JPWO2020138403A1 - External composition for skin and aerosol - Google Patents

Abstract

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

Description

The present invention relates to a skin external composition containing heparinoid and vitamin B _6.
The present invention relates to an aerosol agent containing a heparinoid, an organic acid or a salt thereof for external use on the skin, and a propellant.

Healthy skin has sufficient water retention in the stratum corneum on the surface of the skin. However, when the amount of sebum that covers the skin surface is reduced or the intercellular lipids in the stratum corneum are reduced, the water 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 deteriorates, redness and itchiness due to external stimuli occur, and it may cause dry skin diseases. ..

Conventionally, skin care products containing moisturizing ingredients have been used for the treatment of dry skin. Among the moisturizing ingredients, the heparinoid is a mucopolysaccharide in which chondroitin is polysulfated, and is known to have blood flow promoting action, anti-inflammatory action, moisturizing action, skin structure improving effect, etc., and has few side effects. Therefore, it has been used as an active ingredient of an external drug for skin as a therapeutic agent for dry skin diseases (see, for example, Patent Document 1). Polysaccharides, which are a superordinate concept of heparinoids, are known to be decomposed by hydrolysis under acidic conditions, but the conditions for decomposition differ greatly depending on the properties of the sugars. The external composition for skin containing a heparinoid has good stability, and the factors that inhibit the stability are not well known (see, for example, Non-Patent Document 1).

On the other hand, vitamin B ₆ is known to have an inhibitory / normalizing effect on sebum secretion, and is used as a hair growth promoter, a therapeutic agent for angular cheilitis, and seborrheic dermatitis. Vitamin B ₆ is known to be destabilized by heat or light, is stable under acidic conditions, and is known to be unstable under neutral to alkaline conditions.

Vitamin B ₆ is known to improve photostability by adding sugar alcohols (see, for example, Patent Document 2), but its effect is not sufficient and its use is limited by the addition of sugar alcohols. There was a drawback that it was done.

When the dry state of the skin continues, the sebum that is excessively secreted to supplement the moisture clogs the pores, so that a sebum film is not formed on the skin surface, and the dryness further progresses. _{For such dry skin, by blending a heparinoid having an effect of improving dryness of the skin and vitamin B 6} such as pyridoxin hydrochloride having an action of suppressing and normalizing sebum secretion, the skin as described above is used. Although the effect of improving dryness is expected, there is no example of combining these at the same time, and the problems and effects caused by the combined use have not even been inferred.

Further, since a composition for external use on the skin containing a heparinoid contains a precipitate when stored at a low temperature for a long period of time, stability of the composition at a low temperature has been desired. In addition, the external composition for skin containing a heparinoid and the aerosol containing a propellant have a problem in the stability of the heparinoid.

Japanese Unexamined Patent Publication No. 60-112708 Japanese Unexamined Patent Publication No. 07-206664

Hildoid Pharmaceutical Interview Form

The present inventors have a problem that when a heparinoid and vitamin B ₆ are mixed at the same time, the stability of any of the components is significantly reduced, and it is extremely difficult to stabilize at the same time when both are used in combination. I found. That is, an object of the present invention is to provide a composition for external use on the skin in which both components are stably blended.
Another object of the present invention is to provide a composition for external use on the skin containing a heparinoid, which is stably blended with a heparinoid and has excellent stability at low temperature.

As a result of diligent studies to achieve the above object, the present inventors have _{stabilized both by using a heparinoid and vitamin B 6} in combination and setting the pH of the external composition for skin containing both to 4 or more. It has been found that the property is improved, and the present invention has been made. That is, according to the external composition for skin of the present invention, _{the stability of the heparinoid and vitamin B 6} can be improved, and the decrease in the content of both components over time can be suppressed, so that both components can be stored for a long period of time. Can be effectively exerted by maintaining the action of.
Further, by preparing an aerosol agent containing (A) a heparinoid, (C) an external composition for skin containing at least one selected from an organic acid and a salt thereof, and a propellant, the heparinoid can be obtained. It has been found that the stability is improved and the low temperature storage stability of the external composition for skin containing a heparinoid is improved, and the present invention has been made.

Therefore, the present invention provides the following external composition for skin.
1. 1. A composition for external use on the skin containing (A) a heparinoid and (B) vitamin B ₆ and having a pH of 4 or higher.
2. (B) The composition for external use on the skin according to 1, wherein the component is pyridoxine or a pharmaceutically acceptable salt thereof.
3. 3. The external composition for skin according to 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, lotion, gel, aerosol, spray, emulsion or facial mask.
5. An aerosol agent containing an external composition for skin containing (A) a heparinoid and (C) one or more selected from an organic acid and a salt thereof, and a propellant.
6. The aerosol agent according to 5, which further contains (D) a nonionic surfactant and is ejected in the form of foam.

According to the present invention, it is possible to provide a composition for external use on the skin capable of stably blending _{a heparinoid and vitamin B 6 respectively.}
According to the present invention, it is possible to provide an aerosol agent containing a heparin-like substance-containing external composition containing a heparin-like substance and a propellant, which can stably contain a heparin-like substance and has excellent low-temperature storage stability. ..

Hereinafter, the present invention will be described in detail.
(I) The first invention is a composition for external use on the skin containing (A) a heparinoid and (B) vitamin B ₆ and having a pH of 4 or more.
(II) The second invention is an aerosol agent containing (A) a heparinoid, (C) an external composition for skin containing at least one selected from an organic acid and a salt thereof, and a propellant.
Hereinafter, the external composition for skin of the first invention is simply referred to as the first composition (in the case of an aerosol agent, it means the undiluted solution), and hereinafter, the external composition for skin (undiluted solution) of the second invention is simply referred to as the second composition. In the case of both the first composition and the second composition, it may be described as a composition.
[(A) component]
The component (A) is a heparin-like substance, and has a moisturizing effect, an anti-inflammatory effect, a blood circulation promoting effect, an effect of improving the skin structure, and the like. Heparinoids are polysulfate esters of mucopolysaccharides such as chondroitin polysulfate. The origin of the heparinoid used in the present invention is not particularly limited, but for example, those obtained by polysulfating mucopolysaccharides, tracheal cartilage of edible animal tissues (for example, tracheal cartilage of cattle, pigs, etc.). Examples include those extracted from (lungs containing). Of these, heparinoids defined in the Japanese Pharmacopoeia Non-Pharmaceutical Standards (Standard No .: 108548) are preferably used.

The content ratio of the component (A) is not particularly limited, but from the viewpoint of moisturizing effect, it is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, and further preferably 0.3% by mass or more in the composition. .. The upper limit is not particularly limited, but is preferably 1% by mass or less. A moisturizing effect can be expected when the content is 0.01% by mass or more, and an improvement effect on xerosis can be expected when the content is 0.3% by mass or more.

[(B) component]
The component (B) is commonly known as vitamin B ₆ , and has the effects of normalizing sebum secretion and activating skin cells. Examples of vitamin B ₆ include pyridoxine, pyridoxal, pyridoxamine, and pharmaceutically acceptable salts thereof, and examples thereof include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate. Vitamin B ₆ can be used alone or in combination of two or more. Of these, pyridoxine hydrochloride is preferable.

The content ratio of the component (B) is not particularly limited and can be arbitrarily set in consideration of safety and the effect of improving dryness of the skin, but 0.01 to 2% by mass in the first composition is preferable. More preferably, 0.05 to 2% by mass. When it is 0.01% by mass or more, it can be expected to normalize sebum secretion, improve dryness of the skin and activate cells, and when it is 1 to 2% by mass, it can improve seborrheic dermatitis. You can expect it.

The content mass ratio of the component (A) to the component (B) is not particularly limited, and can be arbitrarily set in consideration of the effect of improving safety and dryness of the skin, but in (B) / (A). The content mass ratio represented is preferably 0.01 to 20, more preferably 0.1 to 10. By setting this ratio to 0.01 or more, it is possible to further obtain the effect of both normalizing sebum secretion and improving dryness of the skin. On the other hand, when it is set to 20 or less, it is possible to obtain a moisturizing effect and an effect of suppressing sebum secretion while being excellent in safety.

The pH of the first composition of the present invention is 4 or more. By setting the pH of the first composition containing the above components (A) and (B) to 4 or more, (A) heparinoid and (B) vitamin B ₆ are stabilized in the first composition. Can be contained in. From this point, the lower limit of the pH of the first composition is preferably 4.5 or more, 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 17th revised Japanese Pharmacopoeia / general test method (measurement temperature: 20 ° C).

As long as the pH of the first composition of the present invention is within the above range, the pH adjuster does not necessarily have to be contained, and can be optionally contained. When a pH regulator is contained, the pH regulator includes, for example, lactic acid, citric acid, malic acid, phosphoric acid, boric acid, hydrochloric acid, sulfuric acid and salts thereof, as well as diisopropanolamine, triethanolamine and sodium hydroxide. , Potassium hydroxide and the like. Examples of the salt include sodium salt, potassium salt, ammonium salt and the like. Specific examples of the phosphate include sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate and the like, and borates include hosand and the like, and the citrates include citrates. Examples include sodium citrate and the like. The pH regulator may be used alone or in combination of two or more. Among them, one or more selected from lactic acid, phosphoric acid, malic acid, boric acid, citric acid and salts thereof is preferable from the viewpoint of stability of (A) heparin-like substance and (B) vitamin B _{6, and boric acid.} , Citric acid and one or more selected from these salts are more preferable. The content ratio when the pH adjuster is blended is appropriately selected so that the first composition has the desired pH, but is preferably 0.01 to 5% by mass, preferably 0.05 to 1% by mass in the first composition. % Is more preferable. By setting the content ratio to 0.01% by mass or more, (A) heparinoid and (B) vitamin B ₆ can be contained more stably. By setting the content ratio to 5% by mass or less, precipitation of the pH regulator over time is less likely to occur.

[Arbitrary ingredient]
In the composition of the present invention, an appropriate amount of any component used in pharmaceuticals, quasi-drugs, cosmetics, etc. shall be blended in an appropriate amount as long as the effect of the present invention is not impaired, either alone or in combination of two or more. Can be done. The following are exemplified as optional components.

(A) heparinoids, (B) other than vitamin B _6, pharmaceuticals, as a variety of active ingredients for use in quasi-drugs and cosmetics, for example, an anti-inflammatory agent other than heparinoids, antihistamines, antipruritic Examples thereof include agents, wound healing agents, local anesthetics, vitamin agents _{other than vitamin B 6} , refreshing agents, moisturizers, bactericides, vasoconstrictors and amino acids. The above also includes herbal ingredients.

Anti-inflammatory agents include, for example, glycyrrhetinic acid, glycyrrhizinic acid or a pharmaceutically acceptable salt thereof, citrus extract, steroid compound (hydrocortisone, prednisolone, methylprednisolone, clobetazone, betamethasone, dexamethasone, cortisone, fulmethasone, beclomethasone, fluticazone or Dexases thereof), indomethacin, ibuprofen, ibuprofen piconol, bufexamac, ufenamate, pyroxicum, ketoprofen, salicylic acid or a derivative thereof, dimethylisopropylazulene, touki extract, cicon extract and the like.

Examples of the antihistamine include diphenhydramine or a pharmaceutically acceptable salt thereof, chlorpheniramine or a pharmaceutically acceptable salt thereof, mequitazine, azelastine, emedastine, ketotifen or a derivative thereof. Of these, diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate and the like are preferable.

Examples of the antipruritic agent include crotamiton, vanillylamide nonylate, capsaicin, benzyl nicotinate, and citrus tincture.
Examples of the wound healing agent include allantoin, zinc oxide and the like.

Local anesthetics include, for example, lidocaine or a pharmaceutically acceptable salt thereof, dibucaine or a pharmaceutically acceptable salt thereof.

Examples of vitamin preparations include vitamin A [vitamin A oil, retinol and derivatives thereof (for example, retinal, retinoic acid, retinol palmitate, etc.)] and vitamin B ₁ [thiamine and its derivatives (for example, thiamine hydrochloride, etc.). Thiamine nitrate, etc.)], Vitamin B ₂ [riboflavin and its derivatives (eg, riboflavin phosphate, sodium riboflavin phosphate, riboflavin butyrate and flavin adenine dinucleotide sodium, etc.)], vitamin B ₃ [nicotinic acid and its derivatives (eg, nicotinic acid and its derivatives) Nicotinic acid amide, tocopherol nicotinate, benzyl nicotinate, etc.)], Vitamin B ₅ [pantothenic acid and its derivatives (eg, calcium pantothenate, pantenol, pantothenyl ethyl alcohol, etc.)], vitamin B ₁₂ [cobalamine and Derivatives thereof (eg, cyanocobalamine, mecobalamine, hydroxocobalamine hydrochloride, etc.)], biotin, folic acid or pharmaceutically acceptable salts thereof, vitamin Cs [ascorbic acid and its derivatives (eg, erythorbic acid, sodium ascorbate, ascorbic acid, etc.) Magnesium, ascorbic acid 2-glucoside, ascorbic acid palmitate, etc.)], vitamin Ds [calciferol and its derivatives (eg, ergocalciferol, cholecalciferol, etc.)], vitamin Es [tocopherol, ubiquinone and its derivatives (tocopherol, ubiquinone and its derivatives, etc.)] For example, tocopherol acetate, tocopherol calcium succinate, etc.)] and other vitamins (eg, hesperidin, carnitine, ferulic acid, γ-orizanol, orotic acid, rutin, eriocitrin, inositol and their pharmaceutically acceptable salts. ) Etc. can be mentioned.

Examples of the refreshing agent include l-menthol, camphor, borneol or related substances thereof, fennel oil, eucalyptus oil, peppermint oil and the like.

Examples of the moisturizer include natural moisturizing factors (urea and the like), ceramides, plant extracts (chamomile extract, aloe extract and the like) and the like.

Examples of the disinfectant include isopropylmethylphenol, chlorhexidine hydrochloride, benzethonium chloride, benzalkonium chloride, cetrimid and the like.

Examples of the vasoconstrictor include naphazoline, tetrahydrozoline, methylephedrine or salts thereof.

Examples of amino acids include glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine) and pharmaceutically acceptable salts thereof (for example, ephedrine hydrochloride, methylephenolin hydrochloride, etc.). ..

The content ratio when these active ingredients are blended is in the range of the effective amount, but is preferably 0.1 to 20% by mass in the composition.

Other optional components include, for example, oils, surfactants, polyhydric alcohols, polymer compounds, organic solvents, stabilizers, preservatives, fragrances, water and the like.

Examples of the oil agent include hydrocarbons such as vaseline, paraffin, liquid paraffin, squalane, selecin, gelled hydrocarbon and microcrystalin wax; higher fatty acids such as stearic acid, isostearic acid, myristic acid, oleic acid and behenic acid; Higher fatty alcohols such as setanol, stearyl alcohol, octyldodecanol and behenyl alcohol; fatty acid esters such as isopropyl myristate, octyldodecyl myristate, isopropul palmitate and diisopropyl adipate; glycerin triisooctanoate and glyceryl tri (capril capric acid) Such as polyhydric alcohol fatty acid ester and the like. The content ratio when the oil agent is blended is preferably 1 to 30% by mass in the composition.

Examples of the surfactant include nonionic surfactants, ionic surfactants and the like.
Examples of the nonionic surfactant include glycerin fatty acid esters such as glyceryl monostearate and glyceryl monooleate, polyglyceryl monolaurate (10), polyglyceryl monostearate (10), polyglyceryl oleate (10), and pentaolein. Polyglycerin fatty acid ester such as polyglyceryl acid (10); polyoxyethylene glycerin fatty acid ester such as polyoxyethylene glyceryl monostearate (15); sorbitan fatty acid ester such as sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate , Polyoxyethylene sorbitan monolaurate (20) (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysolvate 60), polyoxyethylene monooleate (20) sorbitan (polysolvate 80), and other polyoxyethylene sorbitans. Fatty acid ester; Polyoxyethylene sorbit fatty acid ester such as polyoxyethylene sorbit monolaurate (6), polyoxyethylene (60) sorbit tetrastearate, polyoxyethylene (60) sorbit tetraoleate; polyoxyethylene (60) himashi Polyoxyethylene hydrogenated bean oil such as oil; polyoxyethylene hydrogenated bean oil (10), polyoxyethylene hydrogenated bean oil (60) and other polyoxyethylene hydrogenated bean oil; polyethylene glycol monolaurate (for example, 10EO), monostearic acid Polyethylene glycol fatty acid esters such as polyoxyethylene glycol (4EO); polyoxyethylene alkyl ethers such as polyoxyethylene (9) lauryl ether (lauromacrogol), polyoxyethylene (10) cetyl ether and polyoxyethylene oleyl ether, etc. Can be mentioned.
Examples of the ionic surfactant include sodium lauryl sulfate, sodium cetyl sulfate and the like.
The content ratio when the surfactant is blended is preferably 0.1 to 10% by mass in the composition.

Examples of the polyhydric alcohol include glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol (macrogol) and the like.
When the polyhydric alcohol is blended, the content ratio is preferably 0.5 to 20% by mass in the composition.

Examples of the polymer compound include carboxyvinyl polymer, hydroxypropyl cellulose, hypromellose, hydrophobic hydroxypropyl methyl cellulose, acrylic starch 300 and polyvinylpyrrolidone, arabic gum, carrageenan, xanthan gum, carob gum, guar gum, guayaku fat, quince seed, and dammar gum. , Tragant, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextrin, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparan sulfate, hyalron Acids, chondroitin sulfate and the like can be mentioned.
The content ratio when the polymer compound is blended is preferably 0.01 to 5% by mass in the composition.

Examples of the organic solvent include organic solvents such as ethanol, isopropyl alcohol, acetone, methyl ethyl ketone and ethyl acetate.
The content ratio when the organic solvent is blended is preferably 1 to 30% by mass in the composition.

Examples of the stabilizer include sodium chloride, sodium thiosulfate, sodium sulfite, sodium edetate and the like.
When the stabilizer is blended, the content ratio is preferably 0.01 to 5% by mass in the composition.

Examples of the preservative include methyl paraoxybenzoate (methylparaben), propyl paraoxybenzoate (propylparaben), dibutylhydroxytoluene, benzalkonium chloride, benzethonium chloride and the like.
When the preservative is blended, the content ratio is preferably 0.01 to 1% by mass in the composition.

Examples of fragrances include compounded fragrances such as citrus fragrance, floral fragrance, and rose fragrance, eucalyptus oil, bergamot oil, uikyo oil, rose oil, peppermint oil, peppermint oil, spare mint oil, rosemary oil, lavender oil, and lemon oil. Etc. are examples. Typical components contained in these fragrances include terpenoid compounds. Examples of terpenoid compounds include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. Depending on the number of carbon atoms, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes, but the most typical component is monoterpenes. Preferred terpenoid compounds include l-menthol, dl-menthol, d-camfur, dl-camfur, d-bornole, dl-bornole, citral, citronellal, limonene, citronellol, cineol, geraniol, cineol, linalol, nonanal, eugenol, Isooygenol, indol, benzaldehyde, vanillin, limonene, galaxolide, γ-nonalactone, γ-methylionone, iso-e-super, Z-3-hexenyl salicylate, γ-undecalactone, 5-cyclohexadecene-1-one, Examples thereof include 2-methyl-4-phenyl-2-butanol, methyldihydrojasmonate, methyl-β-naphthylketone, cinnamyl acetate, benzyl acetate, α-terpineol, hexylcinnamikaldehyde, γ-undecalactone and the like. .. The content ratio when the fragrance is blended is preferably 0.001 to 1% by mass, more preferably 0.01 to 0.1% by mass in the composition.

The content ratio when water is blended is appropriately selected from the range of 50 to 90% by mass depending on the dosage form.

[Production method]
The composition of the present invention can be prepared, for example, by blending (A) a heparinoid and (B) vitamin B ₆ according to a conventional method, if necessary, together with an arbitrary component.

[External skin composition]
The properties of the composition of the present invention are not particularly limited as long as it can be applied transdermally, and may be liquid, solid, semi-solid (gel, ointment, paste, foam) or the like. In addition, the pharmaceutical form may be any of the pharmaceutical forms for external use of skin, quasi-drugs for external use of skin, cosmetics, skin cleaning agents and the like.

The formulation form of the composition of the present invention is not particularly limited, and for example, an ointment, a cream, a lotion, a gel, a milky lotion, a liquid, a patch, a mist-like, a foam-like spray, or a mist. , Powdered, foamy or pasty sprayed aerosols, ointments, packs, body shampoos, hair shampoos, rinses and the like. Of these, creams, lotions, gels, aerosols, sprays, emulsions, and packs are preferable, and creams, lotions, emulsions, foamy aerosols, and foamy pump sprays. Is more preferable. The emulsified state of the cream or emulsion is not particularly limited, and may be any of W / O, O / W, W / O / W, and O / W / O.

The spray agent containing no propellant is composed of, for example, an airtight container, a pump body, an actuator, a cap, and a first composition. The aerosol agent is basically composed of a pressure-resistant container that can withstand internal pressure, a valve, an actuator, a first composition (undiluted solution), and a propellant. The content ratio of the propellant in the aerosol agent is preferably 1 to 12% by mass, more preferably 1 to 10% by mass, based on the first composition. Examples of the propellant include liquefied gas and compressed gas, and examples of the liquefied gas are liquefied petroleum gas (LPG) containing a hydrocarbon having 3 to 5 carbon atoms (propane, n-butane, i-butane, etc.) as a main component. , Dimethyl ether, fluorinated hydrocarbons, and examples of the compressed gas include carbon dioxide, nitrogen, and nitrous oxide. Of these, liquefied petroleum gas is preferable. Sprays and aerosols can be easily spread on the skin by filling them in a foamy container. Further, by using an aerosol agent, precipitation of the surfactant mixed in the undiluted solution at a low temperature can be suppressed.

As the pressure-resistant container that can withstand the internal pressure, for example, an aluminum can, a tin can, or the like can be used, and the inner surface can be coated with a resin or the like.

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 or spreading it on gauze or the like once or several times a day. It is desirable that the spray agent and the aerosol agent are sprayed at an angle of about upright to 45 degrees.

The effects of the composition of the present invention include dry skin, dry skin in children, rough hands, cracks and cracks in limbs, keratinization of elbows, knees, heels and ankles, and chilblains (excluding sores). Skin lumps / tensions (excluding face) after scratches / burns, swelling / muscle pain / joint pain after striking / chilblains, improvement of skin barrier function, promotion of metabolism, skin cell activation, dryness Examples include (improvement) of skin troubles and cure of dryness (of the face, etc.).

(II) The second invention is an aerosol agent containing (A) a heparinoid, (C) an external composition for skin containing at least one selected from an organic acid and a salt thereof, and a propellant.

[(A) component]
The component (A) is the same as that of the first invention, and the preferable component and range are also the same as those of the first invention.

[(C) component]
(C) One or more selected from organic acids and salts thereof, and one can be used alone or in combination of two or more. By blending the component (C), the heparin-like substance can be stably contained in the aerosol agent containing the heparin-like substance-containing external composition for skin and the propellant. Examples of the component (C) include citric acid, lactic acid, malic acid, tartaric acid, adipic acid, fumaric acid, maleic acid, malonic acid and the like, with citric acid, malic acid and tartaric acid being preferable. Examples of the salt include sodium salt, potassium salt, ammonium salt and the like, and specific examples thereof include sodium citrate. The component (C) may be a derivative of an organic acid such as hydroxycitric acid.

The content ratio of the 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. When the content is 0.01% by mass or more, the (A) heparinoid can be stably contained, and when the content is 5% by mass or less, the low temperature storage stability is improved.

[(D) component]
From the viewpoint of improving low-temperature storage stability, the second composition may contain the (D) nonionic surfactant described in the first invention. Of these, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester, and polyoxyethylene hydrogenated castor oil are preferable, and polyoxyethylene sorbitan monolaurate (20) (polysorbate 20). , Polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monostearate (20) (polysorbate 60), polyoxyethylene sorbitan monooleate (20) (polysorbate 80), polyoxyethylene sorbit monolaurate (6), etc. Polyoxyethylene glycerin fatty acid esters such as polyoxyethylene sorbit fatty acid ester and polyoxyethylene (15) glyceryl oleate are more preferable, and polyoxyethylene sorbitan monostearate (20) (polysorbate 60) and polyoxyethylene sorbitan monooleate are preferable. (20) Polyoxyethylene sorbitan fatty acid ester such as (polysorbate 80) and polyoxyethylene sorbit fatty acid ester such as monolaurate polyoxyethylene sorbit (6) are more preferable.

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

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, further 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 (A) heparinoid can be contained more stably. The pH is measured by the Japanese Pharmacopoeia / general test method (measurement temperature: 20 ° C.).

As long as the pH of the second composition of the present invention is within the above range, the pH adjuster does not necessarily have to be contained, but can be optionally contained. When a pH adjusting agent is contained, examples of the pH adjusting agent include phosphoric acid, boric acid, hydrochloric acid, sulfuric acid and salts thereof, diisopropanolamine, triethanolamine, sodium hydroxide, potassium hydroxide and the like. .. Examples of the salt include sodium salt, potassium salt, ammonium salt and the like. Specific examples of the phosphate include sodium dihydrogen phosphate and the like, and examples of the borate include borax and the like. The pH regulator may be used alone or in combination of two or more. Among them, at least one selected from phosphoric acid, boric acid and salts thereof is preferable, and one or more selected from boric acid and salts thereof is more preferable from the viewpoint that (A) heparinoids can be stably contained. The content ratio when the pH adjuster is blended is appropriately selected so that the composition has the desired pH, but is preferably 0.01 to 5% by mass, more preferably 0.05 to 1% by mass in the composition. .. By setting the content ratio to 5% by mass or less, precipitation of the pH regulator over time is less likely to occur.

Examples of the other optional component of the second composition include those obtained by removing the components (C) and (D) and the pH adjuster from the optional components of the first invention.

[Injection agent]
Examples of the propellant include liquefied gas and compressed gas, and examples of the liquefied gas are liquefied petroleum gas (LPG) containing a hydrocarbon having 3 to 5 carbon atoms (propane, n-butane, i-butane, etc.) as a main component. , Dimethyl ether, fluorinated hydrocarbons, and examples of the compressed gas include carbon dioxide, nitrogen, and nitrous oxide. Of these, liquefied petroleum gas is preferable.

[Production method]
The second composition is prepared, for example, by blending (A) a heparinoid and (C) one or more selected from an organic acid and a salt thereof according to a conventional method, if necessary, together with an arbitrary component. Can be done.

[Aerosol]
The pharmaceutical form of the second composition is an aerosol agent. The emulsified state of the second composition (stock solution) is not particularly limited, and may be any of W / O, O / W, W / O / W, and O / W / O. The aerosol agent containing the propellant is basically composed of a pressure-resistant container that can withstand the internal pressure, a valve, an actuator, a second composition (undiluted solution), and a propellant. The content ratio of the propellant is preferably 1 to 12% by mass with respect to the second composition. By filling a foamy container suitable for ejection, it is discharged as foam, which makes it easier to spread on the skin. Further, by using an aerosol agent, a heparin-like substance can be stably contained, and precipitation of the surfactant blended in the second composition (stock solution) at a low temperature can be suppressed.

As the pressure-resistant container that can withstand the internal pressure, for example, an aluminum can, a tin can, or the like can be used, and the inner surface can be coated with a resin or the like.

The method of use and the effect and efficacy of the second composition of the present invention are the same as those of the first composition.

Hereinafter, the present invention will be specifically described 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%, the ratio indicates mass ratio, and the amount of each component in the table is the amount converted to pure content.

[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 (liquid preparation) for external use on the skin. 50 g of the obtained external composition for skin was filled in a glass vial (capacity: 50 mL), covered and sealed, and then stored at 50 ° C. for 2 months. The pH of the composition before and after storage was measured based on the Japanese Pharmacopoeia / general test method (measurement temperature: 20 ° C.), and the difference in pH before and after storage was calculated as pH fluctuation. The contents of the heparinoid and pyridoxine hydrochloride in the composition were measured by the following method, and the residual rate (%) of the heparinoid and pyridoxine hydrochloride was calculated based on the following formula.
Residual rate (%) = component content after storage / initial component content x 100

For the residual rate of heparinoids, weigh the sample from the external composition for skin, add an ethanol solution of potassium acetate (in some cases, further isooctane may be added), shake, and centrifuge the residue to make it firm. After that, the content was calculated by the ultraviolet visible absorbance measurement method by the organic sulfate group measurement method described in the quantification method (3) of the Japanese Pharmacopoeia Non-Pharmaceutical Ingredient Standard 2002 Heparinoid. The residual rate of pyridoxine hydrochloride was calculated by the HPLC method (absolute calibration curve method).
The initial component content is the component content measured immediately after preparing the external composition for skin (stored at 5 ° C., within 7 days).

Based on the residual rate of heparinoids and the residual rate of pyridoxine hydrochloride, the following evaluation criteria are used.
<Residual rate of heparinoids: Stability of heparinoids>
Less than 85%: 1 point 85% or more and less than 90%: 2 points 90% or more and less than 95%: 3 points 95% or more: 4 points 2 points or more are passed

<Residual rate of pyridoxine hydrochloride: Stability of pyridoxine hydrochloride>
Less than 80%: 1 point 80% or more and less than 85%: 2 points 85% or more and less than 90%: 3 points 90% or more: 4 points 2 points or more are passed

<pH fluctuation: pH stability>
1 or more: 1 point 0.5 or more and less than 1: 2 points 0.2 or more and less than 0.5: 3 points less than 0.2: 4 points 2 points or more are passed

[Example 1-20]
The components 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 in a glass vial (50 mL), covered and sealed, and then stored at 50 ° C. for 2 months.
The pH, pH fluctuation, heparinoid and pyridoxine hydrochloride residual rates of the lotion before and after storage were evaluated by the same method as described above. The results are also shown in the table.

[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 (stock solution). The obtained skin external composition (undiluted solution) was added to a pressure-resistant valve (a polyamide-imide resin layer on the inner layer; an aluminum can coated with a polyester resin layer / printing paint layer / polyester amino resin layer on the outer layer, 30 mL) that can withstand internal pressure. ) 27.0 to 28.5 g, and after installing the valve (S13 valve, stem hole 0.5, housing hole 1.5, manufactured by Mitani Valve Co., Ltd.) under reduced pressure, inject by the through valve method. The agent was filled with 1.5 to 3.0 g, an actuator (FD150, manufactured by Mitani Valve Co., Ltd.) and a cap were attached to obtain an aerosol agent to be ejected in the form of foam. Then, the aerosol agent was stored at 45 ° C. for 3 months. Before and after storage, shake the can well, take out the contents of the aerosol agent from the actuator into a closed container, leave it to release the propellant, and then release the pH, pH fluctuation, heparinoid and pyridoxine hydrochloric acid of the external composition for skin. The residual rate of salt was evaluated by the same method as above. The results are also shown in the table.

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

[Example 1-28]
The components shown in Table 7 were emulsified by a conventional method to obtain an oily emulsion (W / O emulsion). 30 g of the obtained oily emulsion was filled in a polypropylene vial (30 mL), covered and sealed, and then stored at 50 ° C. for 2 months.
The pH, pH fluctuation, heparinoid and pyridoxine hydrochloride residual rates of the oily emulsion before and after storage were evaluated by the same method as described above. The results are also shown in the table.

[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 composition for external use on the skin (stock solution). The obtained skin external composition (undiluted solution) was placed in a pressure-resistant can (30 mL, an aluminum can with a polyamideimide resin layer on the inner layer; a polyester resin layer / printing paint layer / polyesteramino resin layer coated on the outer layer) that can withstand internal pressure. ) 28.2 g, and after installing the valve (S13 valve, stem hole 0.5, housing hole 1.5, manufactured by Mitani Valve Co., Ltd.) under reduced pressure, 1.8 g of propellant by the through valve method. Was filled, an actuator and a cap were attached, and an aerosol agent ejected in the form of foam was obtained. The valves and actuators used were the same as those used in Examples 1-21, and in Comparative Example 2-1 the external composition for skin (stock solution) was prepared according to Example 2-3, and the obtained external composition for skin was obtained. 50 g of the composition was filled in a glass vial (50 mL), covered and sealed. Then, the aerosol agent (Comparative Example 2-1 was the undiluted solution) was stored at 45 ° C. for 3 months. Before and after storage, shake the can well, take out the contents of the aerosol agent from the actuator to the container, leave it to release the propellant (the external composition for skin (undiluted solution) of Comparative Example 2-1 is in the container as it is. The pH, pH fluctuation, and residual rate of heparinoids of the external composition for skin were evaluated by the same method as described above. The results are also shown in the table.

For evaluation of low temperature stability, instead of pressure-resistant cans, pressure-resistant glass bottles were filled in the same manner as above, and stored at −5 ° C. for 2 months. The appearance was observed from the outside of the glass bottle, and the case where a precipitate such as a precipitate was observed after 2 months was evaluated as XX, and the case where no precipitate such as a precipitate was formed after 2 months was evaluated as ◯. The results are also shown in the table.

The raw materials used in the examples are shown below.
・ Heparin-like substances: External regulations, manufactured by Tori Co., Ltd. ・ Pyridoxin hydrochloride: Japanese Bureau, DSM Co., Ltd. ・ Panthenol: External regulations, manufactured by DSM Co., Ltd. ・ Diphenhydramine: Japanese Bureau, Kongo Chemical Co., Ltd. Vitamin A oil manufactured by Japan Bureau, DSM Co., Ltd. Tocopherol acetate: Japan Bureau, DSM Co., Ltd. Isopropylmethylphenol: Nori Sotohara, Osaka Kasei Co., Ltd.
・ Hydrochloride: manufactured by Japan Bureau, Kanto Chemical Co., Ltd. ・ Sodium hydroxide: Japan Bureau, sodium hydroxide "for manufacturing only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. ・ Sodium citrate: Japan Bureau, sodium citrate hydration Manufactured by Fuso Chemical Industry Co., Ltd. Citric acid: Nikkei, Citric acid hydrate, Three F Co., Ltd. Lactobacillus: Nikkei, 90% lactic acid, Showa Kako Co., Ltd. Fuso Citrate L Made by Fuso Chemical Industry Co., Ltd. ・ Sodium dihydrogen phosphate: Yakuseki, Sodium dihydrogen phosphate hydrate Fujifilm Wako Junyaku Co., Ltd.
・ Diisopropanolamine: Yakuhinki, Mitsui Kagaku Fine Co., Ltd.
・ Glycerin: Japan Bureau, Sakamoto Pharmaceutical Co., Ltd.
-Propylene glycol: Japan Bureau, ADEKA Corporation
・ 1,3-BG: Pharmaceutical Supplement, 1,3-butylene Glycol Daicel Chemical Industry Co., Ltd.
・ Ethanol: Japan Bureau, Ethanol "Manufacturing only" Fujifilm Wako Pure Chemical Industries, Ltd.
・ Macrogol 20000: Japan Bureau, Sanyo Chemical Industries, Ltd.
・ Stearyl alcohol: Pharmaceutical supplement, Calcol 8098 Kao Corporation
・ Octyldodecanol: Drug Supplement, Njecol 200A Shin Nihon Rika Co., Ltd.
・ Squalane: Motoi Shobara, Nippon Surfant Industry Co., Ltd.
-Isopropyl myristate: Pharmaceutical supplement, NIKKOL IPM-100 Nippon Surfant Industry Co., Ltd.
・ Xanthan gum: Yakuseki Echo Gum T, DSP Gokyo Food & Fine Chemicals Co., Ltd.
Carboxyvinyl polymer: Yakuhinsho, CRBOPOL980 Noveon Co., Ltd.
・ Methyl paraoxybenzoate: Japan Bureau, Ueno Fine Chemicals Industry Co., Ltd.
・ Propyl paraoxybenzoate: Japan Bureau, Ueno Fine Chemicals Industry Co., Ltd.
・ Dibutylhydroxytoluene: Pharmaceutical Addendum Fujifilm Wako Pure Chemical Industries, Ltd.
・ Sodium edetate hydrate: Japan Bureau, Sodium edetate Chubu Killest Co., Ltd.
・ LPG: Drug supplement LPG 20 ℃ = 0.43MPa, Taiyo Liquefied Gas Co., Ltd.
・ Lauro Macrogol: Japan Bureau, NIKKOL BL-21 Japan Surfactant Industry Co., Ltd.
-Polyethylene glycol monolaurate: Pharmaceutical supplement, NIKKOL MYL-10 Japan Surfactant Industry Co., Ltd.
・ Polysorbate 20: Yakuhinki, NIKKOL TL-10 Japan Surfactant Industry Co., Ltd.
・ Polysorbate 60: Pharmaceutical supplement, NIKKOL TS-10MV Japan Surfactant Industry Co., Ltd.
・ Polyoxyethylene hydrogenated castor oil 10: Chemical supplement NIKKOL HCO-10 Japan Surfactant Industry Co., Ltd.
・ Glycerin fatty acid ester: Food additive NIKKOL Decaglin 5-OV Japan Surfant Industry Co., Ltd.

Claims (6)

A composition for external use on the skin containing (A) a heparinoid and (B) vitamin B ₆ and having a pH of 4 or higher. The composition for external use on the skin according to claim 1, wherein the component (B) is pyridoxine or a pharmaceutically acceptable salt thereof. The external composition for skin according to claim 1 or 2, further containing one or more selected from lactic acid, phosphoric acid, malic acid, boric acid, citric acid and salts thereof. The external composition for skin according to any one of claims 1 to 3, which is a cream, lotion, gel, aerosol, spray, emulsion or facial mask. An aerosol agent containing an external composition for skin containing (A) a heparinoid and (C) one or more selected from an organic acid and a salt thereof, and a propellant. The aerosol agent according to claim 5, further comprising (D) a nonionic surfactant and ejecting in the form of foam.