JP2015232032A - External composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external composition that is highly effective in improving rough skin.SOLUTION: An external composition for rough skin improvement comprises a vitamin A and a heparin analog.

Description

  The present invention relates to a composition for external use that can prevent, treat, or improve rough skin such as xeroderma.

Vitamin A is widely used as an active ingredient of an external preparation because it has an action of maintaining normal epithelial cells such as skin and mucous membrane to prevent keratinization and an antioxidant action.
Patent Document 1 describes that an external preparation for skin containing vitamin A and one or more powders is excellent in prevention and treatment of cutaneous keratosis, prevention of skin aging, and recovery. ing.

Heparin-like substances are widely used as active ingredients for external preparations because they have excellent moisturizing action, anti-inflammatory action, blood circulation promoting action and the like.
In Patent Document 2, an external preparation for skin containing ceramide and a heparin-like substance improves the moisture retention action of the skin and enhances the moisturizing effect, thereby normalizing the moisture retention function or skin barrier function, It describes that it effectively improves dry skin.
However, these documents do not describe that an external preparation for skin containing vitamin A and heparin-like substance has an excellent effect of improving rough skin.

JP-A-6-32722 JP 2009-234957 A

  This invention makes it a subject to provide the composition for external use excellent in the rough skin improvement effect.

The present inventor repeated researches to solve the above problems, and obtained the following knowledge.
(i) When an external composition containing vitamin A and a heparin-like substance is applied to rough skin, the rough skin is effectively improved. In addition, the degree is markedly superior to a composition for external use containing vitamin A or a heparin-like substance alone.
(ii) When an external composition containing vitamin A is applied to rough skin, depending on the concentration of vitamin A, it may have skin irritation. When a heparin-like substance is added to this external composition, skin irritation caused by vitamins A is effectively reduced.

The present invention has been completed based on the above findings, and provides the following external composition and the like.
Item 1. An external composition for improving rough skin while suppressing skin irritation, comprising vitamin A and a heparin-like substance.
Item 2. Item 2. The composition according to Item 1, wherein the content of the heparin-like substance relative to the content of vitamin A is 1: 0.01 to 10 by weight.
Item 3. Item 3. The composition according to Item 1 or 2, wherein the content of vitamin A is 0.0001 to 2% by weight based on the total amount of the composition.
Item 4. Item 4. The composition according to any one of Items 1 to 3, wherein the content of the heparin-like substance is 0.0001 to 10% by weight based on the total amount of the composition.
Item 5. Item 5. The composition according to any one of Items 1 to 4, wherein the vitamin A is retinol palmitate.
Item 6. Item 6. The external composition for improving rough skin according to any one of Items 1 to 5, wherein the rough skin is xeroderma or keratosis.
Item 7. An external composition for improving rough skin, comprising vitamins A and heparin-like substances.
Item 8. Item 8. The external composition for rough skin improvement according to Item 7, wherein the rough skin is xeroderma or keratosis.
Item 9. Item 10. The external composition for improving rough skin according to Item 7 or 8, wherein the rough skin improvement is an improvement of the barrier function.
Item 10. Item 10. The topical composition for improving rough skin according to Item 7 or 8, wherein the rough skin improvement is improvement of skin texture.
Item 11. Item 11. The composition according to any one of Items 7 to 10, 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 12. Item 12. The composition according to any one of Items 7 to 11, wherein the content of vitamin A is 0.0001 to 2% by weight based on the total amount of the composition.
Item 13. Item 13. The composition according to any one of Items 7 to 12, wherein the content of the heparin-like substance is 0.0001 to 10% by weight based on the total amount of the composition.
Item 14. Item 14. The composition according to any one of Items 7 to 13, wherein the vitamin A is retinol palmitate.
Item 15. A method for reducing irritation to rough skin, wherein a heparin-like substance is added to a composition for external use containing vitamin A.

  The composition for external use of the present invention contains both vitamin A and a heparin-like substance. It leads to reduction of skin water loss (improvement of barrier function), normalization or improvement of skin texture, and improvement of skin findings (degree of skin dryness and desquamation). Furthermore, such an improvement is far superior to a composition containing vitamin A and a heparin-like substance alone.

In general, an external composition containing vitamin A may have skin irritation when the concentration of vitamin A is high.
In this regard, in normal skin, the stratum corneum, which constitutes the outermost layer of the epidermis, is composed of stratum corneum, and intercellular lipids and natural moisturizing components are present between these cells. Prevents foreign substances from entering and prevents moisture from evaporating (barrier function). When the skin is rough, for example, in dry skin and keratosis, this barrier function is lowered and the keratin is dry, so that the applied composition is easy to enter the inside, and irritation by vitamin A is particularly Easy to feel. The composition for external use of the present invention can improve skin function (state in which keratinocytes are lined up and intercellular lipids and natural moisturizing substances are present), improve the barrier function, and provide a stimulating feeling due to vitamin A. Since heparin-like substances are suppressed, rough skin such as xeroderma and keratosis can be effectively improved while suppressing skin irritation.

  Therefore, the composition for external use of the present invention has rough skin such as xeroderma and keratosis, specifically rough skin such as fingers; keratinosis of elbows, knees, heels and ankles; Dry skin of children; moist; skin lump and scratches after scratches and burns; composition useful for improving bruise, swelling after sprain, muscle pain, joint pain, sebum deficiency, hypertrophic scar, keloid, etc. It is.

It is a figure which shows that the external composition containing vitamin A and a heparin analog increases a stratum corneum moisture content. It is a figure which shows that the external composition containing vitamin A and a heparin analog reduces the amount of transepidermal water loss. It is a figure which shows that the composition for external use containing vitamin A and a heparin analog arranges the texture of skin.

Hereinafter, the present invention will be described in detail.
This invention includes the external composition for rough skin improvement containing vitamin A and a heparin analog. Moreover, this invention includes the external composition for improving rough skin, suppressing the skin irritation containing vitamin A class and a heparin analog. These compositions of the present invention will be described below.

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 retinoic acid, ethyl retinoic acid, 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 preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, and 0.01% by weight or more based on the total amount of the composition. Even more preferred. Moreover, 2 weight% or less is preferable, 1 weight% or less is more preferable, and 0.5 weight% or less is still more preferable.
If it is in the above range, it can exhibit physiological effects such as keratinization inhibiting action and antioxidant action of vitamin A, and side effects (such as inflammation and stinging such as severe erythema) caused by excessive use of vitamin A. Does not occur.
When the vitamin A is contained in the composition in the form of vitamin A oil, the content and ratio of the vitamin A are the weight of vitamin A oil obtained by dissolving the vitamin A in vegetable oil or the like.

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, preferably 0.05% by weight with respect to the total amount of the composition. % Or more is more preferable, and 0.1% by weight or more is even more preferable. Further, it may be 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 | action and blood circulation promotion effect which a heparin analog has, and it will become a composition by which inflammation-inducing property was fully suppressed. Moreover, the irritation to rough skin by vitamin A can be fully suppressed.
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 content of vitamin A is within the above range, the water content of the stratum corneum is increased, the amount of transepidermal water loss is reduced, the skin texture is normalized, and the skin findings (skin dryness and desquamation The degree of improvement in skin roughness such as improvement of the degree) can be fully exhibited. Moreover, the irritation to rough skin by vitamin A can be fully suppressed.

Formulation The composition for external use of the present invention is prepared by mixing vitamins A and heparin-like substances together with a base or carrier usually used in pharmaceuticals, quasi drugs or cosmetics, and, if necessary, additives. It can be set as the external composition for pharmaceuticals, quasi drugs, or cosmetics.

<Form>
The form of the composition for external use for pharmaceuticals is not particularly limited, and examples thereof include solutions, suspensions, emulsions, creams, ointments, gels, liniments, lotions, and poultices. The pharmaceutical composition for external use is preferably used in the form of an emulsion, cream, ointment, gel, more preferably an emulsion, cream, and even more preferably an emulsion. By setting it as this form, the rough skin improvement effect can fully be exhibited. 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. The composition for external use for quasi-drugs or cosmetics is preferably used in the form of a milky lotion, cream, cosmetic liquid, more preferably a milky lotion, cream, and even more preferably a milky lotion. By setting it as this form, the rough skin improvement effect can fully be exhibited.

<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 oil such as phenyl-modified silicone, silicone resin; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipic acid 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 that are added to pharmaceuticals, quasi drugs, or cosmetics, for example, antioxidants, surfactants, thickeners, as long as the effects of the present invention are not impaired. , Preservatives, pH adjusters, chelating agents, stabilizers, irritation reducers, preservatives, colorants, fragrances, pearlescent agents, and the like can be added.
Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride and the like.
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, arginine; natural moisturizing factors such as sodium lactate, urea, sodium pyrrolidonecarboxylate; lipids such as ceramide, cholesterol, phospholipid; chamomile extract, hamamelis Plant extract such as extract, tea extract, perilla extract and the like can be mentioned.

  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 their derivatives, 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 (e.g., ginseng, ashitaba, arnica, ginkgo, fennel, enmelio, dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, hawthorn, prunus, 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.

  Other active ingredients can be used alone or in combination of two or more.

Viscosity The viscosity of the external composition of the present invention is preferably about 10,000 to 60000, more preferably about 20000 to 45000. This viscosity is a value when measured under conditions of 3 rpm, 1 minute, and 25 ° C. using a B-type viscometer RB-80L and an M-3 rotor. If it is the said viscosity range, the rough skin improvement effect can fully be exhibited.

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.

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 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 preferably used for prevention, treatment or improvement of lumps, swelling, bruise, swelling after sprain, muscle pain, joint pain, sebum deficiency, hypertrophic scar, keloid and the like. Therefore, in addition to healthy people, people with these skin symptoms are suitable for use.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.
(1) Evaluation of rough skin improvement effect
Preparation of composition for external use According to the formulation shown in Table 1, the composition for external use of Example 1 was produced. Specifically, retinol palmitate, concentrated glycerin, 1,3-butylene glycol, absolute ethanol, isopropyl palmitate, dimethylpolysiloxane, cetanol, polysorbate 60, sorbitan monostearate and ethyl paraoxybenzoate are added to about 70 ° C. It melt | dissolved warmly, and mixed solution A was prepared. A heparin analog, carboxyvinyl polymer, sodium edetate hydrate and water were dissolved by heating to about 70 ° C. to prepare a mixed solution B. The mixed solutions A and B were uniformly mixed and then cooled, and triethanolamine was further added to obtain an emulsion composition for external use. When the viscosity of the obtained composition was measured under the conditions of 3 rpm, 1 minute, and 25 ° C. using a B-type viscometer RB-80L and an M-3 rotor, it was 30000-35000 Pa · s.

Evaluation Method and Evaluation Results An appropriate amount of the composition of Example 1 was applied 1 to several times a day for 2 weeks to the forearms of 10 adult women with xeroderma. The following evaluations (1-1) to (1-4) were performed before coating, 5 days after starting coating, and 14 days after coating.

(1-1) The stratum corneum moisture content was measured using a Corneometer [registered trademark] CM825 before application of the stratum corneum water content , and 5 days and 14 days after the start of application. The results are shown in FIG.
As is clear from FIG. 1, it was found that the composition of Example 1 increased the stratum corneum moisture content.

(1-2) Transepidermal water loss The transepidermal water loss was measured using Tewameter (registered trademark) TM300 before application, and 5 days and 14 days after the start of application. The results are shown in FIG.
As is clear from FIG. 2, it was found that the composition of Example 1 reduced the amount of transepidermal water loss.

(1-3) Enlarged image of skin surface An enlarged image of the skin surface was taken with a digital microscope (VHX-900: manufactured by Keyence) 14 days before application and 14 days after the start of application. The results are shown in FIG.
As is clear from FIG. 3, it was found that the composition of Example 1 prepared skin texture.

(1-4) Before application of the skin findings , 5 days and 14 days after the start of the application, the skin findings were observed by a doctor. As skin findings, the degree of skin dryness and desquamation was evaluated according to the criteria in Table 2 below. The results are shown in Table 3.
From Table 3, mild to moderate (average 2.1) skin dryness before application improved to none to slight (average 0.4) after 5 days of application, and further 14 days after application, Disappeared in all subjects. In addition, slight to mild (average 1.7) desquamation before application improved from none to slight (average 0.2) after 5 days of application, and disappeared in all subjects after 14 days of application. did.

(2) Evaluation of skin irritation improvement effect
Preparation of composition for external use An external composition having the composition shown in Table 4 below was prepared. That is, as a base, a composition obtained by mixing white petrolatum, light liquid paraffin, stearyl alcohol, cetanol, polysorbate 60, sorbitan monostearate, polyoxyethylene hydrogenated castor oil 50, and purified water was used. An oil (containing 1 million IU / g retinol palmitate), a heparin-like substance, or a composition containing both of these was prepared.
The formulation of the base was designed based on a JP hydrophilic ointment that can be used as an ointment base for a long time. However, because vitamin A oil and heparin-like substances were blended, the JP emulsified ointment itself could not maintain the emulsified state and stability over time, so the oil agent and emulsifier were changed within the range of the raw materials for pharmaceutical additives. The present formulation that can maintain the emulsified state and stability over time of the preparation was adopted.

Evaluation method and evaluation results
Hos: HR-1 female mice (7 weeks old) were treated by applying absorbent cotton soaked in a mixture of acetone and diethyl ether to the back, and then applying absorbent cotton soaked in water to the back (A / E treatment). This treatment was performed twice a day for 3 days for each group to prepare a dry skin model.
Administration of the test substance was started after the A / E treatment on the third day, and 50 mL was applied twice a day for 2 consecutive days on the back of the mouse. The group composition of mice was 7 mice per group, and 5 groups of no drug application group (normal), base group (control), vitamin A oil group, heparin-like substance group, vitamin A oil + heparin-like substance group .
The skin irritation on the second day after application (48 hours later) was scored according to Table 5 below.

The results are shown in Table 6 below.

It can be seen that skin irritation caused by vitamin A oil (retinol palmitate) was effectively suppressed by the addition of a heparin-like substance.
Formulation Examples Formulation examples of the composition for external use of the present invention are shown below. The unit of numerical values in the formulation examples is “% by weight”.

Example 1 (milky lotion)
1st drug heparin analog 0.3
Vitamin A oil (retinol palmitate, 1 million IU / g) 0.5
Sorbitan monostearate 0.6
Polyoxyethylene sorbitan isostearate (20.EO.) 0.8
Carboxyvinyl polymer 0.2
1,3-butylene glycol 3
Dipropylene glycol 3
Sodium edetate 0.05
Behenyl alcohol 0.3
Stearyl alcohol 0.4
Tri (Capryl / Capric Acid) Glyceryl 4
Alpha olefin oligomer 8
Tri (capryl / caprin / myristin / stearic acid) glyceride 0.5
Hyaluronic acid Na 0.01
Dibutylhydroxytoluene 0.1
pH adjuster Appropriate amount of preservative Appropriate amount of purified water The remaining amount was stored in a glass container.

Example 2 (gel lotion)
Heparin analog 0.3
Vitamin A oil (δ-tocopherol retinoic acid, 1 million IU / g) 0.5
Polyoxyethylene sorbitan isostearate (20. EO.) 0.6
Carboxyvinyl polymer 0.15
Hydroxyethyl cellulose 0.1
Dipropylene glycol 3
Glycerin 5
Sodium edetate 0.05
Tri (capryl / capric) glyceryl 3
Butylhydroxyanisole 0.1
pH adjuster Appropriate amount of preservative Appropriate amount of purified water A residual amount preparation was prepared and stored in a polyethylene container.

Example 3 (Gel serum)
Heparin analog 0.3
Vitamin A oil (retinol palmitate, 1 million IU / g) 0.5
Sorbitan monoisostearate0.4
Polyoxyethylene sorbitan isostearate (20. EO.) 0.4
Carboxyvinyl polymer 0.3
Xanthan gum 0.05
Dipropylene glycol 3
Glycerin 5
Sodium edetate 0.05
Acetylated sodium hyaluronate 0.01
Behenyl alcohol 0.2
Methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer
2
Stearyl alcohol 0.3
Tri (capryl / capric) glyceryl 3
Tocopherol acetate 0.05
pH adjuster Appropriate amount of preservative Appropriate amount of purified water A residual amount preparation was prepared and accommodated in a polyethylene terephthalate container.

Example 4 (Cream)
Heparin analog 0.3
Vitamin A oil (retinol palmitate, 1 million IU / g) 0.5
Dipotassium glycyrrhizinate 0.05
Evening primrose oil 3
Lychee seed extract 0.1
α-Lipoic acid 0.01
Hydrolyzed soy protein 0.1
Grape seed extract 0.00.5
Chigaya Root Extract 0.001
Artemia extract 0.5
2-Ethylhexyl paramethoxycinnamate 10
Diethylaminohydroxybenzoyl hexyl benzoate 5
2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3
5-Triazine 3
Silicone coated zinc oxide 5
Silicone coated titanium oxide 1
Inorganic compound coated zinc oxide 0.05
Glycerin 5
1,3-butylene glycol 2
Lauryl PEG-9 polydimethylsiloxyethyl dimethicone 1
PEG-9 polydimethylsiloxyethyl dimethicone 1
Glyceryl tri-2-ethylhexanoate 1.5
Methylpolysiloxane 3
Decamethylcyclopentasiloxane 30
Methylsiloxane network polymer 5
Alkyl acrylate copolymer methyl polysiloxane ester 0.1
Acrylic acid / alkyl methacrylate copolymer 0.05
Mica 2
Chelating agent Suitable amount Sodium hyaluronate 0.05
Tocopherol acetate 0.05
Preservatives (propyl paraoxybenzoate, phenoxyethanol) appropriate amount pH adjuster appropriate amount perfume appropriate amount water balance

Example 5 (milky lotion)
Heparin analog 0.3
Vitamin A oil (retinol palmitate, 1 million IU / g) 0.5
Sorbitan monostearate 0.6
Polyoxyethylene sorbitan isostearate (20.EO.) 0.8
Carboxyvinyl polymer 0.2
1,3-butylene glycol 3
Dipropylene glycol 3
Soy hydrolyzate 0.01
Sodium edetate 0.05
Behenyl alcohol 0.3
Stearyl alcohol 0.4
Tri (Capryl / Capric Acid) Glyceryl 4
Alpha olefin oligomer 8
Tri (capryl / caprin / myristin / stearic acid) glyceride 0.5
Sodium bisulfite 0.1
pH adjuster Appropriate amount of preservative Appropriate amount of purified water A residual amount preparation was prepared and stored in a polypropylene container.

Example 6 (cream)
Heparin analog 0.3
Vitamin A oil (retinol acetate, 1 million IU / g) 0.5
Sorbitan monostearate1.2
Polyoxyethylene sorbitan isostearate (20. EO.) 1.2
Acrylic acid / alkyl methacrylate copolymer 0.4
Pullulan 0.2
Hydrolyzed collagen 0.05
Hydroxyethyl cellulose 0.05
1,3-butylene glycol 10
Glycerin 10
Sodium edetate 0.05
Behenyl alcohol 2
Tri (Capryl / Capric Acid) Glyceryl 8
Polymethacryloyloxyethyl phosphorylcholine 5
Jojoba oil 5
Tri (capryl / caprin / myristin / stearic acid) glyceride 3
Ascorbic acid 0.1
pH adjuster appropriate amount preservative appropriate amount purified water remaining

Example 7 (cream)
Heparin analog 0.3
Vitamin A oil (retinol palmitate, 1 million IU / g) 0.5
Acrylic acid / alkyl methacrylate copolymer 0.1
Xanthan gum 0.05
Polyglyceryl monostearate 1.5
Glycerol monostearate2.1
1,3-butylene glycol 3
Glycerin 5
Dipropylene glycol 2
Sodium edetate 0.05
Behenyl alcohol 1.5
Cetanol 1.5
Squalane 5
Glyceryl tri-2-ethylhexanoate 5
Shea fat 2
pH adjuster appropriate amount preservative appropriate amount purified water remaining

Example 8 (cream)
Heparin analog 0.3
Vitamin A oil (retinol palmitate, 1 million IU / g) 0.5
Ascorbic acid 2-glucoside 0.5
Glycerol monostearate1.6
Polyglyceryl monostearate2.0
Xanthan gum 0.1
1,3-butylene glycol 5
Glycerin 5
Dipropylene glycol 2
Sodium edetate 0.05
Behenyl alcohol 2
Squalane 5
Glyceryl tri-2-ethylhexanoate 5
Tri (capryl / caprin / myristin / stearic acid) glyceride 3
pH adjuster appropriate amount preservative appropriate amount purified water remaining

  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, sebum deficiency, hypertrophic scar, keloid and the like. Moreover, the composition for external use of this invention is a useful composition with little skin irritation.

Claims (11)

  An external composition for skin comprising vitamin A and a heparin-like substance, wherein the content of vitamin A is 0.3 to 1% by weight based on the total amount of the composition.   The external composition for skin according to claim 1, wherein the content of the heparin-like substance relative to the content of vitamin A is 1: 0.01 to 10 by weight.   The external composition for skin according to claim 1 or 2, wherein the content of the heparin-like substance is 0.0001 to 10% by weight based on the total amount of the composition.   The external composition for skin according to any one of claims 1 to 3, wherein the vitamin A is retinol palmitate.   The external composition for skin according to any one of claims 1 to 4, for improving rough skin while suppressing skin irritation.   The external composition for skin according to claim 5, wherein the rough skin is xeroderma or keratosis.   A topical composition for improving rough skin, comprising vitamin A and a heparin-like substance, wherein the content of vitamin A is 0.3 to 1% by weight based on the total amount of the composition.   The external composition for rough skin improvement according to claim 7, wherein the rough skin is xeroderma or keratosis.   The external composition for rough skin improvement according to claim 7 or 8, wherein the rough skin improvement is an improvement of a barrier function.   The external composition for rough skin improvement according to any one of claims 7 to 9, wherein the content of the heparin-like substance relative to the content of vitamin A is 1: 0.01 to 10 by weight.   The external composition for rough skin improvement according to any one of claims 7 to 10, wherein the vitamin A is retinol palmitate.