JP2007191396A - Skin preparation for external use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a skin preparation for external use excellent in percutaneous absorption of hyaluronic acid, hyaluronic acid derivatives or salts of the same. <P>SOLUTION: The kin preparation for external use excellent in percutaneous absorption of hyaluronic acid, the hyaluronic acid derivatives or the salts of the same is obtained by bringing the preparation to contain a phospholipid and a glycol ether. Therefore, owing to efficient penetration of hyaluronic acid, the hyaluronic acid derivatives or the salts of the same into the skin, high moisturizing effect, anti-wrinkle effect of giving tension and elasticity to the skin, and the like are expected. <P>COPYRIGHT: (C)2007,JPO&INPIT

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.
Hyaluronic acid is a mucopolysaccharide composed of glucuronic acid and N-acetylglucosamine, and is present in the dermis in large quantities as a bonding substance that fills cells and fibers in vivo and has also been confirmed in the epidermis. Since it is a substance and has high water retention and viscoelasticity (Non-patent Document 1: fragrance journal No. 2, 30 (1990)), it is widely used as a skin moisturizer and the like. However, since the molecular weight is very large, such as several thousand to 5 million, it is said that it is blocked by the skin barrier function and stays in the epidermis and does not penetrate into the skin.
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 the transdermal absorbability of hyaluronic acid, a hyaluronic acid derivative or a salt thereof is remarkably improved.

As a result of intensive studies to achieve the above-mentioned object, the present inventors remarkably improve the transdermal absorbability of hyaluronic acid, hyaluronic acid derivatives or salts thereof when phospholipid and glycol ether are contained. As a result, the present invention has been completed.
That is, this invention is a skin external preparation listed to following (1)-(11).
(1) A skin external preparation containing (A) phospholipid, (B) glycol ether and (C) hyaluronic acid, a hyaluronic acid derivative or a salt thereof.
(2) The 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 hyaluronic acid derivative is acetyl hyaluronic acid.
(4) The external preparation for skin according to any one of (1) to (3), wherein the phospholipid is a hydrogenated phospholipid.
(5) The external preparation for skin according to any one of (1) to (3), wherein the phospholipid is a non-hydrogenated phospholipid.
(6) The skin external preparation according to any one of (1) to (4), wherein the hydrogenated phospholipid has an iodine value of 10 to 50.
(7) The skin external preparation according to (1) to (6), further comprising vitamins, whitening agents, anti-wrinkle agents, anti-inflammatory analgesics, antifungal agents, steroid agents, and hair restorers.
(8) The external preparation for skin according to (1) to (7), wherein the external preparation for skin is a liquid crystal type external preparation for skin.
(9) The skin external preparation according to any one of (1) to (7), wherein the skin external preparation is a microemulsion type skin external preparation.
(10) The skin external preparation according to (1) to (7), wherein the skin external preparation is a liposome-type skin external preparation.
(11) A skin external preparation containing glycol ether and hyaluronic acid, a hyaluronic acid derivative or a salt thereof.
The present invention also includes the following methods.
(12) A method for promoting percutaneous absorption of hyaluronic acid, a hyaluronic acid derivative or a salt thereof by containing phospholipid, glycol ether, and hyaluronic acid, a hyaluronic acid derivative or a salt thereof in an external preparation for skin.

  Since the present invention can improve the transdermal absorbability of hyaluronic acid, hyaluronic acid derivatives or salts thereof by containing phospholipid and glycol ether, the skin of hyaluronic acid, hyaluronic acid derivatives or salts thereof can be improved. 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 hyaluronic acid, a hyaluronic acid derivative or a salt thereof. The method for promoting percutaneous absorption of hyaluronic acid, a hyaluronic acid derivative or a salt thereof of the present invention is characterized by containing a phospholipid and a 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 origin of hyaluronic acid used in the present invention is not particularly limited, and hyaluronic acid or a derivative thereof that is usually used for an external preparation for skin can be used.
Hyaluronic acid derivatives include ester derivatives in which the hydroxyl group of hyaluronic acid is acylated and alkylated ether derivatives. Examples of ester derivatives include alkanoyl groups and arylcarbonyl groups. The alkanoyl group preferably has 1 to 12 carbon atoms, and examples thereof include an acetyl group, a propionyl group, and a butyryl group. The arylcarbonyl group preferably has 7 to 15 carbon atoms, and examples thereof include a benzoyl group and a naphthylcarbonyl group. The alkanoyl group, arylcarbonyl group, benzoyl group, and naphthylcarbonyl group may be substituted, and examples of the substituent include an alkyl group, an alkoxy group, a halogen group, an amino group, and a hydroxy group.
Examples of ether derivatives include alkyl ethers, aromatic ethers, allyl ethers, and the like. Specifically, ethyl ether, methyl ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, t-butyl ether, n- Examples include pentyl ether, n-hexyl ether, phenyl ether, vinyl ether and the like.
Among them, the hyaluronic acid derivative is preferably an ester derivative, and particularly preferably an acetyl derivative. The acetyl hyaluronic acid preferably has 2 to 4 substitutions of acetyl groups per structural unit (disaccharide).
Hyaluronic acid or a derivative thereof may be a pharmaceutically / physiologically acceptable salt, such as an alkali metal salt such as sodium or potassium, an alkaline earth metal salt such as magnesium or calcium, an ammonium salt, or a mono salt. Examples thereof include alkanolamine salts such as ethanolamine, and alkali metal salts such as sodium salt are preferred.

  In the external preparation for skin of the present invention, the average molecular weight of hyaluronic acid, hyaluronic acid derivatives or salts thereof is not particularly limited, but is usually 1,000 to 5,000,000, preferably 2,000 to 4,000,000, particularly preferably 3,000 to 2,500,000. is there.

  The amount of hyaluronic acid, hyaluronic acid derivative or salt thereof used in the present invention is not particularly limited as long as the effects of the present invention are exhibited, and may be appropriately selected and used in consideration of the feeling of use and effects on the skin. However, the total amount of the external preparation for skin is usually 0.0001 to 10% by weight, preferably 0.0005 to 8% by weight, particularly preferably 0.001 to 5% by weight.

  Since the present invention can also promote percutaneous absorption of active ingredients other than hyaluronic acid, hyaluronic acid derivatives or salts thereof contained in an external preparation for skin, other useful ingredients can be further blended. An action 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 and a physiologically active ingredient. For example, vitamins (vitamin A, provitamin A, Vitamin E, vitamin B2, nicotinic acid, vitamin C, 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 analgesic agent, antifungal agent, steroid agent, hair restorer, slimming agent, local anesthetic agent, antipruritic agent, antibacterial agent, antiviral agent, keratin softener, moisturizer, astringent, antioxidant Agents, hair growth inhibitors, etc., preferably vitamin A, vitamin C, whitening agent, anti-wrinkle agent, anti-inflammatory agent, antifungal agent, steroid agent, hair restorer, slimming agent, particularly preferred Ku is vitamin A, vitamin B12, vitamin C compounds, vitamin E group.
These components can be used alone or in combination of two or more.
Specifically, the following components can be exemplified.

Examples of vitamins include retinol derivatives such as retinol and retinol acetate, retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, vitamin A oil, vitamin A fatty acid ester, d-δ-tocopheryl retinoate, α Vitamins A such as -tocopheryl retinoate and β-tocopheryl retinoate, provitamins A such as β-carotene, α-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthin, echinone, d -Vitamin E such as α-tocopherol, d-α-tocopherol acetate, dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, riboflavin, flavin Mononucleotide Vitamin B2 such as flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5'-phosphate, riboflavin tetranicotinate, nicotinic acid such as methyl nicotinate, nicotinic acid, nicotinamide, Ascorbic acid stearate, L-ascorbyl dipalmitate, ascorbyl tetraisopalmitate, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, magnesium ascorbate phosphate Vitamin C such as ascorbic acid sodium phosphate, ascorbic acid glucoside, methyl hesperidin, ergocalciferol, Vitamin D such as cholecalciferol, vitamin K such as phylloquinone, 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, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate Vitamin B1 such as acid ester monophosphate, vitamin B6 such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-phosphate pyridoxal, pyridoxamine hydrochloride, cyanocobalamin, Vitamin B12 such as loxocobalamin and deoxyadenosylcobalamin, folic acid such as folic acid and pteroylglutamic acid, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-panthecin, D-panthetin, coenzyme A And pantothenic acids such as pantothenyl ethyl ether, biotins such as biotin and bioticin, and vitamin-like agents such as carnitine, ferulic acid, α-lipoic acid and orotic acid.
Among them, preferably vitamin A oil, vitamin A such as d-δ-tocopheryl retinoate, vitamin B12 such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, ascorbyl tetraisopalmitate, ascorbic acid, ascorbic acid glucoside, etc. Vitamins such as d-α-tocopherol, d-α-tocopherol acetate, dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc. E, particularly preferably vitamin A oil, vitamin A such as d-δ-tocopheryl retinoate, vitamin B12 such as cyanocobalamin, ascorbyl tetraisopalmitate, ascorbic acid, ascorbic acid glucoside, etc. Vitamin E such as vitamin C, d-α-tocopherol acetate, and dl-α-tocopherol acetate.

  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.

  Whitening agents include placenta, arbutin, cysteine, ellagic acid, kojic acid, phytic acid, lucinol, hydroquinone; Iris (Iris), almond, aloe, ginkgo, oolong tea, ages, ogon, oulen, hypericum, licorice, seaweed, cuckoo , 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, miconazole nitrate, econazole nitrate, oxyconazole nitrate, bifonazole, thioconazole, ketoconazole, tolnaphthalate, tolcyclate, lilanaphthalate, cyclopyroxolamine Exalamide, 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.

  Examples of slimming agents include caffeine, aminophylline, theophylline, oxtriphyrin, daphyrin, diisobutylaminobenzoyloxypropyltheophylline, theobromine, diprofilin, proxyphylline, pentoxifylline and other xanthines, capsaicin, etc. , Capsaicin.

  The amount of the slimming 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.

  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, 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, urea, pyrrolidone carboxylic Natural moisturizing factors such as sodium acid, chamomile extract, aloe extract, aloe vera extract, hamamelis extract, rosemary extract, thyme extract, tea extract, perilla extract, etc.

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 smoothen skin, keep lips healthy, moisturize skin and lips, protect skin and lips, prevent dryness, moistness, cracks, bruises, 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.

  Surfactants: 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 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 xylene (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene (20) sorbitan (polysorbate 80) monooleate, 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 hyaluronic acid, a hyaluronic acid derivative or a salt thereof contained in an external preparation for skin. In the method of the present invention, promotion of percutaneous absorption of a topical skin preparation containing hyaluronic acid, a hyaluronic acid derivative or a salt thereof can be achieved by containing a phospholipid and a glycol ether.
In the method of the present invention, the phospholipid, glycol ether, hyaluronic acid, hyaluronic acid derivative or salt thereof, the blending amount thereof, the blending ratio of phospholipid and glycol ether are the same as those used in the above-mentioned external preparation for skin. .

  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
According to the formulation shown in Table 1, a vertical Franz cell (with a radius of 0.75 cm) was prepared for a preparation prepared by dissolving phospholipid in glycol ether, mixing warm purified water, a copolymer previously swollen with water, and sodium hyaluronate. ) Put 10 ml of phosphate buffer solution on the reservoir side of the hairless mouse (strain: HR-1, 7 weeks old, male) after removing all the fat skin between the cells and testing on the donor side 1 g of drug was added. 24 hours after the addition of the test drug, the entire skin was removed from the cell, the stratum corneum surface was washed with purified water and acetone, the entire skin was homogenized and extracted with purified water, and a hyaluronic acid measurement kit (Seikagaku Corporation) Was used to quantify sodium hyaluronate. In addition, 1 g of purified water was added to the donor side of the cell and the test was performed in the same manner. The amount of sodium hyaluronate present from the beginning in the skin of all layers was quantified, and the permeation amount of sodium hyaluronate as a test drug was calculated.
The results are shown in Table 1.

Even Comparative Example 1 containing ethoxydiglycol permeates more than the amount of hyaluronic acid originally present in the skin, and in Example 1 containing soy lecithin, it penetrates three times the initial amount. I found out that This indicates that hyaluronic acid can penetrate into the skin by using the present invention, although hyaluronic acid is said not to penetrate into the skin.
Thus, Example 1 is an external preparation for skin excellent in transdermal absorbability, and is particularly useful because it can sufficiently expect the effect of sodium hyaluronate.
Therefore, high penetration of hyaluronic acid, hyaluronic acid derivatives or salts thereof into the skin can be expected to have a high moisturizing effect and an anti-wrinkle effect that gives skin tension and elasticity.

The formulation examples are given below.
According to the formulation shown in Table 2, phospholipids are dissolved in glycol ether, heated purified water, carboxyvinyl polymer swollen with water and sodium hyaluronate are mixed, and triethanolamine is added to prepare a skin external preparation. did.
In all Examples shown in Table 2, the transdermal absorbability of the blended sodium hyaluronate was excellent.

Claims (5)

A skin external preparation containing (A) phospholipid, (B) glycol ether and (C) hyaluronic acid, a hyaluronic acid derivative or a salt thereof. 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.