Compositions for topical use on the skin and aerosol preparations

Abstract

A composition for external use on the skin, comprising (A) a heparinoid and (B) vitamin B6, and having a pH of 4 or higher. An aerosol preparation comprising a composition for external use on skin containing (A) a heparinoid and (C) one or more selected from organic acids and salts thereof, and a propellant.

Description

[Technical field]

[0001] The present invention relates to a composition for external application to the skin containing a heparinoid and vitamin B6. The present invention relates to an aerosol preparation containing a composition for external use on the skin, which contains a heparin analogue and an organic acid or a salt thereof, and a propellant. [Background technology]

[0002] Healthy skin has sufficient moisture in the stratum corneum on the surface of the skin. However, when the amount of sebum secreted that covers the surface of the skin is reduced or the amount of intercellular lipids in the stratum corneum is reduced, the moisture content of the stratum corneum is reduced, resulting in dry skin. In particular, when the skin becomes dry due to dry air, aging, stress, etc., the barrier function of the skin is reduced, and redness, itching, etc. are caused by external stimuli, which can also cause dry skin diseases, etc.

[0003] Conventionally, skin care products containing moisturizing ingredients have been used to treat dry skin. Among moisturizing ingredients, heparinoids are mucopolysaccharides formed by polysulfating chondroitin, and are known to promote blood flow, have anti-inflammatory effects, moisturize, and improve skin structure, and have few side effects. Therefore, they have been used as active ingredients in skin medicines for treating dry skin diseases (see, for example, Patent Document 1). Polysaccharides, which are a higher concept of heparinoids, are known to decompose by hydrolysis under acidic conditions, but the conditions for decomposition vary greatly depending on the properties of the sugar. Skin compositions for external use containing heparinoids have good stability, and factors that inhibit stability have not been well known (see, for example, Non-Patent Document 1).

[0004] On the other hand, vitamin B6 is known to inhibit and normalize sebum secretion, and is used in hair growth promoters and drugs for treating angular cheilitis and seborrheic dermatitis. Vitamin B6 is known to be destabilized by heat or light, is stable under acidic conditions, and is unstable under neutral to alkaline conditions.

[0005] It is known that the photostability of vitamin B6 can be improved by the addition of sugar alcohols (see, for example, Patent Document 2), but the effect is not sufficient, and the addition of sugar alcohols has the drawback of limiting applications.

[0006] When dry skin continues, excess sebum secreted to replenish moisture clogs the pores, preventing the formation of a sebum film on the skin surface, and further driness progresses. To combat this type of dry skin, a combination of heparinoids, which have an effect of improving dry skin, and vitamin B6 such as pyridoxine hydrochloride, which has an effect of inhibiting and normalizing sebum secretion, is expected to have an effect of improving the above-mentioned dry skin, but there have been no examples of these being combined at the same time, and the issues and effects that arise from using them together have not even been inferred.

[0007] In addition, a composition for external use on the skin containing a heparinoid generates a precipitate when stored at low temperature for a long period of time, and therefore low-temperature storage stability of the composition is desired. In addition, a composition for external use on the skin containing a heparinoid and an aerosol agent containing a propellant have a problem with the stability of the heparinoid. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Publication No. 112708 / 1983 [Patent Document 2] Japanese Patent Application Publication No. 07-206664 [Non-patent literature]

[0009] [Non-Patent Document 1] Hirudoid Pharmaceutical Interview Form Summary of the Invention [Problem to be solved by the invention]

[0010] The present inventors have found that when a heparinoid and vitamin B6 are simultaneously blended, the stability of either component is significantly reduced, and it is extremely difficult to simultaneously stabilize both components when they are used in combination. That is, the present invention aims to provide a skin topical composition in which both components are stably blended. Another object of the present invention is to provide a composition for external use on the skin that contains a heparinoid and has a stable blend of heparinoids and excellent storage stability at low temperatures. [Means for solving the problem]

[0011] As a result of intensive research to achieve the above object, the present inventors discovered that the stability of both heparinoids and vitamin B6 is improved by using them together and setting the pH of a composition for external use on the skin containing both to 4 or more, and thus arrived at the present invention. That is, according to the composition for external use on the skin of the present invention, the stability of the heparinoids and vitamin B6 is improved and the decrease in the contents of both components over time can be suppressed, so that the actions of both components can be maintained and effectively exerted even when stored for a long period of time. In addition, it was discovered that by preparing an aerosol formulation containing (A) a heparin-like substance and (C) one or more organic acids and their salts, and a propellant, the stability of the heparin-like substance is improved and the low-temperature storage stability of the topical skin composition containing the heparin-like substance is also improved, which led to the present invention.

[0012] Accordingly, the present invention provides the following composition for external application to the skin. 1. A composition for topical application to the skin, comprising (A) a heparinoid and (B) vitamin B6, and having a pH of 4 or higher. 2. The topical skin composition described in 1, wherein component (B) is pyridoxine or a pharma- ceutical acceptable salt thereof. 3. The composition for external skin application described in 1 or 2, further comprising one or more selected from lactic acid, phosphoric acid, malic acid, boric acid, citric acid, and salts thereof. 4. The composition for external use on the skin according to any one of 1 to 3, which is a cream, a lotion, a gel, an aerosol, a spray, an emulsion or a pack. 5. An aerosol preparation comprising a composition for external use on the skin containing (A) a heparinoid, and (C) one or more selected from organic acids and their salts, and a propellant. 6. The aerosol preparation according to 5, which further contains (D) a nonionic surfactant and is sprayed in the form of foam. Effect of the Invention

[0013] According to the present invention, it is possible to provide a composition for external use on the skin which can stably combine a heparinoid and vitamin B6. According to the present invention, it is possible to provide a composition for external use on skin containing a heparinoid, which can stably contain a heparinoid and has excellent low-temperature storage stability, and an aerosol preparation containing a propellant. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention will be described in detail below. (I) The first invention is a composition for external application to the skin, which contains (A) a heparinoid and (B) vitamin B6 and has a pH of 4 or higher. (II) The second invention is an aerosol preparation comprising a composition for external use on skin, which contains (A) a heparinoid and (C) one or more organic acids and their salts, and a propellant. Hereinafter, the topical skin composition of the first invention will be referred to simply as the first composition (meaning the undiluted solution in the case of an aerosol), the topical skin composition of the second invention (undiluted solution) will be referred to simply as the second composition, and in the case of both the first and second compositions, the composition will be referred to simply as the composition. [Component (A)] The component (A) is a heparinoid, which has moisturizing, anti-inflammatory, blood circulation promoting, and skin structure improving effects. Heparinoids are polysulfate esters of mucopolysaccharides such as chondroitin polysulfate. The origin of the heparinoid used in the present invention is not particularly limited, and examples thereof include those obtained by polysulfating mucopolysaccharides and those extracted from the tissues of edible animals (e.g., lungs containing tracheal cartilage of cattle, pigs, etc.). Among them, heparinoids defined in the Japanese Pharmacopoeia Extra Pharmaceutical Standards (Standard Number: 108548) are preferably used.

[0015] The content of the (A) component is not particularly limited, but from the viewpoint of moisturizing effect, it is preferably 0.01% by mass or more in the composition, more preferably 0.1% by mass or more, and even more preferably 0.3% by mass or more. The upper limit is not particularly limited, but it is preferably 1% by mass or less. By making it 0.01% by mass or more, a moisturizing effect can be expected, and by making it 0.3% by mass or more, not only moisturizing but also an improvement effect for xerosis can be expected.

[0016] [(B) Component] The component (B) is commonly known as vitamin B6, and has the effect of normalizing sebum secretion and activating skin cells. Examples of vitamin B6 include pyridoxine, pyridoxal, pyridoxamine, or pharma- ceutical acceptable salts thereof, such as hydrochloride, sulfate, nitrate, hydrobromide, and phosphate. Vitamin B6 can be used alone or in combination of two or more. Among them, pyridoxine hydrochloride is preferred.

[0017] The content of component (B) is not particularly limited and can be set arbitrarily taking into consideration safety and the effect of improving dry skin, but is preferably 0.01 to 2 mass %, more preferably 0.05 to 2 mass % in the first composition. By making it 0.01 mass % or more, it is possible to expect the effect of normalizing sebum secretion, improving dry skin, and activating cells, and by making it 1 to 2 mass %, it is possible to expect the effect of improving seborrheic dermatitis.

[0018] The content mass ratio of the (A) component to the (B) component is not particularly limited and can be set arbitrarily taking into consideration safety and the effect of improving dry skin, but the content mass ratio represented by (B) / (A) is preferably 0.01 to 20, more preferably 0.1 to 10. By making this ratio 0.01 or more, it is possible to obtain both the effect of normalizing sebum secretion and the effect of improving dry skin. On the other hand, by making it 20 or less, it is possible to obtain a moisturizing effect and an inhibitory effect on sebum secretion while being excellent in safety.

[0019] The pH of the first composition of the present invention is 4 or more. By adjusting the pH of the first composition containing the above-mentioned components (A) and (B) to 4 or more, the heparinoid (A) and vitamin B6 (B) can be stably contained in the first composition. From this point of view, the lower limit of the pH of the first composition is preferably 4.5 or more, and more preferably 5 or more. The upper limit of the pH of the first composition is preferably 8 or less, more preferably 7 or less, and even more preferably 6 or less. The pH is measured according to the General Tests of the Japanese Pharmacopoeia, 17th Edition (measurement temperature: 20°C).

[0020] If the pH of the first composition of the present invention is within the above range, it is not necessary to contain a pH regulator, and it can be optionally contained. When a pH regulator is contained, examples of the pH regulator include lactic acid, citric acid, malic acid, phosphoric acid, boric acid, hydrochloric acid, sulfuric acid, and their salts, diisopropanolamine, triethanolamine, sodium hydroxide, potassium hydroxide, etc. Examples of the salt include sodium salts, potassium salts, and ammonium salts. Specifically, examples of phosphates include sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate, etc., examples of borates include borax, etc., and examples of citrates include sodium citrate, etc. The pH regulator can be used alone or in appropriate combination of two or more. Among them, from the viewpoint of the stability of (A) heparinoid and (B) vitamin B6, one or more selected from lactic acid, phosphoric acid, malic acid, boric acid, citric acid, and their salts are preferable, and one or more selected from boric acid, citric acid, and their salts are more preferable. The content of the pH adjuster when blended is appropriately selected so that the first composition has a desired pH, and is preferably 0.01 to 5% by mass, more preferably 0.05 to 1% by mass in the first composition. By making the content 0.01% by mass or more, (A) the heparinoid and (B) vitamin B6 can be contained more stably. By making the content 5% by mass or less, precipitation of the pH adjuster over time is less likely to occur.

[0021] [Optional ingredients] The composition of the present invention may contain an appropriate amount of optional ingredients used in medicines, quasi-drugs, cosmetics, etc., either alone or in appropriate combination of two or more, within the scope that does not impair the effects of the present invention. Examples of optional ingredients include the following.

[0022] Examples of various active ingredients used in medicines, quasi-drugs, cosmetics, etc. other than (A) heparinoids and (B) vitamin B6 include anti-inflammatory agents other than heparinoids, antihistamines, antipruritic agents, wound healing agents, local anesthetics, vitamins other than vitamin B6, cooling agents, moisturizers, disinfectants, vasoconstrictors, amino acids, etc. The above also includes herbal ingredients.

[0023] Examples of anti-inflammatory agents include glycyrrhetinic acid, glycyrrhizinic acid or a pharma- ceutically acceptable salt thereof, licorice extract, steroid compounds (hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, cortisone, flumethasone, beclomethasone, fluticasone, or derivatives thereof), indomethacin, ibuprofen, ibuprofen piconol, bufexamac, ufenamate, piroxicam, ketoprofen, salicylic acid or a derivative thereof, dimethylisopropylazulene, Angelica acutiloba extract, and Lithospermum root extract.

[0024] Examples of antihistamines include diphenhydramine or a pharma- ceutically acceptable salt thereof, chlorpheniramine or a pharma- ceutically acceptable salt thereof, mequitazine, azelastine, emedastine, ketotifen or derivatives thereof, etc. Among these, diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, etc. are preferred.

[0025] Examples of antipruritic agents include crotamiton, vanillylamide nonylate, capsaicin, benzyl nicotinate, and capsicum tincture. Wound healing agents include, for example, allantoin, zinc oxide, and the like.

[0026] Examples of local anesthetics include lidocaine or a pharma- ceutically acceptable salt thereof, and dibucaine or a pharma- ceutically acceptable salt thereof.

[0027] Examples of vitamin preparations include vitamin A [vitamin A oil, retinol and its derivatives (e.g., retinal, retinoic acid, retinol palmitate, etc.)], vitamin B1 [thiamine and its derivatives (e.g., thiamine hydrochloride, thiamine nitrate, etc.)], vitamin B2 [riboflavin and its derivatives (e.g., riboflavin phosphate, riboflavin sodium phosphate, riboflavin butyrate, and flavin adenine dinucleotide sodium, etc.)], vitamin B3 [nicotinic acid and its derivatives (nicotinamide, tocopherol nicotinate, benzyl nicotinate, etc.)], vitamin B5 [pantothenic acid and its derivatives (e.g., calcium pantothenate, panthenol, pantothenyl ethyl alcohol, etc.)], vitamin B 12 vitamin C [cobalamin and its derivatives (e.g., cyanocobalamin, mecobalamin, and hydroxocobalamin hydrochloride, etc.)], biotin, folic acid or a pharma- ceutical acceptable salt thereof, vitamin C [ascorbic acid and its derivatives (e.g., erythorbic acid, sodium ascorbate, magnesium ascorbate, ascorbic acid 2-glucoside, ascorbic acid palmitate, etc.)], vitamin D [calciferol and its derivatives (e.g., ergocalciferol, cholecalciferol, etc.)], vitamin E [tocopherol, ubiquinone and its derivatives (e.g., tocopherol acetate, tocopherol calcium succinate, etc.)], other vitamins (e.g., hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, inositol, and a pharma-ceutical acceptable salt thereof), and the like.

[0028] Examples of the freshening agents include 1-menthol, camphor, borneol or related substances thereof, fennel oil, eucalyptus oil, peppermint oil, and the like.

[0029] Examples of moisturizing agents include natural moisturizing factors (urea, etc.), ceramides, and plant extracts (chamomile extract, aloe extract, etc.).

[0030] Examples of the disinfectant include isopropylmethylphenol, chlorhexidine hydrochloride, benzethonium chloride, benzalkonium chloride, cetrimide, and the like.

[0031] Examples of vasoconstrictors include naphazoline, tetrahydrozoline, methylephedrine, and salts thereof.

[0032] Examples of amino acids include glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine), and pharma- ceutical acceptable salts thereof (eg, ephedrine hydrochloride, methylephenoline hydrochloride, etc.).

[0033] The content of these active ingredients when blended is within the effective amount range, preferably 0.1 to 20% by mass in the composition.

[0034] Examples of other optional components include oils, surfactants, polyhydric alcohols, polymeric compounds, organic solvents, stabilizers, preservatives, fragrances, and water.

[0035] 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, octyldodecanol, and behenyl alcohol; fatty acid esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, and diisopropyl adipate; and polyhydric alcohol fatty acid esters such as glycerin triisooctanoate and tri(capryl-capric acid)glyceryl. When an oil is added, the content is preferably 1 to 30% by mass in the composition.

[0036] 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 monolaurate (10), polyglyceryl monostearate (10), polyglyceryl oleate (10), and polyglyceryl pentaoleate (10); polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glyceryl monostearate (15); sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monooleate, and sorbitan sesquioleate; polyoxyethylene sorbitan (20) monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80) polyoxyethylene sorbitan fatty acid esters; polyoxyethylene sorbit fatty acid esters such as polyoxyethylene sorbit (6) monolaurate, polyoxyethylene (60) sorbit tetrastearate, and polyoxyethylene (60) sorbit tetraoleate; polyoxyethylene castor oils such as polyoxyethylene (60) castor oil; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil (10) and polyoxyethylene hydrogenated castor oil (60); polyethylene glycol fatty acid esters such as polyethylene glycol monolaurate (for example, 10EO) and polyoxyethylene glycol (4EO) monostearate; polyoxyethylene alkyl ethers such as polyoxyethylene (9) lauryl ether (lauromacrogol), polyoxyethylene (10) cetyl ether, and polyoxyethylene oleyl ether. Examples of ionic surfactants include sodium lauryl sulfate and sodium cetyl sulfate. When a surfactant is added, its content in the composition is preferably 0.1 to 10% by mass.

[0037] Examples of polyhydric alcohols include glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol (macrogol). When a polyhydric alcohol is added, its content in the composition is preferably 0.5 to 20% by mass.

[0038] Examples of polymeric compounds include carboxyvinyl polymer, hydroxypropyl cellulose, hypromellose, hydrophobized hydroxypropyl methylcellulose, acrylated starch 300 and polyvinylpyrrolidone, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac 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 derivatives thereof, chitosan and derivatives thereof, elastin, heparan sulfate, hyaluronic acid, and chondroitin sulfate. When a polymer compound is added, its content in the composition is preferably 0.01 to 5% by mass.

[0039] Examples of the organic solvent include ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, and ethyl acetate. When an organic solvent is added, its content in the composition is preferably 1 to 30% by mass.

[0040] Examples of stabilizers include sodium chloride, sodium thiosulfate, sodium sulfite, and sodium edetate. When a stabilizer is added, its content in the composition is preferably 0.01 to 5% by mass.

[0041] Examples of preservatives include methyl paraoxybenzoate (methylparaben), propyl paraoxybenzoate (propylparaben), dibutylhydroxytoluene, benzalkonium chloride, and benzethonium chloride. When a preservative is added, its content in the composition is preferably 0.01 to 1% by mass.

[0042] Examples of the fragrance include blended fragrances such as citrus fragrance, floral fragrance, and rose fragrance, and essential oils such as eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, spearmint oil, rosemary oil, lavender oil, and lemon oil. Representative components contained in these fragrances include terpenoid compounds. Terpenoid compounds include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes according to the number of carbon atoms, and the most representative component is monoterpene. Preferred terpenoid compounds include l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, citral, citronellal, limonene, citronellol, cineole, geraniol, cineole, linalool, nonanal, eugenol, isoeugenol, indole, benzaldehyde, vanillin, limonene, galaxolide, γ-nonalanol, and the like. Examples of the aromatic compounds include cinnamyl acetate, benzyl acetate, α-terpineol, hexyl cinnamic aldehyde, γ-undecalactone, etc. When a fragrance is added, the content is preferably 0.001 to 1% by mass, more preferably 0.01 to 0.1% by mass in the composition.

[0043] When water is added, the content is appropriately selected from the range of 50 to 90% by mass depending on the dosage form.

[0044] [Manufacturing method] The composition of the present invention can be prepared, for example, by mixing (A) a heparinoid and (B) vitamin B6 according to a conventional method together with optional ingredients as required.

[0045] [Skin external composition] The form of the composition of the present invention is not particularly limited as long as it can be applied transdermally, and may be any of liquid, solid, semi-solid (gel, ointment, paste, foam), etc. The formulation may be any of pharmaceuticals for external use on the skin, quasi-drugs for external use on the skin, cosmetics, skin cleansing agents, etc.

[0046] The formulation of the composition of the present invention is not particularly limited, and examples thereof include ointments, creams, lotions, gels, emulsions, liquids, patches, sprays that are sprayed in the form of mist or foam, aerosols that are sprayed in the form of mist, powder, foam, or paste, ointments, packs, body shampoos, hair shampoos, rinses, etc. Among these, creams, lotions, gels, aerosols, sprays, emulsions, and packs are preferred, and creams, lotions, emulsions, aerosols that are sprayed in the form of foam, and pump sprays that are sprayed in the form of foam are more preferred. The emulsification state of creams, emulsions, etc. is not particularly limited, and may be any of W / O, O / W, W / O / W, and O / W / O.

[0047] A spray agent that does not contain a propellant is composed of, for example, an airtight container, a pump body, an actuator, a cap, and a first composition. An aerosol agent is basically composed of a pressure-resistant container that can withstand internal pressure, a valve, an actuator, a first composition (undiluted liquid), and a propellant. The content ratio of the propellant in the aerosol agent is preferably 1 to 12 mass% relative to the first composition, and more preferably 1 to 10 mass%. Examples of the propellant include liquefied gas and compressed gas. Examples of the liquefied gas include liquefied petroleum gas (LPG), dimethyl ether, and fluorohydrocarbons, which are mainly composed of hydrocarbons having 3 to 5 carbon atoms (propane, n-butane, i-butane, etc.), and examples of the compressed gas include carbon dioxide, nitrogen, and nitrous oxide. Among these, liquefied petroleum gas is preferable. Spray agents and aerosol agents are easily spread on the skin by filling them in a container that sprays them in a foam form. In addition, by making them into an aerosol agent, it is possible to suppress precipitation of a surfactant blended in the undiluted liquid at low temperatures.

[0048] Examples of pressure-resistant containers that can withstand the internal pressure include aluminum cans and tin cans, and the inside of these can be coated with resin or the like.

[0049] The method of using the 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. In addition, it is preferable to spray the spray agent or aerosol agent at an angle of about upright to 45 degrees.

[0050] The effects and efficacy of the composition of the present invention include treatment for xerosis, dry skin in children, rough hands and fingers, cracked and chapped hands and feet, keratosis of the elbows, knees, heels and ankles, chilblains (excluding sores), lumps and tightness in the skin after cuts and burns (excluding the face), swelling, muscle pain and joint pain after bruises or sprains, as well as improvement of skin barrier function, promotion of metabolism, activating skin cells, (improvement of) skin problems caused by dryness, and treatment of dryness (on the face, etc.).

[0051] (II) The second invention is an aerosol preparation comprising a composition for external use on skin, which contains (A) a heparinoid and (C) one or more organic acids and their salts, and a propellant.

[0052] [Component (A)] The component (A) is the same as in the first invention, and the preferred components and ranges are also the same as in the first invention.

[0053] [(C) component] (C) is one or more selected from organic acids and their salts, and can be used alone or in combination of two or more. By incorporating the (C) component, the heparinoid can be stably contained in an aerosol preparation containing a propellant and a skin topical composition containing the heparinoid. Examples of the (C) component include citric acid, lactic acid, malic acid, tartaric acid, adipic acid, fumaric acid, maleic acid, malonic acid, etc., and among these, citric acid, malic acid, and tartaric acid are preferred. Examples of the salt include sodium salts, potassium salts, ammonium salts, etc., and specifically, sodium citrate can be mentioned. The (C) component may be a derivative of an organic acid such as hydroxycitric acid.

[0054] The content of component (C) is not particularly limited, but is preferably 0.01 to 5% by mass, more preferably 0.05 to 1% by mass in the second composition. By making it 0.01% by mass or more, the heparinoid (A) can be stably contained, and by making it 5% by mass or less, the low-temperature storage stability is improved.

[0055] [(D) component] In order to improve the low-temperature storage stability, the second composition may preferably contain the nonionic surfactant (D) described in the first invention. Among these, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbit fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil are preferred, as are polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan (20) monolaurate (polysorbate 20), polyoxyethylene sorbitan (20) monostearate (polysorbate 60), and polyoxyethylene sorbitan (20) monooleate (polysorbate 80), and monolauric acid. Polyoxyethylene sorbit fatty acid esters such as polyoxyethylene sorbit (6) and polyoxyethylene glycerin fatty acid esters such as polyoxyethylene (15) glyceryl oleate are more preferred, and polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan (20) monostearate (polysorbate 60) and polyoxyethylene sorbitan (20) monooleate (polysorbate 80) and polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbit (6) monolaurate are even more preferred.

[0056] The content of the (D) component in the second composition is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 1 to 5% by mass. By making it 0.1% by mass or more, low-temperature storage stability is further improved. By making it 10% by mass or less, stickiness is reduced and usability is improved.

[0057] The pH of the second composition is preferably 4 or more. The lower limit of the pH of the second composition is more preferably 4.5 or more, and even more preferably 5 or more. The upper limit of the pH of the second composition is preferably 8 or less, more preferably 7 or less, and even more preferably 6 or less. By keeping the pH within the above range, the heparinoid (A) can be contained more stably. The pH is measured according to the Japanese Pharmacopoeia - General Testing Method (measurement temperature: 20°C).

[0058] If the pH of the second composition of the present invention is within the above range, it is not necessary to contain a pH regulator, and it can be optionally contained. When a pH regulator is contained, examples of the pH regulator include phosphoric acid, boric acid, hydrochloric acid, sulfuric acid, and salts thereof, diisopropanolamine, triethanolamine, sodium hydroxide, potassium hydroxide, etc. Examples of the salt include sodium salt, potassium salt, ammonium salt, etc. Specific examples of phosphates include sodium dihydrogen phosphate, etc., and examples of borates include borax, etc. The pH regulator can be used alone or in appropriate combination of two or more. Among them, from the viewpoint of stably containing (A) heparinoids, one or more selected from phosphoric acid, boric acid, and salts thereof are preferred, and one or more selected from boric acid and salts thereof are more preferred. When a pH regulator is added, the content is appropriately selected so that the composition has a target pH, and is preferably 0.01 to 5 mass % in the composition, more preferably 0.05 to 1 mass %. By setting the content ratio to 5% by mass or less, precipitation of the pH adjuster over time is less likely to occur.

[0059] Other optional components of the second composition include the optional components of the first invention described above excluding components (C) and (D) and the pH adjuster.

[0060] [Propellant] Examples of the propellant include liquefied gas and compressed gas. Examples of the liquefied gas include liquefied petroleum gas (LPG), mainly composed of a hydrocarbon having 3 to 5 carbon atoms (propane, n-butane, i-butane, etc.), dimethyl ether, and fluorohydrocarbons. Examples of the compressed gas include carbon dioxide, nitrogen, and nitrous oxide. Among these, liquefied petroleum gas is preferred.

[0061] [Manufacturing method] The second composition can be prepared, for example, by blending (A) a heparinoid and (C) one or more selected from organic acids and salts thereof according to a conventional method, together with optional components as necessary.

[0062] [Aerosol] The formulation of the second composition is an aerosol. The emulsification state of the second composition (undiluted solution) is not particularly limited, and may be any of W / O, O / W, W / O / W, and O / W / O. The aerosol containing a propellant basically comprises a pressure-resistant container that can withstand internal pressure, a valve, an actuator, the second composition (undiluted solution), and a propellant. The content ratio of the propellant is preferably 1 to 12% by mass relative to the second composition. By filling the second composition in a foam-like container suitable for ejection, the foam is ejected, making it easy to spread on the skin. In addition, by forming the second composition into an aerosol, the heparinoid can be stably contained, and the precipitation of the surfactant blended in the second composition (undiluted solution) at low temperatures can be suppressed.

[0063] Examples of pressure-resistant containers that can withstand the internal pressure include aluminum cans and tin cans, and the inside of these can be coated with resin or the like.

[0064] The method of use and the effects of the second composition of the present invention are the same as those of the first composition. EXAMPLES

[0065] The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, unless otherwise specified, "%" in the composition indicates mass %, ratio indicates mass ratio, and the amount of each component in the table is the amount converted into a pure content.

[0066] [Examples and Comparative Examples] [Examples 1-1 to 1-19 and Comparative Examples 1-1 to 1-2] The components shown in Tables 1 to 3 were dissolved in purified water to prepare a composition for external use on the skin (liquid). 50 g of the obtained composition for external use on the skin was filled into a glass vial (capacity 50 mL), sealed with a lid, and stored at 50°C for 2 months. The pH of the composition before and after storage was measured according to the Japanese Pharmacopoeia - General Test Method (measurement temperature: 20°C), and the difference in pH before and after storage was calculated as the pH change. The contents of heparinoids and pyridoxine hydrochloride in the composition were measured by the following method, and the remaining rate (%) of heparinoids and pyridoxine hydrochloride was calculated according to the following formula. Residual rate (%) = component content after storage / initial component content x 100

[0067] The residual rate of heparinoids was determined by precisely weighing a sample from the skin topical composition, adding an ethanol solution of potassium acetate (in some cases, isooctane was also added), shaking, and centrifuging to obtain a residue, which was then solidified and the content was calculated by ultraviolet-visible absorbance measurement using the organic sulfate group measurement method described in the Japanese Pharmacopoeia Extra Pharmaceutical Ingredients Standards 2002 Heparinoids Quantitative Method (3). The residual rate of pyridoxine hydrochloride was calculated by the HPLC method (absolute calibration curve method). The initial ingredient content is the ingredient content measured immediately after the topical skin composition is prepared (stored at 5°C for within 7 days).

[0068] The residual rate of heparinoids and pyridoxine hydrochloride was evaluated according to the following criteria. <Residual rate of heparinoids: stability of heparinoids> Less than 85%: 1 point 85% to less than 90%: 2 points 90% to less than 95%: 3 points 95% or more: 4 points A score of 2 or more is considered a pass.

[0069] <Residual rate of pyridoxine hydrochloride: Stability of pyridoxine hydrochloride> Less than 80%: 1 point 80% to less than 85%: 2 points 85% to less than 90%: 3 points 90% or more: 4 points A score of 2 or more is considered a pass.

[0070] <pH fluctuation: pH stability> 1 or more: 1 point 0.5 or more but less than 1: 2 points 0.2 or more and less than 0.5: 3 points Less than 0.2: 4 points A score of 2 or more is considered a pass.

[0071] [Table 1]

[0072] [Table 2]

[0073] [Table 3]

[0074] [Example 1-20] The ingredients shown in Table 4 were dissolved in purified water according to a conventional method to prepare a lotion. 50 g of the obtained lotion was filled into a glass vial (50 mL), sealed with a lid, and stored at 50°C for 2 months. The pH of the lotion before and after storage, pH change, and residual rate of heparinoid and pyridoxine hydrochloride were evaluated in the same manner as above. The results are shown in the table.

[0075] [Table 4]

[0076] [Examples 1-21 to 1-26] The components shown in Table 5 were dissolved in purified water according to a conventional method to prepare a composition for external use on the skin (undiluted solution). 27.0-28.5 g of the obtained composition for external use on the skin (undiluted solution) was filled into a pressure-resistant can (aluminum can with a polyamideimide resin layer on the inside and a polyester resin layer / printed paint layer / polyester amino resin layer on the outside, 30 mL) and a valve (S13 valve, stem hole 0.5, housing hole 1.5, manufactured by Mitani Valve Co., Ltd.) was attached under reduced pressure, and 1.5-3.0 g of propellant was filled using the through valve method, and an actuator (FD150, manufactured by Mitani Valve Co., Ltd.) and a cap were attached to obtain an aerosol that sprays in the form of foam. The aerosol was then stored at 45°C for 3 months. Before and after storage, the can was shaken well, the contents of the aerosol were removed from the actuator into a sealed container, and the propellant was released by leaving it to stand. The pH, pH fluctuation, and residual rate of heparinoid and pyridoxine hydrochloride of the composition for external use on the skin were evaluated in the same manner as above. The results are shown in the table.

[0077] [Table 5]

[0078] [Example 1-27] The ingredients shown in Table 6 were emulsified by a conventional method to obtain an aqueous cream. 24 g of the obtained aqueous cream was filled into an aluminum tube (manufactured by Taisei Kako Co., Ltd.), sealed, and then stored at 50°C for 2 months. The pH of the aqueous cream before and after storage, pH change, and residual rate of heparinoids and pyridoxine hydrochloride were evaluated in the same manner as above. The results are shown in the table.

[0079] [Table 6]

[0080] [Example 1-28] The ingredients shown in Table 7 were emulsified by a conventional method to obtain an oil-based emulsion (W / O emulsion). 30 g of the obtained oil-based emulsion was filled into a polypropylene vial container (30 mL), sealed with a lid, and stored at 50°C for 2 months. The pH of the oil-based emulsion, pH change, and residual rate of heparinoids and pyridoxine hydrochloride before and after storage were evaluated in the same manner as above. The results are shown in the table.

[0081] [Table 7]

[0082] [Examples 2-1 to 2-3, Comparative Examples 2-1 and 2-2] The components shown in Table 7 were dissolved in purified water according to a conventional method to prepare a skin topical composition (undiluted solution). 28.2 g of the obtained skin topical composition (undiluted solution) was filled into a pressure-resistant can (aluminum can with a polyamideimide resin layer on the inner layer and a polyester resin layer / printed paint layer / polyester amino resin layer on the outer layer, 30 mL) that can withstand internal pressure, and a valve (S13 valve, stem hole 0.5, housing hole 1.5, manufactured by Mitani Valve Co., Ltd.) was attached under reduced pressure, and then 1.8 g of propellant was filled by the through valve method, and an actuator and a cap were attached to obtain an aerosol agent that sprays in a foam form. The valve and actuator were the same as those used in Example 1-21, and in Comparative Example 2-1, a skin topical composition (undiluted solution) was prepared according to Example 2-3, and 50 g of the obtained skin topical composition was filled into a glass vial container (50 mL) and sealed with a lid. The aerosol formulation (undiluted in Comparative Example 2-1) was then stored at 45°C for 3 months. Before and after storage, the can was shaken well, and the contents of the aerosol formulation were removed from the actuator into a container and left to release the propellant (the composition for external use on the skin (undiluted) in Comparative Example 2-1 was removed directly into the container), after which the pH, pH fluctuation, and residual rate of heparinoid of the composition for external use on the skin were evaluated using the same methods as above. The results are also shown in the table.

[0083] For the evaluation of low temperature stability, the product was filled into a pressure-resistant glass bottle instead of a pressure-resistant can in the same manner as above and stored at -5℃ for 2 months. The appearance of the glass bottle was observed from the outside, and if any precipitate was observed after 2 months, it was rated as ×, and if no precipitate was observed after 2 months, it was rated as ○. The results are also shown in the table.

[0084] [Table 8]

[0085] The raw materials used in the examples are shown below. Heparinoids: Extraordinary regulations, manufactured by Tori Co., Ltd. Pyridoxine hydrochloride: Japanese Pharmacopoeia, manufactured by DSM Co., Ltd. Panthenol: Non-regulated, manufactured by DSM Co., Ltd. Diphenhydramine: Japanese Pharmacopoeia, manufactured by Kongo Chemical Co., Ltd. Vitamin A oil: Japan Pharmacopoeia, manufactured by DSM Co., Ltd. Tocopherol acetate: Japanese Pharmacopoeia, manufactured by DSM Co., Ltd. Isopropylmethylphenol: Tonohara, Osaka Kasei Co., Ltd. Hydrochloric acid: Japanese Pharmacopoeia, manufactured by Kanto Chemical Co., Ltd. Sodium hydroxide: Japanese Pharmacopoeia, sodium hydroxide "for manufacturing only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Sodium citrate: Japanese Pharmacopoeia, sodium citrate hydrate, manufactured by Fuso Chemical Co., Ltd. Citric acid: Japanese Pharmacopoeia, citric acid hydrate, manufactured by ThreeF Corporation Lactic acid: Japanese Pharmacopoeia, 90% lactic acid, Showa Kako Co., Ltd. Malic acid: Food additive, Fuso Malic Acid L, manufactured by Fuso Chemical Co., Ltd. Sodium dihydrogen phosphate: Pharmaceutical additive, sodium dihydrogen phosphate hydrate, Fujifilm Wako Pure Chemical Industries, Ltd. Borax: JP Kosakai Pharmaceutical Co., Ltd. Diisopropanolamine: Pharmaceutical Additives Regulations, Mitsui Fine Chemicals Co., Ltd. Glycerin: Japanese Pharmacopoeia, Sakamoto Pharmaceutical Co., Ltd. Propylene glycol: Japan Pharmacopoeia, ADEKA Corporation 1,3-BG: Pharmaceutical additive, 1,3-butylene glycol, Daicel Chemical Industries, Ltd. Ethanol: Japanese Pharmacopoeia, Ethanol "For manufacturing only" Fujifilm Wako Pure Chemical Industries, Ltd. Macrogol 20000: Japanese Pharmacopoeia, Sanyo Chemical Industries, Ltd. Stearyl alcohol: Pharmaceutical additives regulation, Kalcol 8098 Kao Corporation Octyldodecanol: Pharmaceutical additive, N-Jecol 200A, New Japan Chemical Co., Ltd. Squalane: Cosmetic base, Nippon Surfactant Industry Co., Ltd. Isopropyl myristate: Pharmaceutical additives, NIKKOL IPM-100, Nippon Surfactant Industry Co., Ltd. Xanthan gum: Pharmaceutical additive Echo Gum T, DSP Gokyo Food & Fine Chemical Co., Ltd. Carboxyvinyl polymer: Pharmaceutical additive, CRBOPOL980 Noveon Co. Methyl paraoxybenzoate: Japanese Pharmacopoeia, Ueno Pharmaceutical Co., Ltd. Propyl paraoxybenzoate: Japanese Pharmacopoeia, Ueno Pharmaceutical Co., Ltd. Dibutylhydroxytoluene: Pharmaceutical Additives Fujifilm Wako Pure Chemical Industries, Ltd. Sodium edetate hydrate: Japanese Pharmacopoeia, Sodium edetate Chubu Cherest Co., Ltd. ·LPG: Pharmaceutical additives LPG20℃=0.43MPa, Taiyo Liquefied Gas Co., Ltd. Lauromacrogol: Japanese Pharmacopoeia, NIKKOL BL-21, Nippon Surfactant Industries Co., Ltd. Polyethylene glycol monolaurate: Pharmaceutical additives, NIKKOL MYL-10, Nippon Surfactant Industry Co., Ltd. Polysorbate 20: Pharmaceutical additives, NIKKOL TL-10, Nippon Surfactant Industry Co., Ltd. Polysorbate 60: Pharmaceutical additives, NIKKOL TS-10MV, Nippon Surfactant Industry Co., Ltd. Polyoxyethylene hydrogenated castor oil 10: Pharmaceutical additive NIKKOL HCO-10 Nippon Surfactant Industry Co., Ltd. Glycerin fatty acid ester: Food additive NIKKOL Decaglyn 5-OV Nippon Surfactant Industry Co., Ltd.

Claims

1. (A) heparinoids and (B) vitamin B 6 and (E) one or more selected from malic acid, boric acid, citric acid, and salts thereof, wherein the content mass ratio represented by (B) / (A) is 0.01 to 10 and the pH is 4 or more and 7 or less.

2. 2. The composition for external application to skin according to claim 1, wherein component (B) is pyridoxine or a pharma- ceutical acceptable salt thereof.

3. The composition for external use on the skin according to claim 1 or 2, wherein the content of component (E) is 0.01 to 5% by mass.

4. The composition for external use on the skin according to any one of claims 1 to 3, which is in the form of a cream, a lotion, a gel, an aerosol, a spray, an emulsion or a pack.

5. An aerosol formulation which is sprayed in the form of a foam, comprising a composition for external use on the skin which contains (A) a heparinoid, (C) one or more selected from citric acid and its sodium salt, (D) 1 to 5% by mass of a nonionic surfactant, and water, and a propellant.

6. 6. The aerosol of claim 5, wherein the propellant is liquefied petroleum gas.

7. 7. The aerosol according to claim 5 or 6, wherein component (D) is at least one member selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters and polyoxyethylene hydrogenated castor oil.

8. The aerosol preparation according to any one of claims 5 to 7, wherein the content of water in the composition for external use on skin is 50 to 90% by mass.

9. The aerosol according to any one of claims 5 to 8, wherein the content of the propellant is 1 to 12% by mass based on the composition for external use on skin.

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