Composition for external application to skin

Abstract

To provide a composition for external application to skin that comprises a combination of (A) glycyrrhizinic acid and (B) pyridoxine, while ensuring the stability of (A) glycyrrhizinic acid even in the presence of 0.001 mass% or more of (B) pyridoxine.SOLUTION: A composition for external application to skin comprises (A) at least one selected from the group consisting of glycyrrhizinic acid and pharmaceutically acceptable salts thereof, (B) at least one selected from the group consisting of pyridoxine, derivatives thereof and pharmaceutically acceptable salts and (C) a heparinoid. In the composition, the content of the component (B) is 0.001 mass% or more.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a skin external preparation composition. [Background technology]

[0002] Glycyrrhizic acid and its pharma- ceutical acceptable salts (hereinafter sometimes abbreviated as glycyrrhizic acids) are compounds obtained from licorice, and have anti-inflammatory and tissue repairing effects, etc., and are widely used in cosmetics, topical medicines, and topical quasi-drugs. However, it is known that decomposition may occur over time depending on other ingredients contained in the composition. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2011-126818 A [Patent Document 2] Japanese Patent Publication No. 155207 / 1983 Summary of the Invention [Problem to be solved by the invention]

[0004] At least one selected from the group consisting of pyridoxine, its derivatives, and pharma- ceutically acceptable salts thereof (hereinafter sometimes abbreviated as pyridoxines) is known to have an inhibitory and normalizing effect on sebum secretion, and is widely used in cosmetics, topical medicines, and topical quasi-drugs. The present inventors have newly discovered that although the combined use of (A) glycyrrhizic acids and (B) pyridoxines is expected to improve the moisturizing effect and normalization of the skin, the combined use of (B) pyridoxines at 0.001% by mass or more of the above (A) glycyrrhizic acids decreases the stability over time. The present invention aims to provide a skin topical preparation composition (hereinafter sometimes abbreviated as composition) in which the above (A) glycyrrhizic acids and (B) pyridoxines are combined, and the (A) glycyrrhizic acids are stabilized even in the presence of 0.001% by mass or more of the (B) pyridoxines. [Means for solving the problem]

[0005] As a result of intensive research to achieve the above object, the present inventors have found that by further adding (C) a heparinoid to a skin topical composition containing (A) glycyrrhizic acids and (B) pyridoxines at 0.001% by mass or more, the decomposition of (A) glycyrrhizic acids is suppressed, and a skin topical composition having good stability over time of component (A) is obtained, thereby solving the above problems, and have completed the present invention. Although heparinoids are known to have blood flow promoting effects, anti-inflammatory effects, moisturizing effects, and skin structure improving effects, the fact that they have the above effects is a new discovery by the present inventors.

[0006] Therefore, the present invention provides the following skin external preparation composition and stabilization method. 1. (A) one or more members selected from the group consisting of glycyrrhizinic acid and pharma- ceutically acceptable salts thereof; (B) one or more selected from the group consisting of pyridoxine, its derivatives, and pharma- ceutically acceptable salts thereof, and (C) Heparinoids The skin topical composition contains the above component (B), wherein the content of component (B) in the composition is 0.001% by mass or more. 2. The skin topical composition described in 1, wherein component (A) is one or more selected from trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and dipotassium glycyrrhizinate. 3. The skin topical composition according to 1 or 2, wherein component (B) is one or more selected from pyridoxine hydrochloride and pyridoxal phosphate. 4. The skin topical composition according to any one of 1 to 3, wherein the content of component (A) is 0.01 to 3 mass %. 5. The skin topical composition according to any one of 1 to 4, wherein the content mass ratio represented by (C) / [(A)+(B)] is 0.1 to 10. 6. The skin topical composition according to any one of 1 to 5, wherein the content mass ratio represented by (C) / (B) is 0.3 to 100. 7. The skin topical composition described in any one of 1 to 6, having a pH of 4 to 8. 8. The skin external preparation composition according to any one of 1 to 7, further comprising (E) one or more selected from organic acids and salts thereof. 9. A method for stabilizing the above-mentioned component (A), comprising blending (C) a heparinoid with a skin topical composition containing 0.001 mass% or more of (A) one or more members selected from the group consisting of glycyrrhizinic acid and its pharma-ceutical acceptable salts, and (B) one or more members selected from the group consisting of pyridoxine, its derivatives, and its pharma-ceutical acceptable salts. Effect of the Invention

[0007] According to the present invention, it is possible to provide a skin topical preparation composition in which (A) glycyrrhizinic acids are used in combination with (B) pyridoxines, and in which (A) glycyrrhizinic acids are stabilized even in the presence of 0.001% by mass or more of (B) pyridoxines. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will be described in detail below. [Component (A)] The component (A) of the present invention is one or more selected from the group consisting of glycyrrhizinic acid and its pharma- ceutically acceptable salts, and can be used alone or in combination of two or more. As described above, the component (A) has anti-inflammatory and tissue repairing effects. Examples of the component (A) include trisodium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, and dipotassium glycyrrhizinate, with trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and dipotassium glycyrrhizinate being preferred, and dipotassium glycyrrhizinate being more preferred.

[0009] The content of the (A) component in the composition is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and even more preferably 0.07% by mass or more, in order to improve the pharmacological effects (anti-inflammatory action, tissue repair action) of the (A) component and to make it easier to obtain the stability over time of the (A) component. Also, in order to make it easier to obtain the stability over time, the content is preferably 3% by mass or less, more preferably 1% by mass or less, and even more preferably 0.7% by mass or less.

[0010] [(B) Component] The component (B) of the present invention is one or more selected from the group consisting of pyridoxine, its derivatives, and pharma- ceutically acceptable salts thereof, and can be used alone or in combination of two or more. The component (B) has effects such as suppressing and normalizing sebum secretion, and activating skin cells. Examples of the component (B) include pyridoxine, pyridoxal, pyridoxamine, pharma-ceutically acceptable salts thereof (hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), pyridoxine dicaprylate, pyridoxine dipalmitate, pyridoxine trihexyldecanoate, pyridoxine cyclic phosphate, etc. Among them, pyridoxine hydrochloride and pyridoxal phosphate are preferred, and pyridoxine hydrochloride is preferred.

[0011] The content of the (B) component is 0.001% by mass or more in the composition, preferably 0.005% by mass or more, and more preferably 0.01% by mass or more, from the viewpoint of obtaining the effect of improving the stability of the (A) component over time by the (C) component described later, and from the viewpoint of the sebum secretion suppressing / normalizing action and the skin cell activation effect. Also, from the viewpoint of making it easier to obtain the stability of the (A) component over time, the content is preferably 2% by mass or less, more preferably 1% by mass or less, and even more preferably 0.5% by mass or less.

[0012] [(C) component] The component (C) of the present invention is a heparinoid. A heparinoid is a polysulfate ester of a mucopolysaccharide such as chondroitin polysulfate. Heparinoids are known to promote blood flow, have anti-inflammatory effects, moisturize, and improve skin structure. 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 tissues of edible animals (e.g., lungs containing tracheal cartilage of cattle, pigs, etc.). Among them, heparinoids defined in the Japanese Pharmacopoeia Extra Pharmaceutical Standards (Standard Number: 108548) are preferably used.

[0013] The content of the (C) component is not particularly limited, but is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and even more preferably 0.07% by mass or more in the composition, from the viewpoint of improving the pharmacological effect of the (C) component and making it easier to obtain the stability over time of the (A) component. Also, from the viewpoint of making it easier to obtain the stability over time of the (A) component, is preferably 3% by mass or less, more preferably 1% by mass or less, and even more preferably 0.5% by mass or less.

[0014] The content mass ratio represented by (C) / [(A)+(B)] is preferably 0.1 or more, more preferably 0.15 or more, even more preferably 0.17 or more, and particularly preferably 0.4 or more, in order to more easily obtain the stability over time of the (A) component. Also, in order to improve the stability over time of the (C) component, it is preferably 10 or less, more preferably 4 or less, even more preferably 3 or less, and particularly preferably 1.82 or less.

[0015] The content mass ratio represented by (C) / (B) is preferably 0.3 or more, and more preferably 1 or more, since the stability over time of the component (A) is more easily achieved. Also, from the viewpoint of improving the stability over time of the component (C), it is preferably 100 or less, more preferably 30 or less, and even more preferably 20 or less.

[0016] The skin topical preparation composition of the present invention can contain a nonionic surfactant to improve emulsion stability, as long as the effect of the present invention is not impaired (hereinafter, sometimes abbreviated as component (D)). The nonionic surfactant is not particularly limited, and can be used alone or in combination of two or more kinds, and examples thereof include the following.

[0017] Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan monolaurate (polysorbate 20). The numbers in parentheses in the above-listed polyethylene sorbitan fatty acid esters indicate the average degree of polymerization of ethylene oxide, that is, the average number of repeats of oxyethylene groups. The same applies to the following polyoxyethylene hydrogenated castor oil, polyethylene sorbit fatty acid esters, and polyoxyethylene alkyl ethers.

[0018] Examples of polyoxyethylene hydrogenated castor oils include polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, and polyoxyethylene (10) hydrogenated castor oil.

[0019] Examples of the polyethylene glycol fatty acid ester include polyoxyethylene glycol monostearate (4EO), polyethylene glycol monooleate (10EO), and polyethylene glycol monolaurate (10EO).

[0020] Examples of polyglycerol fatty acid esters include polyglyceryl (10) stearate, polyglyceryl (10) laurate, and polyglyceryl (10) oleate. The numbers in parentheses in the above-listed polyglycerol fatty acid esters indicate the average degree of polymerization of glycerin. Examples of polyoxyethylene alkyl ethers include polyoxyethylene (9) lauryl ether, polyoxyethylene (10) cetyl ether, and polyoxyethylene (10) oleyl ether. Examples of glycerin fatty acid esters include glyceryl monostearate, glyceryl monooleate, and glyceryl isostearate.

[0021] Examples of propylene glycol fatty acid esters include propylene glycol stearate. Examples of polyoxyethylene glycerin fatty acid esters include PEG-5 glyceryl stearate and PEG-7 glyceryl coconut oil fatty acid. Examples of sorbitan fatty acid esters include sorbitan stearate, sorbitan monooleate, and sorbitan sesquioleate. Examples of polyoxyethylene sorbitol fatty acid esters include polyoxyethylene (60) sorbitol tetrastearate, polyoxyethylene (60) sorbitol tetraoleate, and the like. Examples of polyoxyalkylene sterols include PEG-5 phytosterol, PEG-10 phytosterol, PEG-20 phytosterol, and PEG-30 phytosterol; examples of polyoxyethylene polyoxypropylene alkyl ethers include polyoxyethylene (20EO) polyoxypropylene (4PO) cetyl ether.

[0022] The content of the (D) component is not particularly limited, but when it is contained, from the viewpoint of improving emulsion stability, it is preferably 0.01 to 10% by mass in the composition, more preferably 0.1 to 5% by mass, and even more preferably 0.5 to 3% by mass. By making it equal to or more than the above lower limit, the emulsion stability of the topical composition is further improved, the (A) component's stability over time effect is more easily obtained, and the feeling of use such as lack of stickiness and sliminess when spread can be obtained. By making it equal to or less than the above upper limit, the emulsion stability of the topical composition is further improved, and the (A) component's stability over time effect is more easily obtained.

[0023] The pH of the composition of the present invention is preferably 4 to 8, more preferably 5 to 8, even more preferably 5 to 7.5, and particularly preferably 5 to 7. By adjusting the pH to be between the lower limit and the upper limit, the stability of component (A) over time is improved and skin irritation is less likely to occur. The pH in the present invention is measured according to the 18th Japanese Pharmacopoeia, General Testing Method (measurement temperature 20°C). Examples of pH adjusters include citric acid, citrates such as sodium citrate, lactic acid, lactates such as sodium lactate, malic acid, malates such as sodium malate, succinic acid, succinate salts such as disodium succinate, tartaric acid or its salts, ascorbic acid, ascorbate salts such as sodium ascorbate, glycolic acid, glycolate salts such as sodium glycolate, organic acids or their salts, diisopropanolamine, triethanolamine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, sodium hydroxide, hydrochloric acid, L-arginine, potassium dihydrogen phosphate, and sodium hydrogen phosphate. Among them, it is preferable to use an organic acid (E) or its salt, since the effect of the stability over time of the (A) component can be more easily obtained. The content of (E) organic acid or its salt, or pH adjuster is appropriately selected from the range of 0.01 to 1% by mass, preferably 0.03 to 0.3% by mass, in the composition so that the composition has the desired pH. Since the (E) component has pH buffering ability, it is considered that the pH does not fluctuate much over time, and the (A) component is effectively inhibited from being oxidized. In the skin external preparation composition of the present invention, the purpose of the (E) component is not limited to a pH adjuster, but may be a dispersant, solubilizer, buffer, solubilizer, or wetting agent.

[0024] [External skin preparation composition] The dosage form of the skin topical composition of the present invention is not particularly limited, as long as it can be applied transdermally, and may be any of liquid, solid, semi-solid (gel, ointment, paste), etc. In addition, the skin topical composition of the present invention may be any of medicines, quasi-drugs, cosmetics, skin cleansing agents, etc. Specific examples of the formulation form (dosage form) of the skin topical composition of the present invention include creams, lotions, gels (gels), emulsions, liquids, patches, pump foams, pump sprays, aerosols sprayed in mist, powder, foam, or paste, ointments, packs, etc. Among these formulation forms, creams, lotions, gels, emulsions, pump foams, pump sprays, aerosols sprayed in foam, and packs are preferred, and creams, lotions, gels, emulsions, pump foams, and aerosols sprayed in foam are more preferred. The emulsified state of creams, milky lotions, etc. is not particularly limited, and may be any of W / O, O / W, W / O / W, and O / W / O.

[0025] The skin topical composition of the present invention contains glycyrrhizinic acids, pyridoxines, and heparinoids, and therefore can be used as a skin topical agent having the effects and efficacy of treating xerosis, dry skin in children, rough fingers, cracks and chapped hands and feet, keratosis of elbows, knees, heels, and ankles, chilblains (excluding sores), lumps and tightness of the skin after a wound or burn (excluding the face), swelling, muscle pain, and joint pain after a bruise or sprain, etc., as well as skin roughness, chapped skin, preventing heat rash, chilblains, cracks, chapped skin, and acne, preventing oily skin, razor burn, preventing spots and freckles due to sunburn, preventing hot flashes after sunburn or snowburn, tightening the skin, and cleansing the skin. It can be used in quasi-drugs with the effects and efficacy of conditioning the skin, keeping the skin healthy, moisturizing the skin, protecting the skin, and preventing dry skin, and in cosmetics with the effects and efficacy of cleansing the skin, preventing acne and heat rash, conditioning the skin, smoothing the skin, keeping the skin healthy, preventing rough skin, moisturizing the skin, replenishing and maintaining moisture and oil in the skin, maintaining the flexibility of the skin, protecting the skin, preventing dry skin, softening the skin, giving the skin firmness, making the skin smooth, conditioning the skin after shaving, preventing sunburn, preventing spots and freckles caused by sunburn, and making fine lines caused by dryness less noticeable. In addition to these, it also has the effects of "improving wrinkles, dullness, firmness, and enlarged pores," "smoothing the skin," "retaining moisture and maintaining moisture," "improving skin structure," "improving barrier function," and "restoring the skin's moisture retention ability that has deteriorated with age." The skin external preparation composition of the present invention is used by spreading an appropriate amount on the skin once to several times a day.

[0026] The skin topical composition of the present invention may contain, in addition to the above-mentioned (A) glycyrrhizic acid and its pharma- ceutical acceptable salts, (B) pyridoxine, its derivatives and their pharma- ceutical acceptable salts, and (C) heparinoids, various active ingredients used in medicines, quasi-drugs, cosmetics, etc., as necessary, within the scope of not impairing the effects of the invention. For example, anti-inflammatory agents (excluding component (A)), antihistamines, herbal ingredients, antipruritics, keratin softeners, wound healing agents, local anesthetics, vitamins (excluding component (B)), cooling agents, moisturizers (excluding component (C)), bactericides, vasoconstrictors, amino acids, whitening agents, etc., and the following components are exemplified.

[0027] Examples of anti-inflammatory agents other than component (A) include glycyrrhetinic acid, allantoin, steroid compounds (hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, cortisone, flumethasone, beclomethasone, fluticasone, or derivatives thereof), indomethacin, ibuprofen, ibuprofen piconol, bufexamac, ufenamate, piroxicam, ketoprofen, salicylic acid or derivatives thereof, dimethylisopropylazulene, Angelica acutiloba extract, and Lithospermum root extract.

[0028] Examples of antihistamines include diphenhydramine, chlorpheniramine, mequitazine, azelastine, emedastine, ketotifen, or derivatives thereof, etc. Among these, diphenhydramine hydrochloride and chlorpheniramine maleate are preferred.

[0029] Examples of herbal ingredients include artichoke leaf extract, althea root extract, arnica flower extract, aloe vera leaf extract, ginkgo leaf extract, unshu mandarin peel extract, scutellaria root extract, ginseng root extract, hypericum flower / leaf / stem extract, olive leaf extract, orange fruit extract, brown algae extract, chamomile flower extract, licorice extract, rubus idaeus fruit extract, phellodendron amplexicaule bark extract, cucumber fruit extract, gardenia fruit extract, sophora flavescens root extract, grapefruit fruit extract, chlorella extract, rice bran extract, hawthorn extract, peony root extract, ginger root extract, white birch bark extract, horsetail extract, and common oak leaf extract. Examples of suitable extracts include alder leaf / stem extract, yarrow extract, peppermint leaf extract, sage leaf extract, mallow flower extract, rosa centifolia flower extract, swertia japonica extract, mulberry bark extract, soybean seed extract, tea leaf extract, angelica root extract, calendula officinalis flower extract, rose multiflora fruit extract, coix seed extract, hamamelis leaf extract, loquat leaf extract, prune hydrolyzate, safflower flower extract, peony extract, horse chestnut extract, peach leaf extract, centaurea cyanus flower extract, eucalyptus leaf extract, saxifrage extract, yuzu fruit extract, lavender flower extract, apple fruit extract, lemon fruit extract, and rosemary leaf extract.

[0030] Examples of antipruritic agents include vanillyl nonyl amide, capsaicin, benzyl nicotinate, and capsicum tincture. Examples of keratin softeners include salicylic acid and its derivatives. Examples of wound healing agents include zinc oxide and the like. Examples of local anesthetics include lidocaine, lidocaine hydrochloride, methyl aminobenzoate, ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, and the like.

[0031] Examples of vitamin preparations other than component (B) include vitamin A [retinol and its derivatives (e.g., retinal, retinoic acid, retinol 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 (nicotinamide, tocopherol nicotinate, benzyl nicotinate, etc.)], vitamin B5 [pantothenic acid and its derivatives (e.g., calcium pantothenate, panthenol, pantothenyl ethyl alcohol)], vitamin B12 [cobalamin and and its derivatives (e.g., cyanocobalamin, mecobalamin, and hydroxocobalamin hydrochloride, etc.)], biotin, folic acid or a pharma- ceutical acceptable salt thereof, vitamin C [ascorbic acid and its derivatives (e.g., erythorbic acid, sodium ascorbate, ascorbyl palmitate, etc.)], vitamin D [calciferol and its derivatives (e.g., ergocalciferol, cholecalciferol, etc.)], vitamin E [tocopherol, ubiquinone and its derivatives (e.g., tocopherol acetate, tocopherol calcium succinate, etc.)], other vitamins (e.g., hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, inositol, and a pharma-ceutical acceptable salt thereof), etc. Examples of the refreshing agent include menthol, camphor, borneol or their analogues, fennel oil, eucalyptus oil, peppermint oil, etc.

[0032] Examples of moisturizers other than component (C) include polyhydric alcohols (glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol, etc.), hyaluronic acid, its derivatives and pharma- ceutically acceptable salts thereof, polymeric compounds (collagen, chitosan, etc.), amino acids (glycine, alanine, aspartic acid, etc.), natural moisturizing factors (sodium lactate, urea, etc.), ceramides, and plant extracts (chamomile extract, aloe extract, etc.).

[0033] Examples of the bactericide include isopropylmethylphenol, chlorhexidine hydrochloride, benzethonium chloride, benzalkonium chloride, cetrimide, and the like. Examples of vasoconstrictors include naphazoline, tetrahydrozoline, methylephedrine, or salts thereof. Examples of amino acids include glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine), and pharma- ceutically acceptable salts thereof.

[0034] Examples of whitening agents include nicotinamide, placenta, arbutin, kojic acid, ellagic acid, phytic acid, tranexamic acid, rucinol, chamomilla ET, hydroquinone, potassium 4-methoxysalicylate, linoleic acid and its derivatives, ascorbic acid and its salts, vitamin C such as ascorbic acid derivatives (sodium ascorbic acid phosphate, magnesium ascorbic acid phosphate, ascorbyl tetra-2-hexyldecanoate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbyl glucoside, disodium isostearyl ascorbyl phosphate, L-ascorbyl dipalmitate, trisodium ascorbyl palmitate phosphate, glyceryl ascorbate, bisglyceryl ascorbate, alkylglyceryl ascorbate, etc.), vitamins such as vitamin A or its derivatives, and pantothenic acid or its derivatives. Furthermore, plant ingredients having a whitening effect may be used as the whitening ingredient. Examples of such plant ingredients include iris, almond, aloe, acerola, oolong tea, Chinese laurel, Scutellaria baicalensis, Coptis chinensis, Hypericum perforatum, white lamb's foot, oryzanol, seaweed, pueraria root, gardenia, lily of the valley, chlorella, rice, rice bran, Chinese laurel, Japanese pepper, perilla, peony, cnidium officinalis, soybean, natto, tea, angelica tree, calendula officinalis, witch hazel, safflower, peonies, coix seed, Acacia oleracea, persimmon (Diospyros kaki), and the like. kaki), kiwi, black bean, gentian, gentian, sage, radish, azalea, parsley, holly, hops, thyme, clove, tangerine, licorice, chamomile, prune, meadowsweet, purple bark, sorrel, grapefruit, thorn, lemon, kiwi, pine, neem, artichoke, horsetail, bark bean, evening primrose, bilberry, geranium gracilis, glasswort, white willow, saxifrage, centella, rosemary, lavender, and Chinese quince.

[0035] The skin external preparation composition of the present invention can be prepared by blending the above-mentioned (A), (B) and (C) components, as well as the above-mentioned optional components and the following various additives according to a conventional method together with various additives. Any of the raw materials generally used as additives can be used for preparing the skin external preparation composition of the present invention.

[0036] Examples of various additives include bases, polyhydric alcohols (including components that overlap with those listed above), polymeric compounds (including components that overlap with those listed above), ionic surfactants, amphoteric surfactants, stabilizers, preservatives, fragrances, water, etc.

[0037] Examples of bases 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, and behenyl alcohol; fatty acid ester oils such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, and diisopropyl adipate; and glycerin triisooctanoate. and triglycerin fatty acid ester oils such as tri(caprylic / capric acid)glyceryl; examples of polyhydric alcohols include glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol; examples of polymeric compounds include carboxyvinyl polymer, hydroxypropyl cellulose, hypromellose, hydrophobized hydroxypropyl methylcellulose, acrylated starch 300, and polyvinylpyrrolidone, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac fats, quince seeds, 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; ionic surfactants include anionic surfactants such as alkyl ether sulfate ester salts and sodium polyoxyethylene lauryl ether sulfate; amphoteric surfactants include 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and coconut oil fatty acid amidopropyl betaine; stabilizers include organic solvents such as ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, and ethyl acetate, sodium chloride, sodium thiosulfate, sodium sulfite, and sodium edetate; and preservatives include, but are not limited to, methylparaben, propylparaben, benzalkonium chloride, and benzethonium chloride. The amount of the base material is appropriately selected depending on the dosage form, and when contained, it is appropriately selected from the range of 0.05 to 30% by mass in the composition.The amount of polyhydric alcohol is appropriately selected depending on the dosage form, but when contained, it is appropriately selected from the range of 1 to 30 mass% in the composition. The amount of polymer compound is appropriately selected depending on the dosage form, but when contained, it is appropriately selected from the range of 0.01 to 5 mass% in the composition.

[0038] Examples of the fragrance include blended fragrances such as citrus fragrance, floral fragrance, and rose fragrance, and essential oils such as eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, spearmint oil, rosemary oil, lavender oil, and lemon oil. Representative components contained in these fragrances include terpenoid compounds. Terpenoid compounds include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes according to the number of carbon atoms, and the most representative component is monoterpene. Preferred terpenoid compounds include l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, citral, limonene, citronellol, geraniol, cineol, linalool, nonanal, eugenol, isoeugenol, indole, benzaldehyde, vanillin, limonene, galaxolide, γ-nonalactone, γ-methylionone, iso-E-super, Z-3-hexenyl salicylate, γ-undecalactone, 5-cyclohexadecen-1-one, 2-methyl-4-phenyl-2-butanol, methyl dihydrojasmonate, methyl-β-naphthyl ketone, cinnamyl acetate, benzyl acetate, α-terpineol, hexyl cinnamic aldehyde, and γ-undecalactone. When a fragrance is contained, the content thereof in the composition is preferably from 0.001 to 1 mass %, and more preferably from 0.01 to 0.1 mass %.

[0039] When water is added, the content is appropriately selected from the range of 50 to 98% by mass in the composition depending on the dosage form.

[0040] [Stabilization method] The present invention provides a method for stabilizing component (A), which improves the stability over time of component (A) by blending (C) a heparinoid with a skin external preparation composition containing 0.001 mass % or more of (A) one or more selected from the group consisting of glycyrrhizic acid and its pharma- ceutically acceptable salts, and (B) one or more selected from the group consisting of pyridoxine, its derivatives, and its pharma- ceutically acceptable salts. The preferred components, amounts, ratios, etc. are the same as those described above. EXAMPLES

[0041] 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 the composition indicates mass %, ratio indicates mass ratio, and the amount of each component in the table is the amount converted into a pure content.

[0042] [Examples, Reference Examples, Comparative Examples] The solid components at room temperature were heated to a liquid state, and the components other than citric acid, sodium citrate, sodium hydroxide, ascorbic acid, sodium ascorbate, lactic acid, succinic acid, disodium succinate, malic acid, glycolic acid, tartaric acid, 2-amino-2-methyl-1,3-propanediol, and L-arginine were stirred at room temperature to solubilize. The pH of the composition was adjusted to the pH indicated in the table using the pH adjuster such as citric acid. 20 g of the prepared composition was filled into a glass vial container (20 mL), sealed with a lid, and stored at 50°C for 1 month and 40°C for 2 months. The content of dipotassium glycyrrhizinate (measured as glycyrrhizic acid) before and after storage was quantified by HPLC (internal standard method), and the residual rate (%) of dipotassium glycyrrhizinate relative to the initial value was calculated according to the following formula. Residual rate (%) = (content of dipotassium glycyrrhizinate after storage) / (initial content of dipotassium glycyrrhizinate) x 100

[0043] [HPLC conditions] Detector: UV spectrophotometer Column: ODS column Column temperature: constant temperature around 40℃ Mobile phase: Water / acetonitrile mixture

[0044] [Table 1]

[0045] [Table 2]

[0046] [Table 3]

[0047] [Table 4]

[0048] [Table 5]

[0049] As is clear from the results of Reference Example 1 and Comparative Example 3, the combination of (A) glycyrrhizic acid and 0.001 mass% or more of (B) pyridoxine reduced the stability of (A) glycyrrhizic acid over time. By including the (C) component of the present invention, the decomposition of (A) glycyrrhizic acid was suppressed, and a skin external preparation composition having good stability of (A) component over time was obtained.

[0050] The raw materials used in the above example are listed below. Unless otherwise specified, the amount of each component in the table is the pure equivalent. The terms "JP", "Extra-Pharmacopoeia Regulations", "Pharmaceutical Additive Regulations", and "Extra-Raw Material Regulations" below refer to raw materials that comply with the 18th Revised Japanese Pharmacopoeia Standards, Japanese Pharmacopoeia Extra-Pharmacopoeia Pharmaceutical Standards, Pharmaceutical Additives Standards (2018), and Quasi-Drug Raw Materials Standards (2021), respectively. Dipotassium glycyrrhizinate: Extra-official regulation, dipotassium glycyrrhizinate, manufactured by Maruzen Pharmaceutical Co., Ltd. Pyridoxine hydrochloride: Japanese Pharmacopoeia, Pyridoxine hydrochloride, manufactured by DMS Co., Ltd. Heparinoids: Extraordinary regulations, Extraordinary heparinoids, manufactured by Tori Co., Ltd. Glycerin: Japanese Pharmacopoeia, Official Glycerin, manufactured by Sakamoto Pharmaceutical Co., Ltd. Propylene glycol: Japanese Pharmacopoeia, propylene glycol, manufactured by ADEKA Corporation Xanthan gum: Pharmaceutical additive Echo Gum T, DSP Gokyo Food & Fine Chemical Co., Ltd. Polyethylene glycol monolaurate 10: Pharmaceutical additives, NIKKOL MYL-10 manufactured by Nippon Surfactant Industries Co., Ltd. Polysorbate 20: Pharmaceutical additives, NIKKOL TL-10 manufactured by Nippon Surfactant Industries Co., Ltd. Polyoxyethylene hydrogenated castor oil (60): Pharmaceutical additive NIKKOL HCO-60, Nippon Surfactant Industry Co., Ltd. Polyglyceryl stearate (10): Pharmaceutical additive NIKKOL Decaglyn 1-SV Nippon Surfactant Industry Co., Ltd. Polyoxyethylene (9) lauryl ether: NIKKOL BL-9EX (Japanese Pharmacopoeia) by Nippon Surfactant Industries Co., Ltd. Glyceryl monostearate: Pharmaceutical additive NIKKOL MGS-ASEV Nippon Surfactant Industries Co., Ltd. Polyoxyethylene (20) Polyoxypropylene (4) Cetyl Ether: Pharmaceutical Additive NIKKOL SG-420 Nippon Surfactant Industry Co., Ltd. Sodium citrate (trisodium citrate): Japanese Pharmacopoeia, sodium citrate hydrate, manufactured by Fuso Chemical Co., Ltd. Citric acid hydrate: Japanese Pharmacopoeia, citric acid hydrate, manufactured by ThreeF Corporation Sodium hydroxide: Japanese Pharmacopoeia, sodium hydroxide "for manufacturing only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Ascorbic acid: Pharmaceutical additive, ascorbic acid (crystal), manufactured by DMS Co., Ltd. Sodium ascorbate (Na ascorbate): Pharmaceutical additive, sodium ascorbate (crystal), manufactured by DMS Co., Ltd. Lactic acid: Japanese Pharmacopoeia, Lactic acid, Showa Kako Co., Ltd. Succinic acid: Succinic acid, manufactured by Kawasaki Chemical Industries, Ltd. Disodium succinate (disodium succinate): Disodium succinate, manufactured by Nippon Shokubai Co., Ltd. Malic acid: Pharmaceutical additive, Fuso Malic Acid M, manufactured by Fuso Chemical Co., Ltd. Glycolic acid: Foreign standard, Gripure 99, manufactured by DuPont Tartaric acid: Japanese Pharmacopoeia, tartaric acid, Showa Kako Co., Ltd. 2-Amino-2-methyl-1,3-propanediol: AMPD ULTRA PC, manufactured by Advancion Corporation L-Arginine: Tonoharaki, L-Arginine, Nippon Rikagaku Yakuhin Co., Ltd. Hydrochloric acid: Japanese Pharmacopoeia, dilute hydrochloric acid, manufactured by Kosakai Pharmaceutical Co., Ltd.

Claims

1. (A) one or more members selected from the group consisting of glycyrrhizinic acid and pharma- ceutically acceptable salts thereof; (B) one or more members selected from the group consisting of pyridoxine, its derivatives, and pharma- ceutically acceptable salts thereof; and (C) Heparinoids The skin topical composition contains the above component (B), and the content of component (B) in the composition is 0.001% by mass or more.

2. 2. The skin external preparation composition according to claim 1, wherein component (A) is one or more selected from the group consisting of trisodium glycyrrhizinate, monoammonium glycyrrhizinate and dipotassium glycyrrhizinate.

3. 2. The composition for external skin preparation according to claim 1, wherein component (B) is at least one member selected from the group consisting of pyridoxine hydrochloride and pyridoxal phosphate.

4. The skin external preparation composition according to claim 1, wherein the content of component (A) is 0.01 to 3 mass %.

5. The skin external preparation composition according to claim 1, wherein the content mass ratio represented by (C) / [(A)+(B)] is 0.1 to 10.

6. The skin external preparation composition according to claim 1, wherein the content mass ratio represented by (C) / (B) is 0.3 to 100.

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

8. The skin external preparation composition according to any one of claims 1 to 7, further comprising (E) one or more selected from the group consisting of organic acids and salts thereof.

9. A method for stabilizing the component (A), comprising blending (C) a heparinoid with a skin topical composition containing 0.001 mass% or more of (A) one or more members selected from the group consisting of glycyrrhizinic acid and pharma- ceutical acceptable salts thereof, and (B) one or more members selected from the group consisting of pyridoxine, its derivatives, and pharma-ceutical acceptable salts thereof.

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