WO2011096330A1 - Pigmentation-ameliorating agent - Google Patents
Pigmentation-ameliorating agent Download PDFInfo
- Publication number
- WO2011096330A1 WO2011096330A1 PCT/JP2011/051696 JP2011051696W WO2011096330A1 WO 2011096330 A1 WO2011096330 A1 WO 2011096330A1 JP 2011051696 W JP2011051696 W JP 2011051696W WO 2011096330 A1 WO2011096330 A1 WO 2011096330A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pigmentation
- skin
- improving agent
- external preparation
- general formula
- Prior art date
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 210000004694 pigment cell Anatomy 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
Definitions
- the present invention relates to a novel pigmentation-improving agent and a skin external preparation suitable for cosmetics, and specifically comprises a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof.
- the present invention relates to a pigmentation-improving agent and a skin external preparation containing the pigmentation-improving agent.
- the term cosmetic is defined as including quasi drugs. (Wherein R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.)
- Pigmentation, blemishes, liver spots, senile pigment spots, etc. after sunburn in the skin are a state in which melanin production is remarkably enhanced by activation of pigment cells (melanocytes) present in the skin.
- Ingredients that have the action of preventing or improving the occurrence and deterioration of skin pigment troubles include compounds having a whitening action (whitening agents) such as ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, and catechol. It is well known (for example, see Non-Patent Document 1 and Non-Patent Document 2). And skin external preparations containing these active ingredients are widely used.
- whitening agents various mechanisms of action of compounds known as whitening agents have been reported, including tyrosinase enzyme inhibition, tyrosinase-related proteolysis, and inhibition of melanin transport by suppressing dendrite elongation in melanocytes.
- target molecules for each mechanism of action.
- a small organic molecule that interacts appropriately with each target molecule is useful.
- the structural characteristics of small organic molecules that interact appropriately with each target molecule are different for each target molecule, it is important to optimize the chemical structure in order to maximize the pharmacological effects of the small organic molecules.
- the current whitening agent research targets compounds that have high efficacy and selectivity against existing target molecules, as well as compounds that simultaneously act on multiple whitening mechanisms, as well as new It spreads to compounds that have a mechanism of action.
- Amino acids are a general term for organic compounds having both amino and carboxyl functional groups in their molecules.
- ⁇ -amino acids are actively used as protein structural units for expressing various functions in living bodies. Research has been done.
- Various physiological activities have been reported for ⁇ -amino acids such as cysteine, arginine, valine, threonine, serine and glycine existing in living bodies, and peptide derivatives containing ⁇ -amino acids as constituent elements.
- the physiological activities of ⁇ -amino acids and derivatives thereof include anti-aging action (see, for example, Patent Document 1), moisturizing action (for example, see Patent Document 2), whitening action (for example, Patent Document) even in the cosmetic field alone.
- amino acids and derivatives thereof are not only effective, but also have excellent solubility, separation and water solubility, and high safety can be expected. Therefore, their incorporation into cosmetics and the like has been actively studied.
- physiological activities such as anti-aging, moisturizing or whitening action of the ⁇ -amino acid and its derivatives are not sufficiently feasible, and research on ⁇ -amino acids and their derivatives that enhance the physiological activity continues. It has been broken.
- glycine derivatives belonging to ⁇ -amino acids betaine-type amphoteric surfactant activity or semipolar surfactant activity (see, for example, Patent Document 4 and Patent Document 5) can be applied to N-acyl and N-long chain alkylglycine derivatives. ) And the like, and is blended as a surfactant in cosmetics, cleaning agents, hair styling agents, toothpastes, and the like.
- whitening action for example, refer to Patent Document 6
- N-alkylglycine derivative especially N-methylglycine (sarcosine), wrinkle improving action ( For example, see Patent Document 7), and no whitening effect is known at all.
- JP 2004-115438 A Japanese Patent Laid-Open No. 2002-087928 Japanese Patent Laid-Open No. 05-301811 JP 2002-322491 A JP 2001-261431 A JP 2004-315384 A WO2007 / 013662 pamphlet
- the present invention has been made under such circumstances, and provides a pigmentation-improving agent having a novel mother nucleus, which is excellent in pigmentation-improving action, and a skin external preparation containing the pigmentation-improving agent.
- the task is to do.
- a pigmentation-improving agent comprising a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof. (Wherein R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.)
- the compound represented by the general formula (1) is a compound represented by the following general formula (2) and / or a pharmacologically acceptable salt thereof, ⁇ 1>
- the pigmentation-improving agent described in 1. In the formula, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms.
- ⁇ 3> The pigmentation-improving agent according to ⁇ 2>, wherein the compound represented by the general formula (2) is N-methylglycine and / or a pharmacologically acceptable salt thereof. .
- a skin external preparation comprising the pigmentation-improving agent according to any one of ⁇ 1> to ⁇ 3>.
- ⁇ 5> The external skin preparation according to ⁇ 4>, wherein the pigmentation-improving agent is contained in an amount of 0.0001% by mass to 20% by mass with respect to the total amount of the external skin preparation.
- ⁇ 6> The external preparation for skin according to ⁇ 4> or ⁇ 5>, which is a cosmetic (including quasi-drugs).
- ⁇ 7> The external preparation for skin according to any one of ⁇ 4> to ⁇ 6>, which is in the form of a water-in-oil emulsifier.
- ⁇ 8> The external preparation for skin according to any one of ⁇ 4> to ⁇ 7>, which is for whitening.
- a method for improving skin pigmentation wherein the compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof is administered to a site where pigmentation improvement is necessary.
- a method characterized by that. wherein R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.
- the pigmentation-improving agent of the present invention comprises the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof.
- the pigmentation-improving agent of the present invention has the effect of preventing pigmentation in addition to the effect of thinning and eliminating the pigmentation that has already been formed, and the compound having the effect of preventing pigmentation. It is included in the pigmentation improving agent of the invention. That is, the pigmentation-improving agent of the present invention is a compound that is contained in the general formula (1) and has an action of preventing or improving pigmentation.
- the pigmentation-improving action in the present invention can be determined, for example, based on whether or not it has a pigmentation-inhibiting action in “Evaluation of pigmentation-inhibiting action by ultraviolet irradiation using colored guinea pigs” described in Examples below.
- having a pigmentation inhibitory action means that the evaluation substance administration group has a pigmentation inhibitory action compared with the control group (solvent control group). . It is preferable that the pigmentation inhibitor of the present invention has a statistically significant difference in the pigmentation inhibitory action of the evaluation substance administration group as compared with the control group.
- the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof has an excellent effect of preventing or improving pigmentation, and is soluble in a hydrophilic or lipophilic medium. It is easy to formulate into a topical skin preparation. Furthermore, since it is excellent in stability and skin retention in the preparation, it exhibits an excellent effect in preventing or improving pigmentation. Also, the pigmentation prevention or amelioration action of such compounds is the inhibition of tyrosinase activity such as tyrosinase enzyme inhibitory action, tyrosinase gene expression inhibitory action, tyrosinase protein expression inhibitory action, tyrosinase-related proteolytic action, etc.
- tyrosinase activity such as tyrosinase enzyme inhibitory action, tyrosinase gene expression inhibitory action, tyrosinase protein expression inhibitory action, tyrosinase-related proteolytic action, etc.
- melanin production is suppressed by a new mechanism of action. Therefore, it exhibits an improving action on pigmentation that cannot be improved by glycine or acylglycine.
- R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms
- R 2 represents a hydrogen atom or a linear or branched group having 1 to 4 carbon atoms.
- R 1 is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group.
- Specific examples of R 1 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group and the like.
- R 2 is preferably a hydrogen atom or a methyl group.
- R 2 include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group.
- R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms.
- R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms.
- R 3 is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group.
- Specific examples of R 3 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group and the like.
- Specific examples of the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof include N-methylglycine, N-ethylglycine, N- (n-propyl) glycine, N- (Isopropyl) glycine, N- (n-butyl) glycine, N- (isobutyl) glycine, N- (tert-butyl) glycine, N- (n-pentylglycine), N- (n-hexylglycine) and their Examples thereof include pharmacologically acceptable salts. More preferably, N-methylglycine, N-ethylglycine, and pharmacologically acceptable salts thereof can be used.
- the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof has a particularly excellent pigmentation preventing or improving action. Moreover, it is excellent in solubility in a hydrophilic or lipophilic medium, and can be easily formulated into a skin external preparation or the like. Furthermore, it has excellent stability and skin retention in the preparation, and exhibits excellent effects in preventing or improving pigmentation.
- Specific examples of the compound represented by the general formula (1) that do not belong to the compound represented by the general formula (2) include N-methylglycine methyl ester, N-methylglycine. Ethyl ester, N-methyl glycine propyl ester, N-methyl glycine butyl ester, N-ethyl glycine methyl ester, N-ethyl glycine ethyl ester, N-ethyl glycine propyl ester, N-ethyl glycine butyl ester, N-propyl glycine methyl Ester, N-propyl glycine ethyl ester, N-propyl glycine propyl ester, N-propyl glycine butyl ester, N-butyl glycine methyl ester, N-butyl glycine ethyl ester, N-butyl glycine propyl ester, N-butyl
- the compound represented by the general formula (1) or the general formula (2) is a commercially available glycine derivative having a protecting group such as a tert-butoxycarbonyl group (Boc group), for example, anhydrous N, It can be produced by performing an alkylation reaction using sodium hydride and the corresponding alkyl halide in an N-dimethylformamide solvent, and then removing the protective group by a deprotection reaction. Moreover, you may use what is marketed and can also purchase from reagent manufacturers, such as Tokyo Chemical Industry Co., Ltd. Such a compound can be used as it is as a pigmentation-improving agent, but can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt.
- a protecting group such as a tert-butoxycarbonyl group (Boc group)
- Boc group tert-butoxycarbonyl group
- inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate; maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; triethylamine salt, triethanolamine salt, ammonium salt, And organic amine salts such as monoethanolamine salt and piperidine salt; basic amino acid salts such as lysine salt and alginate;
- the pigmentation-improving agent of the present invention thus obtained can be used as an active ingredient of an external preparation for skin because it has an excellent pigmentation-preventing and improving action.
- the mechanism of action of the pigmentation-improving agent of the present invention is unknown in detail, tyrosinase activity inhibitory action such as tyrosinase enzyme inhibitory action, tyrosinase gene expression inhibitory action, tyrosinase-related proteolytic action, etc.
- melanin production-suppressing effect by inhibiting melanin transfer by suppressing dendrite elongation in melanocytes, it is estimated that melanin production is suppressed by a new mechanism of action.
- the total amount of the pigmentation-improving agent of the present invention is 0.0001% by mass to 20% by mass, more preferably 0%, based on the total amount of the external preparation for skin.
- the content is preferably 0.001 to 10% by mass, more preferably 0.005 to 5% by mass.
- the pigmentation-improving agent of the present invention and the external preparation for skin containing the pigmentation-improving agent are for preventing or improving pigmentation, and “for preventing or improving pigmentation” is achieved by preventing or improving pigmentation.
- Applications mainly intended for the purpose, for example, "whitening", “stain improvement”, and the like are included.
- the external preparation for skin of the present invention contains the pigmentation-improving agent of the present invention.
- the skin external preparation of the present invention may contain only one type of pigmentation-improving agent of the present invention, or may contain two or more types in combination.
- the preparation for external use of the skin of the present invention is for prevention or improvement of pigment-related abnormalities such as “for pigmentation prevention or improvement”, “for whitening”, “for spot improvement”, etc. by incorporating the pigmentation improving agent of the present invention. As effective.
- the skin external preparation of the present invention can contain optional components usually used in skin external preparations in addition to the pigmentation-improving agent that is an essential component.
- optional ingredients include hydrocarbons such as squalane, petrolatum, microcrystalline wax, esters such as jojoba oil, carnauba wax, octyldodecyl oleate, triglycerides such as olive oil, beef tallow and coconut oil.
- Fatty acids such as stearic acid, oleic acid, retinoic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol, anionic surface activity such as sulfosuccinic acid ester and sodium polyoxyethylene alkyl sulfate Agents, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts thereof, polyoxyethylene alkyl ethers, polyoxyethylenes
- Nonionic surfactants such as fatty acid esters, polyhydric alcohols such as polyethylene glycol, glycerin, 1,3-butanediol, thickening / gelling agents, antioxidants, UV absorbers, Coloring agents, preservatives, powders and the like can be contained. Manufacture can be accomplished without difficulty by treating these
- the pigmentation-improving agent and optional components of the present invention can be processed according to conventional methods to prepare lotions, emulsions, essences, creams, pack cosmetics, cleaning agents, and the like.
- the external preparation for skin of the present invention can be used in any dosage form that can be adapted to the skin, but since the active ingredient penetrates the skin and exerts its effect, Good dosage forms such as lotion, emulsion, cream and essence are preferred.
- Compound 1 and Compound 2 can be synthesized, for example, according to the method described in “Basics and Experiments of Peptide Synthesis” (Maruzen Co., Ltd.). Boc-Gly (Peptide Institute, Inc.) was used as a starting material, dissolved in anhydrous N, N-dimethylformamide (Wako Pure Chemical Industries, Ltd.), sodium hydride and the corresponding alkyl halide (methyl iodide, iodide) After carrying out an alkylation reaction using ethyl, Wako Pure Chemical Industries, Ltd.), a deprotection reaction with an acid such as hydrochloric acid, and further a free base is obtained by ion exchange to obtain the desired compound 1 or compound 2. Can be obtained. Such a compound can also be purchased as a commercially available reagent from a reagent manufacturer such as Tokyo Chemical Industry Co., Ltd. In the examples of the present invention, compounds purchased from Tokyo Chemical Industry Co., Ltd. were used.
- Example 1 Inhibition of pigmentation by ultraviolet irradiation using colored guinea pig>
- the back skin of eight colored guinea pigs was removed and shaved with an electric clipper and shaver, and this part was covered with a black cloth with 2 x 2 cm irradiation windows on the left and right, and then the FL20S / E30 lamp was used as the light source.
- 300 mJ / cm 2 of ultraviolet rays were irradiated. This operation was repeated on the first day, the third day, the fifth day, and the eighth day of the test to induce pigmentation at two test sites.
- Compound 1 was dissolved in a 70% (v / v) ethanol aqueous solution to 5% (w / v) to prepare a Compound 1-containing ethanol aqueous solution.
- a 70% (v / v) ethanol aqueous solution was prepared as a control. From the end of the ultraviolet irradiation on the first day of the test, application of the compound 1-containing ethanol aqueous solution and the ethanol aqueous solution was started. Application was performed once a day at a predetermined test site by 30 ⁇ L, and this was continuously carried out every day for 5 weeks (up to the 35th day of the test).
- Example 2 External preparation for skin of the present invention (Lotion 1), Comparative Examples 1 and 2>
- a cosmetic (lotion) which is an external preparation for skin of the present invention was prepared. That is, the prescription ingredients were heated to 80 ° C., stirred, dissolved, stirred and cooled to obtain a cosmetic (lotion 1).
- the obtained lotion 1 was a uniform composition and a very stable preparation.
- lotion 2 of Comparative Example 1 in which “pigmentation improving agent of the present invention (compound 1)” was replaced with water and arbutin were replaced with “pigmentation improving agent of the present invention (compound 1)”.
- Lotion 3 of Comparative Example 2 was also prepared.
- Example 3 External preparation for skin of the present invention (Cream 1)> A water-in-oil cream was prepared according to the formulation shown in Table 3. That is, the ingredients (a) and (b) were each heated to 80 ° C., and (b) was gradually added to the emulsion, emulsified, and the particles were homogenized with a homogenizer, followed by stirring and cooling to obtain a cosmetic (Cream 1). It was. The obtained cream 1 was a very stable preparation without causing separation.
- Example 4 External preparation for skin of the present invention
- a cosmetic milky lotion 1 which is a composition for external use of the skin of the present invention was prepared. That is, the ingredients of A, B, and C are heated to 80 ° C., and after neutralizing and adding C to B, the emulsion particles are homogenized with a homomixer. (Emulsion 1) was obtained. The obtained emulsion 1 was a very stable preparation without separation.
- ⁇ Test Example 2 Inhibition of pigmentation by ultraviolet irradiation of lotions 1 to 3 in humans> Using the skin external preparations of Lotion 1, Lotion 2 (Comparative Example 1) and Lotion 3 (Comparative Example 2), the pigmentation inhibitory effect was examined. A panel of 1.5 cm ⁇ 1.5 cm was divided into two upper and lower tiers on the inner side of the upper arm of the panelists who participated freely. The site provided with the minimum amount of erythema (1 MED) was irradiated once a day for 3 consecutive days. From the end of the ultraviolet irradiation on the first day of the test, 50 ⁇ L of lotion was applied once a day for 35 consecutive days. One of the four sites was an untreated site.
- erythema (1 MED)
- the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.) 24 hours after the completion of 35 times of application, and the L of the treated site relative to the L * value of the untreated site.
- * Value difference ( ⁇ L * ) value was calculated.
- the L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ⁇ L * value, the better the pigmentation.
- the results are shown in Table 5. This shows that the cosmetic (lotion 1) which is an external preparation for skin of the present invention has an excellent pigmentation-suppressing effect. This is considered to be due to the pigmentation inhibitory action of Compound 1 contained in Lotion 1.
- the present invention can be applied to skin external preparations such as whitening cosmetics.
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Abstract
Disclosed are: a pigmentation-ameliorating agent having a novel mother nucleus; and an external preparation for the skin, which comprises the pigmentation-ameliorating agent.
Specifically disclosed are: a pigmentation-ameliorating agent comprising a compound represented by general formula (1) and/or a pharmacologically acceptable salt thereof, which has an excellent pigmentation-ameliorating activity; and an external preparation for the skin, which can be used for skin whitening purposes and comprises the pigmentation-ameliorating agent.
(In the formula, R1 represents a linear or branched alkyl group having 1 to 6 carbon atoms; R2 represents a hydrogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms.)
Description
本発明は、新規色素沈着改善剤、及び化粧料に好適な皮膚外用剤に関し、詳しくは、下記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩よりなる色素沈着改善剤、及び該色素沈着改善剤を含有する皮膚外用剤に関する。なお、本発明の説明において、化粧料との用語は医薬部外品を含むものとして定義する。
（式中、Ｒ1は、炭素数１～６の直鎖又は分岐のアルキル基を表し、Ｒ2は、水素原子、炭素数１～４の直鎖又は分岐のアルキル基を表す。）
The present invention relates to a novel pigmentation-improving agent and a skin external preparation suitable for cosmetics, and specifically comprises a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof. The present invention relates to a pigmentation-improving agent and a skin external preparation containing the pigmentation-improving agent. In the description of the present invention, the term cosmetic is defined as including quasi drugs.
(Wherein R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.)
皮膚における日焼け後の色素沈着、シミ、肝斑、老人性色素斑などは、皮膚内に存在する色素細胞（メラノサイト）の活性化によりメラニン生成が著しく亢進した状態である。これらの皮膚色素トラブルの発生・悪化を防止又は改善する作用を有する成分としては、アスコルビン酸類、過酸化水素、コロイド硫黄、グルタチオン、ハイドロキノン、カテコ－ル等の美白作用を有する化合物（美白剤）がよく知られている（例えば、非特許文献１及び非特許文献２を参照）。そしてこれらの有効成分を配合した皮膚外用剤が広く使用されている。
現在、美白剤として知られる化合物が有する作用機序としては、チロシナ－ゼ酵素阻害、チロシナ－ゼ関連蛋白分解、メラノサイトにおけるデンドライト伸長抑制によるメラニン移送阻害、などの多様な作用機序が報告されており、それぞれの作用機序に対する標的分子が存する。標的分子に適切に作用し、高い美白効果を発現するためには、個々の標的分子に対し適切に相互作用する有機低分子が有用である。また、それぞれの標的分子に適切に相互作用する有機低分子の構造上の特性は、標的分子それぞれに異なっているため、有機低分子が示す薬理作用を最大限に生かすために化学構造最適化に関する研究が盛んに行われている。また、現在の美白剤の研究は、既存の標的分子に対し高い有効性及び選択性を有する化合物を対象とするほか、その対象が同時に複数の美白作用機序に働きかける化合物、更には、新たな作用機序を有する化合物等に広がっている。 Pigmentation, blemishes, liver spots, senile pigment spots, etc. after sunburn in the skin are a state in which melanin production is remarkably enhanced by activation of pigment cells (melanocytes) present in the skin. Ingredients that have the action of preventing or improving the occurrence and deterioration of skin pigment troubles include compounds having a whitening action (whitening agents) such as ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, and catechol. It is well known (for example, see Non-Patent Document 1 and Non-Patent Document 2). And skin external preparations containing these active ingredients are widely used.
Currently, various mechanisms of action of compounds known as whitening agents have been reported, including tyrosinase enzyme inhibition, tyrosinase-related proteolysis, and inhibition of melanin transport by suppressing dendrite elongation in melanocytes. There are target molecules for each mechanism of action. In order to appropriately act on the target molecule and to exhibit a high whitening effect, a small organic molecule that interacts appropriately with each target molecule is useful. In addition, since the structural characteristics of small organic molecules that interact appropriately with each target molecule are different for each target molecule, it is important to optimize the chemical structure in order to maximize the pharmacological effects of the small organic molecules. There is a lot of research. In addition, the current whitening agent research targets compounds that have high efficacy and selectivity against existing target molecules, as well as compounds that simultaneously act on multiple whitening mechanisms, as well as new It spreads to compounds that have a mechanism of action.
現在、美白剤として知られる化合物が有する作用機序としては、チロシナ－ゼ酵素阻害、チロシナ－ゼ関連蛋白分解、メラノサイトにおけるデンドライト伸長抑制によるメラニン移送阻害、などの多様な作用機序が報告されており、それぞれの作用機序に対する標的分子が存する。標的分子に適切に作用し、高い美白効果を発現するためには、個々の標的分子に対し適切に相互作用する有機低分子が有用である。また、それぞれの標的分子に適切に相互作用する有機低分子の構造上の特性は、標的分子それぞれに異なっているため、有機低分子が示す薬理作用を最大限に生かすために化学構造最適化に関する研究が盛んに行われている。また、現在の美白剤の研究は、既存の標的分子に対し高い有効性及び選択性を有する化合物を対象とするほか、その対象が同時に複数の美白作用機序に働きかける化合物、更には、新たな作用機序を有する化合物等に広がっている。 Pigmentation, blemishes, liver spots, senile pigment spots, etc. after sunburn in the skin are a state in which melanin production is remarkably enhanced by activation of pigment cells (melanocytes) present in the skin. Ingredients that have the action of preventing or improving the occurrence and deterioration of skin pigment troubles include compounds having a whitening action (whitening agents) such as ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, and catechol. It is well known (for example, see Non-Patent Document 1 and Non-Patent Document 2). And skin external preparations containing these active ingredients are widely used.
Currently, various mechanisms of action of compounds known as whitening agents have been reported, including tyrosinase enzyme inhibition, tyrosinase-related proteolysis, and inhibition of melanin transport by suppressing dendrite elongation in melanocytes. There are target molecules for each mechanism of action. In order to appropriately act on the target molecule and to exhibit a high whitening effect, a small organic molecule that interacts appropriately with each target molecule is useful. In addition, since the structural characteristics of small organic molecules that interact appropriately with each target molecule are different for each target molecule, it is important to optimize the chemical structure in order to maximize the pharmacological effects of the small organic molecules. There is a lot of research. In addition, the current whitening agent research targets compounds that have high efficacy and selectivity against existing target molecules, as well as compounds that simultaneously act on multiple whitening mechanisms, as well as new It spreads to compounds that have a mechanism of action.
アミノ酸は、その分子中にアミノ基とカルボキシル基の両方の官能基を有する有機化合物の総称であり、特に、α－アミノ酸は、生体における多様な機能を発現するための蛋白質の構成ユニットとして盛んに研究がなされている。生体に存在するシステイン、アルギニン、バリン、トレオニン、セリン、グリシン等のα－アミノ酸、更には、α－アミノ酸を構成要素に含むペプチド誘導体には、様々な生理活性が報告されている。
α－アミノ酸及びその誘導体が有する生理活性としては、化粧品分野だけでも、抗老化作用（例えば、特許文献１を参照）、保湿作用（例えば、特許文献２を参照）、美白作用（例えば、特許文献３を参照）及び界面活性化作用等の作用が知られており、これらの効果を目的として化粧料等に配合されている。また一般に、アミノ酸及びその誘導体には、有効性に加え、溶解性、取り分け、水溶性に優れるほか、高い安全性が期待出来るため、化粧品等への配合が盛んに研究されている。しかしながら、前記α－アミノ酸及びその誘導体が有する抗老化、保湿又は美白作用等の生理活性は、十分に実行性があるとは言い難く、生理活性を高めるα－アミノ酸及びその誘導体に関する研究が引き続き行われている。 Amino acids are a general term for organic compounds having both amino and carboxyl functional groups in their molecules. In particular, α-amino acids are actively used as protein structural units for expressing various functions in living bodies. Research has been done. Various physiological activities have been reported for α-amino acids such as cysteine, arginine, valine, threonine, serine and glycine existing in living bodies, and peptide derivatives containing α-amino acids as constituent elements.
The physiological activities of α-amino acids and derivatives thereof include anti-aging action (see, for example, Patent Document 1), moisturizing action (for example, see Patent Document 2), whitening action (for example, Patent Document) even in the cosmetic field alone. 3) and surface activation effects are known, and are formulated in cosmetics and the like for these effects. In general, amino acids and derivatives thereof are not only effective, but also have excellent solubility, separation and water solubility, and high safety can be expected. Therefore, their incorporation into cosmetics and the like has been actively studied. However, the physiological activities such as anti-aging, moisturizing or whitening action of the α-amino acid and its derivatives are not sufficiently feasible, and research on α-amino acids and their derivatives that enhance the physiological activity continues. It has been broken.
α－アミノ酸及びその誘導体が有する生理活性としては、化粧品分野だけでも、抗老化作用（例えば、特許文献１を参照）、保湿作用（例えば、特許文献２を参照）、美白作用（例えば、特許文献３を参照）及び界面活性化作用等の作用が知られており、これらの効果を目的として化粧料等に配合されている。また一般に、アミノ酸及びその誘導体には、有効性に加え、溶解性、取り分け、水溶性に優れるほか、高い安全性が期待出来るため、化粧品等への配合が盛んに研究されている。しかしながら、前記α－アミノ酸及びその誘導体が有する抗老化、保湿又は美白作用等の生理活性は、十分に実行性があるとは言い難く、生理活性を高めるα－アミノ酸及びその誘導体に関する研究が引き続き行われている。 Amino acids are a general term for organic compounds having both amino and carboxyl functional groups in their molecules. In particular, α-amino acids are actively used as protein structural units for expressing various functions in living bodies. Research has been done. Various physiological activities have been reported for α-amino acids such as cysteine, arginine, valine, threonine, serine and glycine existing in living bodies, and peptide derivatives containing α-amino acids as constituent elements.
The physiological activities of α-amino acids and derivatives thereof include anti-aging action (see, for example, Patent Document 1), moisturizing action (for example, see Patent Document 2), whitening action (for example, Patent Document) even in the cosmetic field alone. 3) and surface activation effects are known, and are formulated in cosmetics and the like for these effects. In general, amino acids and derivatives thereof are not only effective, but also have excellent solubility, separation and water solubility, and high safety can be expected. Therefore, their incorporation into cosmetics and the like has been actively studied. However, the physiological activities such as anti-aging, moisturizing or whitening action of the α-amino acid and its derivatives are not sufficiently feasible, and research on α-amino acids and their derivatives that enhance the physiological activity continues. It has been broken.
α－アミノ酸に属するグリシンの誘導体に関しては、Ｎ－アシル及びＮ－長鎖アルキルグリシン誘導体に、ベタイン型両性界面活性作用、又は、半極性界面活性作用（例えば、特許文献４、特許文献５を参照）などの界面活性化作用が知られ、化粧料、洗浄剤、整髪剤、歯磨きなどに界面活性剤として配合されている。また、グリシン及びそのアシル誘導体に関しては、美白作用（例えば、特許文献６を参照）が報告されているが、Ｎ－アルキルグリシン誘導体、取り分け、Ｎ－メチルグリシン（サルコシン）に関しては、シワ改善作用（例えば、特許文献７を参照）が知られているのみであり、美白作用に関しては、全く知られていない。
As for glycine derivatives belonging to α-amino acids, betaine-type amphoteric surfactant activity or semipolar surfactant activity (see, for example, Patent Document 4 and Patent Document 5) can be applied to N-acyl and N-long chain alkylglycine derivatives. ) And the like, and is blended as a surfactant in cosmetics, cleaning agents, hair styling agents, toothpastes, and the like. In addition, whitening action (for example, refer to Patent Document 6) has been reported for glycine and its acyl derivative, but for N-alkylglycine derivative, especially N-methylglycine (sarcosine), wrinkle improving action ( For example, see Patent Document 7), and no whitening effect is known at all.
本発明は、この様な状況下において為されたものであり、色素沈着改善作用に優れた、新規母核を有する色素沈着改善剤、並びに、当該色素沈着改善剤を含有した皮膚外用剤を提供することを課題とする。
The present invention has been made under such circumstances, and provides a pigmentation-improving agent having a novel mother nucleus, which is excellent in pigmentation-improving action, and a skin external preparation containing the pigmentation-improving agent. The task is to do.
この様な状況を鑑みて、本発明者等は、化粧料（ただし、医薬部外品を含む）に好適な、色素沈着改善剤を求めて鋭意努力を重ねた結果、一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩が、色素沈着改善作用に優れることを見出し、本発明を完成させるに至った。本発明は、以下に示す通りである。
＜１＞ 下記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩よりなる色素沈着改善剤。
（式中、Ｒ1は、炭素数１～６の直鎖又は分岐のアルキル基を表し、Ｒ2は、水素原子、炭素数１～４の直鎖又は分岐のアルキル基を表す。）
In view of such circumstances, the present inventors have made extensive efforts to find a pigmentation-improving agent suitable for cosmetics (including quasi-drugs). As a result, the general formula (1) The compounds represented and / or pharmacologically acceptable salts thereof have been found to be excellent in pigmentation-improving action, and the present invention has been completed. The present invention is as follows.
<1> A pigmentation-improving agent comprising a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof.
(Wherein R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.)
＜１＞ 下記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩よりなる色素沈着改善剤。
<1> A pigmentation-improving agent comprising a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof.
＜２＞ 前記一般式（１）に表される化合物が、下記一般式（２）に表される化合物及び／又はその薬理学的に許容される塩であることを特徴とする、＜１＞に記載の色素沈着改善剤。
（式中、Ｒ3は、炭素数１～６の直鎖又は分岐のアルキル基を表す。）
<2> The compound represented by the general formula (1) is a compound represented by the following general formula (2) and / or a pharmacologically acceptable salt thereof, <1> The pigmentation-improving agent described in 1.
(In the formula, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms.)
＜３＞ 前記一般式（２）に表される化合物が、Ｎ－メチルグリシン及び／又はその薬理学的に許容される塩であることを特徴とする、＜２＞に記載の色素沈着改善剤。
＜４＞ ＜１＞～＜３＞のいずれかに記載の色素沈着改善剤を含有することを特徴とする、皮膚外用剤。
＜５＞ 皮膚外用剤全量に対し、前記の色素沈着改善剤を、０．０００１質量％～２０質量％含有することを特徴とする、＜４＞に記載の皮膚外用剤。
＜６＞ 化粧料（但し、医薬部外品を含む）であることを特徴とする、＜４＞又は＜５＞に記載の皮膚外用剤。
＜７＞ 油中水乳化剤形であることを特徴とする、＜４＞～＜６＞のいずれかに記載の皮膚外用剤。
＜８＞ 美白用であることを特徴とする、＜４＞～＜７＞のいずれかに記載の皮膚外用剤。 <3> The pigmentation-improving agent according to <2>, wherein the compound represented by the general formula (2) is N-methylglycine and / or a pharmacologically acceptable salt thereof. .
<4> A skin external preparation comprising the pigmentation-improving agent according to any one of <1> to <3>.
<5> The external skin preparation according to <4>, wherein the pigmentation-improving agent is contained in an amount of 0.0001% by mass to 20% by mass with respect to the total amount of the external skin preparation.
<6> The external preparation for skin according to <4> or <5>, which is a cosmetic (including quasi-drugs).
<7> The external preparation for skin according to any one of <4> to <6>, which is in the form of a water-in-oil emulsifier.
<8> The external preparation for skin according to any one of <4> to <7>, which is for whitening.
＜４＞ ＜１＞～＜３＞のいずれかに記載の色素沈着改善剤を含有することを特徴とする、皮膚外用剤。
＜５＞ 皮膚外用剤全量に対し、前記の色素沈着改善剤を、０．０００１質量％～２０質量％含有することを特徴とする、＜４＞に記載の皮膚外用剤。
＜６＞ 化粧料（但し、医薬部外品を含む）であることを特徴とする、＜４＞又は＜５＞に記載の皮膚外用剤。
＜７＞ 油中水乳化剤形であることを特徴とする、＜４＞～＜６＞のいずれかに記載の皮膚外用剤。
＜８＞ 美白用であることを特徴とする、＜４＞～＜７＞のいずれかに記載の皮膚外用剤。 <3> The pigmentation-improving agent according to <2>, wherein the compound represented by the general formula (2) is N-methylglycine and / or a pharmacologically acceptable salt thereof. .
<4> A skin external preparation comprising the pigmentation-improving agent according to any one of <1> to <3>.
<5> The external skin preparation according to <4>, wherein the pigmentation-improving agent is contained in an amount of 0.0001% by mass to 20% by mass with respect to the total amount of the external skin preparation.
<6> The external preparation for skin according to <4> or <5>, which is a cosmetic (including quasi-drugs).
<7> The external preparation for skin according to any one of <4> to <6>, which is in the form of a water-in-oil emulsifier.
<8> The external preparation for skin according to any one of <4> to <7>, which is for whitening.
＜９＞ 皮膚の色素沈着を改善する方法であって、下記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容させる塩を、色素沈着改善が必要な部位に投与することを特徴とする、方法。
（式中、Ｒ1は、炭素数１～６の直鎖又は分岐のアルキル基を表し、Ｒ2は、水素原子、炭素数１～４の直鎖又は分岐のアルキル基を表す。）
<9> A method for improving skin pigmentation, wherein the compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof is administered to a site where pigmentation improvement is necessary. A method characterized by that.
(Wherein R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.)
＜本発明の色素沈着改善剤＞
本発明の色素沈着改善剤は、前記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩よりなることを特徴とする。本発明の色素沈着改善剤は、既に形成された色素沈着を薄くする作用及び消去する色素沈着改善作用に加え、色素沈着を予防する作用を有し、色素沈着を予防する作用を有する化合物も本発明の色素沈着改善剤に包含される。すなわち、本発明の色素沈着改善剤は、前記一般式（１）に含まれ、かつ色素沈着を予防又は改善する作用を有する化合物である。
本発明における色素沈着改善作用は、例えば、後記実施例で説明する「有色モルモットを用いた紫外線照射による色素沈着抑制作用評価」において、色素沈着抑制作用を有するか否かにより判断できる。後記実施例の色素沈着抑制作用評価において、色素沈着抑制作用を有するとは、コントロ－ル群（溶媒対照群）と比較して、評価物質投与群に色素沈着抑制作用が認められることを意味する。本発明の色素沈着抑制剤は、コントロ－ル群と比較して、評価物質投与群の色素沈着抑制作用に統計的な有意差が認められることが好ましい。 <Pigmentation-improving agent of the present invention>
The pigmentation-improving agent of the present invention comprises the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof. The pigmentation-improving agent of the present invention has the effect of preventing pigmentation in addition to the effect of thinning and eliminating the pigmentation that has already been formed, and the compound having the effect of preventing pigmentation. It is included in the pigmentation improving agent of the invention. That is, the pigmentation-improving agent of the present invention is a compound that is contained in the general formula (1) and has an action of preventing or improving pigmentation.
The pigmentation-improving action in the present invention can be determined, for example, based on whether or not it has a pigmentation-inhibiting action in “Evaluation of pigmentation-inhibiting action by ultraviolet irradiation using colored guinea pigs” described in Examples below. In the pigmentation inhibitory action evaluation of Examples described later, having a pigmentation inhibitory action means that the evaluation substance administration group has a pigmentation inhibitory action compared with the control group (solvent control group). . It is preferable that the pigmentation inhibitor of the present invention has a statistically significant difference in the pigmentation inhibitory action of the evaluation substance administration group as compared with the control group.
本発明の色素沈着改善剤は、前記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩よりなることを特徴とする。本発明の色素沈着改善剤は、既に形成された色素沈着を薄くする作用及び消去する色素沈着改善作用に加え、色素沈着を予防する作用を有し、色素沈着を予防する作用を有する化合物も本発明の色素沈着改善剤に包含される。すなわち、本発明の色素沈着改善剤は、前記一般式（１）に含まれ、かつ色素沈着を予防又は改善する作用を有する化合物である。
本発明における色素沈着改善作用は、例えば、後記実施例で説明する「有色モルモットを用いた紫外線照射による色素沈着抑制作用評価」において、色素沈着抑制作用を有するか否かにより判断できる。後記実施例の色素沈着抑制作用評価において、色素沈着抑制作用を有するとは、コントロ－ル群（溶媒対照群）と比較して、評価物質投与群に色素沈着抑制作用が認められることを意味する。本発明の色素沈着抑制剤は、コントロ－ル群と比較して、評価物質投与群の色素沈着抑制作用に統計的な有意差が認められることが好ましい。 <Pigmentation-improving agent of the present invention>
The pigmentation-improving agent of the present invention comprises the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof. The pigmentation-improving agent of the present invention has the effect of preventing pigmentation in addition to the effect of thinning and eliminating the pigmentation that has already been formed, and the compound having the effect of preventing pigmentation. It is included in the pigmentation improving agent of the invention. That is, the pigmentation-improving agent of the present invention is a compound that is contained in the general formula (1) and has an action of preventing or improving pigmentation.
The pigmentation-improving action in the present invention can be determined, for example, based on whether or not it has a pigmentation-inhibiting action in “Evaluation of pigmentation-inhibiting action by ultraviolet irradiation using colored guinea pigs” described in Examples below. In the pigmentation inhibitory action evaluation of Examples described later, having a pigmentation inhibitory action means that the evaluation substance administration group has a pigmentation inhibitory action compared with the control group (solvent control group). . It is preferable that the pigmentation inhibitor of the present invention has a statistically significant difference in the pigmentation inhibitory action of the evaluation substance administration group as compared with the control group.
また、前記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩は、優れた色素沈着予防又は改善作用を有することに加え、親水性又は親油性媒体に対する溶解性に優れ、皮膚外用剤等への製剤化が容易である。さらに、製剤中における安定性及び皮膚貯留性に優れるため、色素沈着の予防又は改善に優れた効果を発揮する。
また、かかる化合物の色素沈着予防又は改善作用は、チロシナ－ゼ酵素阻害作用、チロシナ－ゼ遺伝子発現抑制作用、チロシナ－ゼ蛋白発現抑制作用、チロシナ－ゼ関連蛋白質分解作用等のチロシナ－ゼ活性阻害作用、及びメラノサイトにおけるデンドライト伸長抑制によるメラニン移送阻害等によるメラニン産生抑制作用に加え、新たな作用機序によりメラニン産生を抑制することが推定される。そのため、グリシンやアシルグリシンでは改善しない色素沈着に対して改善作用を示すものである。 In addition, the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof has an excellent effect of preventing or improving pigmentation, and is soluble in a hydrophilic or lipophilic medium. It is easy to formulate into a topical skin preparation. Furthermore, since it is excellent in stability and skin retention in the preparation, it exhibits an excellent effect in preventing or improving pigmentation.
Also, the pigmentation prevention or amelioration action of such compounds is the inhibition of tyrosinase activity such as tyrosinase enzyme inhibitory action, tyrosinase gene expression inhibitory action, tyrosinase protein expression inhibitory action, tyrosinase-related proteolytic action, etc. In addition to the action and the action of inhibiting melanin production by inhibiting melanin transfer by inhibiting dendrite elongation in melanocytes, it is estimated that melanin production is suppressed by a new mechanism of action. Therefore, it exhibits an improving action on pigmentation that cannot be improved by glycine or acylglycine.
また、かかる化合物の色素沈着予防又は改善作用は、チロシナ－ゼ酵素阻害作用、チロシナ－ゼ遺伝子発現抑制作用、チロシナ－ゼ蛋白発現抑制作用、チロシナ－ゼ関連蛋白質分解作用等のチロシナ－ゼ活性阻害作用、及びメラノサイトにおけるデンドライト伸長抑制によるメラニン移送阻害等によるメラニン産生抑制作用に加え、新たな作用機序によりメラニン産生を抑制することが推定される。そのため、グリシンやアシルグリシンでは改善しない色素沈着に対して改善作用を示すものである。 In addition, the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof has an excellent effect of preventing or improving pigmentation, and is soluble in a hydrophilic or lipophilic medium. It is easy to formulate into a topical skin preparation. Furthermore, since it is excellent in stability and skin retention in the preparation, it exhibits an excellent effect in preventing or improving pigmentation.
Also, the pigmentation prevention or amelioration action of such compounds is the inhibition of tyrosinase activity such as tyrosinase enzyme inhibitory action, tyrosinase gene expression inhibitory action, tyrosinase protein expression inhibitory action, tyrosinase-related proteolytic action, etc. In addition to the action and the action of inhibiting melanin production by inhibiting melanin transfer by inhibiting dendrite elongation in melanocytes, it is estimated that melanin production is suppressed by a new mechanism of action. Therefore, it exhibits an improving action on pigmentation that cannot be improved by glycine or acylglycine.
前記一般式（１）に表される化合物中、Ｒ1は、炭素数１～６の直鎖又は分岐のアルキル基を表し、Ｒ2は、水素原子、炭素数１～４の直鎖又は分岐のアルキル基を表す。前記Ｒ1は、炭素数１～４の直鎖又は分岐のアルキル基であることが好ましく、メチル基又はエチル基であることがより好ましい。Ｒ1の具体例は、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ペンチル基、ヘキシル基等が挙げられる。
前記Ｒ2は、水素原子又はメチル基であることが好ましい。Ｒ2の具体例は、水素原子、メチル基、エチル基、プロピル基、ブチル基等が挙げられる。 In the compound represented by the general formula (1), R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched group having 1 to 4 carbon atoms. Represents an alkyl group. R 1 is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group. Specific examples of R 1 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group and the like.
R 2 is preferably a hydrogen atom or a methyl group. Specific examples of R 2 include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group.
前記Ｒ2は、水素原子又はメチル基であることが好ましい。Ｒ2の具体例は、水素原子、メチル基、エチル基、プロピル基、ブチル基等が挙げられる。 In the compound represented by the general formula (1), R 1 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and R 2 represents a hydrogen atom or a linear or branched group having 1 to 4 carbon atoms. Represents an alkyl group. R 1 is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group. Specific examples of R 1 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group and the like.
R 2 is preferably a hydrogen atom or a methyl group. Specific examples of R 2 include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group.
前記一般式（１）に表される化合物の内、より好ましいものとしては、下記一般式（２）に表される化合物及び／又はそれらの薬理学的に許容される塩が好適に例示出来る。さらに好ましいものとしては、Ｎ－メチルグリシン及び／又はそれらの薬理学的に許容される塩が好適に例示出来る。
（式中、Ｒ3は、炭素数１～６の直鎖又は分岐のアルキル基を表す。）
Of the compounds represented by the general formula (1), more preferred are compounds represented by the following general formula (2) and / or pharmacologically acceptable salts thereof. More preferable examples include N-methylglycine and / or pharmacologically acceptable salts thereof.
(In the formula, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms.)
一般式（２）に表される化合物中、Ｒ3は、炭素数１～６の直鎖又は分岐のアルキル基を表す。前記Ｒ3は、炭素数１～４の直鎖又は分岐のアルキル基であることが好ましく、メチル基又はエチル基であることがより好ましい。Ｒ3の具体例は、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ペンチル基、ヘキシル基等が挙げられる。前記一般式（２）に表される化合物及び／又はそれらの薬理学的に許容される塩の具体例は、Ｎ－メチルグリシン、Ｎ－エチルグリシン、Ｎ－（n－プロピル）グリシン、Ｎ－（イソプロピル）グリシン、Ｎ－（ｎ－ブチル）グリシン、Ｎ－（イソブチル）グリシン、Ｎ－（ｔｅｒｔ－ブチル）グリシン、Ｎ－（ｎ－ペンチルグリシン）、Ｎ－（ｎ－ヘキシルグリシン）及びそれらの薬理学的に許容される塩等が挙げられる。より好ましくは、Ｎ－メチルグリシン、Ｎ－エチルグリシン及びそれらの薬理学的に許容される塩が挙げられる。前記一般式（２）に表される化合物及び／又はそれらの薬理学的に許容される塩は、特に優れた色素沈着予防又は改善作用を有する。また、親水性又は親油性媒体に対する溶解性に優れ、皮膚外用剤等への製剤化が容易である。さらに、製剤中における安定性及び皮膚貯留性に優れ、色素沈着の予防又は改善に優れた効果を発揮する。
In the compound represented by the general formula (2), R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms. R 3 is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group. Specific examples of R 3 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group and the like. Specific examples of the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof include N-methylglycine, N-ethylglycine, N- (n-propyl) glycine, N- (Isopropyl) glycine, N- (n-butyl) glycine, N- (isobutyl) glycine, N- (tert-butyl) glycine, N- (n-pentylglycine), N- (n-hexylglycine) and their Examples thereof include pharmacologically acceptable salts. More preferably, N-methylglycine, N-ethylglycine, and pharmacologically acceptable salts thereof can be used. The compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof has a particularly excellent pigmentation preventing or improving action. Moreover, it is excellent in solubility in a hydrophilic or lipophilic medium, and can be easily formulated into a skin external preparation or the like. Furthermore, it has excellent stability and skin retention in the preparation, and exhibits excellent effects in preventing or improving pigmentation.
また、前記一般式（１）に表される化合物の内、前記一般式（２）に表される化合物に属さない化合物を具体的に例示すれば、Ｎ－メチルグリシンメチルエステル、Ｎ－メチルグリシンエチルエステル、Ｎ－メチルグリシンプロピルエステル、Ｎ－メチルグリシンブチルエステル、Ｎ－エチルグリシンメチルエステル、Ｎ－エチルグリシンエチルエステル、Ｎ－エチルグリシンプロピルエステル、Ｎ－エチルグリシンブチルエステル、Ｎ－プロピルグリシンメチルエステル、Ｎ－プロピルグリシンエチルエステル、Ｎ－プロピルグリシンプロピルエステル、Ｎ－プロピルグリシンブチルエステル、Ｎ－ブチルグリシンメチルエステル、Ｎ－ブチルグリシンエチルエステル、Ｎ－ブチルグリシンプロピルエステル、Ｎ－ブチルグリシンブチルエステルなどが挙げられる。
Specific examples of the compound represented by the general formula (1) that do not belong to the compound represented by the general formula (2) include N-methylglycine methyl ester, N-methylglycine. Ethyl ester, N-methyl glycine propyl ester, N-methyl glycine butyl ester, N-ethyl glycine methyl ester, N-ethyl glycine ethyl ester, N-ethyl glycine propyl ester, N-ethyl glycine butyl ester, N-propyl glycine methyl Ester, N-propyl glycine ethyl ester, N-propyl glycine propyl ester, N-propyl glycine butyl ester, N-butyl glycine methyl ester, N-butyl glycine ethyl ester, N-butyl glycine propyl ester, N-butyl glycine butyl Ester and the like.
前記一般式（１）又は一般式（２）に表される化合物は、市販されているｔｅｒｔ－ブトキシカルボニル基（Ｂｏｃ基）等の保護基を有するグリシン誘導体を出発原料とし、例えば、無水Ｎ，Ｎ－ジメチルホルムアミド溶媒中にて、水素化ナトリウム及び対応するハロゲン化アルキルを用いたアルキル化反応を行い、その後、脱保護反応により保護基を除去することにより製造することができる。また、市販されているものを用いても良く、東京化成工業株式会社などの試薬メーカーから購入することも出来る。
かかる化合物は、そのまま色素沈着改善剤として使用することも出来るが、薬理学的に許容される酸又は塩基と共に処理し塩の形に変換し、塩として使用することも可能である。例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩などの無機酸塩；マレイン酸塩、フマル酸塩、シュウ酸塩、クエン酸塩、乳酸塩、酒石酸塩、メタンスルホン酸塩、パラトルエンスルホン酸塩、ベンゼンスルホン酸塩などの有機酸塩；ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；トリエチルアミン塩、トリエタノ－ルアミン塩、アンモニウム塩、モノエタノ－ルアミン塩、ピペリジン塩等の有機アミン塩；リジン塩、アルギン酸塩等の塩基性アミノ酸塩；などが挙げられる。 The compound represented by the general formula (1) or the general formula (2) is a commercially available glycine derivative having a protecting group such as a tert-butoxycarbonyl group (Boc group), for example, anhydrous N, It can be produced by performing an alkylation reaction using sodium hydride and the corresponding alkyl halide in an N-dimethylformamide solvent, and then removing the protective group by a deprotection reaction. Moreover, you may use what is marketed and can also purchase from reagent manufacturers, such as Tokyo Chemical Industry Co., Ltd.
Such a compound can be used as it is as a pigmentation-improving agent, but can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate; maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; triethylamine salt, triethanolamine salt, ammonium salt, And organic amine salts such as monoethanolamine salt and piperidine salt; basic amino acid salts such as lysine salt and alginate;
かかる化合物は、そのまま色素沈着改善剤として使用することも出来るが、薬理学的に許容される酸又は塩基と共に処理し塩の形に変換し、塩として使用することも可能である。例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩などの無機酸塩；マレイン酸塩、フマル酸塩、シュウ酸塩、クエン酸塩、乳酸塩、酒石酸塩、メタンスルホン酸塩、パラトルエンスルホン酸塩、ベンゼンスルホン酸塩などの有機酸塩；ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；トリエチルアミン塩、トリエタノ－ルアミン塩、アンモニウム塩、モノエタノ－ルアミン塩、ピペリジン塩等の有機アミン塩；リジン塩、アルギン酸塩等の塩基性アミノ酸塩；などが挙げられる。 The compound represented by the general formula (1) or the general formula (2) is a commercially available glycine derivative having a protecting group such as a tert-butoxycarbonyl group (Boc group), for example, anhydrous N, It can be produced by performing an alkylation reaction using sodium hydride and the corresponding alkyl halide in an N-dimethylformamide solvent, and then removing the protective group by a deprotection reaction. Moreover, you may use what is marketed and can also purchase from reagent manufacturers, such as Tokyo Chemical Industry Co., Ltd.
Such a compound can be used as it is as a pigmentation-improving agent, but can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate; maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; triethylamine salt, triethanolamine salt, ammonium salt, And organic amine salts such as monoethanolamine salt and piperidine salt; basic amino acid salts such as lysine salt and alginate;
斯くして得られた本発明の色素沈着改善剤は、優れた色素沈着予防及び改善作用を有するため、皮膚外用剤の有効成分として用いることができる。
本発明の色素沈着改善剤の作用機序は、詳細は不明であるが、チロシナ－ゼ酵素阻害作用、チロシナ－ゼ遺伝子発現抑制作用、チロシナ－ゼ関連蛋白質分解作用等のチロシナ－ゼ活性阻害作用、及び、メラノサイトにおけるデンドライト伸長抑制によるメラニン移送阻害等によるメラニン産生抑制作用に加え、新たな作用機序によりメラニン産生を抑制することが推定される。また、本発明の色素沈着改善剤を皮膚外用剤の有効成分として用いる場合、色素沈着改善剤は皮膚外用剤全量に対して、総量で０．０００１質量％～２０質量％、より好ましくは、０．００１質量％～１０質量％、さらに好ましくは、０．００５～５質量％含有することが好ましい。皮膚外用剤全量に対する含有量が０．０００１質量％より少ないと、色素沈着予防又は改善作用が低下する傾向にあり、また２０質量％を超える量を用いても、効果が頭打ちになる傾向にあるため、処方の自由度が低下する恐れがある。 The pigmentation-improving agent of the present invention thus obtained can be used as an active ingredient of an external preparation for skin because it has an excellent pigmentation-preventing and improving action.
Although the mechanism of action of the pigmentation-improving agent of the present invention is unknown in detail, tyrosinase activity inhibitory action such as tyrosinase enzyme inhibitory action, tyrosinase gene expression inhibitory action, tyrosinase-related proteolytic action, etc. In addition to the melanin production-suppressing effect by inhibiting melanin transfer by suppressing dendrite elongation in melanocytes, it is estimated that melanin production is suppressed by a new mechanism of action. When the pigmentation-improving agent of the present invention is used as an active ingredient of a skin external preparation, the total amount of the pigmentation-improving agent is 0.0001% by mass to 20% by mass, more preferably 0%, based on the total amount of the external preparation for skin. The content is preferably 0.001 to 10% by mass, more preferably 0.005 to 5% by mass. When the content relative to the total amount of the external preparation for skin is less than 0.0001% by mass, the effect of preventing or improving pigmentation tends to decrease, and even when the amount exceeds 20% by mass, the effect tends to reach its peak. Therefore, there is a risk that the degree of freedom of prescription will be reduced.
本発明の色素沈着改善剤の作用機序は、詳細は不明であるが、チロシナ－ゼ酵素阻害作用、チロシナ－ゼ遺伝子発現抑制作用、チロシナ－ゼ関連蛋白質分解作用等のチロシナ－ゼ活性阻害作用、及び、メラノサイトにおけるデンドライト伸長抑制によるメラニン移送阻害等によるメラニン産生抑制作用に加え、新たな作用機序によりメラニン産生を抑制することが推定される。また、本発明の色素沈着改善剤を皮膚外用剤の有効成分として用いる場合、色素沈着改善剤は皮膚外用剤全量に対して、総量で０．０００１質量％～２０質量％、より好ましくは、０．００１質量％～１０質量％、さらに好ましくは、０．００５～５質量％含有することが好ましい。皮膚外用剤全量に対する含有量が０．０００１質量％より少ないと、色素沈着予防又は改善作用が低下する傾向にあり、また２０質量％を超える量を用いても、効果が頭打ちになる傾向にあるため、処方の自由度が低下する恐れがある。 The pigmentation-improving agent of the present invention thus obtained can be used as an active ingredient of an external preparation for skin because it has an excellent pigmentation-preventing and improving action.
Although the mechanism of action of the pigmentation-improving agent of the present invention is unknown in detail, tyrosinase activity inhibitory action such as tyrosinase enzyme inhibitory action, tyrosinase gene expression inhibitory action, tyrosinase-related proteolytic action, etc. In addition to the melanin production-suppressing effect by inhibiting melanin transfer by suppressing dendrite elongation in melanocytes, it is estimated that melanin production is suppressed by a new mechanism of action. When the pigmentation-improving agent of the present invention is used as an active ingredient of a skin external preparation, the total amount of the pigmentation-improving agent is 0.0001% by mass to 20% by mass, more preferably 0%, based on the total amount of the external preparation for skin. The content is preferably 0.001 to 10% by mass, more preferably 0.005 to 5% by mass. When the content relative to the total amount of the external preparation for skin is less than 0.0001% by mass, the effect of preventing or improving pigmentation tends to decrease, and even when the amount exceeds 20% by mass, the effect tends to reach its peak. Therefore, there is a risk that the degree of freedom of prescription will be reduced.
また、本発明の色素沈着改善剤及び該色素沈着改善剤を含有する皮膚外用剤は、色素沈着予防又は改善用であり、「色素沈着予防又は改善用」とは、色素沈着予防又は改善により達成しようとする目的を主とした用途、例えば、「美白用」、「シミ改善用」などの用途が含まれる。
Further, the pigmentation-improving agent of the present invention and the external preparation for skin containing the pigmentation-improving agent are for preventing or improving pigmentation, and “for preventing or improving pigmentation” is achieved by preventing or improving pigmentation. Applications mainly intended for the purpose, for example, "whitening", "stain improvement", and the like are included.
＜本発明の皮膚外用剤＞
本発明の皮膚外用剤は、本発明の色素沈着改善剤を含有する。本発明の皮膚外用剤は、本発明の色素沈着改善剤を唯１種含有してもよく、２種以上を組み合わせて含有してもよい。本発明の皮膚外用剤は、本発明の色素沈着改善剤を配合することにより、「色素沈着予防又は改善用」、「美白用」、「シミ改善用」などの色素関連異常に関する予防又は改善用として効果を発揮する。 <Skin external preparation of the present invention>
The external preparation for skin of the present invention contains the pigmentation-improving agent of the present invention. The skin external preparation of the present invention may contain only one type of pigmentation-improving agent of the present invention, or may contain two or more types in combination. The preparation for external use of the skin of the present invention is for prevention or improvement of pigment-related abnormalities such as “for pigmentation prevention or improvement”, “for whitening”, “for spot improvement”, etc. by incorporating the pigmentation improving agent of the present invention. As effective.
本発明の皮膚外用剤は、本発明の色素沈着改善剤を含有する。本発明の皮膚外用剤は、本発明の色素沈着改善剤を唯１種含有してもよく、２種以上を組み合わせて含有してもよい。本発明の皮膚外用剤は、本発明の色素沈着改善剤を配合することにより、「色素沈着予防又は改善用」、「美白用」、「シミ改善用」などの色素関連異常に関する予防又は改善用として効果を発揮する。 <Skin external preparation of the present invention>
The external preparation for skin of the present invention contains the pigmentation-improving agent of the present invention. The skin external preparation of the present invention may contain only one type of pigmentation-improving agent of the present invention, or may contain two or more types in combination. The preparation for external use of the skin of the present invention is for prevention or improvement of pigment-related abnormalities such as “for pigmentation prevention or improvement”, “for whitening”, “for spot improvement”, etc. by incorporating the pigmentation improving agent of the present invention. As effective.
本発明の皮膚外用剤は、必須成分である色素沈着改善剤以外に、通常皮膚外用剤で使用される任意成分を含有することが出来る。この様な任意成分としては、スクワラン、ワセリン、マイクロクリスタリンワックスなどの炭化水素類、ホホバ油、カルナウバワックス、オレイン酸オクチルドデシルなどのエステル類、オリ－ブ油、牛脂、椰子油などのトリグリセライド類、ステアリン酸、オレイン酸、レチノイン酸などの脂肪酸、オレイルアルコ－ル、ステアリルアルコ－ル、オクチルドデカノ－ル等の高級アルコ－ル、スルホコハク酸エステルやポリオキシエチレンアルキル硫酸ナトリウム等のアニオン界面活性剤類、アルキルベタイン塩等の両性界面活性剤類、ジアルキルアンモニウム塩等のカチオン界面活性剤類、ソルビタン脂肪酸エステル、脂肪酸モノグリセライド、これらのポリオキシエチレン付加物、ポリオキシエチレンアルキルエ－テル、ポリオキシエチレン脂肪酸エステル等の非イオン界面活性剤類、ポリエチレングリコ－ル、グリセリン、１，３－ブタンジオ－ル等の多価アルコ－ル類、増粘・ゲル化剤、酸化防止剤、紫外線吸収剤、色剤、防腐剤、粉体等を含有することができる。製造は常法に従いこれらの成分を処理することにより、困難なく為しうる。
The skin external preparation of the present invention can contain optional components usually used in skin external preparations in addition to the pigmentation-improving agent that is an essential component. Such optional ingredients include hydrocarbons such as squalane, petrolatum, microcrystalline wax, esters such as jojoba oil, carnauba wax, octyldodecyl oleate, triglycerides such as olive oil, beef tallow and coconut oil. , Fatty acids such as stearic acid, oleic acid, retinoic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol, anionic surface activity such as sulfosuccinic acid ester and sodium polyoxyethylene alkyl sulfate Agents, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts thereof, polyoxyethylene alkyl ethers, polyoxyethylenes Nonionic surfactants such as fatty acid esters, polyhydric alcohols such as polyethylene glycol, glycerin, 1,3-butanediol, thickening / gelling agents, antioxidants, UV absorbers, Coloring agents, preservatives, powders and the like can be contained. Manufacture can be accomplished without difficulty by treating these components according to conventional methods.
本発明の色素沈着改善剤及び任意成分を常法に従って処理し、ロ－ション、乳液、エッセンス、クリ－ム、パック化粧料、洗浄料などを調製することができる。本発明の皮膚外用剤は、皮膚に適応させることの出来る剤型であればいずれの剤型でも可能であるが、有効成分が皮膚に浸透して効果を発揮することから、皮膚への馴染みの良い、ロ－ション、乳液、クリ－ム、エッセンスなどの剤型が好ましい。
The pigmentation-improving agent and optional components of the present invention can be processed according to conventional methods to prepare lotions, emulsions, essences, creams, pack cosmetics, cleaning agents, and the like. The external preparation for skin of the present invention can be used in any dosage form that can be adapted to the skin, but since the active ingredient penetrates the skin and exerts its effect, Good dosage forms such as lotion, emulsion, cream and essence are preferred.
以下に、本発明について実施例を挙げて更に詳しく説明を加えるが、本発明がかかる実施例のみに限定されないことは言うまでもない。
Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.
＜実施例１：化合物１及び化合物２の製造方法＞
<Example 1: Production method of Compound 1 and Compound 2>
化合物１及び化合物２は、例えば、「ペプチド合成の基礎と実験」（丸善株式会社）等に記載の方法に従い合成することが出来る。出発原料としてＢｏｃ－Ｇｌｙ（株式会社ペプチド研究所）を用い、無水Ｎ，Ｎ－ジメチルホルムアミド（和光純薬工業株式会社）に溶解し、水素化ナトリウム及び相当するアルキルハライド（ヨウ化メチル、ヨウ化エチル、和光純薬工業株式会社）を用いアルキル化反応を行った後、塩酸等の酸により脱保護反応、更には、イオン交換により遊離塩基体とすることにより目的とする化合物１又は化合物２を得ることが出来る。また、かかる化合物は、東京化成工業株式会社等の試薬メーカーより市販の試薬として購入することも出来る。本発明の実施例においては、東京化成工業株式会社より購入した化合物を使用した。
Compound 1 and Compound 2 can be synthesized, for example, according to the method described in “Basics and Experiments of Peptide Synthesis” (Maruzen Co., Ltd.). Boc-Gly (Peptide Institute, Inc.) was used as a starting material, dissolved in anhydrous N, N-dimethylformamide (Wako Pure Chemical Industries, Ltd.), sodium hydride and the corresponding alkyl halide (methyl iodide, iodide) After carrying out an alkylation reaction using ethyl, Wako Pure Chemical Industries, Ltd.), a deprotection reaction with an acid such as hydrochloric acid, and further a free base is obtained by ion exchange to obtain the desired compound 1 or compound 2. Can be obtained. Such a compound can also be purchased as a commercially available reagent from a reagent manufacturer such as Tokyo Chemical Industry Co., Ltd. In the examples of the present invention, compounds purchased from Tokyo Chemical Industry Co., Ltd. were used.
＜化合物１の物理恒数＞
1Ｈ－ＮＭＲ（ｄ6－ＤＭＳＯ）：δ ２．４４（２Ｈ、ｓ）、３．０９（３Ｈ、ｓ）． <Physical constant of compound 1>
1 H-NMR (d 6 -DMSO): δ 2.44 (2H, s), 3.09 (3H, s).
1Ｈ－ＮＭＲ（ｄ6－ＤＭＳＯ）：δ ２．４４（２Ｈ、ｓ）、３．０９（３Ｈ、ｓ）． <Physical constant of compound 1>
1 H-NMR (d 6 -DMSO): δ 2.44 (2H, s), 3.09 (3H, s).
＜化合物２の物理恒数＞
1Ｈ－ＮＭＲ（Ｄ2Ｏ）：δ １．３０（３Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、３．１２（２Ｈ、ｑ、Ｊ＝７．８Ｈｚ）、３，６１（２Ｈ、ｓ）． <Physical constant of compound 2>
1 H-NMR (D 2 O): δ 1.30 (3H, t, J = 7.8 Hz), 3.12 (2H, q, J = 7.8 Hz), 3,61 (2H, s).
1Ｈ－ＮＭＲ（Ｄ2Ｏ）：δ １．３０（３Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、３．１２（２Ｈ、ｑ、Ｊ＝７．８Ｈｚ）、３，６１（２Ｈ、ｓ）． <Physical constant of compound 2>
1 H-NMR (D 2 O): δ 1.30 (3H, t, J = 7.8 Hz), 3.12 (2H, q, J = 7.8 Hz), 3,61 (2H, s).
＜試験例１：有色モルモットを用いた紫外線照射による色素沈着抑制作用＞
有色モルモット８匹の背部皮膚を電気バリカンとシェ－バ－で除毛及び剃毛し、この部位を、２×２cmの照射窓を左右２ヶ所有する黒布で覆った後にＦＬ２０Ｓ・Ｅ３０ランプを光源として３００ｍＪ／ｃｍ2の紫外線を照射した。この操作を試験１日目、３日目、５日目、８日目に繰り返し行い、２ヶ所の試験部位に色素沈着を誘導した。
次に、化合物１を５％（ｗ／ｖ）となるように７０％（ｖ／ｖ）エタノ－ル水溶液に溶解し、化合物１含有エタノール水溶液を調製した。また、コントロールとして７０％（ｖ／ｖ）エタノ－ル水溶液を準備した。
試験１日目の紫外線照射終了時より、化合物１含有エタノール水溶液、及びエタノール水溶液の塗布を開始した。塗布は、所定の試験部位に１日１回、３０μＬずつ塗布し、これを５週間（試験３５日目まで）毎日継続して実施した。塗布開始日（試験１日目）の紫外線照射前及び３週間後（試験２２日目）及び５週間後（試験３６日目）に、色彩色差計（ＣＲ－２００、コニカミノルタ株式会社）を用いて各試験部位の皮膚明度（Ｌ*値）を測定し、試験２２日目及び３６日目のＬ*値から紫外線照射前のＬ*値を差し引いたΔＬ*値を求めた。すなわち、Ｌ*値は、色素沈着の程度が強いほど低い値となるため、ΔＬ*値が大きい程、色素沈着が抑制されたとすることができる。結果を表１に示す。 <Test Example 1: Inhibition of pigmentation by ultraviolet irradiation using colored guinea pig>
The back skin of eight colored guinea pigs was removed and shaved with an electric clipper and shaver, and this part was covered with a black cloth with 2 x 2 cm irradiation windows on the left and right, and then the FL20S / E30 lamp was used as the light source. As a result, 300 mJ / cm 2 of ultraviolet rays were irradiated. This operation was repeated on the first day, the third day, the fifth day, and the eighth day of the test to induce pigmentation at two test sites.
Next, Compound 1 was dissolved in a 70% (v / v) ethanol aqueous solution to 5% (w / v) to prepare a Compound 1-containing ethanol aqueous solution. A 70% (v / v) ethanol aqueous solution was prepared as a control.
From the end of the ultraviolet irradiation on the first day of the test, application of the compound 1-containing ethanol aqueous solution and the ethanol aqueous solution was started. Application was performed once a day at a predetermined test site by 30 μL, and this was continuously carried out every day for 5 weeks (up to the 35th day of the test). Using a color difference meter (CR-200, Konica Minolta Co., Ltd.) on the application start date (Test Day 1) before ultraviolet irradiation and after 3 weeks (Test Day 22) and 5 weeks (Test Day 36) The skin lightness (L * value) of each test site was measured, and the ΔL * value obtained by subtracting the L * value before ultraviolet irradiation from the L * value on the 22nd and 36th day of the test was determined. That is, since the L * value becomes lower as the degree of pigmentation becomes stronger, it can be said that the greater the ΔL * value, the more pigmentation is suppressed. The results are shown in Table 1.
有色モルモット８匹の背部皮膚を電気バリカンとシェ－バ－で除毛及び剃毛し、この部位を、２×２cmの照射窓を左右２ヶ所有する黒布で覆った後にＦＬ２０Ｓ・Ｅ３０ランプを光源として３００ｍＪ／ｃｍ2の紫外線を照射した。この操作を試験１日目、３日目、５日目、８日目に繰り返し行い、２ヶ所の試験部位に色素沈着を誘導した。
次に、化合物１を５％（ｗ／ｖ）となるように７０％（ｖ／ｖ）エタノ－ル水溶液に溶解し、化合物１含有エタノール水溶液を調製した。また、コントロールとして７０％（ｖ／ｖ）エタノ－ル水溶液を準備した。
試験１日目の紫外線照射終了時より、化合物１含有エタノール水溶液、及びエタノール水溶液の塗布を開始した。塗布は、所定の試験部位に１日１回、３０μＬずつ塗布し、これを５週間（試験３５日目まで）毎日継続して実施した。塗布開始日（試験１日目）の紫外線照射前及び３週間後（試験２２日目）及び５週間後（試験３６日目）に、色彩色差計（ＣＲ－２００、コニカミノルタ株式会社）を用いて各試験部位の皮膚明度（Ｌ*値）を測定し、試験２２日目及び３６日目のＬ*値から紫外線照射前のＬ*値を差し引いたΔＬ*値を求めた。すなわち、Ｌ*値は、色素沈着の程度が強いほど低い値となるため、ΔＬ*値が大きい程、色素沈着が抑制されたとすることができる。結果を表１に示す。 <Test Example 1: Inhibition of pigmentation by ultraviolet irradiation using colored guinea pig>
The back skin of eight colored guinea pigs was removed and shaved with an electric clipper and shaver, and this part was covered with a black cloth with 2 x 2 cm irradiation windows on the left and right, and then the FL20S / E30 lamp was used as the light source. As a result, 300 mJ / cm 2 of ultraviolet rays were irradiated. This operation was repeated on the first day, the third day, the fifth day, and the eighth day of the test to induce pigmentation at two test sites.
Next, Compound 1 was dissolved in a 70% (v / v) ethanol aqueous solution to 5% (w / v) to prepare a Compound 1-containing ethanol aqueous solution. A 70% (v / v) ethanol aqueous solution was prepared as a control.
From the end of the ultraviolet irradiation on the first day of the test, application of the compound 1-containing ethanol aqueous solution and the ethanol aqueous solution was started. Application was performed once a day at a predetermined test site by 30 μL, and this was continuously carried out every day for 5 weeks (up to the 35th day of the test). Using a color difference meter (CR-200, Konica Minolta Co., Ltd.) on the application start date (Test Day 1) before ultraviolet irradiation and after 3 weeks (Test Day 22) and 5 weeks (Test Day 36) The skin lightness (L * value) of each test site was measured, and the ΔL * value obtained by subtracting the L * value before ultraviolet irradiation from the L * value on the 22nd and 36th day of the test was determined. That is, since the L * value becomes lower as the degree of pigmentation becomes stronger, it can be said that the greater the ΔL * value, the more pigmentation is suppressed. The results are shown in Table 1.
＜実施例２：本発明の皮膚外用剤（ローション１）、比較例１及び２＞
表２に記載の処方に従って、本発明の皮膚外用剤である化粧料（ロ－ション）を作製した。即ち、処方成分を８０℃に加熱し、攪拌し、溶解させ、攪拌冷却し、化粧料（ロ－ション１）を得た。得られたローション１は均一な組成物であり、非常に安定した製剤であった。同様にして、「本発明の色素沈着改善剤（化合物１）」を水に置換した比較例１のロ－ション２、及び「本発明の色素沈着改善剤（化合物１）」をアルブチンに置換した比較例２のローション３も調製した。 <Example 2: External preparation for skin of the present invention (Lotion 1), Comparative Examples 1 and 2>
According to the formulation shown in Table 2, a cosmetic (lotion) which is an external preparation for skin of the present invention was prepared. That is, the prescription ingredients were heated to 80 ° C., stirred, dissolved, stirred and cooled to obtain a cosmetic (lotion 1). The obtained lotion 1 was a uniform composition and a very stable preparation. Similarly, lotion 2 of Comparative Example 1 in which “pigmentation improving agent of the present invention (compound 1)” was replaced with water and arbutin were replaced with “pigmentation improving agent of the present invention (compound 1)”. Lotion 3 of Comparative Example 2 was also prepared.
表２に記載の処方に従って、本発明の皮膚外用剤である化粧料（ロ－ション）を作製した。即ち、処方成分を８０℃に加熱し、攪拌し、溶解させ、攪拌冷却し、化粧料（ロ－ション１）を得た。得られたローション１は均一な組成物であり、非常に安定した製剤であった。同様にして、「本発明の色素沈着改善剤（化合物１）」を水に置換した比較例１のロ－ション２、及び「本発明の色素沈着改善剤（化合物１）」をアルブチンに置換した比較例２のローション３も調製した。 <Example 2: External preparation for skin of the present invention (Lotion 1), Comparative Examples 1 and 2>
According to the formulation shown in Table 2, a cosmetic (lotion) which is an external preparation for skin of the present invention was prepared. That is, the prescription ingredients were heated to 80 ° C., stirred, dissolved, stirred and cooled to obtain a cosmetic (lotion 1). The obtained lotion 1 was a uniform composition and a very stable preparation. Similarly, lotion 2 of Comparative Example 1 in which “pigmentation improving agent of the present invention (compound 1)” was replaced with water and arbutin were replaced with “pigmentation improving agent of the present invention (compound 1)”. Lotion 3 of Comparative Example 2 was also prepared.
＜実施例３：本発明の皮膚外用剤（クリーム１）＞
表３に示す処方に従って、油中水クリ－ムを作成した。即ち、イ、ロの成分をそれぞれ８０℃に加熱し、イにロを徐々に加え、乳化し、ホモジナイザ－で粒子を均一化した後、撹拌冷却して化粧料（クリ－ム１）を得た。得られたクリーム１は分離が生じることなく、非常に安定した製剤であった。 <Example 3: External preparation for skin of the present invention (Cream 1)>
A water-in-oil cream was prepared according to the formulation shown in Table 3. That is, the ingredients (a) and (b) were each heated to 80 ° C., and (b) was gradually added to the emulsion, emulsified, and the particles were homogenized with a homogenizer, followed by stirring and cooling to obtain a cosmetic (Cream 1). It was. The obtained cream 1 was a very stable preparation without causing separation.
表３に示す処方に従って、油中水クリ－ムを作成した。即ち、イ、ロの成分をそれぞれ８０℃に加熱し、イにロを徐々に加え、乳化し、ホモジナイザ－で粒子を均一化した後、撹拌冷却して化粧料（クリ－ム１）を得た。得られたクリーム１は分離が生じることなく、非常に安定した製剤であった。 <Example 3: External preparation for skin of the present invention (Cream 1)>
A water-in-oil cream was prepared according to the formulation shown in Table 3. That is, the ingredients (a) and (b) were each heated to 80 ° C., and (b) was gradually added to the emulsion, emulsified, and the particles were homogenized with a homogenizer, followed by stirring and cooling to obtain a cosmetic (Cream 1). It was. The obtained cream 1 was a very stable preparation without causing separation.
＜実施例４：本発明の皮膚外用剤（乳液１）＞
表４に示す処方に従って、本発明の皮膚外用組成物である化粧料（乳液１）を調製した。即ち、イ、ロ及びハの成分を８０℃に加熱し、ロにハを攪拌しながら徐々に加え中和した後、イを徐々に攪拌しながら加え、ホモミキサーにより乳化粒子を均一化し化粧料（乳液１）を得た。得られた乳液１は分離が生じることなく、非常に安定した製剤であった。 <Example 4: External preparation for skin of the present invention (Emulsion 1)>
According to the formulation shown in Table 4, a cosmetic (milky lotion 1) which is a composition for external use of the skin of the present invention was prepared. That is, the ingredients of A, B, and C are heated to 80 ° C., and after neutralizing and adding C to B, the emulsion particles are homogenized with a homomixer. (Emulsion 1) was obtained. The obtained emulsion 1 was a very stable preparation without separation.
表４に示す処方に従って、本発明の皮膚外用組成物である化粧料（乳液１）を調製した。即ち、イ、ロ及びハの成分を８０℃に加熱し、ロにハを攪拌しながら徐々に加え中和した後、イを徐々に攪拌しながら加え、ホモミキサーにより乳化粒子を均一化し化粧料（乳液１）を得た。得られた乳液１は分離が生じることなく、非常に安定した製剤であった。 <Example 4: External preparation for skin of the present invention (Emulsion 1)>
According to the formulation shown in Table 4, a cosmetic (milky lotion 1) which is a composition for external use of the skin of the present invention was prepared. That is, the ingredients of A, B, and C are heated to 80 ° C., and after neutralizing and adding C to B, the emulsion particles are homogenized with a homomixer. (Emulsion 1) was obtained. The obtained emulsion 1 was a very stable preparation without separation.
＜試験例２：ヒトにおけるロ－ション１～３の紫外線照射による色素沈着抑制効果＞
ロ－ション１、ローション２（比較例１）及びローション３（比較例２）の皮膚外用剤を用いて、色素沈着抑制効果を調べた。
自由意思で参加したパネラーの上腕内側部に１．５ｃｍ×１．５ｃｍの部位を上下２段に分け、２ケ所ずつ合計４ケ所設けた。最少紅斑量（１ＭＥＤ）の紫外線照射を設けた部位に１日１回、３日連続して３回照射した。試験１日目の紫外線照射終了時より、１日１回３５日連続してローション５０μＬを塗布した。４部位のうち１部位は無処置部位とした。３５回の塗布終了２４時間後に色彩色差計（ＣＲ-３００、コニカミノルタ株式会社）にて各試験部位の皮膚明度（Ｌ＊値）を測定し、無処置部位のＬ*値に対する処置部位のＬ*値の差（ΔＬ*）値を算出した。Ｌ*値は、色素沈着の程度が強いほど低い値となる。従って、ΔＬ*値が大きいほど、色素沈着が改善されたと判断することが出来る。結果を表５に示す。これにより、本発明の皮膚外用剤である化粧料（ロ－ション１）は優れた色素沈着抑制効果を有することが分かる。これは、ロ－ション１に含有される前記化合物１の色素沈着抑制作用によると考えられる。 <Test Example 2: Inhibition of pigmentation by ultraviolet irradiation of lotions 1 to 3 in humans>
Using the skin external preparations of Lotion 1, Lotion 2 (Comparative Example 1) and Lotion 3 (Comparative Example 2), the pigmentation inhibitory effect was examined.
A panel of 1.5 cm × 1.5 cm was divided into two upper and lower tiers on the inner side of the upper arm of the panelists who participated freely. The site provided with the minimum amount of erythema (1 MED) was irradiated once a day for 3 consecutive days. From the end of the ultraviolet irradiation on the first day of the test, 50 μL of lotion was applied once a day for 35 consecutive days. One of the four sites was an untreated site. The skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.) 24 hours after the completion of 35 times of application, and the L of the treated site relative to the L * value of the untreated site. * Value difference (ΔL * ) value was calculated. The L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ΔL * value, the better the pigmentation. The results are shown in Table 5. This shows that the cosmetic (lotion 1) which is an external preparation for skin of the present invention has an excellent pigmentation-suppressing effect. This is considered to be due to the pigmentation inhibitory action of Compound 1 contained in Lotion 1.
ロ－ション１、ローション２（比較例１）及びローション３（比較例２）の皮膚外用剤を用いて、色素沈着抑制効果を調べた。
自由意思で参加したパネラーの上腕内側部に１．５ｃｍ×１．５ｃｍの部位を上下２段に分け、２ケ所ずつ合計４ケ所設けた。最少紅斑量（１ＭＥＤ）の紫外線照射を設けた部位に１日１回、３日連続して３回照射した。試験１日目の紫外線照射終了時より、１日１回３５日連続してローション５０μＬを塗布した。４部位のうち１部位は無処置部位とした。３５回の塗布終了２４時間後に色彩色差計（ＣＲ-３００、コニカミノルタ株式会社）にて各試験部位の皮膚明度（Ｌ＊値）を測定し、無処置部位のＬ*値に対する処置部位のＬ*値の差（ΔＬ*）値を算出した。Ｌ*値は、色素沈着の程度が強いほど低い値となる。従って、ΔＬ*値が大きいほど、色素沈着が改善されたと判断することが出来る。結果を表５に示す。これにより、本発明の皮膚外用剤である化粧料（ロ－ション１）は優れた色素沈着抑制効果を有することが分かる。これは、ロ－ション１に含有される前記化合物１の色素沈着抑制作用によると考えられる。 <Test Example 2: Inhibition of pigmentation by ultraviolet irradiation of lotions 1 to 3 in humans>
Using the skin external preparations of Lotion 1, Lotion 2 (Comparative Example 1) and Lotion 3 (Comparative Example 2), the pigmentation inhibitory effect was examined.
A panel of 1.5 cm × 1.5 cm was divided into two upper and lower tiers on the inner side of the upper arm of the panelists who participated freely. The site provided with the minimum amount of erythema (1 MED) was irradiated once a day for 3 consecutive days. From the end of the ultraviolet irradiation on the first day of the test, 50 μL of lotion was applied once a day for 35 consecutive days. One of the four sites was an untreated site. The skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.) 24 hours after the completion of 35 times of application, and the L of the treated site relative to the L * value of the untreated site. * Value difference (ΔL * ) value was calculated. The L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ΔL * value, the better the pigmentation. The results are shown in Table 5. This shows that the cosmetic (lotion 1) which is an external preparation for skin of the present invention has an excellent pigmentation-suppressing effect. This is considered to be due to the pigmentation inhibitory action of Compound 1 contained in Lotion 1.
本発明は、美白用の化粧料などの皮膚外用剤に応用出来る。
The present invention can be applied to skin external preparations such as whitening cosmetics.
Claims (8)
- 下記一般式（１）に表される化合物及び／又はそれらの薬理学的に許容される塩よりなる色素沈着改善剤。
- 前記一般式（１）に表される化合物が、下記一般式（２）に表される化合物及び／又はその薬理学的に許容される塩であることを特徴とする、請求項１に記載の色素沈着改善剤。
- 前記一般式（２）に表される化合物が、Ｎ－メチルグリシン及び／又はその薬理学的に許容される塩であることを特徴とする、請求項２に記載の色素沈着改善剤。 The pigmentation-improving agent according to claim 2, wherein the compound represented by the general formula (2) is N-methylglycine and / or a pharmacologically acceptable salt thereof.
- 請求項１～３のいずれか１項に記載の色素沈着改善剤を含有することを特徴とする、皮膚外用剤。 An external preparation for skin, comprising the pigmentation-improving agent according to any one of claims 1 to 3.
- 皮膚外用剤全量に対し、前記の色素沈着改善剤を、０．０００１質量％～２０質量％含有することを特徴とする、請求項４に記載の皮膚外用剤。 The skin external preparation according to claim 4, wherein the pigmentation improving agent is contained in an amount of 0.0001 mass% to 20 mass% with respect to the total amount of the external skin preparation.
- 化粧料（但し、医薬部外品を含む）であることを特徴とする、請求項４又は５に記載の皮膚外用剤。 The skin external preparation according to claim 4 or 5, which is a cosmetic (however, including quasi drugs).
- 油中水乳化剤形であることを特徴とする、請求項４～６のいずれか１項に記載の皮膚外用剤。 The external preparation for skin according to any one of claims 4 to 6, which is in the form of a water-in-oil emulsifier.
- 美白用であることを特徴とする、請求項４～７のいずれか１項に記載の皮膚外用剤。 The external preparation for skin according to any one of claims 4 to 7, wherein the preparation is for whitening.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011552748A JPWO2011096330A1 (en) | 2010-02-02 | 2011-01-28 | Pigmentation improver |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2010021291 | 2010-02-02 | ||
| JP2010-021291 | 2010-02-02 |
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| WO2011096330A1 true WO2011096330A1 (en) | 2011-08-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2011/051696 WO2011096330A1 (en) | 2010-02-02 | 2011-01-28 | Pigmentation-ameliorating agent |
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| JP (1) | JPWO2011096330A1 (en) |
| TW (1) | TW201141529A (en) |
| WO (1) | WO2011096330A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000063224A (en) * | 1998-08-20 | 2000-02-29 | Kanebo Ltd | Cosmetic |
| JP2004315384A (en) * | 2003-04-14 | 2004-11-11 | Kyowa Hakko Kogyo Co Ltd | Bleaching agent |
| JP2006241102A (en) * | 2005-03-04 | 2006-09-14 | Kanebo Cosmetics Inc | Scf isolation inhibitor and external composition for skin |
| WO2007013662A1 (en) * | 2005-07-26 | 2007-02-01 | Shiseido Company, Ltd. | Wrinkle-preventive/ameliorating agent |
| JP2008088113A (en) * | 2006-10-03 | 2008-04-17 | Ss Pharmaceut Co Ltd | Skin-brightening composition |
-
2011
- 2011-01-28 JP JP2011552748A patent/JPWO2011096330A1/en active Pending
- 2011-01-28 WO PCT/JP2011/051696 patent/WO2011096330A1/en active Application Filing
- 2011-02-01 TW TW100103810A patent/TW201141529A/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000063224A (en) * | 1998-08-20 | 2000-02-29 | Kanebo Ltd | Cosmetic |
| JP2004315384A (en) * | 2003-04-14 | 2004-11-11 | Kyowa Hakko Kogyo Co Ltd | Bleaching agent |
| JP2006241102A (en) * | 2005-03-04 | 2006-09-14 | Kanebo Cosmetics Inc | Scf isolation inhibitor and external composition for skin |
| WO2007013662A1 (en) * | 2005-07-26 | 2007-02-01 | Shiseido Company, Ltd. | Wrinkle-preventive/ameliorating agent |
| JP2008088113A (en) * | 2006-10-03 | 2008-04-17 | Ss Pharmaceut Co Ltd | Skin-brightening composition |
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|---|---|
| TW201141529A (en) | 2011-12-01 |
| JPWO2011096330A1 (en) | 2013-06-10 |
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