JP2012036174A - Composition for external application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition for external application containing antioxidant, wherein cytotoxicity in antioxidant is reduced.SOLUTION: The composition for external application contains a vitamin A, a heparin analogue and the antioxidant.

Description

  The present invention provides rough skin of fingers and the like; elbows, knees, heels, ankle keratosis; cracks and bruises of hands and feet; dry skin; dry skin of children; moistness; A composition for external use which can prevent, treat or ameliorate bruise, swelling after sprain, muscle pain, joint pain and the like;

Antioxidants are widely used as additives for pharmaceuticals, quasi drugs, cosmetics, foods and the like. Antioxidants keep each component in the composition stable and contribute to maintaining the composition and dosage form of the composition over a long period of time. Moreover, generation | occurrence | production and discoloration of the odor of a composition are prevented.
Antioxidants for pharmaceutical, quasi-drug, and cosmetic compositions for external use include dibutylhydroxytoluene (hereinafter sometimes referred to as “BHT”), butylhydroxyanisole, ascorbic acid or a salt thereof, tocopherol or a salt thereof, erythorbine Antioxidants such as acid salts, sulfites, sulfur dioxide, phytic acid, acetylcysteine, cysteine, manganese gluconate, arbutin, and dilauryl thiodipropionate are used.
Antioxidants may have skin irritation and cytotoxicity depending on the concentration. For example, Non-Patent Document 1 describes that BHT needs to wear protective gloves to induce skin redness. Moreover, as a result of evaluating the cytotoxicity of BHT by trypan blue staining method and LDH (enzyme released from dead cells) activity measurement method, there was no significant change in cell survival rate at low concentration, but high concentration There is also a report that decreased cell survival rate.

National Institute of Health Sciences International Chemical Safety Card (ICSC) Number: 0841

  An object of the present invention is to provide a composition for external use containing an antioxidant, in which the cytotoxicity of the antioxidant is reduced.

  The present inventor has conducted research to solve the above-mentioned problems, and found that the cytotoxicity of the antioxidant is effectively reduced by using the antioxidant in combination with vitamin A and heparin-like substance. It was.

This invention is completed based on the said knowledge, and provides the following external composition.
Item 1. An external composition containing vitamins A, heparin-like substances, and antioxidants.
Item 2. Item 2. The antioxidant is at least one compound selected from the group consisting of dibutylhydroxytoluene, butylhydroxyanisole, pyrosulfite, bisulfite, ascorbic acid, a salt thereof, and a glycoside thereof. Topical composition.
Item 3. Item 3. The external composition according to Item 1 or 2, wherein the content of the antioxidant is 0.001 to 1% by weight based on the total amount of the composition.
Item 4. Item 4. The externally applied composition according to any one of Items 1 to 3, wherein the vitamin A is at least one selected from the group consisting of a retinol ester and a retinoic acid ester.
Item 5. Item 5. The topical composition according to any one of Items 1 to 4, wherein the content of vitamin A is 0.0001 to 2% by weight based on the total amount of the composition.
Item 6. Item 6. The composition for external use according to any one of Items 1 to 5, wherein the content of vitamin A with respect to the content of the antioxidant is 1: 0.03 to 50 by weight.
Item 7. Item 7. The composition for external use according to any one of Items 1 to 6, wherein the content of the heparin-like substance is 0.005 to 10% by weight based on the total amount of the composition. Item 8. The composition for external use according to any one of Items 1 to 7, wherein the content of the heparin-like substance relative to the content of the antioxidant is 1: 0.01 to 50 by weight.
Item 9. Item 9. The composition for external use according to any one of Items 1 to 8, wherein the content of the heparin-like substance with respect to the content of vitamin A is 1: 0.01 to 10 by weight.
Item 10. A method for reducing cytotoxicity of an antioxidant, comprising adding a vitamin A and a heparin-like substance to a composition containing an antioxidant.

Since the composition for external use of the present invention contains an antioxidant, vitamin A, and heparin-like substance, the cytotoxicity of the antioxidant is reduced or eliminated. In contrast to cytotoxicity of antioxidants alone, the addition of heparin-like substances with skin moisturizing action has no effect on reducing cytotoxicity, but heparin-like substances are combined with fat-soluble vitamin A. Together, it synergistically reduces antioxidant cytotoxicity.
As a result, the composition for external use of the present invention can effectively exhibit the original action of the composition containing vitamin A and heparin-like substance, and rough skin such as fingers; elbows, knees, heels, Ankle keratosis; cracks and bruises in hands and feet; dry skin; dry skin in children; moistness; skin lump and scratches after scratches, burns; bruise, swelling after sprain, muscle pain, joint pain, etc. It becomes a composition useful for improvement of.

It is a figure which shows the influence of BHT, retinol palmitate, and a heparin analog on the survival rate of a normal human epidermal cell. It is a figure which shows the influence of sodium pyrosulfite, a retinol palmitate, and a heparin analog on the survival rate of a normal human epidermal cell. It is a figure which shows the influence of a sodium bisulfite, a retinol palmitate, and a heparin analog on the survival rate of a normal human epidermal cell. It is a figure which shows the influence of butylhydroxyanisole, retinol palmitate, and a heparin analog on the survival rate of a normal human epidermal cell. It is a figure which shows the influence of ascorbic acid 2-anisole, retinol palmitate, and a heparin analog on the survival rate of normal human epidermal cells.

Hereinafter, the present invention will be described in detail.
The composition for external use of the present invention is a composition containing vitamins A, heparin-like substances, and antioxidants.

The vitamin A in vitamin A present invention include retinol, retinal, retinoic acid, these dehydro body, these esters and pro-vitamin A.
Esters include retinol acetate, retinol propionate, retinol butyrate, retinol octylate, retinol laurate, retinol palmitate, retinol stearate, retinol myristate, retinol oleate, retinol linolenate, retinol linoleate, retinol palmitate, Examples thereof include retinal acetate, retinal propionate, methyl retinoate, ethyl retinoate, retinol retinoic acid, tocopherol retinoic acid (which may be any isomer of α, β, γ, and δ). Examples of provitamin A include α-carotene, β-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, β-cryptoxanthin, and echinenone.
Among them, retinol or an ester of retinoic acid is preferable, and retinol acetate, retinol palmitate, and δ-retinoic acid tocopherol are more preferable.
Vitamin A can be used individually by 1 type or in combination of 2 or more types.
The vitamin A may be either isolated from natural products such as animal materials or chemically synthesized. Vitamin A can also be used in the form of vitamin A oil. The vitamin A oil may be a natural oil extracted and purified from an animal, or a vitamin A dissolved in a vegetable oil or the like. A typical example of the latter is vitamin A oil (containing 30000 vitamin A units (IU) or more per gram) described in the Japanese Pharmacopoeia.

The content of vitamin A in the external composition of the present invention is usually 0.0001% by weight or more, preferably 0.001% by weight or more, more preferably 0.01% by weight or more, based on the total amount of the composition. And it is sufficient. Further, it is usually 2% by weight or less, preferably 1% by weight or less, more preferably 0.5% by weight or less.
If it is the said range, physiological effects, such as a cornification inhibitory action and an antioxidant action which vitamin A has, can be exhibited, and the cytotoxicity of an antioxidant is suppressed effectively. Moreover, if it is the said range, the side effect (inflammation, such as serious erythema, stinging, etc.) by excessive use of vitamin A will not arise.
In addition, the ratio of the content of vitamin A to the content of antioxidant (antioxidant: vitamin A) is preferably about 1: 0.001 to 50 in terms of weight ratio, and about 1: 0.01 to 30 is more preferred, and about 1: 0.1-20 is even more preferred.
If it is the said range, physiological effects, such as a cornification inhibitory action and an antioxidant action which vitamin A has, can be exhibited, and the cytotoxicity of an antioxidant is suppressed effectively. Moreover, if it is the said range, the side effect (inflammation, such as serious erythema, stinging, etc.) by excessive use of vitamin A will not arise.
The content and ratio of the above vitamin A were calculated based on the weight of vitamin A oil in which vitamin A was dissolved in vegetable oil or the like when vitamin A was included in the composition in the form of vitamin A oil. Value.

Heparin analogs Heparin analogs are polysulfated mucopolysaccharides such as chondroitin polysulfate. It is preferable to have an average of 0.5 to 5 molecules, especially an average of 0.6 to 3 molecules of sulfate group per molecule of monosaccharide constituting the mucopolysaccharide. Examples of heparin-like substances include heparin; chondroitin sulfate D, chondroitin sulfate D such as chondroitin sulfate E, and the like. Among them, heparin-like substances that are included in the Japanese Pharmacopoeia Standards for Drugs can be suitably used.
Heparin-like substances can be obtained by sulfating mucopolysaccharides. It can also be obtained by extracting and purifying from the viscera including the bronchi of animals such as cows and pigs using an aqueous carrier, and further sulfating if necessary. Since heparin-like substances are commercially available as raw materials for pharmaceuticals and cosmetics, commercially available products can also be used.

The content of the heparin-like substance in the composition for external use of the present invention is usually 0.005% by weight or more, preferably 0.01% by weight or more, more preferably 0.05% by weight or more with respect to the total amount of the composition. Even more preferably, it may be 0.1% by weight or more. Further, it is usually 10% by weight or less, preferably 5% by weight or less, more preferably 1% by weight or less, and still more preferably 0.5% by weight or less.
If it is the said range, physiological effects, such as a moisturizing effect and a blood circulation promotion effect which a heparin analog has, can exhibit the cytotoxicity of an antioxidant effectively.
Further, the ratio of the content of the heparin-like substance to the content of the antioxidant (antioxidant: heparin-like substance) is preferably about 1: 0.0001 to 50, and about 1: 0.001 to 50 by weight. 40 is more preferred, and about 1: 0.01 to 35 is even more preferred.
If it is the said range, physiological effects, such as a moisturizing effect and a blood circulation promotion effect which a heparin analog has, can exhibit the cytotoxicity of an antioxidant effectively.
The ratio of the content of the heparin-like substance to the content of vitamin A (vitamin A: heparin-like substance) is preferably about 1: 0.01 to 10 by weight, and about 1: 0.05 to 5 is more preferred, and about 1: 0.1 to 2 is even more preferred.
If the content of the heparin-like substance relative to the vitamin A content is in the above range, rough skin on the fingers, etc .; elbows, knees, heels, ankle keratosis; cracks on the hands and feet; dry skin; Sexual skin; moist; skin lump and scratching after scratches and burns; can prevent, treat, or ameliorate bruises, swelling after sprain, muscle pain, joint pain, etc., and also has the effect of antioxidant cytotoxicity Can be reduced.

Antioxidants Antioxidants include BHT, butylhydroxyanisole (BHA), ascorbic acid, salts thereof (stearate, palmitate, phosphate, etc.) or glycosides thereof (ascorbic acid 2-glucoside, etc.) , Tocopherol or its salt (acetate, nicotinate, succinate), sulfite (sodium salt, potassium salt, etc.), pyrosulfite (sodium salt, potassium salt, etc.), bisulfite (sodium salt, potassium salt) Etc.).
The content of the antioxidant in the external composition of the present invention is usually 0.001% by weight or more, preferably 0.005% by weight or more, more preferably 0.01% by weight or more, based on the total amount of the composition. And it is sufficient. Further, it is usually 1% by weight or less, preferably 0.5% by weight or less, more preferably 0.3% by weight or less.
If it is in the above-mentioned range, it is possible to effectively suppress the cytotoxicity of the antioxidant with the use amount of vitamin A and heparin-like substance that can sufficiently obtain the antioxidant effect and obtain the original medicinal effect. it can.

Preferred combinations of vitamins A, heparin analogs and antioxidants are illustrated in Table 1 below.

Formulation The composition for external use of the present invention comprises vitamins A, heparin-like substances, and antioxidants together with bases or carriers usually used in pharmaceuticals, quasi drugs, or cosmetics, and, if necessary, additives. It can mix and it can be set as the external composition for pharmaceuticals, a quasi-drug, or cosmetics.

<Form>
The form of the composition for external use for pharmaceuticals is not particularly limited, and examples thereof include liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, and poultices. These preparations can be produced according to the method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
The form of the composition for external use for quasi-drugs or cosmetics is not particularly limited, and for example, lotion, milky lotion, cream, serum, cosmetic for sunscreen, pack, hand cream, body lotion, body cream, etc. Basic cosmetics; cleansing cosmetics such as facial cleansers, makeup removers, body shampoos; makeup cosmetics such as foundations, makeup bases, lip balms, lipsticks, and cheek colors; bathing agents.

<Base or carrier>
Bases or carriers include liquid paraffin, squalane, gelled hydrocarbons (such as plastibase), ozokerite, α-olefin oligomers, hydrocarbons such as light liquid paraffin; methyl polysiloxane, cross-linked methyl polysiloxane, highly polymerized methyl Polysiloxane, Cyclic silicone, Alkyl-modified silicone, Cross-linked alkyl-modified silicone, Amino-modified silicone, Polyether-modified silicone, Polyglycerin-modified silicone, Cross-linked polyether-modified silicone, Cross-linked alkyl polyether-modified silicone, Silicone / alkyl chain copolymer Modified polyether-modified silicone, silicone / alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, Silicone oils such as phenyl-modified silicones and silicone resins; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; isopropyl myristate , Esters such as octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate; polysaccharides such as dextrin and maltodextrin; lower levels such as ethanol and isopropanol Alcohol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether , Ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl Examples include glycol ethers such as ethers; polyhydric alcohols such as polyethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, and isoprene glycol; and aqueous bases such as water.

  A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

<Additives>
In the composition for external use of the present invention, known additives to be added to pharmaceuticals, quasi drugs, or cosmetics, for example, surfactants, thickeners, preservatives, as long as the effects of the present invention are not impaired. A pH adjuster, a chelating agent, a stabilizer, an irritation reducing agent, an antiseptic, a coloring agent, a fragrance, a pearl luster imparting agent, and the like can be added.
Examples of the surfactant include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate. Sorbitan fatty acid esters; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hardened Hardened castor oil derivatives such as castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan (polysorbate 20) monolaurate, monostearate Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan (polysorbate 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), polyoxyethylene (20) sorbitan isostearate; Glyceryl alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; amines such as stearylamine and oleylamine; polyoxyethylene / methylpolysiloxane copolymer; And silicone surfactants such as lauryl PEG-9 polydimethylsiloxyethyl dimethicone and PEG-9 polydimethylsiloxyethyl dimethicone.

  Examples of the thickener include guar gum, locust bean gum, carrageenan, xanthan gum, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl methacrylate methacrylate. Copolymers, polyethylene glycol, bentonite, (hydroxyethyl acrylate / acryloyldimethyltaurine Na) copolymer, (acryloyldimethyltaurine ammonium / vinylpyrrolidone) copolymer, and the like.

  Preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, benzyl paraoxybenzoate, paraoxybenzoate Examples include methyl benzoate and phenoxyethanol.

Examples of pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.) ) And organic bases (such as triethanolamine, diisopropanolamine, and triisopropanolamine).
Examples of the chelating agent include EDTA / disodium salt, EDTA / calcium disodium salt, and the like.

Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.
Examples of the irritation reducing agent include licorice extract and sodium alginate.
Examples of the preservative include benzoate, sorbate, dehydroacetate, p-hydroxybenzoate, benzethonium chloride, phenoxyethanol, chlorhexidine gluconate and the like.

  An additive can be used individually by 1 type or in combination of 2 or more types.

<Other active ingredients>
The composition for external use of this invention can contain another active ingredient in the range which does not impair the effect of this invention. Specific examples of active ingredients include moisturizing ingredients, anti-inflammatory ingredients, antibacterial ingredients, vitamins, peptides or derivatives thereof, amino acids or derivatives thereof, cell activation ingredients, anti-aging ingredients, blood circulation promoting ingredients, and the like.

As moisturizing ingredients, polyhydric alcohols such as glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol, diglycerin trehalose; sodium hyaluronate, heparin-like substance, sodium chondroitin sulfate, collagen, elastin, keratin, chitin , Macromolecular compounds such as chitosan; amino acids such as glycine, aspartic acid and arginine; natural moisturizing factors such as sodium lactate, urea and sodium pyrrolidonecarboxylate; lipids such as ceramide, cholesterol and phospholipid; chamomile extract; Examples include plant extract such as Clam essence extract, tea extract, perilla extract.
Examples of the anti-inflammatory component include a plant-derived component (eg Comfrey), allantoin, glycyrrhizic acid or a derivative thereof, zinc oxide, pyridoxine hydrochloride, tocopherol acetate, salicylic acid or a derivative thereof, and ε-aminocaproic acid.

  Antibacterial components include chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, popidone iodine, potassium iodide, iodine, isopropylmethylphenol, triclocarban, triclosan, photosensitizer No. 101 Photosensitive element 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride and the like.

  Vitamins such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate; riboflavin, flavin mononucleotide, flavin adenine dinucleotide Vitamin B2 such as riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5′-phosphate, riboflavin tetranicotinate; nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, β-nicotinic acid β- Nicotinic acids such as butoxyethyl and 1- (4-methylphenyl) ethyl nicotinate; ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate -Vitamin Cs such as ascorbyl; Vitamin Ds such as methyl hesperidin, ergocalciferol and cholecalciferol; Vitamin Ks such as phylloquinone and farnoquinone, γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride; thiamine hydrochloride , Thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate Vitamin B1 such as thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate; pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'- Vitamin B6 such as pyridoxal phosphate and pyridoxamine hydrochloride; Vitamin B12 such as cyanocobalamin, hydroxocobalamin and deoxyadenosylcobalamin; Folic acid such as folic acid and pteroylglutamic acid; Nicotinic acids such as nicotinic acid and nicotinamide; Pantothenic acids such as calcium pantothenate, pantothenyl alcohol (panthenol), D-panthecine, D-panthetin, coenzyme A, pantothenyl ethyl ether; biotins such as biotin and bioticin; ascorbic acid, sodium ascorbate, Vitamin C which is an ascorbic acid derivative such as dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate; carnitine, ferulic acid, α-lipoic acid Such as vitamin-like effect factors such as orotic acid, and the like.

  Peptides or derivatives thereof include keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, elastin-degrading peptide , Conchiolin degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soy proteolytic peptide, hydrolyzed soy protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, casein degrading peptide Acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.).

  As amino acids or derivatives thereof, betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine, methionine Leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine and the like.

Cell activation components include amino acids such as γ-aminobutyric acid and ε-aminoproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid; tannins, Examples include flavonoids, saponins, allantoin, and photosensitizer 301.
Examples of the anti-aging component include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivative, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

  Examples of the blood circulation promoting component include plants (for example, ginseng, ashitaba, arnica, ginkgo, fennel, enamel, Dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, hawthorn, sorghum, nematode, Assembly, thyme, clove, chimney, spruce, spruce, spruce, carrot, garlic, butcher bloom, grape, button, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, chimpy, touki, spruce, peach, apricot, walnut , A component derived from corn); and glucosyl hesperidin.

pH
About 4-9 are preferable and, as for pH of the composition for external use of this invention, about 5-8 are more preferable. If it is the said pH range, a stable formulation can be prepared and the cytotoxicity of an antioxidant can be suppressed effectively.

Method of Use The composition for external use of the present invention varies depending on the skin condition, age, sex, etc. of the subject of use, but may be the following method, for example.
That is, an appropriate amount (for example, about 0.05 to 5 g) may be applied to the skin several times a day (for example, about 1 to 5 times, preferably 1 to 3 times). Further, the composition may be applied so that the daily use amount of vitamin A is preferably about 0.1 to 200 mg, more preferably about 1 to 100 mg, and the daily use amount of the heparin-like substance is preferably What is necessary is just to apply | coat a composition so that it may become about 0.01-100 mg, More preferably, it is about 0.3-75 mg, The amount of daily use of an antioxidant becomes like this. Preferably it is about 0.01-30 mg, More preferably, it is about 0.2-20 mg The composition may be applied as described above. The application period may be, for example, about 1 to 14 days, preferably about 3 to 14 days.
The composition for external use of the present invention has rough skin such as fingers; elbows, knees, heels, ankle keratosis; cracks and bruises of hands and feet; dry skin; childhood dry skin; It can be suitably used for the prevention, treatment, or improvement of lumps, swelling, swelling after spraining, muscle pain, joint pain and the like. Therefore, in addition to healthy people, people with these skin symptoms are suitable for use.

Others The present invention includes a method for reducing cytotoxicity of an antioxidant, which comprises adding vitamins A and a heparin-like substance to a composition containing an antioxidant. The types of antioxidants, vitamins A, and heparin-like substances, amounts used, and other components that may be included in the composition are as described for the externally applied composition of the present invention.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.
(1) Cytotoxicity to normal human epidermis cells 10,000 normal human epidermis cells precultured in a 75 cm ² flask with Dulbecco's Modified Eagle Medium (D-MEM FBS) supplemented with 10% fetal bovine serum per 96-well plate Add. After culturing at 37 ° C. and 5% CO ₂ for 24 hours, the medium was removed, 90 μl of D-MEM FBS was added to the plate, and 10 μl of the test substance dissolved in water or ethanol was added. 10 μl of MEM FBS was added. The number of viable cells was counted after 24 hours of culture. A Cell Counting Kit (Dojindo Laboratories) was used for counting the number of viable cells.
The cell viability (%) was calculated according to the following formula.
Cell viability (%) = (absorbance of test substance / absorbance of control) × 100

(1-1) The types of components in the test solution containing dibutylhydroxytoluene (BHT) as a dibutylhydroxytoluene antioxidant and the final concentrations in the culture solution are shown in Table 2 below.

The results are shown in FIG. In FIG. 1, “heparin” indicates a heparin-like substance, “retinol” indicates retinol palmitate, and “BHT” indicates dibutylhydroxytoluene.
BHT at a concentration of 0.01 w / w% greatly reduced the survival rate of normal human epidermal cells to about 30%. Even when BHT and heparin-like substance were used in combination, the survival rate of normal human epidermal cells was hardly recovered. However, when BHT, heparin-like substance and retinol palmitate were used in combination, the survival rate of normal human epidermis cells was greatly increased. Recovered to about 100%. A synergistic effect of heparin-like substance and retinol palmitate was observed in reducing the cytotoxicity of BHT.

(1-2) Types of components in the test solution containing sodium pyrosulfite as a sodium pyrosulfite antioxidant and the final concentrations in the culture solution are shown in Table 3 below.
The results are shown in FIG. In FIG. 2, “heparin” indicates a heparin-like substance, and “retinol” indicates retinol palmitate.
Sodium pyrosulfite at a concentration of 0.3 w / w% reduced normal human epidermal cell viability to about 30%. When heparin-like substance and retinol palmitate were added thereto, the survival rate of normal human epidermal cells was restored to about 60%.

(1-3) Table 4 below shows the types of components in the test liquid containing sodium hydrogen sulfite as a sodium hydrogen sulfite antioxidant and the final concentrations in the culture liquid.
The results are shown in FIG. In FIG. 3, “heparin” indicates a heparin-like substance, and “retinol” indicates retinol palmitate.
Sodium bisulfite at a concentration of 0.03 w / w% decreased the survival rate of normal human epidermis cells, but when heparin analog and retinol palmitate were added thereto, the survival rate of normal human epidermis cells was restored.

(1-4) Types of components in the test solution containing butylhydroxyanisole as the butylhydroxyanisole antioxidant and the final concentrations in the culture solution are shown in Table 5 below.
The results are shown in FIG. In FIG. 4, “heparin” represents a heparin-like substance, “retinol” represents retinol palmitate, and “BHA” represents butylhydroxyanisole.
The butylhydroxyanisole at a concentration of 0.0075 w / w% almost completely killed normal human epidermis cells (survival rate: about 0%), but when a heparin analog and retinol palmitate were added thereto, normal human epidermis was added. Cell viability recovered to about 60%.

(1-5) Ascorbic acid 2-glucoside Ascorbic acid 2-glucoside as an antioxidant The types of components in the test liquid and the final concentration in the culture liquid are shown in Table 6 below.
The results are shown in FIG. In FIG. 5, “heparin” indicates a heparin-like substance, and “retinol” indicates retinol palmitate.
Ascorbic acid 2-glucoside at a concentration of 1.2 w / w% reduced the survival rate of normal human epidermal cells to about 30%, but when a heparin analog and retinol palmitate were added thereto, normal human epidermal cells The survival rate was recovered to about 60%.

Formulation Examples Formulation examples of the composition for external use of the present invention are shown in Tables 7 and 8 below. The unit of numerical values in the formulation examples is “% by weight”.

  The composition for external use of the present invention has rough skin such as fingers; elbows, knees, heels, ankle keratosis; cracks and bruises of hands and feet; dry skin; childhood dry skin; It can be suitably used as an agent for preventing, treating, or improving lumps, tension; bruise, swelling after sprain, muscle pain, joint pain and the like.

Claims (4)

  An external composition containing vitamins A, heparin-like substances, and antioxidants.   The antioxidant is at least one compound selected from the group consisting of dibutylhydroxytoluene, butylhydroxyanisole, pyrosulfite, bisulfite, and ascorbic acid, a salt thereof, and a glycoside thereof. The external composition as described.   The external composition according to claim 1 or 2, wherein the vitamin A is at least one selected from the group consisting of a retinol ester and a retinoic acid ester.   A method for reducing cytotoxicity of an antioxidant, comprising adding a vitamin A and a heparin-like substance to a composition containing an antioxidant.