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    • 专利摘要:
    An object of the present invention is to improve the skin whitening effect and skin darkening prevention effect, to provide a safe and stable topical for dermatology. For this purpose, 4-hydroxyphenyl-α-D-glucopyranoside is treated with ascorbic acid and its derivatives, crude drugs and their extracts, hydroxycarboxylic acid and its salts, fat-soluble glycyrrhiza extracts. Gentian extracts, phenol derivatives and salts thereof, placental extracts, kojic acid and derivatives thereof, glucosamine and derivatives thereof, azelaic acid and derivatives thereof, retinol and derivatives thereof, pyridoxine and derivatives thereof, tocopherol and And derivatives thereof, chitosan and its degradation products, caffeic acid derivatives, hydroxycinnamate and derivatives thereof, Umbelliferae plant extracts, mycelial cultures and their extracts, plant leaves and their extracts.
    公开号:KR20030020289A
    申请号:KR1020027016089
    申请日:2001-06-01
    公开日:2003-03-08
    发明作者:구리키다카시；나카에다카시；니시무라다카히사；나카야마히로키
    申请人:펜타팜아게；에자끼글리코가부시끼가이샤；
    IPC主号:
    专利说明:

    Topical agent for dermatology containing 4-hydroxyphenyl-alpha-D-glucopyranoside {TOPICAL AGENT FOR DERMATOLOGICAL USE CONTAINING 4-HYDROXYPHENYL-ALPHA-D-GLUCOPYRANOSIDE}
    [2] Various melanogenesis inhibitors have been used to whiten or prevent skin blackening and to prevent or alleviate skin problems such as blemishes and freckles caused by excessive exposure to ultraviolet light. Such formulations include 1,4-dihydroxybenzene, β-arbutin, vitamin C and derivatives thereof, and kojic acid.
    [3] However, vitamin C, 1,4-dihydroxybenzene and kojic acid are extremely unstable against heat and oxidation in water. Therefore, when added to dermatological topical agents, these compounds decompose over time resulting in pigmentation. Their derivatives, such as phosphate-ascorbyl magnesium and β-arbutin, obtained by β-linking glucose to one of the hydroxy groups of 1,4-dihydroxybenzene are more stable than their parent compounds for heat and oxidation, Inevitably, it is not satisfactory in terms of efficacy.
    [4] In order to overcome this problem, various inventions have been made and patented, and for example, in addition to β-arbutin, synergistic effects can be obtained by containing substances having skin whitening effects such as UV absorbers, anti-inflammatory agents and placental extracts. Cosmetics (e.g., Toku-kai-hei 5-186324 Patent Publication), and topical dermatological agents (Toku-kai-) containing pentetin-S-sulfonic acid or its salts and preventing degradation and pigmentation over time hei 5-58926 patent publication). However, these substances cannot be added to cosmetics in an amount sufficient to obtain a clinically significant synergistic effect due to the problems associated with the discomfort and safety encountered upon skin contact.
    [5] The inventors have studied substances that are stable when used in dermatological topical agents, and are safer and more effective than conventional compounds. In this study, the inventors found 4-hydroxyphenyl-α-D-glucopyranoside as a substance meeting this need, and applied for a patent (Tokugan 2000-43366). However, in order to expect clinically significant whitening effects, their efficacy had to be further improved.
    [6] This patent describes amylase X-23 as an enzyme that transfers sugars through α-bonds to phenol groups of 1,4-dihydroxy-benzene.
    [1] The present invention has a skin whitening effect or a skin darkening prevention effect, prevents or alleviates liver spots, freckles, and the like, and is a topical agent for dermatology that exhibits desirable formulation properties in terms of safety and stability. It is about.
    [7] As described above, various attempts have been made to improve the skin whitening effect, but nothing is satisfactory at all. The present invention uses 4-hydroxyphenyl-α-D-glucopyranoside, which exhibits a significant skin whitening effect even when used alone, and enhances the effect of producing topical dermatological agents that are more effective than conventional products. Add other substances to strengthen.
    [8] The present inventors conducted research to solve the above problems, and combined with 4-hydroxyphenyl-α-D-glucopyranoside and a specific component (sometimes referred to herein as "auxiliary component"), Even in the case of the present invention, it was found that the effect of 4-hydroxyphenyl-α-D-gluco-pyranoside, which shows a superior skin whitening effect than the conventional products, was found to be remarkably improved.
    [9] The present invention relates to topical preparations for dermatology containing 4-hydroxyphenyl-α-D-glucopyranoside and at least one accessory ingredient selected from the following ingredients: ascorbic acid and its derivatives, crude drugs ) And their extracts, hydroxycarboxylic acids and salts thereof, fat-soluble glycyrrhiza extracts, gentian extracts, phenol derivatives and salts thereof, placental extracts, kojic acid and derivatives thereof, glucosamine and derivatives thereof, azelaic acid (azelaic acid) and its derivatives, retinol and its derivatives, pyridoxine and its derivatives, tocopherol and its derivatives, vitamin E-nicotinate, diisopropyl-amine-dichloroacetate, chitosan and its degradation products, caffeic acid derivatives, hydride Loxycinnamate and its derivatives, Umbelliferae plant extracts, mycelial cultures and their extracts, plant leaves and Their extracts, plant bark and extracts thereof, hinokithiol, ginseng extract, sulfur, crude sugar extract, molasses extract, mucopolysaccharide, tefrenone, nordihydroguaiaretic acid, UV absorber, γ-pyrone glycoside, hydroxy Salicylic acid glycosides, hydroxysalicylic acid fatty ester glycosides, biphenyl compounds, ceramides, substances having ceramide-like structures, ether compounds represented by the general formula R31-O- (XO) n-R32, wherein R31 and R32 Is the same or different straight chain, branched or cyclic alkyl group containing 1 to 12 carbon atoms, X is an alkylene group containing 1 to 12 carbon atoms, n is 0 or 1, R31, R32 and The number of synthetic carbon atoms in X is 10 to 32), pantothenic acid and derivatives thereof, sodium hydrogen sulfite, anti-inflammatory agents, allantoin and derivatives thereof, amino acids And derivatives thereof, amino ethyl compounds, alkylene diamine carboxylic acid derivatives, betaine derivatives, acyl methyl taurine, fibronectin, tyrosinase inhibitors, hederacosides and salts thereof, gymne saponins, beet saponins and salts thereof, ellagic acid-related compounds And their alkali metal salts, and resorcinol derivatives. The present invention also relates to a topical preparation for dermatology, wherein 4-hydroxyphenyl-α-D-glucopyranoside is obtained using α-amylase and the α-amylase is amylase X-23.
    [10] Auxiliaries under the present invention are whitening of 4-hydroxyphenyl-α-D-glucopyranoside when at least one of them is added to the dermatological topical with 4-hydroxyphenyl-α-D-glucopyranoside Increase the effect or stability. Examples of such adjuvants are provided below.
    [11] Various types of ascorbic acid, L-ascorbic acid, commonly referred to as vitamin C, promote cell regeneration, enzyme activity and collagen formation and reduce melanin due to their strong reducing effect. Ascorbic acid derivatives include ascorbate monoalkyl esters (e.g. ascorbate monostearate, ascorbate monopalmitate and ascorbate monooleate), ascorbate monoester derivatives (e.g. Corbate monophosphate esters and ascorbate-2-sulfate, ascorbate diester derivatives (eg, ascorbate distearate, ascorbate dipalmitate, ascorbate dioleate and ascorbate) Bait diphosphate esters), ascorbate trialkyl esters (eg, ascorbate tristearate, ascorbate tripalmitate and ascorbate trioleate), and ascorbate triester derivatives (eg Ascorbate triphosphate ester) It is hereinafter.
    [12] Efficacy is seen when these ingredients are added in a dermatological topical agent at a concentration of at least 0.01 w / w%. The upper limit of the content for these components is about 10%.
    [13] Useful crude drugs include the following, and their extracts can also be used: mulberry peel, peony root, scutellaria root, chamomile, Japanese angelica root, rosemary, geranium herb, rhododendron ( lithospermum roots, tea leaves, pueraria roots, clove, glyciriza, biwa, bitter orange peel, ginseng, sanzasi, opiopogon tubers, ginger, pine cones, magnolia bark, gambir ), Aloe, Marshmallow, Sawtooth Tree, Watercress, Cinchona, Comfrey, Scopolia rhizome, Swetia Herb and Yarrow (Achillea millefolium Linn) (Compositae). In the present invention, the herbal medicines and their extracts are fine powders obtained by pulverizing (and drying as necessary) the whole plants, roots, leaves, flowers, seeds and the like of the above-described herbal medicines, these substances are immersed in water and / or organic solvents, Extracts obtained by filtering the residue, fluids obtained by removing solvents from these extracts, and extracts or powder products thereof with or without solvents dissolved, dispersed or diluted with a suitable solvent or solubilizer.
    [14] The content of these substances in dermatological topical agents should be 0.001-20 w / w%, preferably 0.01-10 w / w%.
    [15] Hydroxycarboxylic acids include glycolic acid, lactic acid, maleic acid, tauric acid, citric acid, salicylic acid, mevalonic acid, and lactone mevalonate. These salts include metal salts such as Na, K and Mg, and organic salts such as triethanolami and 2-amino-2-methyl-1,3-propanediol.
    [16] The content of these components in dermatological topical agents should be 0.0001-5 w / w%, preferably 0.001-3 w / w%.
    [17] Lipid-soluble glycyrrhiza extract is used to convert perennial Glycyrrhizaglabra linne into lower monohydric alcohols such as methyl alcohol and ethyl alcohol, and fluid polyhydric such as glycerin, propylene glycol and 1,3-butylene glycol. Obtained by extraction with alcohol. As the production method, for example, any method of extraction using various suitable solvents at low temperature or room temperature or while heating may be used. The extraction is preferably carried out as follows: extraction with ethyl alcohol for 2-10 hours while heating; By filtration; The resulting extract is left to mature for 2 to 3 days; Filtrate again. The obtained extract can be condensed and dried as necessary after heating extraction. The fat-soluble glycyrrhiza extract thus obtained is a brown component with a unique smell. They can be used for a variety of purposes, but they can also be purified by deodorizing or decolorizing as long as their efficacy is not impaired. Purification can be carried out, for example, using activated carbon columns. In the purification, any method conventionally applied to the extract may be used.
    [18] Their content may vary between 0.0001 to 5% w / w%, preferably 0.001 to 3% w / w%, depending on the quality of the extract used and other factors.
    [19] Gentiana extract extracts the roots and rhizomes of the gentianaceae family, Gentian litea linne (Gentianaceae), from lower monohydric alcohols such as methyl alcohol and ethyl alcohol, and glycerin, propylene glycol and 1,3-butyl. It can be obtained by extraction with a fluid polyhydric alcohol such as lene glycol. As the production method, for example, any method of extraction using various suitable solvents at low temperature or room temperature or while heating may be used. The extraction is preferably carried out as follows: extraction with 50% 1.3-butylene glycol for 2-10 hours while heating; By filtration; The resulting extract is left to mature for 2 to 3 days; Filtrate again. The obtained extract can be condensed and dried as necessary after heating extraction.
    [20] Their content may vary between 0.0001 to 5% w / w%, preferably 0.001 to 3% w / w%, depending on the quality of the extract used and other factors.
    [21] Phenolic derivatives and salts thereof include 4-ethoxyphenol, 4-n-propoxyphenol, 4-n-butoxyphenol, 4-n-hexadecyloxyphenol, 4-n-octadecyloxyphenol, 4-ethyl Phenol, 4-n-propylphenol, 4-n-butyl-phenol, 4-t-butylphenol, 4-isopropylphenol, 4-hexadecylphenol, 4-octadecylphenol, 4-isopropylcatechol monocutyl Esters, and 4-isopropylcatechol monoheptadecaester.
    [22] Their content in dermatological topical agents can vary between 0.01 and 20 w / w%, preferably between 0.01 and 10 w / w%.
    [23] Placenta extracts include extracts obtained by immersing placenta derived from humans, monkeys, cattle, pigs, sheep, mice and other animals in water and / or organic solvents, extracting residues, fluids obtained by removing solvents from these extracts, and Included above are extracts or powders of these placenta with or without dissolved, dispersed or diluted solvent. More specifically, such placenta can be obtained commercially as water-soluble or fat-soluble placenta extract.
    [24] Their content in dermatological topical agents should be 0.001 to 5 w / w%, preferably 0.01 to 3 w / w%.
    [25] Kojic acid and its derivatives include monoesters such as kojic acid, kojic acid glycosides, kojic acid monobutyrate, kojic acid monocaprate, kojic acid monopalmitate, kojic acid monostearate, kojic acid monocinnamate and kojic acid. Fatty acid monobenzoates, and diesters such as kojic acid dibutyrate, kojic acid dipalmitate, kojic acid distearate, and kojic acid dioleate.
    [26] Their content in dermatological topical agents should be 0.001-30 w / w%, preferably 0.01-10 w / w%, and more preferably 0.01-5 w / w%.
    [27] Glucosamine and its derivatives include glucosamine, glucosamine-6-phosphate and glucosamine-6-sulfate.
    [28] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [29] Azelaic acid and its derivatives include azelane and azelaic acid.
    [30] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [31] Retinol is commonly called vitamin A1 and is effective in maintaining normal functioning of the skin and mucous membranes. Derivatives thereof include retinal and retinoic acid.
    [32] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [33] Pyridoxine is a component having the effect of vitamin B6, and derivatives thereof include pyridoxal, pyridoxamine, pyridoxine-5'-phosphate, pyridoxal-5'-phosphate, pyridoxamine-5'-phosphate, pyridoxal phosphate and Pyridoxic acid is included.
    [34] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [35] Tocopherol, a group of vitamin E derivatives, is effective in the prevention and treatment of hyperkeratosis and other diseases, and in the prevention and treatment of skin aging. This group includes α-tocopherol, β-tocopherol, γ-tocopherol and β-tocopherol. These derivatives can also be used in the present invention.
    [36] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [37] Alpha-tocopherol derivatives include α-tocopheryl retinoate, which is a vitamin A acid ester. Α-tocopherol refers to mixed natural tocopherols containing DL-α-tocopherol, D-α-tocopherol or D-α-tocopherol. Vitamin A acid ester means retinoic acid (all-trans-retinoic acid), 13-cis-retinoic acid, 11-cis-retinoic acid, 9-cis-retinoic acid or mixed isomers thereof. Particular preference is given to esters of DL-α-tocopherol and all-trans-retinoic acid.
    [38] Vitamin E-nicotinate and diisopropylamine dichloroacetate improve blood circulation, activate cells, inhibit melanin formation caused by ultraviolet light, promote melanin excretion, prevent epidermal dryness, and promote skin metabolism It also prevents skin aging caused by ultraviolet rays.
    [39] The content of vitamin E-nicotinate or diisopropylamine dichloroacetate in dermatological topical agents should be 0.01-5 w / w%.
    [40] Chitosan is the result of deacetylation of chitin and has a β-1,4-polyglucosamine structure. Decomposition products of chitosan are obtained as a result of treating chitosan with an enzyme such as chitocinase and contain glucosamine and oligomers thereof.
    [41] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3w / w%.
    [42] The content of caffeic acid derivatives in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [43] Hydroxycinnamate and its derivatives include hydroxycinnamic acid (p-coumarin acid and p-coumaric acid) and copeic acid.
    [44] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [45] Umbelifera plant extracts include Umbelifera plants (e.g., Redeburiella, Glenia root, Noto-pterygium incisium Ting, Knidium rhizome, Angelica dafurica root, Ligusti Extracts obtained by immersing the entire plant, roots, leaves, flowers, seeds, etc. of Comgustens olive (Ligusticum sinense Oliv.), Tokatu, Zenko and Buppleum in water and / or organic solvents and filtering the residues, Fluids obtained by removing solvents from these extracts, and extracts or powder products thereof with or without solvents dissolved, dispersed or diluted with a suitable solvent or solubilizer are included.
    [46] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [47] Mycelial culture refers to the mycelium of mushrooms and reisi cultured in a suitable medium, which includes the culture solution itself in the case of liquid medium and, if necessary, the dried mycelium after drying. Extracts of mycelial cultures include those obtained by immersing the above-mentioned mycelial cultures in water and / or organic solvents and filtering the residues, fluids obtained by removing solvents from these extracts, and dissolved, dispersed or diluted with a suitable solvent or solubilizer. Extracts or powder products thereof, with or without solvent.
    [48] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [49] The leaves of the plant include leaves from plants such as Japanese pearis, Amashiba (Japanese name) and Jimnema. These leaves are ground after drying as needed. Extracts of plant leaves may include extracts obtained by immersing these leaves and their powders in water and / or organic solvents and filtering residues, fluids obtained by removing solvents from these extracts, and dissolved, dispersed or diluted with a suitable solvent or solubilizer. Extracts or powder products thereof, with or without solvent.
    [50] Their content in dermatological topical agents should be 0.001-20 w / w%, preferably 0.1-3 w / w%.
    [51] The bark of the plant includes bark derived from fruit trees such as apple, cherry, peach and pear trees. Bark is crushed after drying as needed. Extracts of tree bark include, but are not limited to, extracts obtained by dipping these bark and their powders in water and / or organic solvents and filtering residues, fluids obtained by removing solvents from these extracts, and dissolving, dispersing or diluting with suitable solvents or solvents Extracts or powder products thereof with or without containing solvents.
    [52] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [53] The content of the hinokithiol in the dermatological topical agent should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [54] Ginseng extracts contain extracts obtained by dipping ginseng or its powder in water and / or organic solvents and filtering residues, fluids obtained by removing solvents from these extracts, and solvents dissolved, dispersed or diluted with suitable solvents or solubilizers. Extracts or powder products thereof, with or without it. Such extracts are commercially available.
    [55] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [56] The sulfur content in the dermatological topical agent should be 0.001-5 w / w%, preferably 0.1-3 w / w%.
    [57] Crude extract is a brown pigment component. Dry powder is hygroscopic, has a rather intense smell and a bitter bitter taste. Their production method is Toku-Kai-Sho No. 60-78912 patent publication. More specifically, crude sugar (brown sugar) or molasses (by-product obtained when white sugar is produced from brown sugar) is dissolved in an appropriate amount of water, and the pigment component is absorbed by contacting them with an absorbent such as a nonpolar polystyrene resin absorbent. Wash the absorbent with water to remove sugar completely. The pigment component absorbed in the absorbent is eluted with a hydrous alcohol at a concentration of at least 20%. After condensation or freeze drying, the pigment component is purified through recrystallization as necessary.
    [58] Their content in dermatological topical agents should be 0.01-10 w / w%, preferably 0.1-5 w / w%.
    [59] The main component of molasses extract is oligosaccharide, which can be obtained by immersing molasses in cold or warm lower alcohols such as methanol and ethanol, filtering, and condensing and decolorizing the obtained fluid.
    [60] Their content in dermatological topical agents should be 0.01-10 w / w%, preferably 0.1-5 w / w%.
    [61] Mucopolysaccharides have a skin moisturizing effect and include hyaluronic acid, chondroitin-4-sulfate, chondroitin-6-sulfate, dermatan sulfate, heparin and salts thereof.
    [62] Their content in dermatological topical agents should be 0.001-10 w / w%, preferably 0.01-5 w / w%.
    [63] Tefrenone, called chemical name geranyl geranyl acetone, protects the mucosa, promotes their regeneration, promotes cell growth, and promotes the synthesis of phospholipids. Tefrenone has also been shown to inhibit tyrosinase, an enzyme associated with the biosynthesis of melanin, which causes liver spots and freckles (Toku-Kai-Hei No. 6-16532 Patent Publication).
    [64] Their content in dermatological topical agents should be 0.01-20 w / w%, preferably 0.5-10 w / w%, more preferably 1.0-10 w / w%.
    [65] Nordihydroguaiaretic acid, commonly known as an antioxidant and lipoxygenase inhibitor, is added to cosmetics and pharmaceuticals to prevent oxidation and to stabilize the formulation.
    [66] Their content in dermatological topical agents should be 0.001-10 w / w%, preferably 0.1-5 w / w%.
    [67] Any UV absorber conventionally used in dermatological topical agents is used as the UV adsorbent of the present invention. Representative UV adsorbents include:
    [68] 1) Benzoate UV absorbers: paraaminobenzoic acid (PABA), PABA monoglycerine ester, N, N-bis- (3-hydroxypropyl) PABA ethyl ester, N, N-bis- (2-hydroxyethyl) PABA Ethyl ester, N, N-dimethyl PABA ethyl ester, N, N-dimethyl PABA butyl ester, N, N-dimethyl PABA amyl ester, and N, N-dimethyl PABA octyl ester.
    [69] 2) anthranilate UV absorbers: homomentyl-N-acetylantranylate.
    [70] 3) Salicylate UV absorbers: amyl salicylate, methyl salicylate, homomentyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, and 4-isopropylphenyl salicylate.
    [71] 4) Cinnamate UV absorbers: octylcinnamate, ethyl-4-isopropylcinnamate, methyl-2,5-diisopropylcinnamate, ethyl-2,4-diisopropylcinnamate, methyl-2,4- Diisopropylcinnamate, propyl-4-methoxycinnamate, isopropyl-4-methoxycinnamate, isoamyl-4-methoxycinnamate, isopropyl-4-methoxycinnamate, isoamyl-4- Methoxycinnamate, octyl-4-methoxy-cinnamate (2-ethylhexyl-4-methoxycinnamate), 2-ethoxyethyl-4-methoxycinnamate, cyclohexyl-4-methoxycinnamate , Ethyl-α-cyano-β-phenylcinnamate, 2-ethylhexyl-α-cyano-β-phenylcinnamate, and glyceryl mono-2-ethylhexanoyl-bis- (paramethoxycinnamate) .
    [72] 5) Benzophenone UV absorbers: 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzo Phenone, 2,2'-4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxy-benzophenone, 2-hydroxy-4-methoxy 4'-methylbenzophenone, 2-hydroxy Roxy-4-methoxy-benzophenone-5-sulfonate, 4-phenylbenzophenone, 2-ethylhexyl-4'-phenylbenzophenone-2-carboxylate, 2-hydroxy-4-n-octoxyl Benzophenone, and 4-hydroxy-3-carboxybenzophenone.
    [73] 6) Other UV Absorbers: 3- (4'-Methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor, uric acid, ethyl urconate, 2-phenyl-5- Methyl benzoxazole, 2- (2'-hydroxy-5'-ethylphenyl) -benzotriazole, 2- (2'-hydroxy-5'-t-butylphenyl) -benzotriazole, 2- ( 2'-hydroxy-5'-methylphenyl) -benzotriazole, dibenzalazine, dianisoylmethane, 4-methoxy-4'-t-butyldibenzoylmethane, 5- (3,3-dimethyl-2- Norbornylidene) -3-pentan-2-one.
    [74] Their content in dermatological topical agents should be 0.01-10 w / w%, preferably 0.5-8 w / w%. If their content is too small, sunburn cannot be prevented, and the whitening effect of 4-hydroxyphenyl-α-D-glucopyranoside is reduced. If their content is too high, the stability of dermatological topical agents is adversely affected.
    [75] γ-pyrone glycosides prevent hepatic spots and freckles caused by sunburn. This is maltol-3-O- (6'-O-apiosyl) -glucoside or maltol-3-O-glucoside, which can be represented by the general formula (I) below. For example, they can be collected from the Pueraria root extract via column chromatography, HPLC, TLC, and the like.
    [76] Their content in dermatological topical agents should be 0.00001-2.5 w / w%, preferably 0.0001-1 w / w%.
    [77] Formula 1
    [78]
    [79] [Formula 1]
    [80] Wherein R is a hydrogen atom or the following group:
    [81]
    [82] Hydroxysalicylic acid glycosides and hydroxysalicylic acid fatty ester glycosides exhibit excellent whitening effects through synergy with 4-hydroxyphenyl-α-D-gluco-pyranoside, represented by the general formulas (2), (3) and (4). Can be.
    [83] Such glycosides can be obtained by reacting hydroxysalicylic acid or hydroxysalicylic acid fatty esters with acetylated sugars (or aceto-brominated sugars such as acetobromoglucose) in the presence of an acidic catalyst.
    [84] Their content in dermatological topical agents should be 0.001-20 w / w%, preferably 0.1-7 w / w%.
    [85] Formula 2
    [86]
    [87] [Formula 2]
    [88]
    [89] [Formula 3]
    [90]
    [91] [Formula 4]
    [92] In the general formulas 2 to 4, R 1 is a hydrogen atom, or a saturated or unsaturated straight or branched hydrocarbon group containing 1 to 20 carbon atoms, and R 2 is a sugar residue.
    [93] Examples of the aforementioned glycosides include the following: 3-β-D-glucopyranosyloxy salicylic acid, 3-β-D-glucopyranosyloxy methyl salicylate, 3-β-D-glucopyranosiloxy Ethyl salicylate, 3-β-D-glucopyranosyloxy propyl salicylate, 3-β-D-glucopyranosyloxy isopropyl salicylate, 4-β-D-glucopyranosyloxy salicylic acid, 4- β-D-glucopyranosyloxy methyl salicylate, 4-β-D-glucopyranosyloxy ethyl salicylate, 4-β-D-glucopyranosyloxy propyl salicylate, 4-β-D-glucose Pyranosyloxy isopropyl salicylate, 5-β-D-glucopyranosyloxy salicylic acid, 5-β-D-glucopyranosyloxy methyl salicylate, 5-β-D-glucopyranosyloxy ethyl salicylate , 5-β-D-glucopyranosyloxy propyl salicylate, 5-β-D-glucopyranosyloxy isopropyl salicylate , 6-β-D-glucopyranosyloxy salicylate, 6-β-D-glucopyranosyloxy methyl salicylate, 6-β-D-glucopyranosyloxy ethyl salicylate, 6-β-D- Glucopyranosyloxy propyl salicylate, 6-β-D-glucopyranosyloxy isopropyl salicylate, 2-β-D-glucopyranosyloxy-3-hydroxybenzoic acid, 2-β-D-glucopyra Nosyloxy-3-methyl hydroxybenzoate, 2-β-D-glucopyranosyloxy-3-ethyl hydroxybenzoate, 2-β-D-glucopyranosyloxy-3-propyl hydroxybenzoate, 2 -β-D-glucopyranosyloxy-3-isopropyl hydroxybenzoate, 2-β-D-glucopyranosyloxy-4-hydroxybenzoic acid, 2-β-D-glucopyranosyloxy-4-methyl Hydroxybenzoate, 2-β-D-glucopyranosyloxy-4-ethyl hydroxybenzoate, 2-β-D-glucopyranosyloxy-4-propyl hydroxybenzoate, 2-β-D-letter Copyranosyloxy-4-isopropyl hydroxybenzoate, 2-β-D-glucopyranosyloxy-5-hydroxybenzoic acid, 2-β-D-glucopyranosyloxy-5-methyl hydroxybenzoate, 2-β-D-glucopyranosyloxy-5-ethyl hydroxybenzoate, 2-β-D-glucopyranosyloxy-5-propyl hydroxybenzoate, and 2-β-D-glucopyranosyloxy- 5-isopropyl hydroxybenzoate.
    [94] The biphenyl compound inhibits tyrosinase activity and melanin formation and can be represented by the general formulas (5) and (6).
    [95] More specifically, the biphenyl compounds include dihydrocresol, dihydrodieugenol and tetrahydromagnolol.
    [96] Their content in dermatological topical agents should be 0.0001-20 w / w%, preferably 0.001-5 w / w%.
    [97] Formula 3
    [98]
    [99] [Formula 5]
    [100]
    [101] [Formula 6]
    [102] In general formulas 5 and 6, R 3 is selected from the group consisting of CH 3 , C 2 H 5 , C 3 H 7 , CH 2 OH, C 3 H 6 OH, and CH 2 CH = CH 2 , and R 4 is a hydrogen atom, Or saturated straight or branched hydrocarbon groups containing from 1 to 8 carbon atoms.
    [103] Materials with ceramides and ceramide-like structures have moisturizing, softening and whitening effects on the skin, relieve inflammation, neutralize oxidation and promote blood circulation. Ceramide may be represented by the general formula (7), materials having a ceramide-like structure may be represented by the general formula (8), 9, 10, 11 and 12.
    [104] Materials having ceramides and ceramide-like structures can be used in combination (combinations of materials having one or more ceramides and / or ceramide-like structures). Their content in dermatological topical agents should be 0.1-50 w / w%, preferably 0.01-20 w / w%, more preferably 0.1-10 w / w%. These ingredients have good stability and feel upon skin contact and prevent and relieve rough skin. Has a moisturizing effect.
    [105] Formula 4
    [106]
    [107] [Formula 7]
    [108]
    [109] [Formula 8]
    [110]
    [111] [Formula 9]
    [112]
    [113] [Formula 10]
    [114]
    [115] [Formula 11]
    [116]
    [117] [Formula 12]
    [118] In formula 7, R5 and R6 are the same or different and are hydroxy group-substituted straight or branched saturated or unsaturated hydrocarbon groups containing 8 to 26 carbon atoms.
    [119] In formula (8), R 7 is a straight or branched saturated or unsaturated hydrocarbon group containing 10 to 26 carbon atoms; R8 is a straight or branched saturated or unsaturated hydrocarbon group containing 9 to 25 carbon atoms; Y and Z are hydrogen atoms or hydroxy groups; a is 0 or 1; c is an integer from 0 to 4; And b and d are integers from 0 to 3.
    [120] In formula (9), R9 and R10 are the same or different and are straight or branched saturated or unsaturated hydroxylated or unhydroxylated hydrocarbon groups containing 1 to 40 carbon atoms; R 11 is a straight or branched alkylene group containing 1 to 6 carbon atoms or a single bond; R12 is a hydrogen atom or a straight or branched alkoxy group or 2,3-dihydroxypropyloxy group containing 1 to 12 carbon atoms. When R11 is a single bond, R12 is a hydrogen atom.
    [121] In formula 10, R 9a is a hydroxylated or unhydroxylated hydrocarbon radical containing 4 to 40 carbon atoms; R 11a is a straight or branched alkylene group containing 3 to 6 carbon atoms; R 12a is a straight or branched alkoxy group containing 1 to 12 carbon atoms.
    [122] In formula (11), R9, R10, R10a and R12a are the same as above.
    [123] In formula 12, R9, R10 and R11 are the same as above; R 12b is a hydrogen atom. Straight or branched alkoxy groups containing 1 to 12 carbon atoms or 2,3-dihydroxypropyloxy groups. When R11 is a single bond, R12b is a hydrogen atom.
    [124] The ether compound represented by the general formula R21-O- (X-O) n-R22 increases the absorption of dermatological topical agents according to the invention through the skin without skin irritation.
    [125] In the above general formula, R21 and R22 may be the same or different, and straight chain containing 1 to 12 carbon atoms, preferably 2 to 22 carbon atoms, more preferably 3 to 20 carbon atoms , A branched or cyclic alkyl group. R21 and / or R22 are preferably branched at two or more sites, preferably at two sites. More specifically, such groups include the following: methyl group, butyl group, n-butyl group, n-decyl group, n-dodecyl group, n-tetradecyl group, n-octadecyl group, n-eicosyl group , n-tetracosyl group, 1-methylpropyl group, 3-methylhexyl group, 2-methylheptadecyl group, 1,3-dimethylbutyl group, 1,3-dimethylpentyl, and cyclopentyl group.
    [126] X is an alkylene group containing 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more specifically a methylene group, an ethylene group, a butylene group and the like.
    [127] The sum of the number of carbon atoms in R21 and R22 should be 10 to 32, preferably 12 to 28.
    [128] n is 0 or 1, preferably 0.
    [129] Such ether compounds are obtained by known methods, for example by direct etherification of the corresponding alcohols and alkyl halides, addition of the corresponding alcohols and olefins in the presence of acid catalysts of Lewis or addition of the corresponding alcohols and alkyl halides in the presence of alkali catalysts. It can be produced through the reduction of the aryl ether obtained by and the reduction of acetal or ketal generated from the alcohol and aldehyde or ketone.
    [130] Their content in dermatological topical agents should be 0.01-50 w / w%, preferably 0.01-20 w / w%, more preferably 0.1-10 w / w%.
    [131] Pantothenic acid is B vitamins. This pantothenic acid not only exerts a skin lightening effect but also increases the stability of 4-hydroxyphenyl-α-D-glucopyranoside in topical dermatological preparations. Derivatives thereof include pentetin-S-sulfonic acid, 4'-phosphopantothenic acid-S-sulfonic acid, pentetin, and glucopyranosyl pantothenate. These compounds can be used in the form of salts as well as free acids. Salts include a wide range of salts of organic and inorganic acids, with the exception of salts of alkali metals and salts of alkaline earth metals, for example calcium d-pantothene-s-sulfonate.
    [132] Their content in dermatological topical agents should be 0.001-5 w / w%, preferably 0.1-3 w / w%. Their content is such that the weight ratio of 4-hydroxyphenyl-α-D-gluco-pyranoside and pantothenic acid and / or derivatives thereof is 1: 0.1, preferably 1: 0.1 to 10, more preferably 1: 0.5 to Adjust to 5 or more.
    [133] Sodium hydrogen sulfite is known to increase the stability of β-arbutin in dermatological topical agents (Patent 2107858). Sodium hydrogen sulfite also increases the stability of 4-hydroxyphenyl-α-D-glucopyranoside in dermatological topical agents.
    [134] Their content should be adjusted so that the weight ratio of 4-hydroxyphenyl-α-D-glucopyranoside: sodium hydrogen sulfite is from 1: 0.0001 to 1, preferably from 1: 0.001 to 0.1.
    [135] Anti-inflammatory agents are used to prevent inflammation and other side effects that may be caused by some adjuvants used in the present invention. Any anti-inflammatory agents applicable to the skin can be used, for example oxybenzone, tranexamic acid and derivatives thereof, ε-aminocaproic acid, glycyrilic acid, azulene, photosensitizer No. 301, photosensitive agent N0. 401, diphenhydramine HCl, adenosine phosphate, calamine, lysium perm root extract, wormwood extract, sarguisorva extract, aminocaproic acid and bisabolol.
    [136] Their content in dermatological topical agents should be 0.01-2 w / w%, preferably 0.1-2 w / w%.
    [137] Allantoin is used to treat various dermatological diseases and is effective in the treatment of skin wounds and the prevention of rough skin. Derivatives thereof include dihydroxy aluminum allantoinate and chlorohydroxy aluminum allantoinate.
    [138] Their content in dermatological topical agents should be 0.01-5 w / w%, preferably 0.1-3 w / w%.
    [139] Amino acids are used to rehydrate aged or hardened epithelium. Natural amino acids (e.g. glycine, serine, cystine, alanine, threonine, cysteine, valine, phenylalanine, methionine, leucine, tyrosine, proline, isoleucine and hydroxy-proline), acidic amino acids (e.g. aspartic acid, asparagine) , Glutamine and glutamic acid), and basic amino acids (arginine, histidine and lysine) can be used. Amino acid derivatives include acylsacosinates and salts thereof, acylglutamic acid and salts thereof, acyl-β-alanine and salts thereof, glutathione, and pyrrolidone carboxylic acids and salts thereof, as well as oligopeptides such as glutathin, carno Cin, chlamididine S, tyrosidin A and tyrosidin B, γ-aminobutyric acid and γ-amino-β-hydroxybutyric acid and salts thereof.
    [140] Their content in dermatological topical agents should be 0.01-20 w / w%, preferably 0.05-10 w / w%. Their content is too small and the skin moisturizing effect may be insufficient. If their content is too high, it becomes difficult to prevent denaturation of amino acids without increasing their useful effects.
    [141] The amino ethyl compound represented by the general formula NH 2 CH 2 CH 2 X (where X is -SO 2 H or -SO 2 SH) is used to prevent and alleviate rough skin and to alleviate subduedness. .
    [142] Their content in dermatological topical agents should be 0.0001-1.0 w / w%, preferably 0.001-0.3 w / w%.
    [143] Alkylene diamine carboxylic acid derivatives are used to increase the stability of dermatological topical agents. Ethylenediamine tetraacetate and its alkali metal salts (eg, Na, K, and Li salts), alkaline earth metal salts (eg, Ca and Mg), ammonium salts, and alkanol salts are preferred, but Na salts are most preferred. Do.
    [144] Their content in dermatological topical agents should be 0.01-0.5 w / w%, preferably 0.05-0.5 w / w%.
    [145] Betaine derivatives are used to increase the adsorption of 4-hydroxyphenyl-α-D-glucopyranoside, and are alkyl dimethyl amino acids represented by formula 13, 2-alkyl-1-carboxy represented by formula 14 -Methyl-1-hydroxyethyl-2-imidazoline, N- (3-acylaminopropyl) -N, N-dimethylamino acetate represented by formula 15, and N-alkyl- represented by formula 16 N, N-dimethyl-3-amino-2-hydroxypropane is preferred.
    [146] Acyl methyl taurine is also used to increase the adsorption of 4-hydroxyphenyl-α-D-glucopyranoside, which can be represented by the general formula (17).
    [147] Formula 5
    [148]
    [149] [Formula 13]
    [150]
    [151] [Formula 14]
    [152]
    [153] [Formula 15]
    [154]
    [155] [Formula 16]
    [156]
    [157] [Formula 17]
    [158] In formulas 13, 14, 15, 16 and 17, R 13 and R 16 are straight or branched alkyl groups containing 8 to 24 carbon atoms; R14, R15 and R17 are straight or branched alkyl groups containing 7 to 23 carbon atoms; M is a monovalent or divalent metal, ammonium, alkanol amine or hydrogen atom.
    [159] The combined content of betaine derivatives and acyl methyl taurine in dermatological topical agents should be 0.01-30 w / w%, preferably 0.1-20 w / w%.
    [160] Fibronectin (cold insoluble globulin) is used to enhance the whitening effect of 4-hydroxyphenyl-α-D-glucopyranoside used in the present invention.
    [161] Their suitable content in dermatological topical agents is 0.000001-0.1 w / w%.
    [162] Tyrosinase inhibitors enhance the inhibition of tyrosinase activity by 4-hydroxyphenyl-α-D-glucopyranoside, or through synergistic action with 4-hydroxyphenyl-α-D-glucopyranoside It is used to enhance the anti-tyrosinase effect on dermatological topical agents found by. To obtain tyrosinase inhibitors, cells of Catharanthus roseus L. (root, cells or strips of tissue such as embryonic axis, cotyledon, adult of young plants) in a medium to which plant growth regulators containing plant hormones such as auxin and cytokinin are added Plant roots, stems, leaf stems, flowers and pollen) were cultured to induce callus, or tumor tissue was produced using the soil bacterium tumefaciien or the soil bacterium rhizogene. 4-hydroxyphenyl-α-D-glucopyranoside containing medium (eg, Murashige-Skoog medium, Linsmaier-Skoog medium, White medium, Gamborg medium, Nitsch medium, Heller medium, Schenk-Hildebrandt medium, Nitzsch- Callus tissue or tumor tissue was cultured using Nitzsch medium and Kohlenbach-Schmidt medium), and the obtained culture was homogenized. The transparent fluid derived from the obtained homogenate is used as a tyrosinase inhibitor directly or as it is after drying.
    [163] Their content should be adjusted so that suitable anti-tyrosinase activity is obtained.
    [164] Hederacoside enhances the whitening effect of dermatological topical agents found by the present invention through synergistic action with 4-hydroxyphenyl-α-D-glucopyranoside. Hederacoside is Sapindus mukurossi Gaertn. Or triterpenoid saponins obtained from extracts of Akebia quinata Decne . Their salts include alkali metal salts such as Na and K salts, ammonium salts, basic amino acid salts, alkanol amine salts and esters. These extracts are used by themselves.
    [165] Their content in dermatological topical agents should be 0.001-20 w / w%, preferably 0.1-5 w / w%.
    [166] Gymnema saponin enhances the whitening effect of dermatological topical agents found by the present invention through synergistic action with 4-hydroxyphenyl-α-D-glucopyranoside. Gymnema saponins are triterpenoid saponins obtained from extracts of Gymnema inodrum or Gymnema sylvestre R. Br. Their salts include alkali metal salts such as Na and K salts, ammonium salts, basic amino acid salts, alkanol amine salts and esters. These extracts are used by themselves.
    [167] Their content in dermatological topical agents should be 0.001-20 w / w%, preferably 0.1-5 w / w%.
    [168] Beet saponin enhances the whitening effect of dermatological topical agents found by the present invention through synergistic action with 4-hydroxyphenyl-α-D-glucopyranoside. Beet saponin is an oleanoic acid glycoside obtained from beet extract. Their salts include alkali metal salts such as Na and K salts, ammonium salts, basic amino acid salts, alkanol amine salts and esters. These extracts are used by themselves.
    [169] Their content in dermatological topical agents should be 0.001-20 w / w%, preferably 0.1-5 w / w%.
    [170] Ellagic acid-related compounds are added to improve the stability of dermatological topical agents found by the present invention and can be represented by the general formula (18). Alkali metal salts of ellagic acid-related compounds include Na and K salts.
    [171] Their content in dermatological topical agents should be 0.001-30 w / w%, preferably 0.05-10 w / w%.
    [172] Formula 6
    [173]
    [174] [Formula 18]
    [175] In Formula 18, R18, R19, R20 and R21 are hydrogen atoms or alkyl groups containing 1 to 20 carbon atoms (e.g., methyl, ethyl and propyl groups), containing 1 to 20 carbon atoms An acyl group (eg, an acetyl group and a propionyl group), a polyoxy alkylene group represented by the general formula-(C m H 2m -O) n H, wherein m is 2 or 3, and n is 1 or more An integer, more preferably an integer between 4 and 50) (for example, a polyoxyethylene group and a polyoxypropylene group), or a sugar residue represented by the general formula (19). Wherein R18, R19, R20 and R21 may be the same or different. R22 is a hydrogen atom or a hydroxyl group or alkoxyoxy group containing 1 to 8 carbon atoms.
    [176] Formula 7
    [177]
    [178] [Formula 19]
    [179] Examples of ellagic acid-related compounds and their alkali metal salts are ellagic acid, 3,4-di-O-methyl ellagic acid, 3,3'-di-O-methyl ellagic acid, 3,3 ', 4-tri-O -Methyl ellagic acid, 3,3 ', 4,4'-tetra-O-methyl-5-methoxy ellagic acid, 3-O-ethyl-4-O-methyl-5-hydroxy ellagic acid and amritoxide And alkali metal salts thereof.
    [180] Such ellagic acid-related compounds are berries,Caesalupinia spinosa, Eucalyptus, apples,Coriaria japonica, Pinus radiators, baby bilberry, pomegranate,Phyllanthus emblica L., Sapium sebiferum leaf, Rhus chinensis leaf, Acacia catechu L., Platycarya strobilacea leaf, Terminalia chebula,Camptotheca acuminata,Polygonum bistorta L., Lagerstroemia subcostata, Sapium discolor root, Sapium discolor leaf, bischofia javanica, Lythrum salicaria L.,Geranium pratense L., Euphorbia hirta L., Eucalyptus citriodora leaf, Euphorbia royleana, Psidium guajava fruit, Psidium guajava cortex,Mangifera indica L., gall,Syzygium cumini fruit, Syzygium cumini cortex, Phyllanthus emblica root, Phyllanthus emblica cortex, Phyllanthus emblica leaf, Agrimonia pilosa root, Psidium guajava leaf,Sapium sebiferum root cortex,SHIDOKON (Kanppo name), CHINSYUSO (Kanppo name) And geranium herbs.
    [181] Resorcinol derivatives exhibit an effect of improving blood circulation and cell activation. They inhibit melanin formation due to ultraviolet light and promote the release of melanin. They also prevent epidermal drying, promote skin metabolism, and prevent skin aging caused by ultraviolet radiation.
    [182] More specifically, resorcinol derivatives include 4-n-ethylresorcinol, 4-n-butyl resorcinol, 4-n-hexyl resorcinol, and 4-isoamyl resorcinol do.
    [183] Their content in dermatological topical agents should be 0.0001-20 w / w%, preferably 0.01-10 w / w%.
    [184] Unless otherwise indicated, all adjuvants described above enhance the whitening effect of the dermatological topical agents of the present invention when used with 4-hydroxyphenyl-α-D-glucopyranoside. Some of these adjuvants also increase the stability and / or safety of the topical agent.
    [185] None of these adjuvants adversely affects 4-hydroxyphenyl-α-D-glucopyranoside in the topical agent when used with 4-hydroxy-phenyl-α-D-glucopyranoside within the specified content ranges. Not crazy They maintain stability for long periods of time and show good whitening effects. Their content can be increased or decreased depending on the expected effect. Each of these adjuvants may be used alone or in combination with one or more other agents.
    [186] 4-hydroxyphenyl-α-D-glucopyranoside to be used in the present invention is described in more detail below.
    [187] 4-hydroxyphenyl-α-D-glucopyranoside is obtained as a result of the α-bonding of the phenol group of 1,4-dihydroxybenzene and D-glucose. Β-albutin obtained as a result of β-bonding of the phenol group of 1,4-dihydroxybenzene and D-glucose is commonly used in topical preparations for dermatology because of its homogeneous whitening effect. 4-hydroxyphenyl-α-D-glucopyranoside is not only more effective than β-arbutin but also more stable and safe when applied to the skin.
    [188] The content of 4-hydroxyphenyl-α-D-glucopyranoside in the dermatological topical agent is 0.01-30 w / w%, preferably 0.05-20 w / w%, more preferably 0.1-10 w / w%.
    [189] 4-hydroxyphenyl-α-D-glucopyranoside may be prepared chemically, or may be obtained by converting 1,4-dihydroxybenzene to glycoside using an enzyme derived from bacteria. For example, they can be obtained using sucrose as a sugar donor and Leuconostoc mesenterioides -derived sucrose phosphorylase as an enzyme.
    [190] 4-hydroxyphenyl-α-D-glucopyranoside can also be obtained using soluble starch as sugar donor and Bacillus subtilis -derived α-amylase as enzyme. In this method, the use of amylase X-23 effectively yields industrial scale 4-hydroxy-phenyl-α-D-glucopyranoside.
    [191] However, 4-hydroxyphenyl-α-D-glucopyranoside used in the present invention can be obtained using amylase X-23, and the amylase type obtained from Bacillus subtilis is outlined below. Amylase X-23 degrades glucans with α-1,4 bonds in the presence of glucans with α-1,4 bonds and phenol related compounds, and transfers sugars to the OH groups of phenolic compounds via α-bonds. The optimal pH for sugar delivery ranges from 5-8. Sugar delivery can be achieved in a stable manner at pH 5.5 and at temperatures of 30-70 ° C. See Patent 2662667 Patent Publication for more details.
    [192] Other ingredients commonly used in the manufacture of dermatological topical preparations, including cosmetics and drugs, may also be added to the dermatological topical preparations of the present invention as needed. Such ingredients include oils, antioxidants, surface active detergents, humectants, humidifiers, fragrances, water, alcohols, viscous agents, preservatives, colorants, powders, drugs, chelating agents, and pH adjusting agents. Such ingredients should be used in amounts that do not qualitatively or quantitatively affect the quality of the dermatological topical agent of the present invention.
    [193] The dermatological topical agents found by the present invention may be in any dosage form such as solutions such as toilet lotions, emulsifying agents such as milky liquids and creams, ointments, viscous gels, dispersions, and powders.
    [194] When the dermatological topical agents found by the present invention are prepared in the form of lotions, emulsions and viscous gels, the following water-soluble viscosity agents can be combined with lower alcohols such as ethanol and isopropanol to achieve greater efficacy: -Derived macromolecules (e.g. Arabian gum, tragacanth gum, galactan, cyamophorsis rubber, carrageenin, pectin, quince seed (quinceo extract) and brown algae powder), microorganism-derived macromolecules Molecules (e.g., xanthan gum, dextran and fruclan), animal-derived macromolecules (e.g. collagen, casein, albumin and gelatin), starches (e.g. carboxymethyl starch and methylhydroxy starch) , Cellulose (for example, methyl cellulose, nitrocellulose, ethyl cellulose, methyl hydroxypropyl cellulose, hydroxyethyl cellulose, cellulose wool sulfate, hydroxyprop Fill cellulose, carboxymethyl cellulose, crystalline cellulose, cellulose powder), vinyl macromolecules (polyvinyl alcohol, polyvinylmethyl ether, polyvinylpyrrolidone and carboxyvinyl polymer), acrylic macromolecules (e.g. polyacrylic acid and its Salts and polyacrylamides), organic viscosity agents (e.g., glycyric acid and alginic acid), and inorganic viscosity agents (e.g., bentonite, hectorite, labonite, aluminum silicate magnesium and silicic anhydride).
    [195] The water-soluble viscosity in the dermatological topical agent should be 0.01-5 w / w%, preferably 0.1-3 w / w%, and the content of lower alcohol in the dermatological topical agent is 0.3-35 w / w. Must be% The weight ratio of 4-hydroxyphenyl-α-D-glucopyranoside and the lower alcohol is preferably adjusted to be 3: 1 to 1: 3.
    [196] 4-hydroxyphenyl-α-D-glucopyranoside used in all the examples presented below are those obtained by acting amylase X-23 in the presence of 1,4-dihydroxybenzene and maltopentaose. All contents given below are based on w / w%.
    [197] Example 1: Toilet Solution
    [198] The eyelet lotion was prepared by a conventional method using the prescription given below.
    [199] Polypropylene Glycol5.0
    [200] Ethanol 14.0
    [201] POE (20) Oleyl Ester0.5
    [202] 4-hydroxyphenyl-α-D-glucopyranoside0.5
    [203] 2-hydroxy-4-methoxybenzophenone-5-sodium0.1
    [204] Sulfonate
    [205] Methylparaben0.1
    [206] Citric Acid0.01
    [207] Sodium Citrate0.1
    [208] Chamomile Extract 2.0
    [209] Water Soluble Placenta Extract 2.0
    [210] Sodium Hyaluronate0.3
    [211] Spices0.05
    [212] Residual ion exchange water
    [213] Example 2: Emulsion
    [214] The emulsion was prepared by conventional methods using the prescription given below.
    [215] Stearate 3
    [216] Cetyl alcohol2
    [217] Petrol Latum 5
    [218] Liquid Paraffin 10
    [219] Polyoxyethylene (10) Monooleate Ester 2
    [220] Polyoxyethylene Glycol 3
    [221] Triethanolamine 1
    [222] 4-hydroxyphenyl-α-D-glucopyranoside5
    [223] Pentetin-S-Sodium Sulfonate 10
    [224] N ', N-dimethyl PABA octyl ester5.0
    [225] Hydroquinone monomethyl ether0.01
    [226] Sodium Hydrogen Sulfite 1.0
    [227] Azela Mountain 0.2
    [228] Pyridoxine0.2
    [229] Residual ion exchange water
    [230] Spices Q.S.
    [231] Preservative Q.S.
    [232] Example 3: Cream
    [233] Creams were prepared by conventional methods using the prescriptions given below.
    [234] Propylene Glycol5.0
    [235] Yellow Beeswax4.0
    [236] Cetyl Alcohol5.0
    [237] Reduced Lanolin 5.0
    [238] Squalane36.0
    [239] Glyceryl Monostearate 2.0
    [240] POE (20) sorbitan monolaurate 2.0
    [241] Methylparaben0.1
    [242] Ethylparaben0.15
    [243] 4-hydroxyphenyl-α-D-glucopyranoside1.0
    [244] Allantoin3.0
    [245] Japanese Angelica Root Extract 0.2
    [246] Crude Extract 1.0
    [247] TEPRENON 1.0
    [248] Kojisan1.0
    [249] Spices0.1
    [250] Residual ion exchange water
    [251] Example 4: Pack
    [252] The pack was prepared by the conventional method using the prescription set forth below.
    [253] Polyvinyl Alcohol16.0
    [254] Polyethylene Glycol4.0
    [255] Propylene Glycol7.0
    [256] Ethanol 11.0
    [257] Methylparaben0.1
    [258] 4-hydroxyphenyl-α-D-glucopyranoside7.0
    [259] Dihydroxy Aluminum Allantoinate 3.0
    [260] Ascorbic acid 1.0
    [261] Nordihydroguaiaretic acid5.0
    [262] Citric Acid0.3
    [263] Sodium Citrate0.7
    [264] Spices0.1
    [265] Residual ion exchange water
    [266] Example 5: Scalp Treatment (Toilet Lotion for Scalp Treatment)
    [267] The eyelet lotion for scalp treatment was prepared by a conventional method using the prescription set forth below.
    [268] 1,3-butylene glycol 6.0
    [269] Propylene Glycol4.0
    [270] Ethanol 11.0
    [271] POE (60) Hydrogenated Castor Oil 2.0
    [272] Potassium Hydroxide0.05
    [273] Carboxyvinyl Polymer0.2
    [274] 2-hexyldecyl palmitate 11.0
    [275] Squalane 5.0
    [276] Yellow Beeswax0.5
    [277] 4-hydroxyphenyl-α-D-glucopyranoside10.0
    [278] Allantoin3.0
    [279] Preservative 0.2
    [280] Spices0.1
    [281] Residual ion exchange water
    [282] Example 6: Ointment
    [283] Ointments were prepared by conventional methods using the prescription given below.
    [284] Petrol Latum 40.0
    [285] Stearyl Alcohol15.0
    [286] Japanese Wax 15.0
    [287] POE (10) oleate0.25
    [288] Glyceryl Monostearate0.25
    [289] 4-hydroxyphenyl-α-D-glucopyranoside6.0
    [290] Allantoin1.0
    [291] Sorbitol5.0
    [292] Propylene Glycol5.0
    [293] Gentian Extract0.3
    [294] Residual ion exchange water
    [295] Example 7: Powder
    [296] Powders were prepared in a conventional manner using the prescription given below.
    [297] Tranexamsan0.1
    [298] Calamine0.1
    [299] Sulfur 0.1
    [300] Fat-soluble Glycirrhi Extracts1.0
    [301] Dextrin 2.0
    [302] Talc95
    [303] Decaglicel Stearate 1.0
    [304] 4-hydroxyphenyl-α-D-glucopyranoside0.7
    [305] Example 8: Toilet Oil
    [306] Toilet oils were prepared by conventional methods using the formulations set forth below.
    [307] Tocopherol0.2
    [308] 4-hydroxycinnamate0.2
    [309] Allantoin0.5
    [310] Ascorbyl Palmitate0.2
    [311] 4-hydroxyphenyl-α-D-glucopyranoside1.0
    [312] Retinol Acetate0.3
    [313] Evening Primrose Oil2.0
    [314] Fat-soluble Glycirrhi Extracts1.0
    [315] Amount of squalene
    [316] All dermatological topical preparations obtained in Examples 1 to 8 exhibited good skin lightening effects with only some skin irritation and potential for sensitization. They also showed good stability over time.
    [317] Test 1
    [318] Cream prepared according to the prescription given in Example 3, except that the content of 4-hydroxyphenyl-α-D-glucopyranoside varied from 1.0 w / w% to 0.5 w / w%, and 4- Clinical trials were performed using a control cream prepared according to the formula shown in Example 3, except that hydroxyphenyl-α-D-gluco-pyranoside was replaced with β-arbutin.
    [319] A total of 12 volunteers (6 males and 6 females between 25 and 55 years old) were recruited. The cream found by the present invention was applied to the medial flank of the right arm of six volunteers (3 males and 3 females). The β-arbutin-containing control cream was applied three times a day (8 hour intervals) for 7 consecutive days. After application three times from the first day using a UVB light source, the application site was exposed to ultraviolet light of 1 MED (minimum erythema dose). The volunteers were crossed over 30 days after completing the first experiment and the experiment was repeated in the same manner on the other part of the middle of the upper right arm. A double restraint design was used.
    [320] 14 days after the start of ultraviolet irradiation, the degree of blackening of the skin was compared visually, and the effect of preventing skin blackening was evaluated. Efficacy was classified into five grades: very effective, effective, somewhat effective, ineffective and worsened.
    [321] The results obtained are shown in Table 1 below.
    [322] TABLE 1
    [323] Contrast CreamCream of the present invention Very effective1 (8.3%)3 (25.0%) Effective3 (25.0%)6 (25.0%) Somewhat effective5 (41.0%)2 (16.7%) Not effective3 (25.0%)1 (8.3%) Worse00
    [324] The cream of the present invention was more effective than the control cream in preventing skin darkening (the β-arbutin content of the control cream was 2 of the 4-hydroxy-phenyl-α-D-glucopyranoside content in the cream of the present invention. Belly), and no side effects were seen. These findings suggest that the cream of the present invention is an excellent product.
    [325] The dermatological topical agent found by the present invention has the effect of 4-hydroxyphenyl-α-D-glucopyranoside due to the synergistic effect obtained by combining with 4-hydroxyphenyl-α-D-glucopyranoside. They are safe, stable and exhibit good skin lightening effects, even when used alone or in combination with various adjuvants. Thus, the dermatological topical agent found by the present invention exhibits a significant skin whitening effect and blackening prevention effect, effectively preventing and alleviating hepatic spots and freckles. They have also been shown to be safe and stable as cosmetics and therapeutics and are very useful.
    权利要求:
    Claims (3)
    [1" claim-type="Currently amended] Topical agents for dermatology comprising 4-hydroxyphenyl-α-D-glucopyranoside, and at least one component selected from the group consisting of: ascorbic acid and derivatives thereof, herbal medicines ( crude drug) and their extracts, hydroxycarboxylic acids and salts thereof, fat soluble glycyrrhiza extracts, gentian extracts, phenol derivatives and salts thereof, placental extracts, kojic acid and derivatives thereof, glucosamine And derivatives thereof, azelaic acid and derivatives thereof, retinol and derivatives thereof, pyridoxine and derivatives thereof, tocopherol and derivatives thereof, vitamin E-nicotinate, diisopropylaminedichloroacetate, chitosan and its degradation products, caffeic acid derivatives, hydride Loxycinnamate and its derivatives, Umbelliferae plant extracts, mycelial cultures and their extracts, plant leaves and them , Extracts of plant bark and extracts thereof, hinokithiol, ginseng extract, sulphur, crude sugar extract, molasses extract, mucopolysaccharide, tefrenone, nordihydroguaiaretic acid, UV absorber, γ-pyrone glycoside, hydroxy Salicylic acid glycosides, hydroxysalicylic acid fatty ester glycosides, biphenyl compounds, ceramides, substances having ceramide-like structures, ether compounds represented by the general formula R31-O- (XO) n-R32, wherein R31 and R32 Is the same or different straight, branched or cyclic alkyl group containing 1 to 12 carbon atoms, X is an alkylene group containing 1 to 12 carbon atoms, n is 0 or 1, R31, R32 And the number of synthetic carbon atoms in X is 10 to 32), pantothenic acid and derivatives thereof, sodium hydrogen sulfite, anti-inflammatory agents, allantoin and derivatives thereof, amino acids and Derivatives, aminoethyl compounds, alkylene diamine carboxylic acid derivatives, betaine derivatives, acyl methyl taurine, fibronectin, tyrosinase inhibitors, hederacosides and salts thereof, gymne saponins, beet saponins and salts thereof, ellagic acid ( ellagic acid) -related compounds and their alkali metal salts, and resorcinol derivatives.
    [2" claim-type="Currently amended] The method of claim 1,
    A topical agent for dermatology, wherein 4-hydroxyphenyl-α-D-glucopyranoside is obtained using α-amylase.
    [3" claim-type="Currently amended] The method of claim 2,
    The topical agent for dermatology, wherein the α-amylase is amylase X-23.
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    同族专利:
    公开号 | 公开日
    JP2001342110A|2001-12-11|
    KR100810589B1|2008-03-06|
    EP1289489B1|2007-12-05|
    DE60131743T2|2008-11-06|
    US20110014141A1|2011-01-20|
    AU6751101A|2001-12-11|
    US20030198610A1|2003-10-23|
    CA2409871A1|2001-12-06|
    ES2299491T3|2008-06-01|
    EP1859835A3|2007-12-05|
    EP1859835A2|2007-11-28|
    WO2001091715A3|2002-07-04|
    AT380054T|2007-12-15|
    WO2001091715A2|2001-12-06|
    CN1635996B|2010-10-06|
    DE60131743D1|2008-01-17|
    CN1635996A|2005-07-06|
    EP1289489A2|2003-03-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-06-02|Priority to JPJP-P-2000-00165590
    2000-06-02|Priority to JP2000165590A
    2001-06-01|Application filed by 펜타팜아게, 에자끼글리코가부시끼가이샤
    2001-06-01|Priority to PCT/EP2001/006281
    2003-03-08|Publication of KR20030020289A
    2008-03-06|Application granted
    2008-03-06|Publication of KR100810589B1
    优先权:
    申请号 | 申请日 | 专利标题
    JPJP-P-2000-00165590|2000-06-02|
    JP2000165590A|JP2001342110A|2000-06-02|2000-06-02|Skin care preparation|
    PCT/EP2001/006281|WO2001091715A2|2000-06-02|2001-06-01|Topical agent for dermatological use containing 4-hydroxyphenyl-alpha-d-glucopyranoside|
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