measurement method using agar plate dilution method> The minimum inhibitory concentrations (MICs) against Staphylococcus aureus (Sa; NBRC 13276 strain, obtained from the National Institute of Technology and Evaluation (NBRC)) and Propionibacterium acnes (Pa; NBRC 107605 strain, obtained from the National Institute of Technology and Evaluation (NBRC)) were determined by the agar dilution method. The topical skin preparation composition was diluted 5-800 times with TSB medium (Nippon Becton Dickinson and Company), and 2 mL of the diluted solution was mixed with 18 mL of Mueller-Hinton agar medium (Fujifilm Corporation) or GAM agar medium (Nissui Pharmaceutical Co., Ltd.) to prepare agar medium. Thereafter, Sa bacteria or Pa bacteria were inoculated, and Sa bacteria were cultured at 35°C for 18 to 24 hours, and Pa bacteria were cultured at 35°C for 48 to 72 hours, and the presence or absence of bacterial growth was observed with the naked eye. The results are shown in terms of the dilution ratio of the topical skin preparation composition. The higher the dilution ratio, the lower the minimum inhibitory concentration, i.e., the stronger the bactericidal effect. Note that "x" in comparative examples indicates no bactericidal effect (bacterial growth was observed even at a 5-fold dilution).

[0055] <Evaluation of usability> Ten female subjects were asked to evaluate the following items regarding the feel when applying a topical skin composition (approximately 0.5 g) to the face immediately after preparation (non-stickiness, no skin irritation after 3 hours) on a four-point scale: 3: very good, 2: good, 1: average, 0: poor. The average scores are shown (rounded to one decimal place).

[0056] [Table 1]

[0057] [Table 2]

[0058] [Table 3]

[0059] [Table 4]

[0060] [Prescription example] External skin preparation compositions were prepared according to the compositions shown in the table below. The obtained external skin preparation compositions had the same effects as those in the above examples.

[0061] [Table 5]

[0062] [Table 6]

[0063] [Table 7]

[0064] The raw materials used in the above examples are listed below. Unless otherwise specified, the amounts of each component in the table are pure amounts. Retinol palmitate: Retinol palmitate [1.74 million IU / g], DSM Nutrition Japan Co., Ltd. Benzethonium chloride: Hyamine crystals, Mitsubishi Chemical Foods Co., Ltd. Benzalkonium chloride: Nissan Cation M2-100R, manufactured by NOF Corporation Cetylpyridinium chloride: Cetylpyridinium chloride, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Isopropyl palmitate: NIKKOL IPP-EX, Nikko Chemicals Co., Ltd. Isopropyl myristate: IPM-R, manufactured by Kokyu Alcohol Kogyo Co., Ltd. Squalane: Squalane, Nikko Chemicals Co., Ltd. Liquid paraffin: No. 350-S, manufactured by Sanko Chemical Industry Co., Ltd. Dibutylhydroxytoluene: Dibutylhydroxytoluene, Fujifilm Wako Pure Chemical Industries, Ltd. Ascorbic acid: Ascorbic acid 100M, manufactured by Fuso Chemical Co., Ltd. Polyoxyethylene (60) hydrogenated castor oil: EMALEX HC-60, Nippon Emulsion Co., Ltd. Sorbitan monostearate: Leodor AS-10V, Kao Corporation 1,3-butylene glycol: 1,3-butylene glycol, Daicel Chemical Industries, Ltd. Carboxyvinyl polymer: Carbopol 981, Lubrizol Japan Co., Ltd. Stearyl alcohol: Stearyl alcohol, Kokyu Alcohol Kogyo Co., Ltd. Octyldodecanol: Lisonol 20SP, Kokyu Alcohol Kogyo Co., Ltd. Tocopherol acetate: Tocopherol acetate, Mitsubishi Chemical Corporation Diisopropanolamine: Diisopropanolamine, Mitsui Fine Chemicals Co., Ltd. Sodium hydroxide: Sodium hydroxide, Kosakai Pharmaceutical Co., Ltd. Polysorbate 60: Polysorbate 60 (HLB 14.9), Nikko Chemicals Co., Ltd. Fragrance: Paragraph of JP 2002-128658 A

[0065] to

[0071] , A to E described in JP-A No. 2003-73249, or 1 to 4 described in Japanese Patent Application No. 2019-023940

[0016] to

[0023] . Isopropylmethylphenol: Biosol, manufactured by Osaka Kasei Co., Ltd.

Claims

1. (A) one or more selected from retinol palmitate and retinol acetate; (B) one or more selected from benzethonium chloride, cetylpyridinium chloride, and benzalkonium chloride; (C) one or more selected from isopropyl palmitate, isopropyl myristate, light liquid paraffin, and liquid paraffin; A skin external preparation composition comprising:

2. 2. The external skin preparation composition according to claim 1, which has a pH of 4 to 8.

3. A topical skin composition as described in claim 1 or 2, wherein the content of component (C) in the topical skin composition is 3% by mass or more and 10% by mass or less.

4. The external skin preparation composition according to any one of claims 1 to 3, further comprising (D) an antioxidant.

5. A skin topical composition according to any one of claims 1 to 4, wherein the component (D) is one or more selected from sodium pyrosulfite, ascorbic acid, dibutylhydroxytoluene, butylhydroxyanisole and vitamin E.

6. A skin topical composition according to any one of claims 1 to 5, further comprising (E) one or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol.

7. The external skin preparation composition according to any one of claims 1 to 4, further comprising (F) ibuprofen piconol.

8. The external skin preparation composition according to any one of claims 1 to 7, which is an O / W cream.

9. The external skin preparation composition according to any one of claims 1 to 8, which is for treating acne.

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