Compositions for topical skin use

Abstract

In a composition combining (A) pyridoxine salts, etc. and (B) heparinoids, the photostability of (A) pyridoxine salts, etc. is improved while maintaining the effect of improving the skin barrier function. [Solution] (A) One or more selected from the group consisting of pyridoxine, its derivatives and pharmaceutically acceptable salts thereof, (B) Heparin-like substances, and (C) Nicotinamide, A topical skin preparation composition containing [a specific ingredient].

Description

Technical Field

[0001] The present invention relates to a composition for external use on the skin containing pyridoxine salts or the like and a heparin-like substance.

Background Art

[0002] "Pyridoxine salts or the like" is known to have effects such as suppression and normalization of sebum secretion, and is widely used in cosmetics, pharmaceuticals or quasi-drugs. By combining "pyridoxine salts or the like" with a "heparin-like substance" known to have effects such as blood circulation promotion, anti-inflammation, and moisturizing, it is expected to be a skin external preparation that increases the expression level of Claudin-4 and improves the skin barrier function (Patent Document 1: Japanese Patent Application Laid-Open No. 2024-95558).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present inventors have found that the above effects can be obtained by combining (A) pyridoxine salts or the like and (B) a heparin-like substance. However, this combination has a problem that the photo stability of (A) pyridoxine salts or the like deteriorates and it is difficult to stably formulate them in the composition. The present invention has been made in view of the above circumstances, and aims to improve the photo stability of (A) pyridoxine salts or the like in a composition combining (A) pyridoxine salts or the like and (B) a heparin-like substance.

Means for Solving the Problems

[0005] As a result of diligent research to achieve the above objective, the present inventors have found that the above problem can be solved by including (C) nicotinamide in a composition combining (A) pyridoxine salt and (B) a heparin-like substance, and have thus come to the present invention.

[0006] Accordingly, the present invention provides the following topical skin preparation compositions. 1. (A) One or more selected from the group consisting of pyridoxine, its derivatives and pharmaceutically acceptable salts thereof, (B) Heparin-like substances, and (C) Nicotinamide, A topical skin preparation composition containing [a specific ingredient]. 2. The topical skin composition according to claim 1, wherein component (A) is one or more selected from pyridoxine hydrochloride and pyridoxal phosphate. 3. A topical skin preparation composition according to claim 1 or 2, wherein the content of component (C) is 0.1 to 5% by mass. 4. A topical skin preparation composition according to any one of 1 to 3, wherein the mass content ratio expressed as (C) / ((A)+(B)) is 0.1 to 90. 5. A topical skin preparation composition according to any one of claims 1 to 4, further containing a pH adjuster and having a pH of 4 to 8. [Effects of the Invention]

[0007] According to the present invention, in a composition combining (A) pyridoxine salt and (B) heparin-like substance, it is possible to improve the photostability of (A) pyridoxine salt while maintaining the effect of improving the skin barrier function. [Modes for carrying out the invention]

[0008] The present invention will be described in detail below. [(A) component] Component (A) of the present invention is one or more selected from the group consisting of pyridoxine, its derivatives, and pharmaceutically acceptable salts thereof, and can be used alone or in combination of two or more. Examples of derivatives include pyridoxal and pyridoxamine, and examples of pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate. Among these, pyridoxine, pyridoxine hydrochloride, and pyridoxal phosphate are preferred, with pyridoxine hydrochloride being more preferred, from the viewpoint of having a high effect in promoting skin tight junction expression and pyridoxine being metabolized to exert its pharmacological effect as the active product pyridoxal phosphate. Component (A) may be synthesized by known methods or can be obtained as a commercially available product.

[0009] The content of component (A) is not particularly limited, but is preferably 0.005 to 0.8% by mass, more preferably 0.005 to 0.7% by mass, and even more preferably 0.01 to 0.5% by mass. Setting it above the lower limit makes it easier to obtain the skin barrier function improvement effect (enhanced Claudin-1 expression), while setting it below the upper limit makes it easier to obtain the content stability of component (A) and makes it less likely to cause skin irritation.

[0010] [(B) Component] The heparinoid, which is component (B) of the present invention, is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is known to have moisturizing effects, improve xerosis, and increase blood flow.

[0011] The origin of the heparin-like substance used in the present invention is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides, or those extracted from the tissues of edible animals (for example, lungs including tracheal cartilage of cattle or pigs). In the topical composition of the present invention, the heparin-like substance is preferably the heparin-like substance defined in the Japanese Pharmacopoeia Standards for Non-Official Drugs (Standard No.: 108548).

[0012] The content of component (B) is not particularly limited, but is preferably 0.005 to 5% by mass, more preferably 0.1 to 0.7% by mass, and even more preferably 0.1 to 0.3% by mass in the topical skin preparation composition. A content above the lower limit makes it easier to obtain moisturizing effects and skin barrier function improvement effects (enhanced Claudin-1 expression). A content below the upper limit improves the photostability of component (A).

[0013] [(C) component] Component (C) of this invention is nicotinamide, which is known for its whitening and anti-wrinkle effects. It is also known by other names such as niacinamide, nicotinamide, D-melano, and wrinkle niacin. In this invention, by incorporating and including component (C), it is possible to suppress the photoinstability of pyridoxine salts, etc., caused by combining them with (A) pyridoxine salts, etc. and (B) heparinoids.

[0014] The content of component (C) is not particularly limited, but from the viewpoint of its effect on the photostability of component (A) and its solubility in the topical skin preparation composition, it is preferably 0.1 to 5% by mass, more preferably 1 to 5% by mass, and even more preferably 3 to 5% by mass. Setting it above the lower limit further improves the photostability of component (A). Setting it below the upper limit makes skin irritation less likely.

[0015] The lower limit of the mass ratio of component (B) to component (A), (B) / (A), is preferably 0.5 or higher, more preferably 1 or higher, and even more preferably 5 or higher. Setting the mass ratio above the lower limit makes skin irritation less likely. The upper limit of the mass ratio is preferably 50 or lower, and more preferably 30 or lower. Setting the mass ratio below the upper limit makes it easier to obtain the skin barrier function improvement effect (skin tight junction expression promotion effect, hypersensitive skin improvement effect, chronic itching improvement effect) by using component (A) and component (B) in combination.

[0016] The content mass ratio represented by (C) / ((A)+(B)) is preferably from 0.1 to 90, more preferably from 1 to 47, still more preferably from 4 to 46, particularly preferably from 15 to 46, and most preferably from 30 to 46. By setting it to be not less than the lower limit value, the light stability of component (A) is further improved. By setting it to be not more than the upper limit value, the appearance stability of the skin external preparation composition is further improved (the generation of oiliness is more suppressed).

[0017] In addition to the above components (A) to (C), the skin external preparation composition of the present invention may contain various active ingredients used in pharmaceuticals, quasi-drugs, cosmetics, etc. as long as the effects of the invention are not impaired. For example, anti-inflammatory agents, antihistamines, crude drug components, antipruritics, wound healing agents, local anesthetics, vitamins, cooling agents, moisturizing agents, bactericides, vasoconstrictors, amino acids, whitening agents, etc. can be contained, and the following components are exemplified.

[0018] Examples of anti-inflammatory agents include glycyrrhetinic acid, allantoin, steroid compounds (hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, cortisone, fluocinolone, beclomethasone, fluticasone or their derivatives), indomethacin, ibuprofen, ibuprofen picolol, bufexamac, ufenamate, piroxicam, ketoprofen, salicylic acid or its derivatives, dimethylisopropylazulene, toki extract, shikonin extract, etc.

[0019] Examples of antihistamines include diphenhydramine, chlorpheniramine, mequitazine, azelastine, emedastine, ketotifen or their derivatives, etc. Preferably, diphenhydramine hydrochloride and chlorpheniramine maleate are included.

[0020] Examples of crude drug components include artichoke leaf extract, althaea root extract, arnica flower extract, aloe vera leaf extract, ginkgo leaf extract, unshu mikan pericarp extract, saffron root extract, carrot root extract, viola flower / leaf / stem extract, olive leaf extract, orange fruit extract, brown algae extract, chamomile flower extract, licorice extract, strawberry fruit extract, phellodendron bark extract, cucumber fruit extract, gardenia fruit extract, clara root extract, grapefruit fruit extract, chlorella extract, yeast extract, Japanese quince extract, peony root extract, ginger root extract, birch bark extract, shepherd's purse extract, common yarrow leaf / stem extract, English plantain extract, sage leaf extract, zinnia flower extract, centifolia rose flower extract, centella extract, sophora flavescens extract, soybean seed extract, tea leaf extract, atractylodes root extract, flos carthami extract, raspberry fruit extract, coix seed extract, witch hazel leaf extract, loquat leaf extract, prune decomposition product, carnation flower extract, button extract, elm extract, peach leaf extract, echinacea flower extract, eucalyptus leaf extract, saxifrage extract, yuzu fruit extract, lavender flower extract, apple fruit extract, lemon fruit extract, rosemary leaf extract, etc.

[0021] Examples of antipruritics include salicylic acid or its derivatives, nonyl vanillylamide, capsaicin, benzyl nicotinate, capsicum tincture, etc.

[0022] Examples of wound healing agents include zinc oxide, allantoin, etc.

[0023] Examples of local anesthetics include lidocaine, lidocaine hydrochloride, methyl aminobenzoate, ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, etc.

[0024] Examples of vitamins other than (A) component include vitamin A [retinol and its derivatives (e.g., retinal, retinoic acid, retinyl palmitate, etc.)], vitamin B1 [thiamine and its derivatives (e.g., thiamine hydrochloride, thiamine nitrate, etc.)], vitamin B2 [riboflavin and its derivatives (e.g., riboflavin phosphate, riboflavin sodium phosphate, riboflavin butyrate, and flavin adenine dinucleotide sodium, etc.)], vitamin B3 [nicotinic acid and its derivatives (e.g., tocopherol nicotinate, benzyl nicotinate, etc.)], vitamin B5 [pantothenic acid and its derivatives (e.g., calcium pantothenate, panthenol, pantothenyl ethyl alcohol)], vitamin B 12 Examples include cobalamin and its derivatives (e.g., cyanocobalamin, mecobalamin, and hydroxocobalamin hydrochloride), biotin, folic acid or its pharmaceutically acceptable salts, vitamin C derivatives (e.g., ascorbic acid and its derivatives (e.g., erythorbic acid, sodium ascorbate, ascorbic palmitate), vitamin D derivatives (calciferol and its derivatives (e.g., ergocalciferol, cholecalciferol)), vitamin E derivatives (tocopherol, ubiquinone and its derivatives (e.g., tocopherol acetate, tocopherol calcium succinate)), and other vitamins (e.g., hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, inositol, and their pharmaceutically acceptable salts).

[0025] Examples of cooling agents include camphor, borneol or related substances, fennel oil, eucalyptus oil, peppermint oil, ethanol, and menthol.

[0026] Examples of moisturizers other than component (B) include polyhydric alcohols (glycerin, 1,3-butylene glycol, etc.), hyaluronic acid or its derivatives, high molecular weight compounds (collagen, chitosan, etc.), natural moisturizing factors (sodium lactate, urea, etc.), ceramides, and plant extracts (chamomile extract, aloe extract, etc.).

[0027] Examples of fungicides include isopropylmethylphenol, chlorhexidine hydrochloride, benzethonium chloride, benzalkonium chloride, and cetrimide.

[0028] Examples of vasoconstrictors include naphazoline, tetrahydrozoline, methyl ephedrine, or their salts.

[0029] Examples of amino acids include glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine), and their pharmaceutically acceptable salts.

[0030] Examples of whitening agents other than ingredient (C) include placenta, arbutin, kojic acid, ellagic acid, phytic acid, tranexamic acid, lucinol, chamomile ET, hydroquinone, potassium 4-methoxysalicylate, linoleic acid and its derivatives, ascorbic acid and its salts, vitamin C derivatives such as sodium ascorbate phosphate, magnesium ascorbate phosphate, ascorbyl tetra-2-hexyldecanoate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbic acid glucoside, disodium isostearyl ascorbyl phosphate, L-ascorbyl dipalmitate, trisodium ascorbyl palmitate phosphate, glyceryl ascorbate, bisglyceryl ascorbate, alkylglyceryl ascorbate, etc., vitamin A or its derivatives, pantothenic acid or its derivatives, and other vitamins. Furthermore, plant-derived ingredients with whitening properties may be used as whitening ingredients. Such plant-derived ingredients include iris, almond, aloe, acerola, oolong tea, rosehip, scutellaria, coptis japonica, St. John's wort, deadnettle, seaweed, kudzu, gardenia, Sophora flavescens, chlorella, rice, rice husk, oryzanol, rice bran, Asarum sieboldii, Japanese pepper, perilla, peony, Cnidium officinale, mulberry bark, soybean, natto, tea, angelica, calendula, witch hazel, safflower, peony bark, coix seed, catechu, and persimmon (Diospyros). The ingredients include those derived from kaki, kiwi, black bean, gentian, genjin, sage, radish, azalea, parsley, holly, hops, thyme, clove, dried tangerine peel, licorice, chamomile, prune, meadowsweet, purple beautyberry, water oats, grapefruit, thornless berry, lemon, kiwi, pine, neem, artichoke, horsetail, Phellodendron bark, evening primrose, bilberry, geranium, glasswort, white willow, saxifrage, centella asiatica, rosemary, lavender, and Cornus officinalis.

[0031] The topical skin preparation composition of the present invention can be prepared by combining the above components (A) to (C), and optionally other active ingredients, with various additives described later, according to conventional methods. Any of the pharmaceutical additives or cosmetic ingredients that can be included in topical preparations can be used to prepare the topical skin preparation composition of the present invention.

[0032] Other optional ingredients (various additives) include, for example, oils, surfactants, polyhydric alcohols (including those that overlap with the above), polymer compounds (including those that overlap with the above), stabilizers, antioxidants, preservatives, pH adjusters, fragrances, water, etc.

[0033] Examples of oily agents include hydrocarbons such as petrolatum, paraffin, liquid paraffin, squalane, ceresin, gelling hydrocarbons, and microcrystalline wax; higher fatty acids such as stearic acid, isostearic acid, myristic acid, oleic acid, and behenic acid; higher fatty alcohols such as cetanol, stearyl alcohol, cetostearyl alcohol, octyldodecanol, and behenyl alcohol; fatty acid esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, and diisopropyl adipate; and triglycerides such as glyceryl triisooctanoate and tri(caprylic / capric acid)glyceryl. When oily agents are included, their content is preferably 0.05 to 30% by mass in the topical skin preparation composition.

[0034] Examples of surfactants include nonionic surfactants and ionic surfactants. Examples of nonionic surfactants include glycerin fatty acid esters such as glyceryl monostearate and glyceryl monooleate, polyglyceryl-10 monolaurate, polyglyceryl-10 monostearate, polyglyceryl-10 monooleate, and polyglyceryl-10 pentaoleate; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene(15) glyceryl monostearate; sorbitan monostearate, sorbitan monooleate, and sesquicarbonate. Sorbitan fatty acid esters such as sorbitan oleate, polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and other polyoxyethylene sorbitan fatty acid esters; polyoxyethylene (6) sorbitan monolaurate, polyoxyethylene (60) sorbitan tetrastearate, polyoxyethylene tetraoleate Examples include polyoxyethylene sorbitol fatty acid esters such as (60) sorbitol; polyoxyethylene castor oil such as polyoxyethylene (60) castor oil; polyoxyethylene hydrogenated castor oil such as polyoxyethylene (10) hydrogenated castor oil and polyoxyethylene (60) hydrogenated castor oil; polyethylene glycol fatty acid esters such as polyethylene glycol monolaurate (10EO), polyethylene glycol monooleate (10EO), polyethylene glycol monostearate (40EO), polyethylene glycol monostearate (45EO), and polyethylene glycol monostearate (55EO); polyoxyethylene alkyl ethers such as polyoxyethylene (9) lauryl ether (lauromcrogol), polyoxyethylene (10) cetyl ether, and polyoxyethylene (15) oleyl ether; and polyoxyethylene alkyl ethers such as polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene (20) polyoxypropylene (8) cetyl ether.In the above examples, the number at the end of the polyglycerin fatty acid ester notation represents the average degree of polymerization of glycerin, and the number in parentheses in the above examples of nonionic surfactant notation represents the average degree of polymerization of ethylene oxide or propylene oxide, that is, the average number of repeating oxyethylene groups or oxypropylene groups.

[0035] Examples of ionic surfactants include sodium lauryl sulfate and sodium cetyl sulfate. When surfactants are included, the content is preferably 0.1 to 10% by mass in the topical skin preparation composition.

[0036] Examples of polyhydric alcohols include glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol (macrogol 300, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 20000). Among these, glycerin, propylene glycol, 1,3-butylene glycol, and macrogol 400 are preferred from the viewpoint of usability (ease of spreading) of the topical skin preparation composition. When polyhydric alcohols are included, the content is preferably 0.05 to 40% by mass, and more preferably 1 to 30% by mass, in the topical skin preparation composition.

[0037] Examples of high-molecular-weight compounds include carboxyvinyl polymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydrophobized hydroxypropyl methylcellulose, acrylic starch 300, polyvinylpyrrolidone (K-30, K-90, etc.), gellan gum, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, dammar gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparan sulfate, hyaluronic acid, chondroitin sulfate, and the like. When high-molecular-weight compounds are included, the content is preferably 0.01 to 5% by mass in the topical skin preparation composition.

[0038] Examples of stabilizers include sodium chloride, sodium thiosulfate, sodium sulfite, sodium edetate, boric acid, and borax. Among these, boric acid, borax, and sodium edetate are particularly suitable from the viewpoint of content stability of component (B). When a stabilizer is included, the amount is preferably 0.01 to 5% by mass, and more preferably 0.02 to 1% by mass, in the topical skin preparation composition.

[0039] Examples of antioxidants include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid, sodium ascorbate, quercetin, tocopherol acetate, ascorbyl palmitate, sodium pyrosulfite, gallic acid, propyl gallate, and rutin. When antioxidants are included, the amount is preferably 0.001 to 0.1% by mass in the topical skin preparation composition. Including the above amount further improves the photostability of component (A).

[0040] Examples of preservatives include methyl parahydroxybenzoate (methylparaben), propyl parahydroxybenzoate (propylparaben), butyl parahydroxybenzoate (butylparaben), sodium benzoate, chlorobutanol, phenoxyethanol, dibutylhydroxytoluene, benzalkonium chloride, and benzethonium chloride. When preservatives are included, the content is preferably 0.01 to 5% by mass, and more preferably 0.05 to 1% by mass, in the topical skin preparation composition.

[0041] Examples of pH adjusting agents include citric acid, sodium citrate, sodium citrate hydrate, diisopropanolamine, triethanolamine, sodium hydroxide, hydrochloric acid, potassium dihydrogen phosphate and sodium hydrogen phosphate, lactic acid, sodium lactate, malic acid, and sodium malate. When incorporating a pH adjusting agent, the amount should be sufficient to achieve the desired pH as described later. For example, 0.01 to 5% by mass is preferred, and 0.03 to 1% by mass is more preferred, in the skin topical preparation composition.

[0042] Examples of fragrances include blended fragrances such as citrus, floral, and rose scents, as well as essential oils such as eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, spearmint oil, rosemary oil, lavender oil, and lemon oil. Typical components contained in these fragrances include terpenoid compounds. Terpenoid compounds include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. They are also classified into monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes depending on the number of carbon atoms, but monoterpenes are the most representative components. Preferred terpenoid compounds include l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, citral, limonene, citronellol, geraniol, cineole, linalool, nonanal, eugenol, isoeugenol, indole, bensaldehyde, vanillin, limonene, galaxolide, γ-nonalactone, γ-methylionone, iso-E-super, Z-3-hexenyl salicylate, γ-undecalactone, 5-cyclohexadecene-1-one, 2-methyl-4-phenyl-2-butanol, methyldihydrojasmonate, methyl-β-naphthylketone, cinnamyl acetate, benzyl acetate, α-terpineol, hexyl cinnamicaldehyde, and γ-undecalactone. If fragrance is included, the amount is preferably 0.001 to 1% by mass, and more preferably 0.01 to 0.1% by mass, in the topical skin preparation composition.

[0043] When water is included, its content is appropriately selected from a range of 10 to 98% by mass in the topical skin preparation composition, depending on the dosage form.

[0044] [Manufacturing method] The topical skin preparation composition of the present invention can be obtained, for example, by mixing components (A) to (C) and, if necessary, any other components (other active ingredients, various additives).

[0045] [Skin topical preparation composition] The dosage form of the topical skin preparation composition of the present invention is not particularly limited, as long as it can be applied transdermally, and may be liquid, solid, semi-solid (gel, ointment, paste), etc. Furthermore, the topical skin preparation composition of the present invention may be a pharmaceutical, quasi-drug, cosmetic, skin cleanser, etc. The topical skin preparation composition is not particularly limited as long as it is for external use, and skin includes the scalp.

[0046] Specific formulations of the topical skin preparation composition of the present invention include ointments, creams, gels, emulsions, liquids (lotions, toners), patches (packs), aerosol foams, pump foams, pump sprays, and spray-type aerosols. Among these formulations, creams, lotions, gels, aerosol foams, pump foams, emulsions, and packs are preferred, and lotions, gels, creams, emulsions, aerosol foams, and pump foams are more preferred. The emulsification state of creams, emulsions, etc., is not particularly limited and may be W / O, O / W, W / O / W, or O / W / O. The manufacturing method is simply to mix the above components (A) to (C) and to use the conventional method for each dosage form.

[0047] A pump foam formulation without a propellant consists, for example, an airtight container, a pump body, an actuator, a cap, and a stock solution. An aerosol foam formulation containing a propellant basically consists of a pressure-resistant container that can withstand internal pressure, a valve, an actuator, a stock solution, and a propellant. In the case of an aerosol foam formulation, the skin topical formulation composition is used as the stock solution, and the propellant is combined with it to form the aerosol foam formulation. The propellant content is preferably 1 to 10 parts by mass per 100 parts by mass of stock solution. Examples of propellants include liquefied gas and compressed gas. Examples of liquefied gases include liquefied petroleum gas (LPG) mainly composed of hydrocarbons with 3 to 5 carbon atoms (propane, n-butane, i-butane, etc.), dimethyl ether, and fluorinated hydrocarbons. Examples of compressed gases include carbon dioxide, nitrogen, and nitrous oxide. Among these, liquefied petroleum gas is preferred. By using a pump foam formulation or an aerosol foam formulation, the product is dispensed as a foam, making it easier to spread on the skin. Furthermore, by using an aerosol foam formulation, the precipitation of surfactants blended in the stock solution at low temperatures can be suppressed.

[0048] (C) The inclusion of nicotinamide improves the photostability of (A) pyridoxine salts, etc. Therefore, the container used to fill the topical skin preparation composition does not need to consider the light transmittance described later, and can be appropriately selected from containers used for pharmaceuticals, quasi-drugs, and cosmetics, depending on the purpose, and a topical skin preparation product can be made by filling the container with the topical skin preparation composition. For example, general glass bottles and resin containers (both bottle type and single-use type can be used) can be used, and glass bottles are an example of glass bottles. As for the resin material, general polyethylene, polypropylene, polybutylene, polyethylene terephthalate, polyacrylonitrile, polycarbonate, polyarylate, vinyl chloride, etc. can be used, with polyethylene, polypropylene, polyethylene terephthalate, etc. being preferred. Packaging containers (pouches, etc.) made of a laminate of metal foil and resin film can be used. As for the resin film material, the above general materials can be used, and in particular, polyethylene, polypropylene, polyethylene terephthalate, etc. can be used for the innermost layer. Aluminum foil, etc. can be used as the metal foil. (C) The effect of improving the photostability of pyridoxine salts, etc., due to the inclusion of nicotinamide (A) can be more effectively exhibited, and a colorless, transparent or colorless, semi-transparent container body can be used, and a part of the container body may be colorless, transparent or colorless, semi-transparent. The visible light transmittance (wavelength range of 450 to 800 nm) of the container body is preferably 20% or more, more preferably 40% or more, even more preferably 70% or more, and particularly preferably 90% or more. By setting the light transmittance to the lower limit or higher, the effects of the present invention are more easily exhibited, and the remaining amount of the topical skin preparation composition becomes clearer. For the same reasons as above, it is preferable that the area of ​​colorless, transparent or colorless, semi-transparent material on the total surface area of ​​the container body be 30% or more, more preferably 50% or more, even more preferably 70% or more, and particularly preferably 90% or more.

[0049] When the topical skin preparation composition is an aerosol foam or pump foam, pressure-resistant containers that can withstand internal pressure can be, for example, aluminum cans, tin cans, glass containers, etc., and it is also possible to coat the inner surface with resin or the like.

[0050] The container capacity can be appropriately set according to the amount of topical skin preparation composition to be filled, but 10 to 500 mL is preferred. The filling rate of the topical skin preparation composition relative to the container capacity is preferably 70 to 95%. The shape of the container is not particularly limited, and examples include rectangular tubes, cylindrical shapes, etc. The cap can be made of the same material as the container body, and it is preferable that it be made of the same material as the container body.

[0051] The pH of the topical skin preparation composition is preferably 4 to 8 from the viewpoint of the thermal and photostability of component (A). Considering skin irritation, a pH of 5 to 8 is more preferable. Examples of pH adjusting agents include citric acid, sodium citrate, diisopropanolamine, triethanolamine, sodium hydroxide, hydrochloric acid, phosphoric acid, potassium dihydrogen phosphate and sodium hydrogen phosphate, lactic acid, sodium lactate, malic acid, sodium malate, and boric acid, as mentioned above. These pH adjusting agents can be used individually or in appropriate combinations of two or more. Among these, from the viewpoint of the stability of component (A), one or more selected from citric acid, phosphoric acid, lactic acid, malic acid, boric acid and their salts are preferred, and one or more selected from citric acid, boric acid and their salts are more preferable. When incorporating a pH adjusting agent, the content ratio is appropriately selected so that the topical skin preparation composition reaches the desired pH, but 0.01 to 5% by mass is preferred, and 0.03 to 1% by mass is more preferred. By setting the content ratio to 0.01% by mass or more, component (A) can be contained more stably. The pH in this invention is measured according to the general test methods of the 18th edition of the Japanese Pharmacopoeia (measurement temperature 20°C).

[0052] When the formulation of the topical skin preparation composition of the present invention is a lotion, emulsion, liquid, pump foam, or aerosol (in the case of an aerosol, the composition as a concentrated solution), the viscosity of the composition (at 20°C) is preferably 10 mPa·s or higher from the viewpoint of adhesion to the skin, and preferably 3,000 mPa·s or lower from the viewpoint of usability (ease of spreading). When the formulation is an ointment, cream, or gel, the viscosity of the composition is preferably 7,000 mPa·s or higher from the viewpoint of shape retention, and preferably 800,000 mPa·s or lower from the viewpoint of usability (ease of spreading). The viscosity in the present invention is the value measured using a BM type viscometer (for example, manufactured by Toki Sangyo Co., Ltd.), rotor No. 1, 12 rpm, and 1 minute.

[0053] The effects and efficacy of the topical skin preparation composition of the present invention include (A) one or more selected from the group consisting of pyridoxine, its derivatives and pharmaceutically acceptable salts thereof, (B) a heparin-like substance, and (C) nicotinamide, and include treating xerosis, dry skin in children, rough hands and fingers, cracks and chapping of hands and feet, keratosis of elbows, knees, heels and ankles, chilblains (excluding sores), skin hardening and tightness after wounds and burns (excluding the face), swelling, muscle pain and joint pain after bruises and sprains, moisturizing the skin, conditioning the skin, keeping the skin healthy, preventing rough skin, chapped skin, heat rash, chilblains, cracks, chapping and acne. In addition, it has blood circulation promoting effects and skin roughness improving effects, as well as melanin production inhibiting effects, whitening effects and anti-wrinkle effects. The dosage and administration of the topical skin preparation composition of the present invention is to apply an appropriate amount to the skin one to several times a day. [Examples]

[0054] The present invention will be specifically described 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 composition refers to mass%, and ratios refer to mass ratios.

[0055] [Examples and Comparative Examples] A topical skin preparation composition with the following composition was prepared by the following method. All components except sodium hydroxide were added to purified water and stirred at room temperature to solubilize them. The solution was then prepared with citric acid hydrate or sodium hydroxide to the pH shown in the table. Ten mL of the obtained composition was filled into a glass vial (manufactured by Nichiden Rika Glass Co., Ltd., model number 250507, colorless), sealed with a white plastic lid, and then continuously irradiated with light at approximately 5000 lux·h so that the total illuminance reached 700,000 lux at room temperature (after harsh testing and storage).

[0056] <Quantitative determination of pyridoxine hydrochloride> Using HPLC, the pyridoxine hydrochloride content was quantified before storage (initial value immediately after manufacturing) and after the above storage, and the residual rate of pyridoxine hydrochloride relative to the initial value was calculated according to the following formula. [HPLC conditions] Detector: UV absorbance spectrophotometer Column: ODS column Column temperature: Constant temperature around 40°C Mobile phase: Water / methanol / sodium 1-hexanesulfonate solution (47→5000) / phosphoric acid mixture (500:300:200:1) Pyridoxine hydrochloride retention rate (vs. initial value) = (Pyridoxine hydrochloride content after storage) / (Pyridoxine hydrochloride content before storage began) × 100

[0057] [Confirmation of skin barrier function improvement effect: Evaluation test of tight junction expression promotion effect] The effect of improving skin barrier function was confirmed by measuring the increase or decrease in the mRNA level of Claudin-1, a tight junction factor present in epidermal keratinocytes. Normal human epidermal keratinocytes (NHEKs) were placed in 2 × 10⁶ wells of a 96-well plate. 4 Cells were seeded in a well. Two days after cell seeding, the samples were replaced with culture media adjusted to the specified concentration and incubated for 24 hours at 37°C under 5% CO2 humidity. The concentrations of the test substances, heparinoid, pyridoxine hydrochloride, and nicotinamide, were adjusted, and both individual components and combinations were used.

[0058] Subsequently, RNA was extracted from each sample using an RNA extraction kit (RNeasy mini kit, QIAGEN). Reverse transcription was performed using a conventionally known method to obtain cDNA, which was then quantified using a real-time PCR instrument (reverse transcription: ReverTra Ace 2, TOYOBO; polymerase: KOD SYBR qPCR mix, TOYOBO). The primer used, Claudin-1, is listed below. The mRNA levels of Claudin-1 were calculated as target genes, and then corrected using the mRNA levels of GAPDH as a correction gene. Ctrl refers to a composition that does not contain the test substances (A), (B), and (C) (composition obtained by removing component (A) from Comparative Example 1). This value was used as the baseline (1.0), and the barrier function improvement effect was compared according to the following criteria. 〇: More than 1.5 △: More than 1.0 to less than 1.5 ×: 1.0 or less (reference value) The results are shown below.

[0059] [Table 1]

[0060] [Table 2]

[0061] [Table 3]

[0062] [Table 4]

[0063] As is clear from the results of Comparative Examples 1-3, combining component (A) with component (B) improved the skin barrier function, but worsened the photostability of component (A). In the example containing component (C), the photostability of component (A) improved while maintaining the skin barrier function improvement effect. On the other hand, creatinine and urea, which are known as additives that stabilize light-sensitive components, did not have an insufficient effect on improving photostability.

[0064] A topical skin preparation composition was prepared according to the following formulation. The same evaluation as in the above examples was obtained.

[0065] [Table 5]

[0066] [Table 6]

[0067] [Table 7]

[0068] [Table 8]

[0069] [Table 9]

[0070] The raw materials used in the above example are shown below. Unless otherwise specified, the amounts of each component in the table are on a pure content basis. The terms "JP" and "Non-JP" below refer to raw materials that conform to the 18th Revised Japanese Pharmacopoeia Standards and the Japanese Pharmacopoeia Non-JP Standards 2002, respectively. • Pyridoxine hydrochloride: Japanese Pharmacopoeia, Pyridoxine hydrochloride, manufactured by DSM Co., Ltd. • Heparin-like substance: Non-pharmaceutical standard, manufactured by Tori Co., Ltd. Nicotinamide: Japanese Pharmacopoeia, Nicotinamide, manufactured by DSM Co., Ltd. • 1,3-Butylene glycol: Japanese Pharmacopoeia, manufactured by Daicel Corporation Methyl parahydroxybenzoate: Japanese Pharmacopoeia, manufactured by Ueno Pharmaceutical Co., Ltd. • Sodium citrate hydrate (Na citrate hydrate): Japanese Pharmacopoeia, Sodium citrate hydrate "For manufacturing purposes only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. • Citric acid hydrate: Japanese Pharmacopoeia, Citric acid hydrate, manufactured by Fuso Chemical Industries, Ltd. • Sodium hydroxide: Japanese Pharmacopoeia, Sodium hydroxide "For manufacturing purposes only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. • Sodium hyaluronate: Japanese Pharmacopoeia, purified sodium hyaluronate JP-E, manufactured by Blue Mage Biotechnology Japan Co., Ltd. • Carboxyvinyl polymer: Pharmaceutical additive, CRBOPOL980, manufactured by Noveon Co. • Xanthan gum: Pharmaceutical additives, Echogum T, manufactured by DSP Gokyo Food & Fine Chemicals Co., Ltd. • Polyoxyethylene hydrogenated castor oil: Pharmaceutical additive standard, NIKKOL HCO-10, manufactured by Nippon Surfactant Industry Co., Ltd. Glycerin fatty acid ester: Food additive, NIKKOL Decaglyn 5-OV, manufactured by Nippon Surfactant Industry Co., Ltd. • Polyoxyl stearate: Japanese Pharmacopoeia, MYS-40MV, manufactured by Nikko Chemicals Co., Ltd. • N-Stearoyldihydrosphingosine (Ceramide 2): CERAMIDE 2, manufactured by Croda Japan Co., Ltd. • N-Stearoylphytosphingosine (Ceramide 3): Ceramide III, manufactured by Evonik Japan Co., Ltd. • Hydroxystearyl phytosphingosine (Ceramide 6II): Ceramide VI MB, manufactured by Evonik Japan Co., Ltd.

[0071] Sequence ID 1 in the sequence listing: Forward primer used in PCR (hClaudin-1) Sequence ID 2 in the sequence listing: Reverse primer used for PCR (hClaudin-1) Sequence ID 3 in the sequence listing: Forward primer used in PCR (hGAPDH) Sequence ID 4 in the sequence listing: Reverse primer used for PCR (hGAPDH)

Claims

1. (A) One or more selected from the group consisting of pyridoxine, its derivatives and pharmaceutically acceptable salts thereof, (B) Heparin-like substances, and (C) Nicotinamide, A topical skin preparation composition containing [a specific ingredient].

2. (A) The topical skin composition according to claim 1, wherein component (A) is one or more selected from pyridoxine hydrochloride and pyridoxal phosphate.

3. The topical skin preparation composition according to claim 1, wherein the content of component (C) is 0.1 to 5% by mass.

4. The topical skin composition according to claim 1, wherein the mass ratio of (C) / ((A)+(B)) is 0.1 to 90.

5. The topical skin preparation composition according to any one of claims 1 to 4, further containing a pH adjusting agent and having a pH of 4 to 8.

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