Compositions for topical skin use

Abstract

The present invention provides a topical skin preparation composition containing a heparin-like substance that has an excellent effect in improving the skin barrier function. [Solution] A topical skin preparation composition containing a heparin-like substance (A) in which the proportion of disaccharide units consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine is 7 to 22 mol%.

Description

Technical Field

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

Background Art

[0002] Heparin-like substances are known to have effects such as promoting blood flow, anti-inflammatory effects, moisturizing effects, and improving skin structure, and are widely used in cosmetics, quasi-drugs for external use, or pharmaceuticals for external use. Among the above-mentioned pharmacological effects, skin external preparations having a higher moisturizing effect and a more improved effect on xerosis have been developed. A formulation combining a heparin-like substance and other active ingredients (tocopherol or its derivatives) (Patent Document 1), and a plant extract component that enhances the moisturizing ability and barrier function of the skin by enhancing ceramide production have been proposed (Patent Document 2). Heparin-like substances are poly-sulfated products of mucopolysaccharides (mainly polysaccharides (chondroitin sulfate) having a disaccharide composed of D-glucuronic acid and N-acetyl-D-galactosamine as a repeating unit). By containing a large number of sulfate groups in the structure, as a functional component of a skin external preparation, it can hold water and obtain an excellent moisturizing effect. So far, for chondroitin sulfate, which is a non-poly-sulfated product, components with different numbers of added sulfate groups have been studied (Patent Document 3). However, research on the number of added sulfate groups at specific positions in the structure of heparin-like substances has not been advanced, and the relationship between structure and function regarding the skin barrier function has not been clarified.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present invention has been made in view of the above circumstances, and aims to provide a topical skin preparation composition containing a heparin-like substance that has an excellent effect in improving the skin barrier function. [Means for solving the problem]

[0005] Heparin-like substances are polysulfur oxides of mucopolysaccharides (polysaccharides (chondroitin sulfate) mainly composed of disaccharides consisting of D-glucuronic acid and N-acetyl-D-galactosamine as repeating units). The present invention was made by newly discovering that the skin barrier function is significantly improved when heparin-like substances have Δdi-tri(2,4,6)S (a disaccharide unit in which the C2 position of D-glucuronic acid and the C4 and C6 positions of N-acetyl-D-galactosamine are sulfated) in a specific ratio, as observed in disaccharide analysis.

[0006] Accordingly, the present invention provides the following topical skin preparation compositions. 1. A topical skin preparation composition containing a heparin-like substance (A) in which the proportion of disaccharide units consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine is 7 to 22 mol%. 2. A topical skin preparation composition according to claim 1, comprising a heparin-like substance (A) in which the proportion of disaccharide units consisting of C2-sulfated D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine is 2 to 10 mol%. 3. A topical skin preparation composition according to 1 or 2, comprising a heparin-like substance (A) in which the proportion of disaccharide units consisting of D-glucuronic acid and N-acetyl-D-galactosamine is 5 to 18.5 mol%. 4. A topical skin preparation composition according to any one of 1 to 3, wherein the sulfate group content of component (A) is 25.8 to 37.3% by mass. 5. A topical skin preparation composition according to any one of 1 to 4, wherein the number average molecular weight of component (A), as measured by gel filtration chromatography, is 10,000 to 40,000. 6. A topical skin preparation composition according to any one of 1 to 5, for improving the skin barrier function. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a topical skin preparation composition containing a heparin-like substance that has an excellent effect in improving the skin barrier function. [Modes for carrying out the invention]

[0008] The present invention will be described in detail below. As mentioned above, heparinoids are polysulfated mucopolysaccharides and are known to have moisturizing effects, improve xerosis, and increase blood flow.

[0009] The origin of the heparin-like substance used in the present invention is not particularly limited, but examples include substances obtained by polysulfating mucopolysaccharides, or substances extracted from the tissues of edible animals (for example, lungs including tracheal cartilage of cattle or pigs).

[0010] The heparin-like substance (A) of the present invention is a polysaccharide having disaccharide repeating units as described above, and is a heparin-like substance in which the proportion of disaccharide units consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine is 7 to 22 mol%.

[0011] In this invention, the proportion of disaccharide units is calculated by analyzing the decomposition products obtained by decomposing a heparin-like substance with chondroitinase ABC at 37°C for 16 hours using high-performance liquid chromatography (HPLC) to determine the proportion of disaccharide units to the total disaccharide units. Further details are as described in the examples.

[0012] The proportion of disaccharide units (mol%) can be obtained by calculating the ratio (area ratio) of each specific disaccharide unit to the total disaccharide units from the peak area of ​​each disaccharide unit in the HPLC chart. The composition of disaccharide units is shown below. ΔDi-0S: A disaccharide unit (non-sulfated disaccharide unit) consisting of D-glucuronic acid and N-acetyl-D-galactosamine. ΔDi-6S: A disaccharide unit consisting of D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine. ΔDi-4S: A disaccharide unit consisting of D-glucuronic acid and C4-sulfated N-acetyl-D-galactosamine. ΔDi-di(2,6)S: A disaccharide unit consisting of C2-sulfated D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine. ΔDi-di(4,6)S: A disaccharide unit consisting of D-glucuronic acid and C4 and C6 sulfated N-acetyl-D-galactosamine. ΔDi-di(2,4)S: A disaccharide unit consisting of sulfated D-glucuronic acid at the C2 position and sulfated N-acetyl-D-galactosamine at the C4 position. ΔDi-tri(2,4,6)S: A disaccharide unit consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine. Sulfate group:-SO3Na

[0013] The disaccharide unit consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine is a disaccharide containing a total of three sulfate groups, with one sulfate group at the C2 position of D-glucuronic acid and one sulfate group each at the C4 and C6 positions of N-acetyl-D-galactosamine (ΔDi-tri(2,4,6)S). From the viewpoint of improving skin barrier function, the ratio of the disaccharide unit consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine is 7 to 22 mol%, preferably 8 to 21 mol%, and more preferably 9 to 20 mol%. The topical skin preparation composition of the present invention preferably contains a heparin-like substance (A) in which, as a result of disaccharide analysis, the disaccharide units consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine are in the above proportion.

[0014] The disaccharide unit consisting of C2-sulfated D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine is a disaccharide having one sulfate group at the C2 position of D-glucuronic acid and one sulfate group at the C6 position of N-acetyl-D-galactosamine, and is also referred to as chondroitin sulfate D (ΔDi-di(2,6)S). From the viewpoint of the effect of improving the skin barrier function, the ratio of the disaccharide unit consisting of C2-sulfated D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine is preferably 2 to 10 mol%, more preferably 3 to 9 mol%, and even more preferably 3.5 to 8 mol%. The skin external preparation composition of the present invention preferably contains a heparin-like substance (A) in which the disaccharide unit consisting of C2-sulfated D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine is in the above ratio as a result of disaccharide analysis.

[0015] From the viewpoint of the effect of improving the skin barrier function, the ratio of the disaccharide unit (Δdi-0S) consisting of D-glucuronic acid and N-acetyl-D-galactosamine is preferably 5 to 18.5 mol%, more preferably 8 to 18 mol%, and even more preferably 10 to 17.5 mol%. The skin external preparation composition of the present invention preferably contains a heparin-like substance (A) in which the disaccharide unit consisting of D-glucuronic acid and N-acetyl-D-galactosamine is in the above ratio as a result of disaccharide analysis.

[0016] From the viewpoint of the skin moisturizing effect, the sulfate group content of the heparin-like substance (A) is preferably 25.8 to 37.3% by mass, more preferably 28.0 to 37.3% by mass. The sulfate group content is determined by the test method described in the specifications for components of pharmaceuticals outside the Japanese Pharmacopoeia.

[0017] From the viewpoint of the effect of improving the skin barrier function, the intrinsic viscosity of the heparin-like substance (A) is preferably 0.09 to 0.18, more preferably 0.09 to 0.16. The intrinsic viscosity is determined by the test method described in the specifications for components of pharmaceuticals outside the Japanese Pharmacopoeia.

[0018] The number-average molecular weight of heparinoid (A) is preferably 10,000 to 40,000, preferably 15,000 to 40,000, and more preferably 20,000 to 36,000, from the viewpoint of improving skin barrier function. The number-average molecular weight was measured by gel filtration chromatography, and the details are described in the examples.

[0019] [Manufacturing method] The method for producing the heparin-like substance (A) of the present invention is not particularly limited, and it is sufficient to obtain the desired proportion of disaccharide units containing sulfate groups. For example, it can be obtained by alkaline treatment of a known heparin-like substance. The treatment water used for alkaline treatment may be, for example, a 2 (mol / L) sodium hydroxide aqueous solution. The treatment temperature and time are appropriately selected from, for example, 60°C and 2 to 5 hours, depending on the raw material heparin-like substance, molecular weight distribution, and the molar percentage of the desired disaccharide units.

[0020] Furthermore, the heparin-like substance (A) of the present invention can also be obtained by mixing the heparin-like substance before treatment, the alkali-treated heparin-like substance, and the fractionated heparin-like substance.

[0021] The heparin-like substance (A) of the present invention can be evaluated by the dextran permeability test described in the examples below. The dextran permeability test is a test method for measuring the barrier function of the skin by adding fluorescently labeled dextran to cells in which an intercellular barrier has been formed and measuring the amount of dextran that permeates. The stronger the intercellular junctions that constitute the skin barrier, the lower the fluorescence intensity value of the permeate. The dextran permeability test is commonly used as a method to evaluate the skin barrier function, for example, by assessing the strengthening and restorative effects of the active ingredient, the inhibitory effect against skin inflammation induced by ultraviolet rays or stress, etc.

[0022] From the viewpoint of improving skin barrier function, the content of the heparin-like substance (A) of the present invention is preferably 0.05% by mass or more, more preferably 0.1 to 0.4% by mass, and even more preferably 0.1 to 0.3% by mass in the topical skin preparation composition.

[0023] [Other ingredients] In addition to the heparin-like substance (A) of the present invention, the skin topical composition of the present invention may contain, as necessary, various active ingredients (sometimes referred to as other active ingredients) used in pharmaceuticals, quasi-drugs, cosmetics, etc., to the extent that they do not impair the effects of the invention. Examples of other active ingredients include anti-inflammatory agents, keratinization inhibitors, keratolytic agents, antihistamines, antipruritics, wound healing agents, local anesthetics, vitamins, moisturizers, cooling agents, bactericides, vasoconstrictors, amino acids, whitening ingredients, sebum secretion promoters, antioxidants, and the like. These can be used individually or in combination of two or more in appropriate amounts.

[0024] Examples of anti-inflammatory agents include glycyrrhetinic acid and its pharmaceutically acceptable salts (e.g., glycyrrhetinic acid, stearyl glycyrrhetinate, etc.), glycyrrhizic acid and its pharmaceutically acceptable salts (e.g., dipotassium glycyrrhizinate, etc.), tranexamic acid and its pharmaceutically acceptable derivatives, licorice extract, steroid compounds (hydrocortisone, prednisolone, methylprednisolone, clobetazone, betamethasone, dexamethasone, cortisone, flumetazone, beclomethasone, fluticasone, and their pharmaceutically acceptable derivatives), indomethacin, ibuprofen, ibuprofen piconol, bufexamac, ufenamate, piroxicam, ketoprofen, dimethylisopropylazulene, Angelica acutiloba extract, Lithospermum erythrorhizon extract, etc. When anti-inflammatory agents are included, the content is preferably 0.001 to 15% by mass in the topical skin preparation composition. Examples of keratinization inhibitors include adapalene and azelaic acid. When a keratinization inhibitor is included, its content is preferably 0.01 to 20% by mass, and more preferably 0.01 to 10% by mass, in the topical skin preparation composition. Examples of keratolytic agents include salicylic acid or its derivatives. When a keratolytic agent is included, its content is preferably 0.01 to 10% by mass in the topical skin preparation composition.

[0025] Examples of antihistamines include diphenhydramine, chlorpheniramine, mequitazine, azelastine, emedastine, ketotifen, and pharmaceutically acceptable salts or derivatives thereof. Preferably, diphenhydramine hydrochloride and chlorpheniramine maleate are included. When an antihistamine is included, the content is preferably 0.01 to 15% by mass, and more preferably 0.01 to 5% by mass, in the topical skin preparation composition.

[0026] Examples of antipruritic agents include crotamiton, salicylic acid and its pharmaceutically acceptable derivatives, nonyl vanillylamide, capsaicin, benzyl nicotinate, and capsicum tincture. When an antipruritic agent is included, its content is preferably 0.001 to 10% by mass in the topical skin preparation composition.

[0027] Examples of wound healing agents include allantoin, zinc oxide, and zinc chloride. When a wound healing agent is included, its content is preferably 0.1 to 30% by mass in the topical skin preparation composition.

[0028] Examples of local anesthetics include lidocaine and its pharmaceutically acceptable salts, dibucaine and its pharmaceutically acceptable salts, procaine, methyl aminobenzoate, and ethyl aminobenzoate. When local anesthetics are included, the content is preferably 0.001 to 10% by mass in the topical skin preparation composition.

[0029] Examples of vitamin supplements include, for example, vitamin A [retinol and its pharmaceutically acceptable derivatives (e.g., retinal, retinoic acid, retinyl palmitate, vitamin A oil, etc.)], vitamin B1 [thiamine and its pharmaceutically acceptable derivatives (e.g., thiamine hydrochloride, thiamine nitrate, etc.)], vitamin B2 [riboflavin and its pharmaceutically acceptable derivatives (e.g., riboflavin phosphate, riboflavin sodium phosphate, riboflavin butyrate, and flavin adenine dinucleotide sodium, etc.)], vitamin B3 [nicotinic acid and its pharmaceutically acceptable derivatives (nicotinamide, tocopherol nicotinate, benzyl nicotinate, etc.)], vitamin B5 [pantothenic acid and its pharmaceutically acceptable derivatives (e.g., calcium pantothenate, panthenol, pantothenyl ethyl alcohol)], vitamin B6 [pyridoxine, pyridoxal and pharmaceutically acceptable salts], vitamin B 12 Examples include cobalamin and its pharmaceutically acceptable derivatives (e.g., cyanocobalamin, mecobalamin, and hydroxocobalamin hydrochloride), biotin, folic acid and its pharmaceutically acceptable salts, vitamin C derivatives (e.g., ascorbic acid and its pharmaceutically acceptable derivatives (e.g., erythorbic acid, sodium ascorbate, ascorbic palmitate, L-ascorbic acid 2-glucoside), vitamin D derivatives (e.g., calciferol and its pharmaceutically acceptable derivatives (e.g., ergocalciferol, cholecalciferol)), vitamin E derivatives (e.g., tocopherol acetate, tocopherol calcium succinate)), and other vitamins (e.g., hesperidin, carnitine, orotic acid, rutin, eriocitrin, inositol, and their pharmaceutically acceptable salts). When vitamins are included, their content is preferably 0.01 to 20% by mass, more preferably 0.01 to 10% by mass, and even more preferably 0.02 to 3% by mass in the topical skin preparation composition.

[0030] Examples of moisturizing agents include petrolatum, polyhydric alcohols (glycerin, 1,3-butylene glycol, etc.), hyaluronic acid and its pharmaceutically acceptable derivatives, high molecular weight 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.). When moisturizing agents are included, the amount is preferably 0.001 to 15% by mass of the topical skin preparation composition.

[0031] Examples of cooling agents include l-menthol, camphor, borneol and related substances, fennel oil, eucalyptus oil, peppermint oil, and the like.

[0032] Examples of disinfectants include isopropylmethylphenol, chlorhexidine hydrochloride, benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride, cetrimide, chlorhexidine gluconate, resorcinol, and hinokitiol.

[0033] Examples of vasoconstrictors include naphazoline, tetrahydrozoline, methyl ephedrine, and their pharmaceutically acceptable salts.

[0034] Examples of amino acids include glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine), and pharmaceutically acceptable salts thereof. When amino acids are included, the amount is preferably 0.001 to 10% by mass in the topical skin preparation composition. Including 0.001% by mass in the topical skin preparation composition provides a moisturizing effect, thereby improving the user experience (moisture and skin retention).

[0035] Examples of whitening ingredients include placenta, arbutin, kojic acid, ellagic acid, phytic acid, rucinol, chamomile ET, hydroquinone, potassium 4-methoxysalicylate, linoleic acid, and its derivatives. By combining a whitening ingredient with the heparin-like substance (A) of the present invention, it becomes useful as a treatment for acne scars.

[0036] An example of a sebum secretion promoter is γ-oryzanol. Examples of antioxidants include ferulic acid and plant extracts (such as eucalyptus leaf extract, rice bran extract, and olive leaf extract).

[0037] The present invention allows for the preparation of a topical skin preparation composition by combining the heparin-like substance (A) described above, and, if necessary, other active ingredients, with various additives described later, according to conventional methods. Any of the ingredients commonly used as pharmaceutical additives or cosmetic raw materials that can be incorporated into topical preparations can be used to prepare the topical skin preparation composition of the present invention.

[0038] 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, preservatives, pH adjusters, fragrances, water, etc.

[0039] 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, the amount is preferably 0.05 to 30% by mass in the topical skin preparation composition.

[0040] 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.

[0041] Examples of ionic surfactants include sodium lauryl sulfate and sodium cetyl sulfate. When surfactants are included, the amount is preferably 0.1 to 10% by mass in the topical skin preparation composition.

[0042] 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 amount is preferably 0.05 to 40% by mass, and more preferably 1 to 30% by mass, in the topical skin preparation composition.

[0043] Examples of polymer compounds include carboxyvinyl polymer, hydroxypropyl cellulose, hypromellose, hydrophobized hydroxypropyl methylcellulose, acrylated starch 300, polyvinylpyrrolidone, 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 polymer compounds are included, the amount is preferably 0.01 to 5% by mass in the topical skin preparation composition.

[0044] Examples of stabilizers include sodium chloride, sodium thiosulfate, sodium sulfite, sodium edetate, boric acid, and borax, among which boric acid, borax, and sodium edetate are preferably used. 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 skin topical preparation composition.

[0045] 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 amount is preferably 0.01 to 5% by mass, and more preferably 0.05 to 1% by mass, in the skin topical preparation composition.

[0046] Examples of pH adjusting agents include diisopropanolamine, triethanolamine, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, lactic acid, sodium lactate, malic acid, sodium malate, potassium dihydrogen phosphate, and sodium hydrogen phosphate. When incorporating a pH adjusting agent, the amount should be sufficient to achieve the desired pH. For example, 0.01 to 5% by mass is preferred, and 0.05 to 1% by mass is more preferred, in the skin topical preparation composition.

[0047] 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 found in these fragrances include terpenoid compounds. Terpenoid compounds include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. They are further classified by the number of carbon atoms into monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes, 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. When 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.

[0048] When water is added, the appropriate proportion is selected from a range of 50 to 98% by mass in the topical skin preparation composition, depending on the dosage form.

[0049] [Manufacturing method] The topical skin preparation composition of the present invention can be obtained, for example, by mixing the heparin-like substance (A) of the present invention with any optional components (other active ingredients, various additives) as needed.

[0050] [Skin topical preparation composition] The properties of the topical skin preparation composition of the present invention may be liquid, solid, or semi-solid (gel, ointment, paste, foam, etc.). It may also be in any formulation form, such as a topical skin drug, a topical quasi-drug, a cosmetic, or a skin cleanser.

[0051] The formulation form of the topical skin preparation composition of the present invention is not particularly limited, but examples include ointments, creams, gels, emulsions, liquids (lotions, toners), patches (packs, poultices), sprays that are dispensed as a mist, pump foams that are dispensed as a foam, and aerosols that are dispensed as a mist, powder, foam, or paste. Among these, liquids, gels, emulsions, creams, pump foams, or aerosols are 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.

[0052] The upper limit of the pH of the topical skin preparation composition of the present invention at 20°C is preferably 8 or less, more preferably 7.5 or less, and even more preferably 7 or less. The lower limit of the pH is preferably 3 or more, more preferably 4 or more, and even more preferably 5 or more. Furthermore, the lower and upper limits of the pH are preferably between 3 and 7.5, more preferably between 4 and 7, and even more preferably between 5 and 7. The pH in the present invention is measured according to the General Test Methods of the 18th Edition of the Japanese Pharmacopoeia (measurement temperature 20°C).

[0053] The topical skin preparation composition of the present invention is not particularly limited as long as it is for external use, and the skin includes the scalp.

[0054] The topical skin preparation composition of the present invention is a topical skin medicine that has the effects and efficacy of treating acne, pimples, 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, etc., as well as preventing rough skin, chapped skin, heat rash, chilblains, cracks, chapping and acne, oily skin, razor burn, sunspots and freckles caused by sunburn, and sunburn and snowburn. It can be used in quasi-drugs and cosmetics that have the following effects and benefits: preventing redness after shaving, tightening the skin, cleansing the skin, conditioning the skin, keeping the skin healthy, moisturizing the skin, protecting the skin, preventing dryness, refining the skin's texture, preventing rough skin, replenishing and retaining the skin's moisture and oil, maintaining skin's flexibility, softening the skin, giving the skin firmness, smoothing the skin, conditioning the skin after shaving, preventing sunburn, preventing sunspots and freckles caused by sunburn, and reducing the appearance of fine lines caused by dryness. In addition to these, it also provides the effects of "improving wrinkles, dullness, firmness, and enlarged pores," "retaining skin moisture and maintaining hydration," "improving skin structure," "improving skin barrier function," "restoring the skin's ability to retain moisture that has declined with age," and "preventing acne scars." Among these, it is particularly suitable for improving skin barrier function. Because the topical skin preparation composition of the present invention contains the heparin-like substance (A) of the present invention, it is particularly effective for xerosis, dry skin in children, moisturizing the skin, preventing skin dryness, improving skin texture, preventing rough skin, reducing the appearance of fine lines caused by dryness, maintaining skin moisture and providing long-lasting hydration, improving skin structure, and improving barrier function.

[0055] Furthermore, the topical skin preparation composition of the present invention is suitable for use as a preventative and therapeutic agent for acne caused by dry skin, as it prevents skin dryness, maintains skin moisture, and provides sustained hydration. When used as a preventative and therapeutic agent for acne, in addition to the heparin-like substance (A) of the present invention, other active ingredients (sometimes referred to as other active ingredients) used in acne pharmaceuticals, quasi-drugs, and cosmetics may be added, to the extent that they do not impair the effects of the invention. Examples of other active ingredients include the components mentioned above, among which anti-inflammatory agents, keratinization inhibitors, keratolytic agents, vitamins, moisturizers, and bactericides are preferred. These can be used individually or in combination of two or more. Preferred anti-inflammatory agents include glycyrrhetinic acid and its pharmaceutically acceptable salts (e.g., glycyrrhetinic acid, stearyl glycyrrhetinate, etc.), glycyrrhizic acid and its pharmaceutically acceptable salts (e.g., dipotassium glycyrrhizate, etc.), and ibuprofen piconol. Preferred keratinization inhibitors include adapalene and azelaic acid. Preferred keratolytic agents include salicylic acid and its pharmaceutically acceptable derivatives (e.g., salicylic acid, salicylic acid macrogol, salicylic acid ethanol, etc.). Preferred vitamins include vitamin A compounds [retinol and its pharmaceutically acceptable derivatives (e.g., retinal, retinoic acid, retinyl palmitate, vitamin A oil, etc.)], vitamin C compounds [ascorbic acid and its pharmaceutically acceptable derivatives (e.g., erythorbic acid, sodium ascorbate, ascorbic palmitate, L-ascorbic acid 2-glucoside, magnesium ascorbyl phosphate, etc.)], and vitamin E compounds [tocopherol, ubiquinone and its pharmaceutically acceptable derivatives (e.g., tocopherol acetate, etc.)]. Preferred moisturizers include, for example, petrolatum, polyhydric alcohols (glycerin, 1,3-butylene glycol, etc.), hyaluronic acid and its pharmaceutically acceptable derivatives, high molecular weight 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.).Preferred disinfectants include isopropylmethylphenol, chlorhexidine hydrochloride, benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride, cetrimide, chlorhexidine gluconate, resorcinol, and hinokitiol. When used as an acne prevention and treatment, it is suitable as a topical skin composition for acne that prevents acne, treats acne, and improves acne symptoms, as well as a moisturizing topical skin composition. The amounts of other active ingredients included are as described above. [Examples]

[0056] 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, the "%" in the composition indicates mass%, and the amounts of each component in the table are the amounts converted to pure content.

[0057] [Sample preparation method] Heparin-like substances manufactured by Tori Co., Ltd., Api Co., Ltd., and Nippon Rikagaku Yakuhin Co., Ltd. were used. 1.75 g of each heparin-like substance was dissolved in 87.5 mL of 2 M (mol / L) sodium hydroxide aqueous solution and heated at 60°C (for 2.5 to 5 hours). After cooling to room temperature, 10% hydrochloric acid was added while stirring to adjust the pH to 5-8. Ethanol was added to a volume percentage of 80% to precipitate the treated heparin-like substance. Then, centrifugation was performed at 15,000 rpm for 10 minutes. After removing the supernatant, the solid was dried at 80°C, and the resulting dry product was dissolved in purified water and desalted using a PD-10 (gravity-feed / centrifugal column for desalting and buffer exchange, manufactured by Cytiva). After freezing at -80°C, it was dried using a freeze-dryer to obtain heparin-like substances (A) for each example.

[0058] The above procedure was applied to each manufacturer's heparin-like substance, and the heparin-like substances (A) of Examples 1 to 3 were obtained by varying the heating time (2.5 to 5 hours) with added sodium hydroxide. Comparative Examples 1 to 4 were heparin-like substances prepared in the same manner as in the examples, except that the heparin-like substance manufactured by Tori was treated with sodium hydroxide for 7.5 hours, and heparin-like substances manufactured by Opocrin, Tori, and Api Corporation were not treated with sodium hydroxide.

[0059] [Disaccharide analysis] (Preparation of the measurement sample) The dried heparinoid was dissolved in purified water (heparinoid solution 25 mg / mL), and 100 μL of the heparinoid solution was mixed with 900 μL of Tris acetate buffer (pH 8) and 300 mU of chondroitinase ABC (SIGMA Aldrich, C2905). After incubation at 37°C for 16 hours, the mixture was heated in a boiling bath for 5 minutes to inactivate the enzyme. The mixture was filtered through a 0.45 μm filter, and the filtrate was measured by HPLC. (HPLC measurement conditions) Column: Hypersil SAX, 5um, 4.6mm, 250mm (Thermo Fisher Scientific) Mobile phase: Mobile phase A (water pH 3.5), mobile phase B (1.0M NaCl aqueous solution pH 3.5) Analysis mode: Gradient (0-4 min: B 0 vol%; 4-100 min: B 0-40 vol% (Linear); 100-140 min: B 0 vol%) Flow rate: 0.6mL / min Detector: UV 232nm Measurement temperature: A constant temperature around 40°C

[0060] (Calculation of ratios) The content (mol%) of disaccharide units was obtained by calculating the ratio (area ratio) of the following specific disaccharide units to the total disaccharide units from the peak area of ​​each peak in the obtained HPLC chart (decomposition products of the test substance by chondroitinase ABC). ΔDi-0S: A disaccharide unit (non-sulfated disaccharide unit) consisting of D-glucuronic acid and N-acetyl-D-galactosamine. ΔDi-6S:: A disaccharide unit consisting of D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine ΔDi-4S: A disaccharide unit consisting of D-glucuronic acid and C4-sulfated N-acetyl-D-galactosamine. ΔDi-di(2,6)S: A disaccharide unit consisting of C2-sulfated D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine. ΔDi-di(4,6)S: A disaccharide unit consisting of D-glucuronic acid and C4 and C6 sulfated N-acetyl-D-galactosamine. ΔDi-di(2,4)S: A disaccharide unit consisting of sulfated D-glucuronic acid at the C2 position and sulfated N-acetyl-D-galactosamine at the C4 position. ΔDi-tri(2,4,6)S: A disaccharide unit consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine. Sulfate group:-SO3Na

[0061] [Molecular weight analysis] (Preparation of the measurement sample) The dried heparinoid was dissolved in purified water (heparinoid solution 5 mg / mL), filtered through a 0.45 μm filter, and measured by HPLC. (Measurement conditions) Column: GPC column, Shodex OHpak SB-806M HQ, particle size 13μm, 300×8mm Mobile phase: 0.1% NaCl aqueous solution Flow rate: 1.0mL / min Detector: RI (Differential Refractometer) Column temperature: Constant temperature around 40°C Standard material: Pullulan (Shodex Standard P-82 for GFC (aqueous GPC) columns)

[0062] (Calculation of number-average molecular weight) The molecular weight was calculated by applying the elution time of the test substance to the pullulan calibration curve, and then the number-average molecular weight (Mn) was calculated. The number-average molecular weight (Mn) is calculated as follows when a polymer with a molecular weight of Mi contains Ni molecules: Number average molecular weight (Mn)=Σ(Ni·Mi) / Σ(Ni) This is the value represented by [formula].

[0063] [Sulfate group content] The tests were conducted in accordance with the test methods listed in the Japanese Pharmacopoeia Standards for Non-Official Drug Ingredients.

[0064] [Barrier function evaluation (dextran permeability test)] Approximately 5.0 x 10 in the insert of Transwell (Corning Incorporated Transwell®, Cat No. 3470-Clear) 4 Normal human epidermal keratinocytes were seeded at a cell / well ratio. Additionally, 700 μL of warmed culture medium was added to a 24-well plate, and the cells were cultured at 37°C under moist conditions of 5 vol. % CO2. After reaching confluence, the cells were transferred to a control medium (without added components) and 1.8 mM Ca. 2+250 μL of the culture medium containing the substance (comparative) or the culture medium containing 0.1% heparinoid was added to the insert and 700 μL was added to the well plate, and incubated for 24 hours. After removing the culture medium, the inserts were washed once with PBS (Gibco, Cat No. 10010023), 600 μL of P buffer (10 mM HEPES buffer [pH 7.4], 1 mM sodium pyruvate, 10 mM D-(+)-glucose, 145 mM NaCl, 1 mM gCl2, Ultratrapure water) was added to the outside of the insert, and 100 μL of a solution of Dextran (Thermo, Cat No. D1821, Dextran, Fluorescein, 10,000 MW, Anionic) diluted 100-fold with P buffer was added to the inside of the insert. Under humid conditions of 37°C and 5 vol.% CO2, the inserts were allowed to stand for 3 hours. Then, 50 μL of P buffer from the outside of the inserts was added to each of the 96-well flat-bottom plates, and fluorescence measurements were taken using a plate reader (excitation: 485 nm / fluorescence: 528 nm). The barrier function-enhancing effect of each test substance was assessed using Ca, which is generally known as a positive control for barrier function enhancement. 2+ The percentage change was calculated and shown, with the enhancement effect set to 100%. The results are shown in the table below. The higher the skin barrier function, the higher the percentage change in barrier function. Barrier function change rate (%) = (fluorescence of control medium without components - fluorescence of medium containing 0.1% heparinoid) / (fluorescence of control medium without components - 1.8 mMCa) 2+ (Fluorescence of the culture medium (positive control)) × 100

[0065] [Table 1]

[0066] Based on the above results, heparinoid (A), in which D-glucuronic acid and N-acetyl-D-galactosamine have specific ratios of ΔDi-tri(2,4,6)S, ΔDi-di(2,6)S, and ΔDi-0S, showed a high effect in improving the skin barrier function in disaccharide analysis.

[0067] As a topical skin preparation composition containing the heparin-like substance (A) of the present invention, a topical skin preparation composition (pharmaceutical or quasi-drug) with the following formulation was prepared. Similar evaluations as in the above examples were obtained, and a topical skin preparation composition that improves skin dryness and a topical preparation composition for acne prevention and treatment were obtained.

[0068] [Table 2]

[0069] [Table 3]

[0070] [Table 4]

[0071] [Table 5]

[0072] [Table 6]

[0073] The raw materials used in preparing the examples, comparative examples, and formulation examples are shown below. The following references to "JP," "Non-Pharmacopoeia Standards," "Pharmacopoeia Additives Standards," and "Non-Pharmacopoeia Standards" refer to raw materials that conform to the 18th Revised Japanese Pharmacopoeia Standards, the Japanese Pharmacopoeia Non-Pharmacopoeia Drug Standards 2002, the Pharmaceutical Additives Standards (2018), and the Quasi-Drug Raw Material Standards (2021), respectively. The heparinoid substance described in the example formulation is a raw material that satisfies claim 1. • Heparin-like substances: Non-official Japanese standard, non-official Japanese standard heparin-like substances, manufactured by Tori Co., Ltd., manufactured by Api Co., Ltd., manufactured by Nippon Rikagaku Yakuhin Co., Ltd., manufactured by Opocrin Inc. • Pyridoxine hydrochloride: Japanese Pharmacopoeia, Pyridoxine hydrochloride, manufactured by DSM Co., Ltd. • Dipotassium glycyrrhizinate: Non-pharmacopoeial standard, Dipotassium glycyrrhizinate, manufactured by Maruzen Pharmaceutical Co., Ltd. • Allantoin: Non-governmental standard, allantoin, manufactured by Permakem Asia Co., Ltd. L-ascorbic acid 2-glucoside: Vitamin C derivative (ascorbic acid derivative), manufactured by Nagase Vita Co., Ltd. • Tocopherol acetate: Japanese Pharmacopoeia, Tocopherol acetate, manufactured by Mitsubishi Chemical Corporation. • Isopropylmethylphenol: Isopropylmethylphenol, manufactured by Osaka Chemical Industries, Ltd. • Retinol palmitate: Japanese Pharmacopoeia, Retinyl palmitate 1,740,000 IU / g, manufactured by DSM Co., Ltd. • Tranexamic acid: Japanese Pharmacopoeia, Tranexamic acid, manufactured by Kyowa Pharma Chemical Co., Ltd. • Diphenhydramine: Japanese Pharmacopoeia, Diphenhydramine, manufactured by Kongo Chemical Co., Ltd. • Placenta extract: External standard, virgin placenta extract KX-1, manufactured by Yoshihide Kogyo Co., Ltd. • Dibutylhydroxytoluene: Pharmaceutical additive standard, BHT, manufactured by Fujifilm Wako Pure Chemical Corporation • Hydroxypropyl methylcellulose: External standard, Metrolose, manufactured by Shin-Etsu Chemical Co., Ltd. • Dimethylpolysiloxane: Pharmaceutical additives, Q7-9120 Silicone Fluid 20cSt, manufactured by Toray Dow Corning Co., Ltd. • Squalane: External standard, squalane, manufactured by Nikko Chemicals Co., Ltd. Glycerin: Japanese Pharmacopoeia, Pharmacopoeia Method Glycerin, manufactured by Sakamoto Pharmaceutical Co., Ltd. • Propylene glycol: Japanese Pharmacopoeia, Propylene Glycol, manufactured by ADEKA Corporation • 1,3-Butylene glycol (1,3-BG): Pharmaceutical additives, 1,3-butylene glycol, manufactured by Daicel Chemical Industries, Ltd. • Macrogol 20000: Japanese Pharmacopoeia, Macrogol 20000, manufactured by Sanyo Chemical Industries, Ltd. • Ethanol: (General Incorporated Association) Alcohol Association Standard, General Alcohol 95% Alcohol, Synthetic and Undenatured, Manufactured by Nippon Synthetic Alcohol Co., Ltd. • Polyoxyethylene sorbitan monostearate (Polysorbate 60): Pharmaceutical additive standard, NIKKOL TS-10MV, manufactured by Nippon Surfactant Industry Co., Ltd. • Polyoxyethylene hydrogenated castor oil 10: Pharmaceutical additive standard, HCO-10, manufactured by Nippon Surfactant Industry Co., Ltd. • Polyoxyethylene (9) lauryl ether (lauromacrogol): Japanese Pharmacopoeia, NIKKOL BL-21, manufactured by Nippon Surfactant Industries Co., Ltd. Glycerin fatty acid ester: Food additive, NIKKOL Decaglyn 5-OV, manufactured by Nippon Surfactant Industry Co., Ltd. • Stearyl alcohol: Pharmaceutical additives, Calcol 8098, manufactured by Kao Corporation. Octyldodecanol: Pharmaceutical additives, N-JECOL 200A, Shin Nippon Rika Co., Ltd. Isopropyl myristate: Pharmaceutical additive standard, NIKKOL IPM-100, manufactured by Nippon Surfactant Industry Co., Ltd. • Xanthan gum: Pharmaceutical additives, Echogum T, manufactured by DSP Gokyo Food & Fine Chemicals Co., Ltd. • Carboxyvinyl polymer: Pharmaceutical additive, CRBOPOL980, manufactured by Noveon Co. • Sodium edetate hydrate: Japanese Pharmacopoeia, Sodium edetate, manufactured by Chubu Kirest Co., Ltd. • Methyl parahydroxybenzoate: Japanese Pharmacopoeia, Methyl parahydroxybenzoate, manufactured by Ueno Pharmaceutical Co., Ltd. • Propyl parahydroxybenzoate: Japanese Pharmacopoeia, Propyl parahydroxybenzoate, manufactured by Ueno Pharmaceutical Co., Ltd. • Sodium citrate: Japanese Pharmacopoeia, Sodium citrate hydrate, manufactured by Fuso Chemical Industries, Ltd. • Citric acid: Japanese Pharmacopoeia, Citric Acid Hydrate, manufactured by Three F Co., Ltd. • Diisopropanolamine: Pharmaceutical additives, diisopropanolamine, manufactured by Mitsui Chemicals Fine, Inc. • Borax: Japanese Pharmacopoeia, Borax, manufactured by Kosakai Pharmaceutical Co., Ltd. • Fragrance: Fragrances A to D described in paragraphs

[0065] to

[0071] of Japanese Patent Publication No. 2002-128658, A to E described in Japanese Patent Publication No. 2003-73249, or 1 to 4 described in

[0016] to

[0023] of Japanese Patent Publication No. 2020-132680 are appropriately selected. Sodium hydroxide: Japanese Pharmacopoeia, Sodium hydroxide, manufactured by Kosakai Pharmaceutical Co., Ltd.

Claims

1. A topical skin preparation composition containing a heparin-like substance (A) in which the proportion of disaccharide units consisting of C2-sulfated D-glucuronic acid and C4,C6-disulfated N-acetyl-D-galactosamine is 7 to 22 mol%.

2. The topical skin composition according to claim 1, comprising a heparin-like substance (A) in which the proportion of disaccharide units consisting of C2-sulfated D-glucuronic acid and C6-sulfated N-acetyl-D-galactosamine is 2 to 10 mol%.

3. The topical skin composition according to claim 1, comprising a heparin-like substance (A) in which the proportion of disaccharide units consisting of D-glucuronic acid and N-acetyl-D-galactosamine is 5 to 18.5 mol%.

4. The topical skin preparation composition according to claim 1, wherein the sulfate group content of component (A) is 25.8 to 37.3% by mass.

5. The topical skin preparation composition according to claim 1, wherein the number average molecular weight of component (A), as measured by gel filtration chromatography, is 10,000 to 40,000.

6. A topical skin preparation composition according to any one of claims 1 to 5, for improving the skin barrier function.

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