JP2024095558A - Skin care composition - Google Patents

Abstract

The present invention provides a skin topical composition having an effect of promoting the expression of skin tight junctions.
[Solution] A skin topical composition containing (A) a heparinoid and (B) vitamin _B6 , in which the mass ratio (A)/(B) of component (A) to component (B) is 0.5 to 10.
[Selection diagram] None

Description

The present invention relates to a skin care composition containing a heparinoid and vitamin _B6 .

In general dry dermatitis, itching is caused. Methods for suppressing itching include the use of active ingredients corresponding to antihistamines, antipruritics, and local anesthetics, or combinations of these active ingredients. One cause of itching is a decrease in skin barrier function, and in particular, in the case of hypersensitive skin with a decreased skin barrier function, it is difficult to obtain a sufficient effect of improving the skin barrier function even with these active ingredients or their combinations, and the skin is easily affected by external stimuli. Under these circumstances, there has been a demand for a skin topical composition that is effective against dry dermatitis accompanied by a decrease in skin barrier function.

JP 2010-184903 A

Minowa, E. et al. Med. Mol. MorphoI. 54, p346-355 (2021)

In recent years, it has been reported that physical or chemical stimuli cause the extension of epidermal itch nerve fibers in patients with atopic dermatitis, and that dermal tight junctions are a factor that controls itch by inhibiting the extension of nerve fibers (Minowa, E. et al. Med. Mol. Morphol. 54, 346-355 (2021)). The present invention focuses on the promotion of dermal tight junction expression and aims to provide a skin topical agent composition that promotes dermal tight junction expression.

The present inventors have conducted extensive research to achieve the above object, and have found that a significant effect of promoting the expression of skin tight junctions can be obtained by combining (A) heparinoids and (B) vitamin _B6 at a specific ratio, leading to the present invention. (A) heparinoids have been known for their blood circulation promoting effect, anti-inflammatory effect, and skin moisturizing effect, and (B) vitamin _B6 , such as pyridoxine hydrochloride, is a water-soluble vitamin preparation that has anti-inflammatory and metabolic promoting effects. Although these components are known to have antipruritic effects due to their anti-inflammatory effects, the antipruritic effect of a single agent is not sufficient, and it is the new knowledge of the present inventors that a significant effect can be obtained in promoting the expression of skin tight junctions.

Accordingly, the present invention provides the following skin external preparation composition.
1. A skin external preparation composition comprising (A) a heparinoid and (B) vitamin _B6 , wherein the mass ratio (A)/(B) of the component (A) to the component (B) is 0.5 to 10.
2. The skin external preparation composition according to 1, which is a skin tight junction expression promoter.
3. The skin external preparation composition according to 1, which is an agent for improving sensitive skin.
4. The skin external preparation composition according to 1, which is an agent for relieving chronic itch.
5. The skin external preparation composition according to any one of 1 to 4, wherein component (B) is one or more selected from pyridoxine, pyridoxine hydrochloride, and pyridoxal phosphate.
6. The skin external preparation composition according to any one of 1 to 4, further comprising (C) one or more members selected from tranexamic acid and pharma-ceutically acceptable salts thereof.
7. The skin external preparation composition according to any one of 1, 3 and 4, further comprising (D) one or more selected from diphenhydramine, chlorpheniramine, and pharma- ceutically acceptable salts thereof.

The present invention provides a skin topical composition that has the effect of promoting the expression of skin tight junctions.

The present invention will be described in detail below.
[Component (A)]
The heparinoid, which is component (A) of the present invention, is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is known to have moisturizing effects, improve xerosis, increase blood flow, and the like.

The origin of the heparinoid used in the present invention is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides and those extracted from the tissues of edible animals (e.g., lungs containing tracheal cartilage of cattle, pigs, etc.). In the topical composition of the present invention, a heparinoid defined in the Japanese Pharmacopoeia Extra Pharmaceutical Standards (Standard No.: 108548) is preferably used as the heparinoid.

The content of component (A) in the skin topical preparation composition is preferably 0.005 to 5% by mass, more preferably 0.01 to 1% by mass, even more preferably 0.1 to 0.5% by mass, and particularly preferably 0.1 to 0.3% by mass. By making the content 0.005% by mass or more, it becomes easier to obtain the effects of promoting the expression of skin tight junctions, improving sensitive skin, and improving chronic itching. On the other hand, by making the content 5% by mass or less, the content stability of component (A) is further improved. Note that content stability refers to the stability of the component content during storage over time.

[Component (B)]
The component (B) of the present invention is vitamin _B6 , which can be used alone or in combination of two or more. Examples of vitamin _B6 include pyridoxine, pyridoxal, and pharma- ceutical acceptable salts (hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.). From the viewpoint of high skin tight junction expression promoting effect and pyridoxal phosphate, which is the active form of pyridoxine metabolized, exerting its medicinal effect, pyridoxine, pyridoxine hydrochloride, and pyridoxal phosphate are preferred. Vitamin _B6 can be synthesized by a known method or obtained as a commercially available product.

The content of component (B) in the skin topical preparation composition 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. By making the content 0.005% by mass or more, it becomes easier to obtain the effects of promoting the expression of skin tight junctions, improving sensitive skin, and improving chronic itching. On the other hand, by making the content 0.8% by mass or less, the content stability of component (A) is further improved, making it less likely that skin irritation will occur.

The mass ratio (A)/(B) of the (A) component to the (B) component is 0.5 to 10, preferably 1 to 10, and more preferably 5 to 10. By making the mass ratio 0.5 or more, skin irritation is unlikely to occur. By making the mass ratio 10 or less, the combined use of the (A) component and the (B) component can achieve a significant effect of promoting the expression of skin tight junctions, improving sensitive skin, and improving chronic itching.

[Component (C)]
The skin external preparation composition of the present invention may further contain a (C) component. The (C) component of the present invention is one or more selected from tranexamic acid and its pharma- ceutical acceptable salts, and two or more can be used in combination. Examples of the pharma- ceutical acceptable salt include metal salts such as magnesium salt, calcium salt, sodium salt, and potassium salt, and inorganic salts such as phosphate, hydrochloride, hydrobromide, and sulfate. Tranexamic acid and its pharma- ceutical acceptable salts have an antiplasmin effect and are widely used as hemostatic agents, as well as antiallergic, anti-inflammatory, and whitening effects. By further containing the (C) component in a skin external preparation composition containing the above-mentioned (A) component and (B) component in a specific mass ratio, the effect of promoting the expression of skin tight junctions, the effect of improving hypersensitive skin, and the effect of improving chronic itching are further improved.

The content of component (C) in the skin topical preparation composition is preferably 0.01 to 20% by mass, more preferably 0.1 to 10% by mass, and even more preferably 0.5 to 3% by mass. By making it 0.01% by mass or more, it becomes easier to obtain the effects of promoting the expression of skin tight junctions, improving sensitive skin, and improving chronic itching. Furthermore, by making it 0.5% by mass or more, it becomes easier to obtain the effect of softening the skin tone caused by scratches. On the other hand, by making it 20% by mass or less, the content stability of component (C) is further improved.

[Component (D)]
The skin external preparation composition of the present invention may further contain component (D). The component (D) of the present invention is one or more selected from diphenhydramine, chlorpheniramine, and their pharmaceutically acceptable salts, and two or more can be used in combination. The pharmaceutically acceptable salt is not particularly limited, but specifically includes acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyl disulfonate, tannate, lauryl sulfate, and sulfate. Among them, diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine, and chlorpheniramine maleate are preferred from the viewpoint of further improving the effect of improving hypersensitive skin and chronic itching. The component (D) is a component expected to have an antipruritic/antipruritic effect, and has a common feature of having a strong antihistamine effect. By further containing such a (D) component in the skin topical preparation composition having the above-mentioned (A) component and (B) component in a specific mass ratio, the effect of improving hypersensitive skin and the effect of improving chronic itching are further improved. In addition, the skin topical preparation composition of the present invention may contain both the (C) component and the (D) component.

The content of component (D) in the skin topical preparation composition is preferably 0.01 to 5% by mass, more preferably 0.1 to 3% by mass, and even more preferably 0.1 to 2% by mass. By making it 0.01% by mass or more, it becomes easier to obtain antipruritic and antipruritic effects (chronic itch improvement effect). Furthermore, by making it 0.1% by mass or more, sebum secretion is promoted more effectively, and the antipruritic effect (chronic itch improvement effect) is further enhanced. On the other hand, by making it 5% by mass or less, the content stability of component (D) is further improved.

[Skin tight junction expression promoter]
It is known that the skin barrier function is reduced by the deficiency of tight junction factors such as Claudin. As is clear from the examples described below, the skin external preparation composition containing the (A) component and the (B) component of the present invention at a specific ratio increases the mRNA amount of the tight junction factor involved in the skin barrier function and promotes the expression of tight junctions in the skin due to the blending ratio of the components described in the present invention. The increase in the mRNA amount of the tight junction factor involved in the skin barrier function, which is one of the indicators of the effect, is preferably 1.0 times or more, more preferably 1.25 times or more, relative to the additive effect of the (A) component + the (B) component. In addition, by further containing the (C) component, the above-mentioned effect is further improved.

[Hypersensitive skin improvement agent]
A person suffering from hypersensitive skin is sensitive to external stimuli that a healthy person cannot feel, such as sweating or rubbing of clothes. One of the reasons is that nerve fibers are excessively extended by protruding tight junction factors. The skin external preparation composition of the present invention containing the (A) component and the (B) component in a specific ratio can control abnormal activation of nerve fibers that protrude outward more than usual by newly forming tight junction factors, thereby improving hypersensitive skin. In addition, by further containing the (C) component and the (D) component, the effect of alleviating the hypersensitive state of the skin is further improved.

[Chronic itching relief agent]
For the skin condition of patients with chronic skin pruritus, such as atopic dermatitis, the skin topical agent composition of the present invention containing the (A) component and the (B) component in a specific ratio softens the stratum corneum of the skin, so that the active ingredient penetrates into the granular layer of the skin.Furthermore, by increasing the tight junction factor present under the stratum corneum, the extension of nerve fibers, which is often seen in patients with atopic dermatitis, etc., is controlled.Therefore, it is effective in dealing with chronic itching.In addition, by further containing the (C) component and the (D) component, the effect of alleviating chronic itchy skin condition is further improved.

[Other ingredients]
In addition to the above-mentioned (A) and (B) components, the skin topical preparation composition of the present invention may be blended (contained) with various active ingredients (sometimes referred to as other active ingredients) used in medicines, quasi-drugs, cosmetics, etc., as necessary, within the scope of not impairing the effects of the invention. Examples of other active ingredients include anti-inflammatory agents (excluding the (A), (B), and (C) components), antihistamines (excluding the (D) component), antipruritic agents, wound healing agents, local anesthetics, vitamin preparations (excluding the (B) component), moisturizers (excluding the (A) component), cooling agents, bactericides, vasoconstrictors, amino acids, etc. These may be used alone or in combination of two or more kinds, and the content of each is within the effective amount range, but is preferably 0.1 to 20% by mass in the skin topical preparation composition.

Examples of anti-inflammatory agents other than components (A), (B), and (C) include glycyrrhetinic acid and its pharma- ceutical acceptable salts (e.g., glycyrrhetinic acid, stearyl glycyrrhetinate, etc.), glycyrrhizinic acid and its pharma-ceutical acceptable derivatives, placenta, licorice extract, steroid compounds (hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, cortisone, flumethasone, beclomethasone, fluticasone, and their pharma-ceutical acceptable derivatives), indomethacin, ibuprofen, ibuprofen piconol, bufexamac, ufenamate, piroxicam, ketoprofen, salicylic acid and its pharma-ceutical acceptable derivatives, dimethylisopropylazulene, Angelica acutiloba extract, Lithospermum root extract, etc. When anti-inflammatory agents other than components (A), (B), and (C) are contained, the content is preferably 0.001 to 15% by mass in the topical skin preparation composition.

Examples of antihistamines other than component (D) include mequitazine, azelastine, emedastine, ketotifen, and pharma- ceutically acceptable salts or pharma-ceutically acceptable derivatives thereof. When an antihistamine other than component (D) is contained, the content is preferably 0.01 to 5% by mass in the topical skin composition.

Examples of antipruritic agents include crotamiton, salicylic acid and its pharma- ceutical acceptable derivatives, vanillylamide nonylate, capsaicin, benzyl nicotinate, and capsicum tincture. When an antipruritic agent is contained, the content is preferably 0.001 to 10% by mass in the skin topical agent composition.

Examples of wound healing agents include allantoin, zinc oxide, zinc chloride, etc. When a wound healing agent is contained, the content is preferably 0.1 to 30% by mass in the skin topical preparation composition.

Local anesthetics include, for example, lidocaine and its pharma- ceutically acceptable salts, dibucaine and its pharma- ceutically acceptable salts, procaine, methyl aminobenzoate, and ethyl aminobenzoate. When a local anesthetic is contained, the content is preferably 0.001 to 10% by mass in the skin topical preparation composition.

Examples of vitamin preparations other than component (B) include vitamin A [retinol and its pharma- ceutical acceptable derivatives (e.g., retinal, retinoic acid, retinol palmitate, vitamin A oil, etc.)], vitamin _B1 [thiamine and its pharma- ceutical acceptable derivatives (e.g., thiamine hydrochloride, thiamine nitrate, etc.)], vitamin _B2 [riboflavin and its pharma- ceutical acceptable derivatives (e.g., riboflavin phosphate, riboflavin sodium phosphate, riboflavin butyrate, and flavin adenine dinucleotide sodium, etc.)], vitamin _B3 [nicotinic acid and its pharma- ceutical acceptable derivatives (nicotinamide, tocopherol nicotinate, benzyl nicotinate, etc.)], vitamin _B5 [pantothenic acid and its pharma- ceutical acceptable derivatives (e.g., calcium pantothenate, panthenol, pantothenyl ethyl alcohol)], vitamin B _Vitamin C [cobalamin and its pharma- ceutical acceptable derivatives (e.g., cyanocobalamin, mecobalamin, and hydroxocobalamin hydrochloride)], biotin, folic acid and its pharma-ceutical acceptable salts, vitamin C [ascorbic acid and its pharma-ceutical acceptable derivatives (e.g., erythorbic acid, sodium ascorbate, ascorbic acid palmitate, L-ascorbic acid-2-glucoside), vitamin D [calciferol and its pharma-ceutical acceptable derivatives (e.g., ergocalciferol, cholecalciferol)], vitamin E [tocopherol, ubiquinone and its pharma-ceutical acceptable derivatives (e.g., tocopherol acetate, tocopherol calcium succinate)], other vitamins (e.g., hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, inositol, and their pharma-ceutical acceptable salts). When a vitamin preparation other than component (B) is contained, the content thereof in the skin external preparation composition 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.

Examples of moisturizing agents other than component (A) include petrolatum, polyhydric alcohols (glycerin, 1,3-butylene glycol, etc.), hyaluronic acid and its pharma- ceutically acceptable derivatives, 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.). When a moisturizing agent other than component (A) is contained, the content of the moisturizing agent in the skin topical composition is preferably 0.001 to 15% by mass.

Examples of cooling agents include l-menthol, camphor, borneol and related substances, fennel oil, eucalyptus oil, and peppermint oil.

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

Examples of vasoconstrictors include naphazoline, tetrahydrozoline, methylephedrine, and pharma- ceutically acceptable salts thereof.

Examples of amino acids include glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine), and pharma- ceutical acceptable salts thereof. When amino acids are contained, the content is preferably 0.001 to 10% by mass in the topical skin composition. By containing 0.001% by mass in the topical skin composition, a moisturizing effect is obtained, improving the feel when used (moist feeling and feeling left on the skin).

The topical skin composition of the present invention can be prepared by blending the above-mentioned components (A) and (B), as well as components (C) and (D), and other active ingredients as necessary, together with various additives described below, in a conventional manner. Any of the pharmaceutical additives that can generally be contained in topical preparations and ingredients used as cosmetic raw materials can be used to prepare the topical skin composition of the present invention.

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

Examples of oils 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 tri-fatty acid glycerides such as glycerin triisooctanoate and tri(caprylic/capric acid)glyceryl. When an oil is contained, the content of the oil in the skin topical composition is preferably 0.05 to 30% by mass.

Examples of the surfactant include a nonionic surfactant and an ionic surfactant.
Examples of nonionic surfactants include glycerin fatty acid esters such as glyceryl monostearate and glyceryl monooleate, polyglycerin fatty acid esters such as 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, sesquioxane, and the like. Sorbitan fatty acid esters such as sorbitan oleate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80); polyoxyethylene (6) sorbitan monolaurate, polyoxyethylene (60) sorbitan tetrastearate, and polyoxyethylene tetraoleate polyoxyethylene hydrogenated castor oils 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 (lauromacrogol), 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. The numerical value at the end of the notation of the above-mentioned exemplified polyglycerol fatty acid esters indicates the average degree of polymerization of glycerin, and the numerical value in parentheses in the notation of the above-mentioned exemplified nonionic surfactants indicates the average degree of polymerization of ethylene oxide or propylene oxide, that is, the average number of repetitions of oxyethylene groups or oxypropylene groups.

Examples of ionic surfactants include sodium lauryl sulfate and sodium cetyl sulfate. When a surfactant is contained, the content is preferably 0.1 to 10% by mass in the skin topical preparation composition.

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 composition. When a polyhydric alcohol is contained, the content is preferably 0.05 to 40% by mass, and more preferably 1 to 30% by mass, in the topical skin composition.

Examples of polymeric 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 fat, 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, and chondroitin sulfate. When a polymeric compound is contained, the content of the polymeric compound in the skin topical composition is preferably 0.01 to 5% by mass.

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

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

Examples of pH adjusters 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. The amount of a pH adjuster to be added may be any amount sufficient to achieve the desired pH, and is preferably 0.01 to 5% by mass, more preferably 0.05 to 1% by mass, in the skin topical preparation composition.

Examples of fragrances include compound fragrances such as citrus fragrances, floral fragrances, and rose fragrances, 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 depending on the number of carbon atoms, but 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. If a fragrance is included, the content is preferably 0.001 to 1% by mass, and more preferably 0.01 to 0.1% by mass, in the skin topical preparation composition.

When water is added, the content is appropriately selected from the range of 50 to 98% by mass in the topical skin composition depending on the formulation.

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

[External application composition]
The external skin preparation composition of the present invention may be in any form, such as liquid, solid, semi-solid (gel, ointment, paste, foam), etc. In addition, it may be in any formulation, such as a drug for external skin application, a quasi-drug for external skin application, a cosmetic, or a skin cleanser.

The formulation of the skin topical composition of the present invention is not particularly limited, but examples thereof include ointments, creams, lotions, gels, emulsions, liquids, patches, sprays that are sprayed as a mist, pump foams that are sprayed as a foam, aerosols that are sprayed as a mist, powder, foam or paste, packs, etc. Among these, liquids, gels, emulsions, creams, pump foams or aerosols are preferred due to the good content stability of component (A). Pump foams containing components (A), (B), (C), (D) and (E) are preferred. The emulsification state of creams, emulsions and the like is not particularly limited, and may be any of W/O, O/W, W/O/W and O/W/O.

A pump foam that does not contain a propellant is composed of, for example, an airtight container, a pump body, an actuator, a cap, and a concentrate, while an aerosol foam that contains a propellant is basically composed of a pressure-resistant container that can withstand internal pressure, a valve, an actuator, a concentrate, and a propellant. In the case of an aerosol foam, the skin topical agent composition is used as the concentrate, and the aerosol foam is made by combining the concentrate with the propellant. The content ratio of the propellant is preferably 1 to 10 parts by mass per 100 parts by mass of the concentrate. Examples of propellants include liquefied gas and compressed gas. Examples of liquefied gas include liquefied petroleum gas (LPG), dimethyl ether, and fluorohydrocarbons, which are mainly composed of hydrocarbons with 3 to 5 carbon atoms (propane, n-butane, i-butane, etc.), and examples of compressed gas include carbon dioxide, nitrogen, and nitrous oxide. Among these, liquefied petroleum gas is preferred. By making it into a pump foam or an aerosol foam, it is discharged as a foam, making it easier to spread on the skin. In addition, by making it into an aerosol foam, it is possible to prevent the surfactant contained in the concentrate from precipitating at low temperatures.

Examples of pressure-resistant containers that can withstand internal pressure include aluminum cans and tin cans, and the inside of these can be coated with resin or the like.

The method of use of the topical skin preparation composition of the present invention is not particularly limited, but it can be used by rubbing an appropriate amount into the affected area once to several times a day, or by spreading it on gauze or the like and applying it. Note that pump sprays, aerosol foams, pump foams, and aerosol sprays are preferably sprayed at an angle of upright to about 45 degrees.

The pH of the skin topical composition of the present invention at 20°C is preferably 8 or less, more preferably 7.5 or less, and even more preferably 3 to 7.5. The pH in the present invention is measured according to the 18th revised edition of the Japanese Pharmacopoeia, General Testing Method (measurement temperature 20°C).

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

There are no particular limitations on the skin topical composition as long as it is for external use, and the skin includes the scalp.

The present invention will be specifically explained below with 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 to a pure content.

The compositions shown in the table below were evaluated for their ability to promote tight junction expression and for their cytotoxicity using the methods described below. The results are also shown in the table.

[Evaluation test of the effect of promoting tight junction expression]
Increases in the mRNA levels of Claudin-4, Occludin, and ZO-1, which are tight junction factors present in epidermal keratinocytes, were confirmed.
Normal human epidermal keratinocytes (NHEK) were seeded on a 96-well plate at 2 x ¹⁰⁴ cells/well. Two days after cell seeding, the medium was replaced with a sample adjusted to a specified concentration, and the cells were cultured for 24 hours at 37°C in a humidified state of 5% _CO2 . The concentrations of the test substances were adjusted to 0 and 0.1% by mass for heparinoids (HP), and 0, 0.005, 0.01, 0.02, and 0.1% by mass for pyridoxine hydrochloride (Pin), and each single component and a combination of components (HP x Pin) were used.

After that, RNA was extracted from the cells of each sample using an RNA extraction kit (RNeasy mini kit, manufactured by QIAGEN). Reverse transcription reaction was performed using a known method to obtain cDNA, which was then quantified using a real-time PCR device (reverse transcription: ReverTra Ace2, TOYOBO, polymerase: KOD SYBR qPCR mix, TOYOBO). The sequences of the primers used; Claudin-4, Occludin, and ZO-1 are shown below. The amounts of mRNA of the three target genes, Claudin-4, Occludin, and ZO-1, were calculated and corrected with the amount of mRNA of GAPDH as a correction gene.

[Cytotoxicity evaluation results]
Normal human epidermal keratinocytes (NHEK) were seeded on a 96-well plate at 5 x ¹⁰⁴ cells/well. Two days after cell seeding, the medium was replaced with a sample adjusted to a specified concentration, and the cells were cultured for 24 hours at 37°C under humidified _CO2 . The concentrations of the test substances were adjusted to the concentrations shown in the table, and each single component and the combination of components (A) + (B) (HP + Pin) were used. In addition, a medium containing 1% by mass of triton was prepared as a high control to confirm cytotoxicity.
All of the medium was collected, and absorbance at a wavelength of 490 nm was measured with a plate reader using an LDH assay kit (Nacalai Tesque).

From the above results, in terms of the tight junction expression promoting effect, when (A) heparinoid and (B) pyridoxine hydrochloride were combined in a specific mass ratio, a significant increase in the mRNA amount of the tight junction factors Claudin-4, Occludin, and ZO-1 was observed. In particular, the composition of the present invention achieved a higher effect than the additive effect of components (A) and (B). On the other hand, in Comparative Example 1, which exceeded the specific mass ratio (having a relatively high content of heparinoid), the increase in the mRNA amount was smaller than that of the present invention. In addition, when (A) heparinoid and (B) pyridoxine hydrochloride were combined in a specific mass ratio and further tranexamic acid (C) was added, a higher effect was achieved than the additive effect of components (A), (B), and (C) (a significant increase in the mRNA amount of Occludin). The additive effects in the table are (A) the results for heparinoids (HP) alone, (B) the results for pyridoxine hydrochloride (Pin) alone, and in Table 9, (C) the results for tranexamic acid alone are added together.

From the above results, it was found that when (A) heparinoid and (B) pyridoxine hydrochloride were combined at a specific mass ratio, the cytotoxicity was low. In Comparative Example 2, which has a mass ratio lower than that of the present invention, it was found that the combination of heparinoid and pyridoxine hydrochloride caused cytotoxicity, so the evaluation test of the tight junction expression promoting effect was not performed.
The additive effect in the table is the sum of the results for (A) heparinoid (HP) alone and (B) pyridoxine hydrochloride (Pin) alone.

The skin external preparation compositions having the following compositions were prepared by a conventional method, and were subjected to an application test evaluation on the subjects suffering from chronic itching as described below. The results are also shown in the table.
[Application test on subjects with chronic itching]
Three subjects with chronic itching were asked to rate the degree of itching before application of the skin topical composition (sample) on their skin as "1," and the degree of improvement in itching two days after application of the sample was evaluated on a five-point scale as follows. The results are shown as the average scores of the three subjects.
Amount applied: 0.5 mL applied to a 2 cm square area. Number of doses: applied once a day for 2 days (total of 2 applications), evaluated 2 days after the last application. Evaluation criteria
1: Unable to bear and scratched the applied area 2: Unable to bear and scratched slightly the applied area 3: Scratched slightly the applied area, but tolerable level 4: Almost no scratching at the applied area 5: Did not scratch the applied area

As is clear from the above results, the skin topical composition of the example was more effective in improving chronic itching than 1% diphenhydramine hydrochloride alone or a 1% diphenhydramine solution containing dipotassium glycyrrhizinate. In order to eliminate the cloudiness caused by the combined use of components (A) and (D), the skin topical composition of the present invention was formulated with dipotassium glycyrrhizinate and sodium chloride, but this had no effect on chronic itching.

A lotion, an aqueous cream (O/W formulation), and an oil-based cream (W/O formulation) of the following formulation were prepared in a standard manner. The products obtained were effective in improving sensitive skin, chronic itching, and improving the skin barrier function.

The raw materials used in preparing the Examples, Comparative Examples and Formulation Examples are shown below.
In addition, the terms "Japanese Pharmacopoeia,""Extra-PharmacopoeiaRegulations,""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 Standards, Pharmaceutical Additives Standards (2018), and Quasi-drug Raw Materials Standards (2021), respectively.
Heparinoids: Extraordinary Regulation, Extraordinary Heparinoids, Manufactured by Tori Co., Ltd. Pyridoxine hydrochloride: Japanese Pharmacopoeia, Pyridoxine hydrochloride, Manufactured by DSM Co., Ltd. Dipotassium glycyrrhizinate: Extraordinary Regulation, Dipotassium glycyrrhizinate, Manufactured by Maruzen Pharmaceutical Co., Ltd. Glycyrrhetinic acid: Extraordinary Regulation, Glycyrrhetinic acid, Manufactured by Maruzen Pharmaceutical Co., Ltd. Diphenhydramine hydrochloride: Japanese Pharmacopoeia, Diphenhydramine hydrochloride, Manufactured by Kongo Kagaku Co., Ltd. Allantoin: Extraordinary Regulation, Allantoin, Manufactured by PermaChem Asia Co., Ltd. Ascorbic acid: Japanese Pharmacopoeia, Ascorbic acid, Manufactured by Kyowa Pharma Chemical Co., Ltd. Tocopherol acetate: Japanese Pharmacopoeia, Japanese Pharmacopoeia Tocopherol acetate, manufactured by Mitsubishi Chemical Foods Corporation; Tranexamic acid: Japanese Pharmacopoeia; Tranexamic acid, manufactured by Kyowa Pharma Chemical Co., Ltd.; Placenta: Placenta extract, manufactured by Japan Bio Products Co., Ltd.; Retinol palmitate: Japanese Pharmacopoeia; Retinol palmitate, manufactured by DSM Co., Ltd.; Panthenol: Extraordinary Pharmacopoeia regulations; Panthenol, manufactured by DSM Co., Ltd.; Squalane: Extraordinary Pharmacopoeia regulations; Squalane, manufactured by Nikko Chemicals Co., Ltd.; Glycerin: Japanese Pharmacopoeia; Pharmacopoeia glycerin, manufactured by Sakamoto Pharmaceutical Co., Ltd.; Propylene glycol: Japanese Pharmacopoeia; Propylene glycol, manufactured by ADEKA Co., Ltd.; 1,3-butylene glycol (1,3-BG): Pharmaceutical additive regulations; 1,3-butylene glycol Daicel Chemical Industries, Ltd. Macrogol 20000: Japanese Pharmacopoeia, Macrogol 20000, Sanyo Chemical Industries, Ltd. Polyoxyethylene (9) lauryl ether (lauromacrogol): Japanese Pharmacopoeia, NIKKOL BL-21, Nippon Surfactant Industry Co., Ltd. Polyoxyethylene (20) sorbitan monostearate (polysorbate 60): Pharmaceutical additives, NIKKOL TS-10MV, Nippon Surfactant Industry Co., Ltd. Polyoxyethylene hydrogenated castor oil (10): Pharmaceutical additives, NIKKOL HCO-10, Nippon Surfactant Industry Co., Ltd. Glycerin fatty acid ester: Food additive, NIKKOL Decaglyn 5-OV, manufactured by Nippon Surfactant Industries Co., Ltd.; Stearyl alcohol, manufactured by the Pharmaceutical Additives Standards; Kalcol 8098, manufactured by Kao Corporation; Octyldodecanol, manufactured by the Pharmaceutical Additives Standards; N-Jecol 200A, manufactured by New Japan Chemical Co., Ltd.
Isopropyl myristate: Pharmaceutical additive, NIKKOL IPM-100, manufactured by Nippon Surfactant Industries Co., Ltd. Xanthan gum: Pharmaceutical additive, Echo Gum T, manufactured by DSP Gokyo Food & Fine Chemicals Co., Ltd. Carboxyvinyl polymer: Pharmaceutical additive, CRBOPOL980, manufactured by Noveon Co.・Sodium edetate hydrate: JP, sodium edetate, manufactured by Chubu Cherest Co., Ltd. ・Methyl parahydroxybenzoate: JP, methyl parahydroxybenzoate, manufactured by Ueno Pharmaceutical Co., Ltd. ・Propyl parahydroxybenzoate: JP, propyl parahydroxybenzoate, manufactured by Ueno Pharmaceutical Co., Ltd. ・Dibutylhydroxytoluene: Pharmaceutical Additives Regulations, BHT, manufactured by Fujifilm Wako Pure Chemical Co., Ltd. ・Sodium citrate: JP, sodium citrate hydrate, manufactured by Fuso Chemical Co., Ltd. ・Citric acid: JP, citric acid hydrate, manufactured by Fuso Chemical Co., Ltd. Sodium chloride: Japanese Pharmacopoeia, sodium chloride, manufactured by Tomita Pharmaceutical Co., Ltd. Diisopropanolamine: Pharmaceutical Additives Regulations, diisopropanolamine, manufactured by Mitsui Fine Chemicals, Inc. Borax: Japanese Pharmacopoeia, borax, manufactured by Kosakai Pharmaceutical Co., Ltd. Fragrance: appropriately selected from fragrances a to d described in paragraphs [0065] to [0071] of JP2002-128658A, A to E described in JP2003-73249A, or 1 to 4 described in Japanese Patent Application No. 2019-023940, [0016] to [0023].

SEQ ID NO: 1 in the sequence listing: forward primer used in PCR (hClaudin-4) SEQ ID NO: 2 in the sequence listing: reverse primer used in PCR (hClaudin-4) SEQ ID NO: 3 in the sequence listing: forward primer used in PCR (hOccludin) SEQ ID NO: 4 in the sequence listing: reverse primer used in PCR (hOccludin) SEQ ID NO: 5 in the sequence listing: forward primer used in PCR (hZO-1) SEQ ID NO: 6 in the sequence listing: reverse primer used in PCR (hZO-1) SEQ ID NO: 7 in the sequence listing: forward primer used in PCR (hGAPDH) SEQ ID NO: 8 in the sequence listing: reverse primer used in PCR (hGAPDH)

Claims (7)

A skin external preparation composition comprising (A) a heparinoid and (B) vitamin _B6 , wherein the mass ratio (A)/(B) of the (A) component to the (B) component is 0.5 to 10. The skin topical composition according to claim 1, which is a skin tight junction expression promoter. The skin topical composition according to claim 1, which is an agent for improving sensitive skin. The skin topical composition according to claim 1, which is an agent for improving chronic itching. The skin topical composition according to any one of claims 1 to 4, wherein component (B) is one or more selected from pyridoxine, pyridoxine hydrochloride, and pyridoxal phosphate. The skin topical composition according to any one of claims 1 to 4, further comprising (C) one or more selected from tranexamic acid and pharma- ceutically acceptable salts thereof. The skin topical composition according to any one of claims 1, 3 and 4, further comprising (D) one or more selected from diphenhydramine, chlorpheniramine and pharma- ceutically acceptable salts thereof.