JP2006213696A - External preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external preparation for the skin, excellent in percutaneous absorption of vitamin As, specific vitamin Cs and xanthine derivatives. <P>SOLUTION: The external preparation for the skin, excellent in percutaneous absorption of the vitamin As, the specific vitamin Cs and the xanthine derivatives contains a phospholipid and a glycol ether. As a result, the efficient penetration of the vitamin As, the specific vitamin Cs and the xanthine derivatives to the skin is expected. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an external preparation for skin with significantly improved transdermal absorbability.

There are various types of external preparations applied to the skin and mucous membranes, such as patches, ointments, creams, lotions, solid preparations, etc., but they are blocked by the stratum corneum that prevents foreign substances from entering the outside. Therefore, it is not easy to efficiently infiltrate the skin with useful components blended in the external preparation. For this reason, various studies have been made to promote transdermal absorption. For example, as an external preparation with improved transdermal absorption, liposomes containing lecithin and a hydrophilic nonionic surfactant (Patent Document) 1: JP-A-62-95134) and absorption promoting compositions containing phospholipids and specific polyhydric alcohols (Patent Document 2: JP-A-10-194994) are known.
On the other hand, phospholipids are present in natural animals and plants such as soybeans and egg yolks, and most of them are safe and can be used in foods. They have surface-active effects, have moisturizing properties, and are blended into external preparations. Then, it is known to promote percutaneous absorption. However, the effect of combining phospholipids and glycol ethers is not known.
In addition, vitamins A are used as therapeutic agents for night blindness, dry conjunctiva, dry cornea, corneal softening, and keratinous skin disease. In particular, among vitamin A acid tocopherol ester (tocopheryl retinoate) which is an ester compound of vitamin A acid and tocopherol, δ-tocopheryl retinoate has a dermatological therapeutic agent, a digestive tract ulcer therapeutic agent and an antitumor agent. It has an excellent pharmacological effect (Patent Document 3: JP-A-4-244076) and an active oxygen removing action.
In addition, ascorbic acid or its derivatives are an anti-inflammatory effect, an acne-improving effect, a whitening effect, an anti-aging effect, an antioxidant effect, a cell activation effect by promoting the synthesis of biological components such as collagen, and cell damage caused by ultraviolet rays on epidermal keratinocytes. It is known to exhibit various effects such as an effect of suppressing DNA damage.
On the other hand, xanthine derivatives typified by caffeine have a central excitatory action, and are incorporated in pharmaceuticals and food compositions mainly as a composition for internal use and in an external preparation in order to improve sleepiness.
Furthermore, since external preparations for skin are often applied directly to the application site, not only the transdermal absorbability of the preparation, but also excellent preparations such as a long-term stable preparation and good usability are desired. It is rare.

  An object of the present invention is to provide an external preparation for skin in which transdermal absorbability of vitamin A, specific vitamin C, and xanthine derivative is remarkably improved.

As a result of intensive studies to achieve the above object, the present inventors have found that when phospholipids and glycol ethers are contained, the transdermal absorbability of vitamins A, specific vitamins C, and xanthine derivatives is remarkable. As a result, the present invention has been completed.
That is, this invention is a skin external preparation listed to following (1)-(11).
(1) From phospholipids, glycol ethers and vitamin A, ascorbic acid, sodium ascorbate, dehydroascorbic acid, ascorbyl glucoside, ascorbyl stearate, L-ascorbyl dipalmitate, ascorbyl tetra-2-hexyldecanoate and xanthine derivatives An external preparation for skin containing one or more selected from the group consisting of:
(2) glycol ether is ethylene glycol monoether, ethylene glycol diether, propylene glycol monoether, propylene glycol diether, butylene glycol monoether, butylene glycol diether, diethylene glycol monoether, diethylene glycol monoether, diethylene glycol diether, di The skin external preparation according to (1), which is one or more selected from the group consisting of propylene glycol monoether, dipropylene glycol diether and dibutylene glycol monoether or dibutylene glycol diether.
(3) The external preparation for skin according to (1) or (2), wherein the phospholipid is a hydrogenated phospholipid.
(4) The external preparation for skin according to (1) or (2), wherein the phospholipid is a non-hydrogenated phospholipid.
(5) The skin external preparation according to (1) to (3), wherein the iodine value of the hydrogenated phospholipid is 10 to 50.
(6) Vitamin A is retinol, retinol acetate, retinol palmitate, retinal, retinoic acid, retinoic acid methyl, retinoic acid ethyl, retinoic acid retinol, vitamin A oil, vitamin A fatty acid ester, d-δ-tocopheryl retino The topical skin preparation according to any one of (1) to (5), which is one or more selected from the group consisting of ate, α-tocopheryl retinoate and β-tocopheryl retinoate.
(7) One type of xanthine derivative selected from the group consisting of caffeine, aminophylline, theophylline, oxtriphyrin, diphylline, diisobutylaminobenzoyloxypropyltheophylline, theobromine, diprofylline, proxyphylline, pentoxyphylline and salts thereof Or the skin external preparation as described in (1)-(6) which is 2 or more types.
(8) The skin external preparation according to (1) to (6), further comprising a whitening agent, an anti-wrinkle agent, an anti-inflammatory analgesic agent, an antifungal agent, a steroid agent, and a hair restorer.
(9) The skin external preparation according to any one of (1) to (8), wherein the skin external preparation is a liquid crystal type skin external preparation.
(10) The skin external preparation according to any one of (1) to (8), wherein the skin external preparation is a microemulsion type skin external preparation.
(11) The external preparation for skin according to (1) to (8), wherein the external preparation for skin is a liposome-type external preparation for skin.
The present invention also includes the following methods.
(12) A method for promoting percutaneous absorption of vitamin A, vitamin C, or xanthine derivative by containing phospholipid, glycol ether, and vitamin A, vitamin C, or xanthine derivative in an external preparation for skin.

  Since the present invention can improve the transdermal absorbability of vitamin A, vitamin C or xanthine derivative by containing phospholipid and glycol ether, the skin of vitamin A, vitamin C or xanthine derivative can be obtained. Can be expected to penetrate efficiently.

BEST MODE FOR CARRYING OUT THE INVENTION

  The external preparation for skin of the present invention is characterized by containing phospholipid, glycol ether and vitamin A, specific vitamin C, and xanthine derivative. In addition, the method for promoting percutaneous absorption of vitamin A, specific vitamin C, and xanthine derivative according to the present invention is characterized by containing phospholipid and glycol ether in a skin external preparation.

Examples of the phospholipid used in the present invention include glycerophospholipid and sphingophospholipid.
Glycerophospholipid is a substance having a glycerophosphoric acid skeleton, and has a fatty acid ester, a long-chain alkyl ether, a vinyl ether or the like as a lipophilic group. Specifically, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphadiylinositol, phosphatidylinositol polyphosphate, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, lysophosphatidylserine, Examples include phosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidic acid.
Sphingophospholipids have long-chain bases or long-chain fatty acids such as sphingosine and phytosphingosine, and phosphoric acid or phosphonic acid. Ceramide 1-phosphate derivatives (such as sphingomyelin), ceramide 1-phosphonic acid derivatives ( Ceramide aminoethylphosphonic acid and the like).
Among these phospholipids, glycerophospholipid is preferable, and phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol are particularly preferable.

The phospholipid used in the present invention may be a natural product extracted and purified from animals and plants, or may be chemically synthesized, and may be subjected to processing such as hydrogenation or hydroxylation. Commercial products may also be used. The natural product is preferably lecithin, which is an extract / purified product from soybean or egg yolk.
The lecithin may be non-hydrogenated lecithin, hydrogenated lecithin, hydroxylated lecithin and the like, and non-hydrogenated lecithin and hydrogenated lecithin are preferable. The iodine value of lecithin is usually 10 to 50, preferably 20 to 45, and particularly preferably 30 to 45.

  The amount of the phospholipid used in the present invention is not particularly limited as long as the effects of the present invention are exhibited, but as a whole external preparation for skin, it is usually 0.01 to 15% by weight, preferably 0.05 to 10% by weight, particularly preferably 0.1 to 0.1%. It may be 8% by weight.

  In the present invention, the glycol ether is not particularly limited as long as one or both of the hydroxyl groups of glycol are etherified. The glycol may be a single oligomer, a polymer, or two or more oligomers. good. For example, ethylene glycol monoether, ethylene glycol diether, diethylene glycol monoether, diethylene glycol diether, triethylene glycol monoether, triethylene glycol diether, tetraethylene glycol monoether, tetraethylene glycol diether, polyethylene glycol monoether, propylene Glycol monoether, propylene glycol diether, dipropylene glycol monoether, dipropylene glycol diether, tripropylene glycol monoether, tripropylene glycol diether, polypropylene glycol monoether, butylene glycol monoether, butylene glycol diether, alkylene glycol Such as acetate That. Examples of ethers include alkyl ethers, alkoxy ethers, aromatic ethers, and allyl ethers. Specifically, ethyl ether, methyl ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, t-butyl ether. N-pentyl ether, n-hexyl ether, phenyl ether, vinyl ether and the like.

  Specific examples of glycol ethers include ethylene glycol monovinyl ether, ethylene glycol monoethyl ether, ethylene glycol mono-n-propyl ether, ethylene glycol monoisopropyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol monoisobutyl ether, ethylene glycol Mono-t-butyl ether, ethylene glycol mono-2-methylpentyl ether, ethylene glycol mono-n-hexyl ether, ethylene glycol mono-2,4-hexadiene ether, ethylene glycol mono-2,6,8-trimethyl-4- Ethylene glycol monoethers such as nonyl ether, ethylene glycol monophenyl ether, and ethylene glycol monomethyl phenyl ether; ethylene glycol dimethyl ether And ethylene glycol diethers such as ethylene glycol diethyl ether; diethylene glycol monomethyl ether, diethylene glycol monoethyl ether (hereinafter also referred to as ethoxy diglycol), diethylene glycol mono-n-propyl ether, diethylene glycol mono-n-butyl ether, diethylene glycol monoisobutyl ether Diethylene glycol monoethers such as diethylene glycol mono-n-hexyl ether and diethylene glycol monomethyl phenyl ether; diethylene glycol diethers such as diethylene glycol dimethyl ether and diethylene glycol divinyl ether; triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol Triethylene glycol monoethers such as coal mono-n-butyl ether and triethylene glycol monovinyl ethyl ether; Triethylene glycol diethers such as triethylene glycol dimethyl ether and triethylene glycol divinyl ether; Tetraethylene glycols such as tetraethylene glycol monophenyl ether Monoether; tetraethylene glycol diether such as tetraethylene glycol diethyl ether; polyethylene glycol monoether such as polyethylene glycol monomethyl ether; propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol-n-monopropyl ether, propylene glycol mono Isopropyl ether, propylene glycol Propylene glycol monoethers such as mono-n-butyl ether, propylene glycol monoisobutyl ether, propylene glycol monoallyl ether, propylene glycol monophenyl ether; propylene glycol dimethyl ether, propylene glycol diethyl ether, propylene glycol-n-dipropyl ether, propylene glycol Propylene glycol diethers such as diisopropyl ether, propylene glycol di n-butyl ether, propylene glycol diisobutyl ether, propylene glycol diallyl ether, propylene glycol diphenyl ether; dipropylene glycol monoethyl ether, and dipropylene glycol mono-n-butyl ether, dipropylene glycol Monoisobutyl Dipropylene glycol monoethers such as ether and dipropylene glycol allyl ether; dipropylene glycol diethers such as dipropylene glycol diethyl ether and dipropylene glycol di n-butyl ether, dipropylene glycol diisobutyl ether and dipropylene glycol allyl ether; Propylene glycol monomethyl ether, tripropylene glycol monoethyl ether, and tripropylene glycol mono-ether such as tripropylene glycol mono-n-butyl ether, tripropylene glycol monoisobutyl ether, tripropylene glycol monoallyl ether; tripropylene glycol dimethyl ether, tripropylene Glycol diethyl ether and tripropylene glycol Tripropylene glycol diethers such as polypropylene n-butyl ether, tripropylene glycol diisobutyl ether, tripropylene glycol diallyl ether; polypropylene glycol monoethers such as polypropylene glycol monobutyl ether; butylene glycol monomethyl ether, butylene glycol monoethyl ether, and butylene glycol mono -butylene glycol monoethers such as n-butyl ether; butylene glycol dimethyl ether, butylene glycol diethyl ether, butylene glycol diethers such as butylene glycol di n-butyl ether; ethylene glycol monomethyl ether acetate, ethylene glycol monoethyl ether acetate, ethylene Glycol mono-n-butyl ether Acetate, diethylene glycol monoethyl ether acetate, diethylene glycol mono -n- butyl ether acetate, alkylene glycol acetate and propylene glycol monomethyl ether acetate; and the like.

  Preferred glycol ethers are ethylene glycol monoether, ethylene glycol diether, diethylene glycol monoether, diethylene glycol diether, triethylene glycol monoether, tetraethylene glycol monoether, tetraethylene glycol diether, polyethylene glycol monoether, propylene glycol mono Ether, propylene glycol diether, dipropylene glycol monoether, dipropylene glycol diether, tripropylene glycol monoether, specifically ethylene glycol monovinyl ether, ethylene glycol monoethyl ether, ethylene glycol mono-n-propyl ether , Ethylene glycol monoisopropyl ether, ethyl Glycol mono-n-butyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono-t-butyl ether, ethylene glycol mono-2-methylpentyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, Diethylene glycol mono-n-propyl ether, diethylene glycol mono-n-butyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono-n-hexyl ether, diethylene glycol monomethyl phenyl ether, diethylene glycol dimethyl ether, diethylene glycol divinyl ether, diethylene glycol ethyl vinyl ether, triethyl Glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol mono-n-butyl ether, triethylene glycol monovinyl ethyl ether, tetraethylene glycol monophenyl ether, tetraethylene glycol diethyl ether, polyethylene glycol methyl mono ether, propylene glycol monomethyl Ether, propylene glycol monoethyl ether, propylene glycol-n-monopropyl ether, propylene glycol monoisopropyl ether, propylene glycol mono-n-butyl ether, propylene glycol phenyl ether, propylene glycol monomethyl ether, propylene glycol dimethyl ether, propylene glycol diethyl ether, Professional Pyrene glycol-n-dipropyl ether, propylene glycol diisopropyl ether, propylene glycol di n-butyl ether, propylene glycol diisobutyl ether, propylene glycol diallyl ether, propylene glycol diphenyl ether, dipropylene glycol monoethyl ether, dipropylene glycol mono-n-butyl ether , Dipropylene glycol diethyl ether, and dipropylene glycol di n-butyl ether, dipropylene glycol diisobutyl ether, dipropylene glycol allyl ether, tripropylene glycol monomethyl ether, tripropylene glycol monoethyl ether, and tripropylene glycol mono-n-butyl ether It is.

  More preferably, the glycol ether is ethylene glycol monoether, propylene glycol monoether, dipropylene glycol monoether, specifically ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, Diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether.

  The blending amount of the glycol ether used in the present invention is not particularly limited as long as the effects of the present invention are exhibited, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. Usually, 0.01 to 80% by weight, preferably 1 to 75% by weight, particularly preferably 5 to 70% by weight.

  Further, in the external preparation for skin of the present invention, the ratio of the glycol ether to the phospholipid is not particularly limited as long as the effect of the present invention is exerted, but when the total amount of phospholipid is 1 part by weight, usually 0.01 to 300 parts by weight, Preferably it is 0.05-100 weight part, Most preferably, it is 0.1-20 weight part.

  The vitamin A used in the present invention includes vitamin A fatty acid esters such as retinol, retinol acetate, retinol palmitate, retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, vitamin A oil, retinol palmitate, d -δ-tocopheryl retinoate, α-tocopheryl retinoate, β-tocopheryl retinoate and the like can be mentioned, and retinol palmitate and d-δ-tocopheryl retinoate are preferable.

  The amount of vitamin A used in the present invention is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. As 0.01 to 5% by weight, preferably 0.1 to 3% by weight, particularly preferably 0.2 to 1% by weight.

  Ascorbic acid, sodium ascorbate, dehydroascorbic acid, ascorbic acid glucoside, ascorbyl stearate, L-ascorbyl dipalmitate, ascorbyl tetra-2-hexyldecanoate (ascorbyl tetraisopalmitate) used in the present invention are known vitamin Cs. Preferred are ascorbic acid, ascorbic acid glucoside, and ascorbyl tetra-2-hexyldecanoate.

  The amount of the specific vitamin C used in the present invention is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the agent is usually 0.01 to 50% by weight, preferably 0.05 to 40% by weight, particularly preferably 0.1 to 30% by weight.

  Examples of the xanthine derivative used in the present invention include caffeine, aminophylline, theophylline, oxtriphyrin, diphylline, diisobutylaminobenzoyloxypropyltheophylline, theobromine, diprofylline, proxyphylline, pentoxyphylline, preferably caffeine, aminophylline, Theophylline, diprofylline, proxyphylline, theobromine.

  The amount of the specific xanthine derivative used in the present invention is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. As a whole, it is usually 0.01 to 5% by weight, preferably 0.1 to 3% by weight, particularly preferably 0.2 to 1% by weight.

  The composition of the present invention can also promote percutaneous absorption of active ingredients other than vitamins A, specific vitamins C, and xanthine derivatives blended in an external preparation for skin. Other useful effects can be added.

In the present invention, the active ingredient is not particularly limited as long as it has a useful effect on the skin such as a pharmacologically active ingredient or a physiologically active ingredient. For example, vitamins (provitamin A, vitamin E, Vitamin B2, nicotinic acid, vitamin D, vitamin K, vitamin B1, vitamin B6, vitamin B12, folic acid, pantothenic acid, biotin, vitamin-like agent), whitening agent, anti-wrinkle agent, anti-inflammatory Analgesics, antifungals, steroids, hair restorers, local anesthetics, antipruritics, antibacterial agents, antiviral agents, keratin softeners, moisturizers, astringents, antioxidants, hair growth inhibitors, etc. Whitening agents, anti-wrinkle agents, anti-inflammatory analgesics, antifungal agents, steroid agents, hair restorers, slimming agents are preferred.
These components can be used alone or in combination of two or more.
Specifically, the following components can be exemplified.

  As vitamins, β-carotene, α-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthine, echinone and other provitamins A, succinic acid dl-α-tocopherol, succinic acid dl-α- Vitamin E such as tocopherol calcium, vitamin B2 such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5'-phosphate ester, riboflavin tetranicotinate, nicotinic acid Nicotinic acids such as methyl, nicotinic acid and nicotinamide, vitamin D such as methyl hesperidin, ergocalciferol and cholecalciferol, vitamin K such as phylloquinone and farnoquinone , Γ-oryzanol, dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate , Vitamin B1 such as thiamine monophosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate, thiamine triphosphate, thiamine triphosphate monophosphate, pyridoxine hydrochloride, pyridoxine acetate, Vitamin B6 such as pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, vitamin B12 such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, folic acid, ptero Folic acids such as irglutamic acid, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), pantothenic acid, pantothecin, coenzyme A, pantothenic acid such as pantothenyl ethyl ether, biotin such as biotin and biotisin And other vitamin-like agents such as carnitine, ferulic acid, α-lipoic acid, orotic acid, and the like.

  The amount of vitamins used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the external preparation for skin is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  As whitening agents, placenta, arbutin, cysteine, ellagic acid, kojic acid, phytic acid, lucinol, hydroquinone; , Chamomile, licorice, gardenia, cucumber, wheat, rice, rice haiga, oryzanol, rice bran, perilla, peony, nematode, perch, soy, tea, terminaria, toki, pearl millet, hamamelis, safflower, buttonpi, yokuinin, okie Ingredients derived from plants such as oysters (Diospyros kaki) and clove, extracts, essential oils and the like can be mentioned, and arbutin, cysteine and terminaria extract are preferable.

  The blending amount of the whitening agent used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the external preparation for skin is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Examples of the anti-wrinkle agent include coenzyme Q10, kinetin, glycolic acid, aldiline, acylated glucosamine, collagen, hyaluronic acid, aloe extract, seaweed extract, maronier extract, rosemary extract, cornflower extract, preferably coenzyme Q10, It is kinetin.

  The compounding amount of the anti-wrinkle agent used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the external preparation for skin is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Anti-inflammatory analgesics include indomethacin, felbinac, methyl salicylate, glycol salicylate, allantoin or derivatives thereof, ibuprofen, ibuprofen piconol, bufexamac, butyl fenfenac, bendazac, piroxicam, ketoprofen, etc., preferably indomethacin, felbinac, It is methyl salicylate.

  The amount of the anti-inflammatory analgesic used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the external preparation for skin is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Antifungal agents include terbinafine hydrochloride, sulconazole nitrate, clotrimazole, isoconazole nitrate, croconazole nitrate, naconconate nitrate, miconazole nitrate, econazole nitrate, oxyconazole nitrate, bifonazole, thioconazole, ketoconazole, tolnaphthalate, tolcyclate, lirannaphthate, cyclohexane Examples include piroxolamine, exeramide, siccanin, undecylenic acid, zinc undecylenate, pyrrolnitrin, butenafine hydrochloride, amorolfine hydrochloride, neticonazole hydrochloride and the like, preferably terbinafine hydrochloride and sulconazole nitrate.

  The amount of the antifungal agent used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the external preparation for skin is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Steroid agents include dexamethasone acetate, dexamethasone acetate, dexamethasone propionate, dexamethasone acetate, dexamethasone valerate, prednisolone valerate acetate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone, hydrocortisone butyrate propionate, cortisone acetate, prednisolone acetate, prednisone acetate, , Betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, clobetasol propionate, diflurozone acetate, diflucortron valerate, beclomethasone propionate, flumetasone pivalate, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, amcinonide, amcinonide, Difluprednate and the like, preferably hydrocortiacetate Emissions, prednisolone valerate acetate, butyrate clobetasone.

  The compounding amount of the steroid used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the external preparation for skin is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Hair growth agents include procyanidins, dipotassium glycyrrhizinate, capronium chloride, cephalanthin, menthol, hinokitiol, L-hydroxyproline, acetylhydroxyproline, fucoidan, capsicum tincture, cephalanthin, swellthianin, symphonginidine, flavonosteroid, immunotect, minoxidil, FGF -10 、 Emisodia extract (extract), assembly extract (extract), beetle extract (extract), flax extract (extract), hypericum extract (extract), gentian extract (extract), sage extract (extract) ), Peppermint extract (extract), Hop extract (extract), Yokuinin extract (extract), Bamboo leaf extract (extract), Ginger extract (extract), Carrot extract (extract), Body Ju extract (extract), moutan bark extract (extract) and the like, preferably procyanidins, assembly extract (extract), Mitsuishikonbu extract (extract).

  The blending amount of the hair restorer used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the external preparation for skin is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Other examples of local anesthetics, antipruritics, antibacterial agents, antiviral agents, keratin softeners, moisturizers, astringents, antioxidants, and hair growth inhibitors include the following.

Local anesthetics: lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, ethyl aminobenzoate, eucalyptus oil, eugenol, camphor, mint oil, etc.
Antipruritics: crotamiton, chlorpheniramine, chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate, salicylic acid, nonylic acid vanillylamide, mequitazine, camphor, thymol, eugenol, polyoxyethylene lauryl ether, comfrey extract, perilla extract, etc.

Antibacterial agents: isopropylmethylphenol, chlorhexidine gluconate, chlorhexidine hydrochloride, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, decalinium chloride, triclosan, trichlorocarbanilide and the like.
Antiviral agents: acyclovir, penciclovir, etc.

  Keratin softener: ethyl alcohol, isopropyl alcohol, propanol, butanol, polyethylene glycol, benzyl alcohol, phenylethyl alcohol, propylene carbonate, hexyl decanol, allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl Laurylate, lanolin, fatty acid dialkyrolamide, urea, sulfur, resorcin, phytic acid, lactic acid, lactate, sodium hydroxide, potassium hydroxide, etc.

  Moisturizer: polyethylene glycol, diglycerin trehalose, sodium hyaluronate, heparin analog, chondroitin sulfate sodium, collagen, elastin, keratin, chitin, chitosan and other high molecular compounds, glycine, aspartic acid, arginine and other amino acids, sodium lactate, Natural moisturizing factors such as urea and sodium pyrrolidonecarboxylate, plant extract extracts such as chamomile extract, aloe extract, aloe vera extract, hamamelis extract, rosemary extract, thyme extract, tea extract and perilla extract.

Astringent: citric acid, tartaric acid, lactic acid, aluminum chloride, aluminum sulfate, allantoinchlorohydroxyaluminum, allantoindihydroxyaluminum, aluminum phenolsulfonic acid, zinc paraphenolsulfonic acid, zinc sulfate, zinc lactate, aluminum chlorohydroxide and the like.
Antioxidants: Dibutylhydroxytoluene, butylhydroxyanisole, disodium ethylenediaminetetraacetate dihydrate (hereinafter also referred to as sodium edetate), sorbic acid, sodium sulfite and the like.

  Hair growth inhibitor: isoflavone, cypress extract, docami extract, iris root extract, papain enzyme, etc.

  The amount of the local anesthetic, antipruritic agent, antibacterial agent, antiviral agent, keratin softener, moisturizer, astringent, antioxidant, hair growth inhibitor is not particularly limited as long as the effect of the present invention is exerted, Desirably, it can be appropriately selected and used within the upper limit of the amount allowed in the Pharmaceutical Affairs Law. Specifically, it can be prepared according to the purpose from the range of usually 0.001 to 20 parts by weight, preferably 0.001 to 10 parts by weight, more preferably 0.001 to 5 parts by weight per 100 parts by weight of the external preparation for skin.

  The method for preparing the external preparation for skin of the present invention is not particularly limited, and can be prepared by a conventional method by appropriately selecting and blending various components necessary for preparing an ordinary external preparation for skin. Moreover, the application amount and usage of the external preparation for skin of the present invention to the outer skin are not particularly limited, and it can be used usually by applying an appropriate amount to the outer skin such as skin several times a day.

  The external preparation for skin of the present invention can be prepared in various forms. For example, ointments, creams, liquids (including oils, lotions, emulsions, aerosols), gels (including liquid crystals, microemulsions, liposomes), patches (including packs), solids (sticks) In particular, it is useful when applied to liquids (including lotions, oils, and emulsions) and gels (including liquid crystals, microemulsions, and liposomes). Of these, gel agents (including liquid crystals, microemulsions and liposomes) are particularly preferred as an embodiment of the present invention because of the effect of stabilizing the preparation at high temperatures.

A liquid crystal is a liquid with a high degree of crystallinity, generally having a long orientation in the constituent molecules, a fluidity and viscosity that is intermediate between solid and liquid, and exhibits optical anisotropy. There are many. The liquid crystal forms a hexagonal layer and a lamellar layer, and this structure causes refraction and reflection due to colored stripes and polarized light in white light, so it is easy to identify birefringence under the microscope and visual observation of liquid crystal formation. can do.
Since liquid crystals are similar in structure to biological bilayer membranes and intercellular lipids, they have the advantage that they are easy to adapt to the skin and can promote percutaneous absorption of useful components.
In the present invention, the skin external preparation preferably contains liquid crystal.

A microemulsion is generally defined as a transparent or translucent one-liquid phase consisting of an oil-water-amphiphile, and a system in which large swollen micelles are dispersed. It is said that. The average particle size of the microemulsion is preferably 0.5 μm or less from the viewpoint of optical transparency.
Microemulsions have the advantage that the formulation is more easily absorbed into the skin from the stratum corneum than normal emulsions because the micelles dispersed are small enough to have optical transparency.

A liposome is an endoplasmic reticulum composed of a lipid bilayer assembled in a spherical shape. A structure in which multiple layers of this lipid bilayer overlap each other in an onion shape is called a multilamellar liposome.
Liposomes are similar in structure to biological bilayer membranes, and thus have an advantage that they can be easily adapted to the skin and can promote percutaneous absorption of useful components.

In the present invention, the liquid crystal type external preparation for skin indicates one containing liquid crystal in the external preparation for skin.
When the skin external preparation of the present invention is a liquid crystal type skin external preparation, prepared by adding and stirring phospholipids, water-soluble compounds, a small amount of water, etc. to glycol ether, and appropriately adding and stirring oils and oil-soluble compounds. can do. Moreover, although the liquid crystal type skin external preparation of this invention can mix | blend a small amount of water, it can prepare also as a substantially anhydrous formulation, without mix | blending water separately.

In the present invention, the microemulsion-type external preparation for skin indicates one containing a microemulsion in the external preparation for skin.
When the skin external preparation of the present invention is a microemulsion type skin external preparation, phospholipids and the like are added to and stirred in glycol ether, and oils and oil-soluble compounds are appropriately added and stirred, and then water-soluble compounds and water are added. And emulsified and prepared using a high-pressure homomixer.

In the present invention, the liposome-type external preparation for skin refers to those containing liposomes in the external preparation for skin.
When the skin external preparation of the present invention is a liposome-type skin external preparation, the preparation method is not particularly limited, and various known preparation methods can be used. For example, phospholipid, water-soluble It can be prepared by adding and stirring a compound, water and the like, and appropriately adding and stirring an oil and an oil-soluble compound.

  The skin external preparation of the present invention may further contain water, and the amount of water is not particularly limited as long as the effect of the present invention is exhibited, but is generally 0.001 to 90% by weight, preferably 0.01 to 80% as a whole. % By weight, particularly preferably 0.1 to 70% by weight.

  Since the external preparation for skin of the present invention may belong to any category of pharmaceuticals, quasi-drugs, and cosmetics, it can be used for various applications. Examples of the use of the external preparation for skin of the present invention include eczema, rash, dry pruritus, xerosis, moisturized skin, bruise and other dermatitis therapeutic agents or antipruritics, cuts, scratches, etc. Infectivity to treat antiseptics, wound healing agents, athlete's foot, acne, etc. to promote and prevent deterioration of shoes, scratches, scratches, scissors, burns, purulent wounds, wrinkles, cracks, scratches, etc. Treatment for skin diseases or antibacterial agents, cheilitis, keratitis, lip cracks, sores, etc. Treatment for lips, finger contact, keratosis such as elbows, knees, heels, and ankles, shark skin Drugs such as keratin softeners and anti-inflammatory analgesics for treatment, agents for scalp such as hair growth, hair growth promotion and hair growth, hair care agents such as shampoo and rinse, rough hands, rough skin, rough lips, hot flashes after sunburn, Wrinkles, sagging, skin conditioning, lip A quasi-drug used to keep the skin and lips healthy, moisturize the skin and lips, protect the skin and lips, prevent skin dryness, moistness, cracks, scratches, rashes, etc. Cosmetics used for moisturizing, whitening, anti-wrinkle, keratin softening, cleansing and the like can be exemplified as suitable applications, but are not particularly limited thereto.

  The external preparation for skin of the present invention does not impair quality such as storage stability and viscosity, and within the quantitative and qualitative range that does not impair the effects of the present invention, as necessary, in the pharmaceutical, quasi-drug or cosmetic field. Ingredients commonly used in the formulation, such as bases, surfactants, thickeners, preservatives, pH adjusters, stabilizers, irritation reducers, preservatives, colorants, dispersants, fragrances, etc. can do. In addition, these components can be mix | blended individually by 1 type or in combination of 2 or more types.

  Base: hydrocarbons such as paraffin, gelled hydrocarbon, ozokerite, ceresin, petrolatum, hard fat, microcrystalline wax, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, oleic acid, linoleic acid Fatty acids such as, highly polymerized methylpolysiloxane, dimethylsiloxane methyl (polyoxyethylene) siloxane methyl (polyoxypropylene) siloxane copolymer, dimethylsiloxane methyl (polyoxyethylene) siloxane copolymer, dimethylsiloxane methyl (Polyoxypropylene) siloxane copolymer, polyoxyethylene / methylpolysiloxane copolymer, poly (oxyethylene / oxypropylene) / methylpolysiloxane copolymer, dimethylsiloxane / methyl Cetyloxysiloxane copolymer, dimethylsiloxane / methylstearoxysiloxane copolymer, alkyl acrylate copolymer methylpolysiloxane ester, crosslinked methylpolysiloxane, crosslinked methylphenylpolysiloxane, crosslinked polyether-modified silicone, crosslinked Type alkyl polyether-modified silicone, polymerization type silicone such as cross-linked alkyl-modified silicone, ethylene glycol monoacetate, ethylene glycol diacetate, triethylene glycol diacetate, hexylene glycol diacetate, and 2-methyl-2 -Glycol acetates such as propene-1,1-diol diacetate, triethylene glycol divalerate, 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate, 2,2,4-trimethyl 1,3-pentanediol Glycol esters such as diisobutyrate, ethylene glycol diacrylate, diethylene glycol diacrylate, propylene glycol monoacrylate, 2,2-dimethyl-trimethylene glycol diacrylate, and 1,3-butylene glycol diacrylate Glycol dinitrates such as glycol acrylate, ethylene glycol dinitrate, diethylene glycol dinitrate, triethylene glycol dinitrate, and propylene glycol dinitrate, 2,2 '-[1,4-phenylenedioxy] diethanol, dioxane, butylene glycol Adipic acid polyester and so on.

  Surfactant: Sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate Glyceryl fatty acids such as glyceryl monostearate and glyceryl monostearate malic acid, polyglyceryl fatty acids such as polyglyceryl monoisostearate and polyglyceryl diisostearate, propylene glycol fatty acid esters such as propylene glycol monostearate, polyoxyethylene cured Hardened castor oil derivatives such as castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, polylauric acid poly Polyoxyethylene sorbitan fatty acid esters such as xylethylene (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene monooxylate (20) sorbitan (polysorbate 80), poly Oxyethylene monococonut oil fatty acid glyceryl, glycerin alkyl ether, alkyl glucoside, polyoxyethylene cetyl ether, stearylamine, oleylamine and the like.

  Thickener: Guar gum, locust bean gum, carrageenan, xanthan gum, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, polyvinyl alcohol, polyvinylpyrrolidone , Polyvinyl methyl ether, carboxyvinyl polymer, alkyl methacrylate copolymer, sodium polyacrylate, polyethylene glycol, bentonite, dextrin fatty acid ester, pectin and the like.

  Preservatives: Benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, benzyl paraoxybenzoate, paraoxybenzoic acid Methyl, phenoxyethanol, etc.

  pH adjusters: inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, sodium succinate, oxalic acid, gluconic acid, Fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic base (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, Calcium hydroxide, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.).

  These components can be used alone or in combination of two or more. Moreover, those compounding amounts are not particularly limited as long as the effects of the present invention are obtained, but can be suitably selected and used as long as the upper limit compounding amount allowed by the Pharmaceutical Affairs Law is desirable. Specifically, it can be prepared according to the purpose from the range of usually 0.001 to 20 parts by weight, preferably 0.001 to 10 parts by weight, more preferably 0.001 to 5 parts by weight per 100 parts by weight of the external preparation for skin.

The present invention also includes a method for promoting percutaneous absorption of vitamins A, vitamins C, or xanthine derivatives blended in a skin external preparation. In the method of the present invention, promotion of percutaneous absorption of an external preparation for skin containing vitamin A, vitamin C or xanthine derivative can be achieved by containing phospholipid and glycol ether.
In the method of the present invention, phospholipids, glycol ethers, vitamins A and xanthine derivatives, their blending amounts, and blending ratios of phospholipids and glycol ethers are the same as those used in the above-mentioned external preparation for skin.

As vitamins C, ascorbic acid stearate, L-ascorbyl dipalmitate, ascorbyl tetra-2-hexyldecanoate (ascorbyl tetraisopalmitate), ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate , Magnesium ascorbate phosphate, magnesium ascorbate phosphate, sodium ascorbate phosphate, glucoside ascorbate, etc., ascorbic acid, sodium ascorbate, dehydroascorbic acid, ascorbyl glucoside, ascorbyl stearate, di Preferred are L-ascorbyl palmitate and ascorbyl tetra-2-hexyldecanoate (ascorbyl tetraisopalmitate). Rubic acid, ascorbic acid glucoside, and ascorbyl tetra-2-hexyldecanoate are particularly preferred. The amount of vitamin C is not particularly limited as long as the effects of the present invention are achieved, and is appropriately determined in consideration of the feeling of use and effects on the skin. Although it can be selected and used, the total amount of the external preparation for skin is usually 0.01 to 50% by weight, preferably 0.05 to 40% by weight, particularly preferably 0.1 to 30% by weight.

  The composition obtained by using this method can be used in a dosage or administration by a known or commonly used method, divided into 1 to several times per day according to the formulation form. it can.

  EXAMPLES The present invention will be specifically described below with reference to examples, but these examples do not limit the scope of the present invention. In addition, a compounding quantity etc. represent weight% altogether about purified water or a thing without the description of a unit.

Test Example 1 Transdermal absorbability test
In accordance with the formulation shown in Table 1, each phospholipid was dissolved in glycol ether or polyhydric alcohol by heating and added to a separately heated ascorbic acid aqueous solution (liposome type except for Comparative Example 3). Put 10 ml of phosphate buffer (pH 7.4) into the reservoir of a vertical Franz cell, and remove the fat skin of hairless mice (strain: HR-1, 7 weeks old, male) between the cells. After fixation, 1 mL of the test preparation was added to the donor side. Sampling was performed from the reservoir side 30 hours after the addition, and ascorbic acid was immediately quantified by HPLC.
The results are shown in Table 1.

The permeation amount of Example 1 was found to be significantly improved to 2.8 times or more compared to Comparative Examples 1 and 2, and 6.4 times or more compared to Comparative Example 3 containing 20% ascorbic acid. In addition, Example 2 uses unhydrogenated soybean phospholipid, which is about 16 times or more that of Comparative Examples 1 and 2, and 36 times or more that of Comparative Example 3, which is further remarkably improved. I found out.
Thus, Examples 1 and 2 are skin external preparations excellent in skin permeability, and are particularly useful because they can sufficiently expect the pharmacological effect of the active ingredient.

Test Example 2 Transdermal absorbability test
Prepared by dissolving glyceryl solution of phospholipid, d-δ-tocopheryl retinoate in tri (capryl / capric acid) glyceryl in glycol ether and polyhydric alcohol, and mixing with purified water separately heated according to the formulation shown in Table 2. For the prepared liposomal preparation, 10 mL of phosphate buffer solution (pH 7.4) was added to the reservoir side of the vertical Franz cell, and the fat layer of the hairless mouse (strain: HR-1, 7 weeks old, male) was removed. After fixing the skin between the cells, 1 mL of the test drug was added to the donor side. 24 hours after addition of the test drug, the skin of all layers was removed from the cell, and the stratum corneum surface was washed with water and ethyl acetate, and then the skin of all layers was homogenized and extracted with ethyl acetate, and d-δ-tocopheryl retinoate by HPLC. Was quantified.
The results are shown in Table 2.

Example 1 using ethoxydiglycol and 1,3-butyleneglycol retains rather than Comparative Example 1 using dipropyleneglycol, which is said to have a higher transdermal absorption effect than 1,3-butyleneglycol. It was found that the amount was remarkably improved by 3 times.
Thus, Example 1 is an external preparation for skin excellent in transdermal absorbability, and is particularly useful since it can sufficiently expect the pharmacological effect of the active ingredient.

Test Example 3 Transdermal absorbability test
According to the formulation shown in Table 3, a tri (capryl / capric acid) glyceryl solution of phospholipid and d-δ-tocopheryl retinoate is dissolved in glycol ether and polyhydric alcohol and mixed with separately heated purified water. For the prepared liposomal preparation, 10 mL of phosphate buffer solution (pH 7.4) was added to the reservoir side of the vertical Franz cell, and the fat layer of the hairless mouse (strain: HR-1, 7 weeks old, male) was removed. After fixing the skin between the cells, 1 mL of the test drug was added to the donor side. 24 hours after addition of the test drug, the skin of all layers was removed from the cell, and the stratum corneum surface was washed with water and ethyl acetate, and then the skin of all layers was homogenized and extracted with ethyl acetate, and d-δ-tocopheryl retinoate by HPLC. Was quantified.
The results are shown in Table 3.

It was found that the amount of storage in Example 4 using phospholipids was significantly improved by 4.9 times compared to Comparative Example 5 using a frequently used surfactant.
Thus, Example 4 is an external preparation for skin excellent in transdermal absorbability, and is particularly useful because it can sufficiently expect the pharmacological effect of the active ingredient.

Test Example 4 Transdermal absorbability test
According to the formulation shown in Table 4, a phospholipid was dissolved in glycol ether or polyhydric alcohol by heating and added to a separately heated caffeine aqueous solution. After 10 ml of acid buffer (pH 7.4) is added and the skin of hairless mice (strain: HR-1, 7 weeks old, male) from which fat has been removed is fixed between the cells, the test drug is placed on the donor side. 1 mL was added. Sampling was performed from the reservoir side 30 hours after the addition, and caffeine was immediately quantified by HPLC.
The results are shown in Table 4.

It was found that the permeation amount was significantly improved by 3.8 times in Example 6 using ethoxydiglycol than in Comparative Example 6 using 1,3-butylene glycol. Further, from Comparative Example 7, it was confirmed that the percutaneous absorption effect of only hydrogenated soybean phospholipid was not so high.
Furthermore, it was found from Examples 7 and 8 that when soybean phospholipids that were not hydrogenated were used, the amount of permeation significantly increased to 4 times or more that in Example 6, and the effect was further high.
Further, from Comparative Example 6 and Example 9, it was found that the permeation amount was improved by 1.5 times or more simply by replacing 5% of 1,3-butylene glycol with ethoxydiglycol.
Thus, Examples 5 to 9 are skin external preparations excellent in transdermal absorbability, and are particularly useful because they can sufficiently expect the pharmacological effects of the active ingredients.

  The formulation examples are given below. In addition, the compounding quantity in the following Examples represents weight% about all the things which have no description of a unit especially.

Claims (7)

From the group consisting of phospholipids, glycol ethers, and vitamins A, ascorbic acid, sodium ascorbate, dehydroascorbic acid, ascorbyl glucoside, ascorbyl stearate, L-ascorbyl dipalmitate, ascorbyl tetra-2-hexyldecanoate and xanthine derivatives A skin external preparation containing one or more selected. Glycol ether is ethylene glycol monoether, ethylene glycol diether, propylene glycol monoether, propylene glycol diether, butylene glycol monoether, butylene glycol diether, diethylene glycol monoether, diethylene glycol monoether, diethylene glycol diether, dipropylene glycol mono. The skin external preparation according to claim 1, which is one or more selected from the group consisting of ether, dipropylene glycol diether, dibutylene glycol monoether and dibutylene glycol diether. The skin external preparation according to claim 1 or 2, wherein the phospholipid is a hydrogenated phospholipid. The skin external preparation according to claim 1 or 2, wherein the phospholipid is a non-hydrogenated phospholipid. The iodine external value of hydrogenated phospholipid is 10-50, The skin external preparation in any one of Claims 1-3. Vitamin A is retinol, retinol acetate, retinol palmitate, retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinoic acid retinol, vitamin A oil, vitamin A fatty acid ester, d-δ-tocopheryl retinoate, α The skin external preparation according to any one of claims 1 to 5, which is one or more selected from the group consisting of -tocopheryl retinoate and β-tocopheryl retinoate. One or two xanthine derivatives selected from the group consisting of caffeine, aminophylline, theophylline, oxtriphyrin, diphylline, diisobutylaminobenzoyloxypropyltheophylline, theobromine, diprofylline, proxyphylline, pentoxyphyllin and their salts It is the above, The skin external preparation in any one of Claims 1-6.