JP7690289B2 - Skin penetration enhancer - Google Patents

Description

The present invention relates to a skin penetration enhancer that can enhance the penetration of a physiologically active substance into the skin.

Medicines, quasi-drugs, cosmetics, etc. that contain skin-active substances such as skin whitening agents, anti-aging agents, blood circulation promoters, vitamins, amino acids, wound healing promoters, irritation relievers, painkillers, cell activators, enzyme components, etc., usually contain skin penetration enhancers to promote the penetration of the contained biologically active substances into the skin.

Examples of such skin penetration enhancers include a mixture of 1,2-octanediol and 1,2-pentanediol and/or 1,2-hexanediol described in Patent Document 1, 3-methyl-1,3-butanediol described in Patent Document 2, a lipopeptide compound or a salt thereof described in Patent Document 3, and a sugar-modified linear silicone described in Patent Document 4. However, even with these penetration enhancers, the effect of enhancing the penetration of physiologically active substances into the skin is insufficient, and there is still a demand on the market for superior skin penetration enhancers.

JP 2006-045140 A JP 2019-137695 A International Publication No. 2012/096276 JP 2010-189532 A

Therefore, the present invention aims to provide a novel skin penetration enhancer that can enhance the penetration of biologically active substances into the skin.

The inventors conducted extensive research and discovered that a specific compound can enhance the penetration of a physiologically active substance into the skin, leading to the present invention. That is, the present invention is a skin penetration enhancer for a physiologically active substance, which comprises a compound represented by the following chemical formula (1).

The present invention makes it possible to enhance the penetration of a physiologically active substance into the skin by using a compound represented by chemical formula (1) in combination with the physiologically active substance.

The present invention will be described in detail below. The skin penetration enhancer of the present invention is a skin penetration enhancer for a physiologically active substance, which comprises a compound represented by the following chemical formula (1).

The method for producing the compound represented by chemical formula (1) is not particularly limited, and any known method can be used. Examples of such methods include a method of subjecting a cycloalkanol and glycerin to a dehydration condensation reaction, a method of subjecting cyclohexyl chloride or cyclohexyl bromide and glycerin to a dehalogenation reaction, a method of subjecting cyclohexanol and 1-chloro-2,3-propanediol to a dehydrochlorination reaction, a method of reacting cyclohexanol with epichlorohydrin and then ring-opening the resulting cyclohexyl glycidyl ether, a method of reacting cyclohexanol with glycidol and then ring-opening the resulting cyclohexyl glycidyl ether, a method of subjecting cyclohexanol and allyl chloride to a dehydrochlorination reaction, followed by oxidation with hydrogen peroxide or the like to ring-open the resulting cyclohexyl glycidyl ether, and the like. In addition, in the case of a reaction using glycerin, a highly pure product can be obtained by carrying out the above reaction using glycerin partially esterified with a lower fatty acid and then saponifying the product after the reaction to remove the fatty acid, or by carrying out the above reaction using a partially ketalized product of glycerin and then removing the ketal after the reaction. Among these, the method of reacting cyclohexanol with epichlorohydrin and then ring-opening the resulting cyclohexyl glycidyl ether is preferred because it is inexpensive and easy to produce industrially.

The physiologically active substances that can be promoted by the skin permeation enhancer of the present invention to permeate into the skin are not particularly limited as long as they have effective physiological activity on the skin, such as known whitening agents, anti-aging agents, blood circulation enhancers, anti-inflammatory agents, wound healing enhancers, analgesics, cell activators, vitamins, amino acids, enzyme components, etc. In the present invention, the concept of skin includes not only the body surfaces such as the face, head, neck, chest, abdomen, waist, back, but also mucous membranes such as the oral mucosa, nasal mucosa, and conjunctival mucosa.

In the present invention, the physiologically active substances are specifically ascorbic acid, its salts or derivatives (sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl 2-glucoside, etc.), hydroquinone derivatives such as arbutin, tranexamic acid and its salts or derivatives, kojic acid and its salts or derivatives, placenta extract, skin whitening agents such as glutathione, coral grass extract, rice leaf extract, eggplant extract, euterpe gracilis extract, eelgrass extract, rice extract, germinated rice extract, fermented germinated rice, black soybean extract, gentian extract, licorice extract, carrot extract, aloe extract, kelp extract, Ulva pertusa extract, beech extract, Aloe arborescens extract, Rose wax extract, ginkgo extract, horsetail extract, safflower extract, ginseng extract, elderberry extract, silverleaf extract, astragalus extract, mango extract, mangosteen extract anti-aging agents such as collagen, yeast extract, animal-derived collagen, fish-derived collagen, elastin, intercellular lipids, glycyrrhizic acid, t-cycloamino acid derivatives, diisopropylamine dichloroacetate, gamma-amino-beta-hydroxybutyric acid, coenzyme Q-10, alpha-lipoic acid, ergothioneine, allantoin, diisopropylamine dichloroacetate, eggshell membrane extract protein, potassium deoxyribonucleic acid, pollen extract, and salts or derivatives thereof; zingerone, cantharides tincture, ichthammol, tannic acid, alpha-borneol, inositol hexanicotinate, cyclandelate, cinnarizine, tolazoline, acetylcholine, verapamil, nonylic acid valenylamide, Swertia japonica extract, cepharanthine, oryzanol, capsicum tincture, saokyo tincture, cantharides tincture, nicotinic acid benzyl ester, nicotinic acid tocopherol, nicotinic acid beta -butoxyethyl esters and other blood circulation promoters; glycyrrhizinic acid, glycyrrhetinic acid, allantoin, azulenes, salicylic acid, hinokitiol, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, tranexamic acid, thiotaurine, hypotaurine, salts thereof or derivatives thereof and other anti-inflammatory agents; retinol, fusidic acid, and derivatives thereof, wound healing promoters; glycol salicylate; Painkillers such as methyl salicylate, aminobenzoic acid esters, camphor, pramoxine, lidocaine, capsaicin, and isobutylpropanoic phenolic acid, DNA, placenta extract, chlorella extract, bilberry leaf extract, aloe extract, pueraria root extract, chlorella extract, placenta extract, sugar maple sap, royal jelly, yeast extract, mucopolysaccharide fluid, Belamcanda chinensis extract, soybean extract, whey, photosensitizers, cholesterol These include cell activators such as vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, and salts or derivatives thereof; amino acids such as aliphatic amino acids, branched-chain amino acids, hydroxyamino acids, sulfur-containing amino acids, amide amino acids, imino acids, aromatic amino acids, aspartic acid, glutamic acid, lysine, arginine, histidine, hydroxyproline, hydroxylysine, tranexamic acid, dihydroxyphenylalanine, theanine, γ-aminobutyric acid, β-alanine, sarcosine, citrulline, ornithine, ε-aminocaproic acid, and salts or derivatives thereof; and enzyme components such as trypsin, lysozyme chloride, chymotrypsin, semi-alkaline proteinase, serrapeptase, lipase, and hyaluronidase.

In the present invention, the physiologically active substance is preferably selected from ascorbic acid, its salts, or its derivatives, and more preferably an ascorbyl phosphate salt such as sodium ascorbyl phosphate or magnesium ascorbyl phosphate is used. That is, in the present invention, the compound represented by chemical formula (1) is preferably used as a skin penetration enhancer that enhances the penetration of ascorbic acid, its salts, or its derivatives into the skin, and more preferably as a skin penetration enhancer that enhances the penetration of ascorbyl phosphate salts such as sodium ascorbyl phosphate or magnesium ascorbyl phosphate into the skin.

The skin penetration enhancer of the present invention can be used by being added to, for example, cosmetics, quasi-drugs, pharmaceuticals, and the like.
Here, "cosmetics,""quasi-drugs," and "drugs" are defined as equivalent to "cosmetics,""quasi-drugs," and "drugs" in Article 2 of the "Act on Ensuring Quality, Efficacy, and Safety of Pharmaceuticals, Medical Devices, etc." in Japan.
Furthermore, the "quasi-drugs" and "drugs" of the present invention can be used in humans and non-human animals (dogs, cats, etc.).

The dosage forms of the cosmetics, quasi-drugs, medicines, etc. at this time are not particularly limited, and can be aqueous solutions, solubilized systems, emulsions, powders, powder dispersions, oils, gels, ointments, aerosols, etc. In the present invention, the skin penetration enhancer consisting of a compound represented by chemical formula (1) is added to cosmetics, quasi-drugs, or medicines containing at least one physiologically active substance, thereby promoting the penetration of the physiologically active substance in the cosmetics, quasi-drugs, or medicines into the skin. Among these, from the viewpoint of the effect of promoting the penetration of the physiologically active substance into the skin, it is preferable to add it to cosmetics, quasi-drugs, and medicines such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, and packs. At this time, from the viewpoint of the effect of the present invention, it is preferable to use cosmetics, quasi-drugs, or medicines containing ascorbic acid and its salts or derivatives as the physiologically active substance, and it is preferable to use cosmetics, quasi-drugs, or medicines containing ascorbyl phosphate salts such as sodium ascorbyl phosphate and magnesium ascorbyl phosphate as the physiologically active substance.

From the viewpoint of the effect of promoting the penetration of a physiologically active substance into the skin, the skin penetration enhancer of the present invention preferably contains a compound represented by chemical formula (1) in an amount of 0.01 to 20% by mass, more preferably 0.02 to 10.0% by mass, and even more preferably 0.03 to 5.0% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical.

The cosmetic, quasi-drug, or pharmaceutical of the present invention is a cosmetic, quasi-drug, or pharmaceutical that contains a skin penetration enhancer consisting of a compound represented by chemical formula (1) and a physiologically active substance. Examples of the physiologically active substance in this case include the physiologically active substances described above. From the viewpoint of the effect of promoting the penetration of a physiologically active substance into the skin by the skin penetration enhancer consisting of a compound represented by chemical formula (1), it is preferable that the content of the skin penetration enhancer consisting of a compound represented by chemical formula (1) in the cosmetic, quasi-drug, or pharmaceutical is 0.01% by mass to 20% by mass relative to the total amount of the cosmetic, quasi-drug, or pharmaceutical, and the content of the physiologically active substance is 0.001% by mass to 10% by mass relative to the total amount of the cosmetic, quasi-drug, or pharmaceutical. In this case, when the cosmetic, quasi-drug, or pharmaceutical contains two or more physiologically active substances, the content of the physiologically active substance in the cosmetic, quasi-drug, or pharmaceutical represents the total amount of the contents of each physiologically active substance. The content of the skin penetration enhancer consisting of the compound represented by chemical formula (1) in the cosmetic, quasi-drug, or pharmaceutical is more preferably 0.02 to 10.0% by mass, and even more preferably 0.03 to 5.0% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical. The content of the physiologically active substance in the cosmetic, quasi-drug, or pharmaceutical is more preferably 0.01 to 5% by mass, and even more preferably 0.1 to 3% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical.

The content ratio of the skin penetration enhancer consisting of a compound represented by chemical formula (1) to the physiologically active substance in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not limited and can be adjusted appropriately depending on the purpose. However, from the viewpoint of the effect of promoting the penetration of the physiologically active substance into the skin by the skin penetration enhancer consisting of a compound represented by chemical formula (1), the content ratio of the skin penetration enhancer consisting of a compound represented by chemical formula (1) to the physiologically active substance (the total amount when two or more types are used) in the cosmetic, quasi-drug, or pharmaceutical product is preferably 1:99 to 99.9:0.1 by mass, and more preferably 10:90 to 99:1.

In the present invention, the cosmetic, quasi-drug, or pharmaceutical of the present invention preferably contains one or more selected from ascorbic acid, its salts, or its derivatives as a physiologically active substance, and more preferably contains an ascorbyl phosphate such as sodium ascorbyl phosphate or magnesium ascorbyl phosphate as a physiologically active substance. Specifically, it is even more preferable that the cosmetic, quasi-drug, or pharmaceutical contains an ascorbyl phosphate such as sodium ascorbyl phosphate or magnesium ascorbyl phosphate as a physiologically active substance in an amount of 0.01% to 5% by mass, and particularly preferably 0.1 to 3% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical. In this case, the ratio of the content of the skin penetration enhancer consisting of the compound represented by chemical formula (1) in the cosmetic, quasi-drug, or pharmaceutical to the content of the ascorbyl phosphate such as sodium ascorbyl phosphate or magnesium ascorbyl phosphate as a physiologically active substance is preferably 1:99 to 99.9:0.1 by mass, and more preferably 10:90 to 99:1.

The cosmetic, quasi-drug, or pharmaceutical product of the present invention may further contain components used for each application to improve or modify various properties (solubility, dispersibility, stability, usability, application, permeability, moisture retention, safety, design, optical properties, fragrance, etc.) during storage, during use, and after use, depending on the purpose and application of use. Examples of such components include solvents, cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants, hydrocarbon oils, silicone oils, ester oils, higher alcohols, polyhydric alcohols, sugars and their derivatives, moisturizers, preservatives, sequestering agents, pH adjusters, fragrances, etc., and one or more of these may be contained.

Examples of the solvent include ethanol, isopropyl alcohol, butanol, isobutyl alcohol, acetone, ethyl acetate, ethylene glycol monoethyl ether, water, etc., and one or more of these can be used. The content of the solvent in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 10% by mass to 99% by mass, and more preferably 20% by mass to 95% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of cationic surfactants include lauryl trimethyl ammonium chloride, cetyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, alkyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, stearyl trimethyl ammonium saccharin, cetyl trimethyl ammonium saccharin, behenyl trimethyl ammonium methyl sulfate, behenyl dimethyl amine, behenic acid diethyl amino ethyl amide, behenic acid dimethyl amino propyl amide, behenic acid dimethyl amino ethyl amide, stearyl dimethyl amine, palmitoxy propyl dimethyl amine, stearoxy propyl dimethyl amine, etc., and one or more of these can be used. The content of the cationic surfactant in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.001% by mass to 10% by mass, and more preferably 0.01% by mass to 5% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of anionic surfactants include alkyl ether sulfates, alkyl sulfates, alkyl ether sulfate ester salts, alkenyl ether sulfates, alkenyl sulfates, olefin sulfonates, alkanesulfonates, saturated or unsaturated fatty acid salts, alkyl or alkenyl ether carboxylates, α-sulfonic fatty acid salts, N-acylamino acid surfactants, mono- or diester phosphate surfactants, sulfosuccinates, N-alkyloylmethyl taurine salts, and derivatives thereof, and one or more of these can be used. Specific examples of counter ions of anionic groups include sodium ions, potassium ions, triethanolamine, and the like, and one or more of these can be used. The content of the anionic surfactant in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.001% by mass to 10% by mass, and more preferably 0.01% by mass to 5% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as coconut oil fatty acid amidopropyl dimethyl acetate betaine, lauryl dimethyl amino acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxymethyl imidazolinium betaine, lauryl hydroxysulfobetaine, lauroyl amidoethyl hydroxyethyl carboxymethyl betaine, and metal salts of hydroxypropyl phosphate, amino acid-type amphoteric surfactants such as metal salts of β-lauryl aminopropionic acid, sulfate ester-type amphoteric surfactants, and sulfonic acid-type amphoteric surfactants, and one or more of these may be used. The content of the amphoteric surfactant in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.001% by mass to 10% by mass, and more preferably 0.01% by mass to 5% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of nonionic surfactants include POE cetyl ether (ceteth), POE stearyl ether (steareth), POE behenyl ether, POE oleyl ether (oleth), POE lauryl ether (laureth), POE octyldodecyl ether, POE hexyldecyl ether, POE isostearyl ether, POE nonylphenyl ether, POE octylphenyl ether, POE polyoxypropylene cetyl ether, POE polyoxypropylene decyltetradecyl ether, POE sorbitan monooleate, POE sorbitan monostearate, POE sorbitan monopalmitate, POE sorbitan monolaurate, POE sorbitan trioleate, POE glycerin monostearate, POE glycerin monomyristate, POE sorbitan tetraoleate, and POE hexastearate. Examples of the glyceryl monostearate include OE sorbitol, POE sorbitol monolaurate, POE sorbitol beeswax, polyethylene glycol monooleate, polyethylene glycol monostearate, polyethylene glycol monolaurate, lipophilic glycerin monooleate, lipophilic glycerin monostearate, self-emulsifying glycerin monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sucrose fatty acid esters, decaglyceryl monolaurate, decaglyceryl monostearate, decaglyceryl monooleate, decaglyceryl monomyristate, alkyl glucoside, POE methyl glucoside, and POE methyl glucoside dioleate. One or more of these may be used. The content of the nonionic surfactant in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.001% by mass to 10% by mass, and more preferably 0.01% by mass to 5% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of hydrocarbon oils include liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum, polyisobutene, polyisoprene, isodecane, isododecane, isohexadecane, normal pentane, isopentane, normal hexane, isohexane, kerosene, decalin, tetralin, microcrystalline wax, etc., and one or more of these can be used. The content of the hydrocarbon oil in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.1% by mass to 50% by mass, and more preferably 0.5% by mass to 30% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of silicone oils include linear silicone oils such as dimethylpolysiloxane, diphenylpolysiloxane, diphenylsiloxyphenyltrimethicone, and octamethyltrisiloxane; cyclic silicone oils such as decamethylcyclotetrasiloxane, dodecamethylcyclotetrasiloxane, octamethylcyclotetrasiloxane, cyclopentasiloxane, dodecamethylcyclopentasiloxane, octamethylcyclopentasiloxane, decamethylcyclohexasiloxane, dodecamethylcyclohexasiloxane, and octamethylcyclohexasiloxane; and modified silicone oils such as alkyl-modified dimethylpolysiloxane, polyether-modified dimethylpolysiloxane, fatty acid-modified polysiloxane, higher alcohol-modified polysiloxane, amino-modified polysiloxane, and fluorine-modified polysiloxane. One or more of these can be used. The content of silicone oil in the cosmetic, quasi-drug, or pharmaceutical of the present invention is not particularly limited, but for example, it is preferably 0.1% by mass to 50% by mass, and more preferably 0.5% by mass to 30% by mass, relative to the total amount of the cosmetic, quasi-drug, or pharmaceutical.

Examples of ester oils include ethyl acetate, butyl acetate, hexyl acetate, decyl acetate, butyl propionate, cetyl octanoate, hexyldecyl dimethyloctanoate, isononyl isononanoate, isotridecyl isononanoate, ethyl laurate, hexyl laurate, myristyl myristate, isopropyl myristate, isopropyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, decyl oleate, oleyl oleate, octyldodecyl oleate, isocetyl stearate, glycerin stearate, butyl stearate, ethylhexyl hydroxystearate, ethylene glycol stearate, oxystearyl stearate, glyceryl ... Examples of the ester oil include synthetic ester oils such as octyl ester, diethyl phthalate, triethyl citrate, 2-ethylhexyl succinate, diisopropyl sebacate, di-2-ethylhexyl sebacate, cetyl lactate, myristyl lactate, diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, cetyl ethylhexanoate, triethylhexanoin, polyglyceryl-2 triisostearate, neopentyl glycol dioctanoate, neopentyl glycol dicaprate, and pentaerythrityl tetraisostearate; and animal and vegetable ester oils such as lanolin, mink oil, cacao butter, coconut oil, palm kernel oil, camellia oil, sesame oil, castor oil, and olive oil. One or more of these may be used. The content of ester oil in the cosmetic, quasi-drug, or pharmaceutical of the present invention is not particularly limited, but for example, it is preferably 0.1% by mass to 50% by mass, and more preferably 0.5% by mass to 30% by mass, relative to the total amount of the cosmetic, quasi-drug, or pharmaceutical.

Examples of higher alcohols include cetyl alcohol, isostearyl alcohol, lauryl alcohol, hexadecyl alcohol, octyldodecanol, etc., and one or more of these can be used. The content of higher alcohol in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.1% by mass to 30% by mass, and more preferably 0.5% by mass to 20% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of polyhydric alcohols include ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, highly polymerized polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, isoprene glycol, 1,3-butylene glycol, glycerin, diglycerin, polyglycerin, etc., and one or more of these may be used. The content of the polyhydric alcohol in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.1% by mass to 30% by mass, and more preferably 0.5% by mass to 20% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.
However, the polyhydric alcohol does not include the compound represented by the chemical formula (1).

Examples of sugars and their derivatives include xylose, D-glucose, sucrose, trehalose, fructose, maltose, mannose, cyclodextrin, β-glucan, chitin, chitosan, pectin, arabinogalactan, dextrin, dextran, glucosylethyl methacrylate polymer or copolymer, and one or more of these can be used. The content of sugars and their derivatives in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.001% by mass to 10% by mass, and more preferably 0.01% by mass to 5% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of moisturizing agents include polyethylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, caronic acid, atelocollagen, cholesteryl-12-hydroxystearate, sodium lactate, bile salts, dl-pyrrolidone carboxylate, short-chain soluble collagen, Rosa roxburghii extract, Achillea millefolium extract, and Melilot extract. The content of the moisturizing agent in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.01% to 30% by mass, and more preferably 0.1% to 20% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of preservatives include benzoic acid, salicylic acid, carbolic acid, sorbic acid, potassium sorbate, paraoxybenzoic acid esters, sodium benzoate, parachlormetacresol, hexachlorophene, benzalkonium chloride, chlorhexidine chloride, trichlorocarbanilide, photosensitizers, chlorphenesin, phenoxyethanol, methylparaben, ethylparaben, butylparaben, caprylyl glycol, resorcinol, triclosan, isopropylmethylphenol (IPMP), zinc bis(2-pyridylthio-1-oxide), alkyldiaminoethylglycine hydrochloride, piroctone olamine, hinokitiol, vitamin B6 hydrochloride (pyridoxine hydrochloride), phenol, lysozyme chloride, cetylpyridinium chloride (CPC), etc. The content of the preservative in the cosmetic, quasi-drug, or pharmaceutical of the present invention is not particularly limited, but is preferably 0.01% by mass to 10% by mass, and more preferably 0.1% by mass to 5% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical.

Examples of sequestering agents include 1-hydroxyethane-1,1-diphosphonic acid, 1-hydroxyethane-1,1-diphosphonic acid tetrasodium salt, disodium edetate, trisodium edetate, tetrasodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, succinic acid, edetic acid, trisodium ethylenediaminehydroxyethyltriacetate, and the like. The content of the sequestering agent in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.001% by mass to 5% by mass, and more preferably 0.01% by mass to 3% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

Examples of pH adjusters include citric acid, glycolic acid, succinic acid, tartaric acid, lactic acid, malic acid, levulinic acid, acetic acid, butyric acid, valeric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, phosphoric acid, pyrophosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, etc., and one or more of these can be used. The pH adjuster in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is preferably added so that the pH of the cosmetic, quasi-drug, or pharmaceutical product is 3.0 to 13.0.

Fragrances include, for example, acetyl cedrene, allyl amyl glycolate, β-ionone, isobutylquinoline, iris oil, irone, indole, undecanal, undecenal, γ-undecalactone, estragole, eugenol, oakmoss, opoponax resinoid, orange oil, eugenol, aurantiol, galacsolid, carvacrol, camphor, carrot seed oil, clove oil, methyl cinnamate, geraniol, geraniol, Nitrile, Isobornyl Acetate, Geranyl Acetate, Dimethylbenzylcarbinyl Acetate, Styraryl Acetate, Cedryl Acetate, Terpinel Acetate, Vetiveryl Acetate, Benzyl Acetate, Linalyl Acetate, Isopentyl Salicylate, Benzyl Salicylate, Sandalwood Oil, Santalol, Cyclamen Aldehyde, Cyclopentadecanolide, Methyl Dihydrojasmonate, Dihydromyrcenol, Jasmine Absolute, Jasmine Lactone, Citral, Citronenol , citronellal, cinnamon bark oil, styrax resinoids, cedarwood oil, cedrene, cedrol, celery seed oil, thyme oil, damascone, damascenone, thymol, tuberose absolute, terpineol, gamma-terpinene, tripral, vanilla absolute, vanillin, basil oil, patchouli oil, hydroxycitronellal, alpha-pinene, piperitone, balsam of Peru, vetiver oil, vetiverol, peppermint oil, pepper oil, heliotropic Examples of the fragrance include tropine, bergamot oil, benzyl benzoate, borneol, myrrhizinoid, musk ketone, methylnonylacetaldehyde, γ-methylionone, menthol, L-menthol, L-menthone, eucalyptus oil, β-ionone, lime oil, lavender oil, D-limonene, linalool, lyral, lilial, lemon oil, rose absolute, rose oxide, rose oil, and rosemary oil, and one or more of these can be used. The content of the fragrance in the cosmetic, quasi-drug, or pharmaceutical product of the present invention is not particularly limited, but is preferably 0.001% by mass to 5% by mass, and more preferably 0.01% by mass to 3% by mass, based on the total amount of the cosmetic, quasi-drug, or pharmaceutical product.

The present invention will be specifically explained below with reference to examples. In the following examples, percentages are by weight unless otherwise specified.

<Preparation of test solutions 1 to 3>
Test solution 1 was prepared by adding the compound represented by chemical formula (1) as a skin permeation enhancer and magnesium ascorbyl phosphate, a skin whitening agent as a physiologically active substance, to phosphate buffered saline such that the content of the compound represented by chemical formula (1) in the test solution was 2% by mass and the content of magnesium ascorbyl phosphate in the test solution was 1% by mass. Similarly, test solution 2 was prepared by adding 1,2-hexanediol as a skin permeation enhancer of the comparative example and magnesium ascorbyl phosphate to phosphate buffered saline such that the content of 1,2-hexanediol in the test solution was 2% by mass and the content of magnesium ascorbyl phosphate in the test solution was 1% by mass. Similarly, test solution 3 was prepared by adding magnesium ascorbyl phosphate to phosphate buffered saline such that the content of magnesium ascorbyl phosphate in the test solution was 1% by mass.

<Evaluation of skin penetration enhancement effect>
After adding 2 ml of phosphate buffered saline as a receptor to each well of a 12-well plate, a three-dimensional cultured epidermal model (EPISKIN, EpiSkin (registered trademark)-LM) that had been acclimatized overnight in a medium was placed in each well. Then, 0.15 ml of each of test solutions 1 to 3 was dropped onto the stratum corneum side of the epidermal model, and the model was allowed to stand at 37°C. After 3 hours and 6 hours, 0.20 ml of receiver solution was collected and 0.20 ml of phosphate buffered saline was added. After 9 hours, 0.20 ml of receiver solution was similarly collected, and the content of magnesium ascorbyl phosphate in each receiver solution was quantified by HPLC, to calculate the amount of magnesium ascorbyl phosphate permeation (μg) after each time of standing. The above test was performed three times, and the average value of the content of magnesium ascorbyl phosphate in each receiver solution for each test solution and standing time was taken as the amount of magnesium ascorbyl phosphate permeation. The test results are shown in Table 1. In Table 1, the test example using test solution 1 is denoted as Example 1, the test example using test solution 2 is denoted as Comparative Example 1, and the test example using test solution 3 is denoted as Comparative Example 2.

These results show that the compound represented by chemical formula (1) significantly promoted the penetration of magnesium ascorbyl phosphate into the skin. On the other hand, in the case where 1,2-hexanediol was used as the penetration enhancer, the amount of magnesium ascorbyl phosphate permeated was slightly higher than when no skin penetration enhancer was added, but no significant difference was observed in the amount of permeation. Therefore, it can be seen that the skin penetration enhancer consisting of the compound represented by chemical formula (1) can promote the penetration of biologically active substances in cosmetics, quasi-drugs, or pharmaceuticals into the skin.

Claims (2)

A skin penetration enhancer for ascorbic acid or a salt thereof (excluding a composition for forming a lipid membrane structure containing a hydrogenated phospholipid having an acid value of 5 mgKOH/g or more), comprising a compound represented by the following chemical formula (1):

A cosmetic, quasi-drug, or pharmaceutical product (excluding cosmetics, quasi-drugs, and pharmaceutical products containing hydrogenated phospholipids having an acid value of 5 mg KOH/g or more) comprising the skin penetration enhancer according to claim 1 and ascorbic acid or a salt thereof .