composition

Abstract

The present invention addresses the problem of providing a composition that exhibits the effect of improving skin texture, the effect of promoting skin elasticity, the effect of improving wrinkles, or an anti-aging effect, and a composition exhibiting the effect of promoting collagen expression, the effect of promoting elastin expression, the effect of inhibiting hyaluronidase expression, the effect of promoting hyaluronic acid production, or the effect of inhibiting MMP-1 expression.　The present invention for solving the above problem is a composition for promoting skin elasticity, for improving wrinkles, or for anti-aging, and contains at least one compound selected from the group consisting of compounds represented by formula (I) below and salts thereof. In formula (I), R1, R2, R3, R4, R5, and R6 each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, an aryl group, an acyl group, a heteroarylcarbonyl group, an alkoxycarbonyl group, –CHO, –COOH, or –OH.

Description

composition

[0001] The present invention relates to a composition.

[0002] Currently, cosmetics, functional foods, supplements, etc. that have skin-beautifying or anti-aging effects have created a large market. However, in the fields of skin-beautifying and anti-aging, it is difficult to fully satisfy people's pursuit of beauty with existing materials alone, and new materials with excellent effects continue to be sought.

[0003] To achieve beautiful skin and anti-aging, it is necessary to maintain or improve the condition of the skin. Skin has a three-layer structure consisting of the epidermis, dermis, and subcutaneous tissue. Of these, the dermis, which can be said to be the main body of the skin, contains a large amount of extracellular matrix. Examples of extracellular matrix include collagen (particularly type I collagen), which is the main component of the dermis, elastin, which is an elastic fiber, and hyaluronic acid, which is a moisturizing component. In recent years, compositions that increase the expression levels of these extracellular matrices in dermal cells have been investigated as an approach to beauty and anti-aging.

[0004] As such a composition, for example, an elastin production-enhancing composition containing diisopropylamine dichloroacetate has been proposed (see Patent Document 1). According to this document, the composition promotes elastin production and prevents or improves skin aging. However, even with the use of the composition, it is difficult to fully satisfy the demands for beautiful skin and anti-aging effects.

[0005] Japanese Patent Application Laid-Open No. 2023-174219

[0006] The present invention has been made under these circumstances, and aims to provide a composition that has a skin texture improving effect, a skin elasticity enhancing effect (including an effect of improving skin sagging), a wrinkle improving effect, or an anti-aging effect (hereinafter, these may be collectively referred to as "skin-beautifying effect"), and a composition that has a collagen expression promoting effect, an elastin expression promoting effect, a hyaluronidase expression suppressing effect, a hyaluronic acid production promoting effect, or an MMP-1 expression suppressing effect.

[0007] The present inventors have discovered that a compound represented by formula (I) described below can regulate the expression of extracellular matrix-related genes in human skin fibroblasts, and that the compound is effective in improving wrinkles and sagging skin, and have thus completed the present invention.

[0008] That is, the gist of the present invention is as follows.

[0009] [1] A composition for improving skin texture, increasing skin elasticity, improving wrinkles, or anti-aging, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH. [2] A composition for promoting collagen expression, promoting elastin expression, suppressing hyaluronidase expression, promoting hyaluronic acid production, or suppressing MMP-1 expression, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH. [3] In the formula (I), R １ represents an alkoxy group having 1 to 3 carbon atoms; R ２ and R ３ each independently represents a hydrogen atom or —CHO; ４ and R ５ each independently represents a hydrogen atom or an acyl group having from 2 to 4 carbon atoms; R ６ [4] The composition according to [1] or [2], wherein the compound represented by formula (I) is represented by the following formula (I-1): [5] The composition described in any one of [1] to [4], which is an external composition or an oral composition.

[0010] According to the present invention, it is possible to provide a composition having an excellent effect of improving skin texture, an effect of increasing skin elasticity (including an effect of improving skin sagging), an effect of improving wrinkles, or an anti-aging effect, and a composition having an effect of promoting collagen expression, an effect of promoting elastin expression, an effect of suppressing hyaluronidase expression, an effect of promoting hyaluronic acid production, or an effect of suppressing MMP-1 expression.

[0011] Figure 1 shows the results of an investigation into the effect of the compound represented by formula (I-1) on the expression level of type I collagen gene in human dermal fibroblasts (in vitro). Figure 2 shows the results of an investigation into the effect of the compound represented by formula (I-1) on the expression level of elastin gene in human dermal fibroblasts (in vitro). Figure 3 shows the results of an investigation into the effect of the compound represented by formula (I-1) on the expression level of mammalian hyaluronidase 1 gene in human dermal fibroblasts (in vitro). Figure 4 shows the results of an investigation into the effect of the compound represented by formula (I-1) on the expression level of MMP-1 gene in human dermal fibroblasts (in vitro). Figure 5 shows the results of an investigation into the effect of the compound represented by formula (I-1) on the hyaluronic acid concentration in human dermal fibroblasts (in vitro). Figure 6 shows the results of an investigation into the effect of the compound represented by formula (I-1) on the secretion level of MMP-1 protein in human dermal fibroblasts (in vitro). FIG. 7 shows the results of an investigation into the effect of a compound represented by formula (I-1) on the width of crow's feet in humans (in vivo). FIG. 8 shows images of changes in crow's feet in one of the subjects treated with a compound represented by formula (I-1) (in vivo). FIG. 9 shows the results of an investigation into the effect of a compound represented by formula (I-1) on the width of human nasolabial folds (in vivo). FIG. 10 shows images of changes in nasolabial folds in one of the subjects treated with a compound represented by formula (I-1) (in vivo). FIG. 11 shows the results of an investigation into the effect of a compound represented by formula (I-1) on human collagen density (in vivo). FIG. 12 shows the results of an investigation into the effect of a compound represented by formula (I-1) or (I-2) on the expression level of serotonin protein in a human neuronal cell model (in vitro).

[0012] The present invention will be described in detail below. The terms used in this specification are to be interpreted in the sense commonly used in the art unless otherwise specified.

[0013] [Composition] The composition according to the first embodiment of the present invention is a composition for improving skin texture, increasing skin elasticity, improving wrinkles, or anti-aging, which contains at least one compound (hereinafter, may be referred to as a "specific compound") selected from the group consisting of compounds represented by the following formula (I) and salts thereof:

[0014]

[0015] In formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH.

[0016] The composition according to the second embodiment of the present invention is a composition for promoting collagen expression, promoting elastin expression, suppressing hyaluronidase expression, promoting hyaluronic acid production, or suppressing MMP-1 expression, which contains at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof:

[0017]

[0018] In formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH.

[0019] Collagen is a fibrous protein that makes up skin, tendons, cartilage, etc., and accounts for approximately 30% of all proteins in the human body. Collagen exists mainly outside cells and plays a role in connecting cells together. Collagen is the main component of the dermis, accounting for approximately 70% of its weight, and is a very important factor in skin elasticity and strength.

[0020] Elastin is a fibrous protein that accounts for approximately 5% of the weight of the dermis. It is a component of elastic fibers that support collagen fibers and plays an important role in skin firmness and elasticity.

[0021] As shown in the examples, the specific compound can promote the expression of collagen (particularly type I collagen) and elastin. When the composition according to the second embodiment of the present invention is used as a collagen expression promoter or an elastin expression promoter, a skin-beautifying effect (particularly an effect of improving wrinkles and sagging) can be expected by promoting the production of collagen or elastin in the skin.

[0022] Hyaluronidase is an enzyme that hydrolyzes hyaluronic acid. Hyaluronic acid is a type of mucopolysaccharide with high water retention, and is a component that improves the skin's moisturizing ability and prevents dryness. Hyaluronidase may reduce the skin's moisturizing ability by breaking down this hyaluronic acid.

[0023] MMP-1, an abbreviation for matrix metalloproteinase-1, is an enzyme that breaks down collagen. MMP-1 is involved in tissue regeneration and wound healing, but its expression level increases due to ultraviolet rays, and it may reduce skin elasticity and strength by breaking down collagen.

[0024] As shown in the examples, the specific compound can suppress the expression of hyaluronidase (particularly mammalian hyaluronidase 1) and MMP-1. When the composition according to the second embodiment of the present invention is used as a hyaluronidase expression inhibitor or an MMP-1 expression inhibitor, skin-beautifying effects (particularly, improvements in wrinkles and sagging) can be expected by suppressing the production of hyaluronidase or MMP-1 in the skin and promoting the production of hyaluronic acid.

[0025] The composition according to the first embodiment of the present invention is substantially the same as the composition according to the second embodiment of the present invention except for the different uses. Hereinafter, the composition according to the first embodiment of the present invention and the composition according to the second embodiment of the present invention may be collectively referred to as the "composition of the present invention."

[0026] The composition of the present invention can improve wrinkles and sagging because the specific compound promotes the production or inhibits the degradation of the extracellular matrix in the skin. Therefore, the composition of the present invention exhibits excellent skin-beautifying effects and can be used for beauty, anti-aging, or skin trouble improvement applications. Thus, the composition of the present invention can be suitably used as a pharmaceutical, quasi-drug, cosmetic, food (functional food, supplement, etc.), etc. Examples of extracellular matrices that the composition of the present invention promotes the production or inhibits the degradation of include collagen (especially type I collagen), elastin, hyaluronic acid, chondroitin sulfate, proteoglycan, fibronectin, etc. Among these, the composition of the present invention is considered to be particularly effective in promoting the production or inhibiting the degradation of collagen, elastin, or hyaluronic acid.

[0027] In this specification, a salt of a compound represented by formula (I) refers to a salt of a compound represented by formula (I) with an anion or a cation. Examples of anions include anions of inorganic acids (e.g., hydrochloric acid, phosphoric acid, etc.) and anions of organic acids (e.g., lactic acid, acetic acid, etc.). Examples of cations include ammonium cations and metal cations (e.g., lithium ion, sodium ion, potassium ion, magnesium ion, calcium ion, etc.).

[0028] In formula (I), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. The halogen atom is preferably a chlorine atom.

[0029] In formula (I), the alkyl group having 1 to 6 carbon atoms may be either a linear alkyl group or a branched alkyl group. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. As the alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 3 carbon atoms is preferred, and a methyl group or an ethyl group is more preferred.

[0030] In formula (I), the alkenyl group having from 2 to 6 carbon atoms may be either a linear alkenyl group or a branched alkenyl group. Examples of the alkenyl group having from 2 to 6 carbon atoms include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group.

[0031] In formula (I), the alkynyl group having from 2 to 6 carbon atoms may be either a linear alkynyl group or a branched alkynyl group. Examples of the alkynyl group having from 2 to 6 carbon atoms include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, and a hexynyl group.

[0032] In formula (I), the alkoxy group having from 1 to 6 carbon atoms may be either a linear alkoxy group or a branched alkoxy group. Examples of the alkoxy group having from 1 to 6 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. As the alkoxy group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms is preferred, and a methoxy group or an ethoxy group is preferred.

[0033] In formula (I), the cycloalkyl group having from 3 to 8 carbon atoms may be either a monocyclic cycloalkyl group or a polycyclic cycloalkyl group. Examples of the cycloalkyl group having from 3 to 8 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloheptyl group, and a cyclooctyl group.

[0034] In formula (I), the aryl group having 6 to 10 carbon atoms may be either a monocyclic aryl group or a polycyclic aryl group. Examples of the aryl group having 6 to 10 carbon atoms include a phenyl group and a naphthyl group.

[0035] In formula (I), the acyl group having from 2 to 21 carbon atoms is a group represented by R—(C═O)—. R is an alkyl group or an aryl group. Examples of the acyl group having from 2 to 21 carbon atoms include an acetyl group, a propionyl group, a butyryl group, a valeryl group, a pivaloyl group, a benzoyl group, and a naphthoyl group. As the acyl group having from 2 to 21 carbon atoms, an acyl group having from 2 to 7 carbon atoms is preferred, an acyl group having from 2 to 4 carbon atoms is more preferred, and an acetyl group is even more preferred.

[0036] In formula (I), the heteroarylcarbonyl group is a carbonyl group to which a heteroaryl group is bonded. Examples of the heteroarylcarbonyl group include a picolinoyl group, a nicotinoyl group, an isonicotinoyl group, and a pyrazine-2-carbonyl group.

[0037] In the formula (I), examples of the alkoxycarbonyl group having from 2 to 7 carbon atoms include a methoxycarbonyl group, an ethoxycarbonyl group, and a propyloxycarbonyl group.

[0038] In formula (I), examples of the substituent that substitutes the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, aryl group, acyl group, heteroarylcarbonyl group, or alkoxycarbonyl group include a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), —OH, —SH, a nitro group, a cyano group, —CHO, —COOH, an amino group, and a silyl group.

[0039] In formula (I), R １ R preferably represents an alkoxy group having 1 to 3 carbon atoms. ２ and R ３ Preferably, each independently represents a hydrogen atom or —CHO. ４ and R ５ Preferably, R each independently represents a hydrogen atom or an acyl group having 2 to 4 carbon atoms. ６ preferably represents a hydrogen atom.

[0040] Examples of the compound represented by formula (I) include a compound represented by the following formula (I-1) and a compound represented by the following formula (I-2). As the compound represented by formula (I), a compound represented by the following formula (I-1) is preferred.

[0041]

[0042]

[0043] The composition of the present invention can be used as a topical composition or an oral composition, and specifically, can be used in various forms, such as pharmaceuticals, quasi-drugs, topical or systemic skin cosmetics, various topical skin preparations including medicinal or cosmetic preparations for application to the scalp or hair, bath additives, oral pharmaceutical and quasi-drug compositions, general foods and beverages, supplements, energy drinks, and food compositions such as functional foods.

[0044] The content of the specific compound in the composition of the present invention may be adjusted appropriately depending on the dosage form and intended use, and is not particularly limited. When the composition of the present invention is a topical composition, the content of the specific compound in the composition of the present invention is, for example, 0.0001% by mass to 10.0% by mass, preferably 0.0005% by mass to 1.0% by mass, more preferably 0.0005% by mass to 0.5% by mass, and even more preferably 0.001% by mass. When the composition of the present invention is an oral composition, the amount of the specific compound contained in a daily dose of the composition of the present invention is, for example, 0.0001 mg / day to 10.0 mg / day, preferably 0.001 mg / day to 5.0 mg / day, and more preferably 0.003 mg / day to 3.0 mg / day. When the composition of the present invention is an oral composition, the recommended frequency of ingestion may be once a day, multiple times a day (e.g., 2 to 3 times a day), or once every several days.

[0045] The composition of the present invention may contain other ingredients in addition to the specific compound, which is an essential ingredient, as long as the ingredients do not impair the effects of the present invention. The composition of the present invention can be used in combination with, for example, drugs used in treating conventional external or internal use materials. Combinations with drugs that make the effects of the present invention more likely to be exhibited are particularly preferred.

[0046] Examples of these other components include anti-inflammatory agents, refreshing agents, disinfectants, vitamins, organic acids, moisturizing components, polyhydric alcohols, scrubbing agents, ultraviolet absorbing components, ultraviolet scattering components, astringent components, peptides or derivatives thereof, amino acids or derivatives thereof, cleansing components, keratin softening components, cell activating components, anti-aging components, anti-glycation components, blood circulation promoting components, whitening components, polyphenols, etc. In the composition of the present invention, these components may be used alone or in combination of two or more.

[0047] Examples of the anti-inflammatory agent include plant-derived components, allantoin and derivatives thereof, glycyrrhetinic acid and derivatives thereof, glycyrrhizinic acid and salts or derivatives thereof, salicylic acid derivatives, aminocaproic acid, azulene and derivatives thereof, zinc oxide, calamine, tocopherol acetate, hydrocortisone, prednisolone, and salts thereof.

[0048] Examples of the cooling agent include menthol and its derivatives, camphor, terpenes such as borneol, geraniol, cineole, anethole, limonene, and eugenol (which may be in the d-, l-, or dl-form); and essential oils such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, peppermint oil, cinnamon oil, rose oil, and turpentine.

[0049] Examples of the disinfectant include isopropylmethylphenol, chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, povidone-iodine, potassium iodide, iodine, triclocarban, triclosan, photosensitizer No. 101, photosensitizer No. 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride, piroctoolamine, and miconazole.

[0050] The vitamins may be either water-soluble or oil-soluble, and examples thereof include vitamin B6s such as pyridoxine, pyridoxal, pyridoxamine, 5'-pyridoxal phosphate, and salts thereof (e.g., pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, pyridoxamine hydrochloride); pantothenic acids such as pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl ethyl ether, and salts thereof; nicotinic acids such as nicotinic acid, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1-(4-methylphenyl)ethyl nicotinate, nicotinamide, and salts thereof; γ-oryzanol, thiamine, dibenzoylthiamine, thiamine cetyl, thiamine monophosphate, thiamine diphosphate, and thiamine triphosphate. Vitamin B1 compounds such as esters and salts thereof (e.g., dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine diphosphate hydrochloride, thiamine triphosphate monophosphate); vitamin B2 compounds such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, and salts thereof; biotins such as biotin, biocytin, and salts thereof; folates such as folic acid, pteroylglutamic acid, and salts thereof; vitamin B12 compounds such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, and salts thereof;Water-soluble vitamin C compounds such as ascorbic acid, dehydroascorbic acid, ascorbic acid phosphate, ascorbic acid-2-glucoside, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, glyceryl ascorbic acid, bisglyceryl ascorbic acid, and alkylglyceryl ascorbic acid, and salts thereof (for example, sodium ascorbate, sodium ascorbyl phosphate, and magnesium ascorbyl phosphate); vitamin E compounds such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, tocopherol linoleate, tocopherol (linoleate / oleate), tocopherol, and potassium (ascorbyl / tocopheryl) phosphate; ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipotassium phosphate, hydroxybenzoate ... Oil-soluble vitamin C and its salts, such as L-ascorbyl lumitate and ascorbyl tetra-2-hexyldecanoate; vitamin Ds, such as ergocalciferol and cholecalciferol; vitamin Ks, such as phylloquinone and farnoquinone; vitamin A, such as retinol, retinal, retinoic acid, 3-dehydroretinol, 3-dehydroretinal, 3-dehydroretinoic acid, and hydrogenated retinol, and their derivatives, such as retinol palmitate and propionate. Vitamin A derivatives such as retinol phosphate, retinol linoleate, and retinol acetate; provitamin A such as α-carotene, β-carotene, γ-carotene, and cryptoxanthin; hesperidin derivatives such as ferulic acid, pyrroloquinoline quinone or a salt thereof, hesperidin and glucosyl herperidin; vitamin-like factors such as ubiquinone, glucurolactone, glucuronic acid amide, orotic acid, L-carnitine, α-lipoic acid, and orotic acid;

[0051] Examples of the organic acids include gluconic acid, aspartic acid, aminoethylsulfonic acid, citric acid, glutamic acid, succinic acid, oxalic acid, fumaric acid, malonic acid, maleic acid, propionic acid, malic acid, salicylic acid, glycolic acid, phytic acid, tartaric acid, acetic acid, lactic acid, pantothenic acid, glycyrrhetinic acid, alginic acid, ascorbic acid, benzoic acid, adipic acid, glutamic acid, azelaic acid, and salts thereof. Examples of the salts include salts of mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, salts of organic acids such as maleic acid and methanesulfonic acid, salts of alkali metals such as sodium and potassium, alkaline earth metal salts, ammonium salts, salts of basic amino acids, and amine salts such as triethanolamine.

[0052] Examples of the moisturizing components include diglycerin trehalose; mucopolysaccharides such as heparinoids and sodium chondroitin sulfate; MPC polymer; keratin, chitin, chitosan, etc. and their hydrolysates; amino acids such as glycine, aspartic acid, arginine, etc.; natural moisturizing factors such as sodium lactate, urea, and sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol, phytosterol, and phospholipid; glycerin, polyoxyalkylene alkyl glucoside, PEG / PPG / polybutylene glycol-8 / 5 / 3 glycerin, Examples include polyhydric alcohols or derivatives thereof such as glyceryl glucoside; 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, 2-methacryloyloxyethyl phosphorylcholine-containing polymers such as polymethacryloyloxyethyl phosphorylcholine; alkylene oxides such as PPG-17 buteth-17, PPG-25 sorbitol, polyoxyalkylene alkyl glucoside, PEG / PPG / polybutylene glycol-8 / 5 / 3 glycerin, and polyoxyalkylene diglyceryl; and hydroxyethyl urea.

[0053] The polyhydric alcohol is preferably one having 2 to 10 carbon atoms, and examples thereof include glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-propanediol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1,3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol, decanediol, and neopentyl glycol.

[0054] Examples of the scrubbing agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride granules, olive kernel powder, seawater dried granules, candelilla wax, walnut shell powder, cherry kernel powder, coral powder, charcoal powder, hazelnut shell powder, polyethylene powder, and silicic anhydride.

[0055] Examples of the ultraviolet absorbing component include octocrylene, polysilicone, octyl triazone, dimethoxybenzylidene dioxoimidazolidine octyl propionate, 2-ethylhexyl paramethoxycinnamate, phenylbenzimidazole sulfonic acid, diethylaminohydroxybenzoyl hexyl benzoate, bisethylhexyloxyphenol methoxyphenyl triazine, trisethylhexyloxycarbonylanilinotriazine, t-butylmethoxydibenzoylmethane, paraaminobenzoic acid and derivatives thereof, octyl paradimethylaminobenzoate, dihydroxybenzophenone, and methylenebisbenzotriazolyltetramethylbutylphenol.

[0056] Examples of the ultraviolet scattering component include inorganic compounds such as hydrous silicic acid, zinc silicate, cerium silicate, titanium silicate, zirconium oxide, cerium oxide, titanium oxide, zinc oxide, iron oxide, and silicic anhydride; these inorganic compounds coated with inorganic powder such as hydrous silicic acid, aluminum hydroxide, mica, and talc; compounds composited with resin powder such as polyamide, polyethylene, polyester, polystyrene, and nylon; and compounds further treated with silicone oil, aluminum salt of a fatty acid, or the like.

[0057] Examples of the astringent component include metal salts such as ethanol, zinc sulfate, aluminum chloride, and zinc sulfocarbonate, and organic acids such as tannic acid.

[0058] Examples of the above peptides or derivatives thereof include keratin hydrolyzed peptides, hydrolyzed keratin, gelatin, conchiolin hydrolyzed peptides, hydrolyzed conchiolin, silk proteolytic peptides, hydrolyzed silk, sodium lauroyl hydrolyzed silk, wheat protein, wheat proteolytic peptides, hydrolyzed wheat protein, casein hydrolyzed peptides, acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.), and the like.

[0059] Examples of the amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine, methionine, leucine, isoleucine, valine, histidine, threonine, tyrosine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine, epsilon-aminocaproic acid, tryptophan, ornithine, etc. Furthermore, these amino acids or derivatives thereof may be in the form of a solvate such as a hydrate, and may be in any of the d-, l-, or dl-forms.

[0060] Examples of the cleansing component include soaps selected from alkali metal salts such as potassium laurate, potassium myristate, potassium palmitate, and potassium stearate, alkanolamide salts, and amino acid salts; amino acid surfactants such as sodium cocoyl glutamate, sodium cocoyl methyl taurate, sodium cocoyl methyl taurate, and potassium cocoyl methyl glutamate; ether sulfate ester salts such as sodium laureth sulfate; ether carboxylate salts such as sodium lauryl ether acetate; sulfosuccinate ester salts such as sodium alkyl sulfosuccinate; and fatty acids such as coconut oil fatty acid monoethanolamide and coconut oil fatty acid diethanolamide. Examples of the surfactant include fatty acid alkanolamides; monoalkyl phosphate salts such as sodium lauryl phosphate and sodium polyoxyethylene lauryl ether phosphate; betaine-type amphoteric surfactants such as coconut oil fatty acid amidopropyl dimethylaminoacetic acid betaine, lauryl dimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, lauryl hydroxysulfobetaine, cocamidopropyl betaine, and lauroyl amidoethyl hydroxyethyl carboxymethyl betaine hydroxypropyl sodium phosphate; and amino acid-type amphoteric surfactants such as sodium lauryl aminopropionate.

[0061] Examples of the keratin softening ingredients include lanolin, lactic acid, salicylic acid, gluconic acid, glycolic acid, citric acid, malic acid, fruit acid, phytic acid, urea, sulfur, and the like.

[0062] Examples of the cell activating component include components derived from plants (for example, bilberry, etc.), amino acids such as γ-aminobutyric acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids, etc.; α-hydroxy acids such as glycolic acid, lactic acid, etc.; tannin, flavonoid, saponin, photosensitizer No. 301, etc.

[0063] Examples of the anti-aging ingredients include retinoids (retinol and its derivatives, retinoic acid, retinal, etc.), pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, etc.

[0064] Examples of the anti-glycation component include plant extracts such as Budreja axillaris leaf extract, evening primrose oil, Amla fruit, fruit juice or extracts thereof, L-arginine, L-lysine, hydrolyzed casein, hydrolyzable tannin, carnosine, etc.

[0065] Examples of the blood circulation-promoting component include components derived from plants (e.g., ginseng, Angelica tree, arnica, ginkgo, fennel, emmeisou, Dutch oak, chamomile, Roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake mushroom, ginger, European hawthorn, European juniper, cnidium rhizome, Swertia japonica, thyme, clove, tangerine peel, chili pepper, angelica acutiloba, peach kernel, spruce, carrot, garlic, butcher's broom, grape, peony, horse chestnut, melissa, yuzu, coix seed, ryokucha, rosemary, rose hip, tangerine peel, angelica acutiloba, spruce, peach, apricot, walnut, corn, golden chamomile, etc.); acetylcholine, ichthammol, cantharides tincture, gamma-oryzanol, cepharanthine, tolazoline, tocopherol nicotinate, glucosyl hesperidin, etc.).

[0066] Examples of the whitening ingredient include tocopherol, tranexamic acid, ascorbic acid and its salts, vitamin C such as ascorbic acid derivatives (such as sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl tetra-2-hexyldecanoate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, and ascorbic acid glucoside), arbutin, kojic acid, placenta, ellagic acid, nicotinamide, hydroquinone, potassium 4-methoxysalicylate, and linoleic acid and derivatives thereof.

[0067] Examples of the polyphenols include flavonoid polyphenols such as curcuminoids, flavanones, stilpenoids, polymethoxyflavonoids, flavonols, xanthonoids, chalcones, lignoids, flavanols, and isoflavones, and phenolic acid polyphenols.

[0068] (pH) The pH of the composition of the present invention is usually 2.0 to 9.0, preferably 3.0 to 8.5, more preferably 3.5 to 8.0, and even more preferably 5.0 to 8.0. This pH can be adjusted by using a pH adjuster.

[0069] (Method for producing the composition of the present invention) The method for producing the composition of the present invention is not particularly limited, and the composition can be produced by a conventional method by appropriately selecting and mixing the specific compound, which is an essential component, with the other components described above that are mixed as needed, bases or carriers, additives, etc. that are necessary for producing various formulations. As the specific compound, a commercially available product or a synthetic product may be used.

[0070] The composition of the present invention can also be prepared into a topical composition in various formulations by mixing the specific compound and the other ingredients described above, if necessary, with a base or carrier commonly used in cosmetics, pharmaceuticals, quasi-drugs, foods, etc., and the additives described below, according to a conventional method, and emulsifying or solubilizing as necessary.

[0071] Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, petrolatum, gelling hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomer, polyethylene wax, and light liquid paraffin; silicone oils such as methylpolysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone / alkyl chain co-modified polyether-modified silicone, silicone / alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; fats and oils such as coconut oil, olive oil, rice bran oil, and shea butter; waxes such as jojoba oil, beaucoupon wax, candelilla wax, and lanolin; cetyl alcohol, cetostearyl alcohol, stearic acid, and the like. higher alcohols such as butyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, and cholesterol; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; esters such as diisopropyl adipate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate, and triethylhexanoin; polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymers and alkyl-modified carboxyvinyl polymers; lower alcohols such as ethanol and isopropanol;Examples of suitable bases or carriers include glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, and batyl alcohol; and water. The bases or carriers described above may be used alone or in combination of two or more. The amounts used may be appropriately selected from ranges known to those skilled in the art.

[0072] To the composition of the present invention, known additives added to cosmetics, pharmaceuticals, quasi-drugs, foods, etc., such as surfactants, stabilizers, antioxidants, colorants, pearlescent agents, dispersants, chelating agents, pH adjusters, preservatives (antiseptics), thickeners, irritation reducers, texture improvers, excipients, lubricants, binders, disintegrants, solvents, oils and fats, ester oils, emulsifiers, dispersants, suspending agents, stabilizers, thickeners, sweeteners, colorants, flavorings, antioxidants, acidulants, and food additives such as fruit juice, may be added, provided that the effects of the present invention are not impaired. These additives may be used alone or in combination of two or more.

[0073] The surfactant may be any of a nonionic surfactant, a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and the like, and examples thereof include sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate; propylene glycol fatty acid esters such as propylene glycol monostearate; hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), and polyoxyethylene (20) monostearate. Examples of surfactants include polyoxyethylene sorbitan fatty acid esters such as sorbitan (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ethers; lipophilic glyceryl monostearate; glyceryl isostearate; polyethylene glycol monostearate; alkyl glucosides; polyoxyalkylene alkyl ethers such as polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, and PPG-13 decyltetradeceth-24; amines such as stearylamine and oleylamine; and silicone surfactants such as polyoxyethylene-methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone.

[0074] Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole.

[0075] Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, sodium ascorbate, ascorbyl stearate, ascorbyl sodium stearate, ascorbyl palmitate, tocopherol, tocopherol acetate, tocotrienol, bisulfite, sodium hyposulfite, sulfur dioxide, calcium disodium EDTA, erythorbic acid, sodium erythorbate, L-cysteine ​​hydrochloride, ubiquinones such as coenzyme Q10, lignans such as sesamin, curcumin, capsaicin, gingerol, resveratrol, anthocyanin, cyanidin, bilberry extract, and analogs or derivatives thereof. Of these, dibutylhydroxytoluene, ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, coenzyme Q10, resveratrol, anthocyanin, sesamin, curcumin, capsaicin, gingerol, and bilberry extract are preferred.

[0076] Examples of the colorant include inorganic pigments and natural dyes.

[0077] Examples of the pearly luster imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

[0078] Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinylpyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, and organic acids.

[0079] Examples of the chelating agent include EDTA disodium salt, EDTA calcium disodium salt, and caprylhydroxamic acid.

[0080] Examples of the pH adjuster include inorganic acids (phosphoric acid, hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, gluconic acid, sodium malate, etc.), potassium carbonate, sodium bicarbonate, carbon dioxide, inorganic bases (potassium hydroxide, sodium hydroxide, etc.), and organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.).

[0081] Examples of the preservative (antiseptic) include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl parahydroxybenzoate, methyl parahydroxybenzoate (methylparaben), phenoxyethanol, chlorobutanol, benzyl alcohol, phenethyl alcohol, sorbic acid, and salts thereof.

[0082] Examples of the thickener include vinyl thickeners such as polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers; cellulose thickeners such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose; guar gum, pectin, pullulan, gelatin, locust bean gum, carrageenan, agar, glucomannan, curdlan, gellan gum, xanthan gum, and acrylic and methacrylic acid alkyl esters. Examples of suitable acrylic acid copolymers include polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, sodium chondroitin sulfate, hyaluronic acid, sodium hyaluronate, (hydroxyethyl acrylate / sodium acryloyldimethyltaurate) copolymer, (ammonium acryloyldimethyltaurate / vinylpyrrolidone) copolymer, polyacrylic acid amide, polyethylene glycol-decyltetradeceth-20-hexamethylene diisocyanate copolymer ((PEG-240 / decyltetradeceth-20 / HDI) copolymer), and the like.

[0083] Examples of the irritation reducer include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymers, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol alginate, licorice extract, and 2-methacryloyloxyethyl phosphorylcholine.

[0084] Examples of the feel improver include diisostearyl malate.

[0085] Examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, maltitol, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid.

[0086] Examples of the binder include polysaccharides such as refined sucrose, glucose, trehalose, lactose, maltose, saccharin sodium, aspartame, acesulfame potassium, and maltodextrin; corn starch, potato starch, wheat starch, and pregelatinized starches thereof; sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, and sucralose; cellulose-based polymers such as crystalline cellulose, methyl cellulose, ethyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carmellose calcium, hypromellose phthalate, and cellulose acetate phthalate; calcium phosphate; and polyvinylpyrrolidone.

[0087] Examples of the disintegrants include starch, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, partially pregelatinized starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose.

[0088] Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane (dimethicone), beeswax, white beeswax, borax, polyethylene glycol, and silica.

[0089] Examples of the fats and oils include natural vegetable oils such as palm oil, palm kernel oil, coconut oil, corn oil, sunflower oil, safflower oil, peanut oil, cocoa butter, cottonseed oil, soybean oil, rapeseed oil, rice oil, rice germ oil, perilla oil, and linseed oil; animal fats and oils such as beef tallow, milk fat, lard, cacao butter, fish oil, whale oil, butter, and butter oil; and hardened oils thereof; glycerides (glycerides, diglycerides, triglycerides, etc.) of fatty acids (including medium-chain fatty acids); meadowfoam oil; and beeswax.

[0090] Examples of ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, isopropyl isostearate, octyl palmitate, octyl isopalmitate, cetyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, isodecyl oleate, hexyldecyl dimethyloctanoate, diisopropyl sebacate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, diisopropyl adipate, L-pil, 2-hexyldecyl adipate, isononyl isononanoate, isotridecyl isononanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, isostearyl isostearate, cholesteryl 12-hydroxystearate, cholesteryl stearate, cholesteryl oleate, phytosteryl macadamiate, phytosteryl oleate, dextrin palmitate, inulin stearate, hydrogenated jojoba oil, ethylene glycol di-2-ethylhexylate, 2-ethylhexane Cetyl ester, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glycerin di-2-heptylundecanoate, tri-2-ethylhexyl trimellitate, tritridecyl trimellitate, trimethylolpropane tri-2-ethylhexylate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane triisostearate, cetyl 2-ethyl Hexanoate, glycerin trimyristate, caprylic / capric triglyceride, caprylic / capric / myristic / stearic triglyceride, tri-2-heptylundecanoic acid glyceride, castor oil fatty acid methyl ester, oleyl oleate, 2-heptylundecyl palmitate, diisobutyl adipate, di-(phytosteryl / octyldodecyl) lauroyl glutamate, di-(octyldodecyl / phytosteryl / behenyl) lauroyl glutamate, di-2-heptylundecyl adipate, ethyl laurate,Bisethoxydiglycol Cyclohexane-1,4-dicarboxylate, 2-Ethylhexyl Succinate, Diethoxyethyl Succinate, Triethyl Citrate, Decaglyceryl Eicosandioate / Tetradecanedioate, Ethyl Acetate, Butyl Acetate, Amyl Acetate, Triethyl Citrate, Phytosteryl / Isostearyl / Cetyl / Stearyl / Behenyl Dimer Dilinoleate, Polyglyceryl-2 Triisostearate, Dimer Dilinoleyl Dimer Dilinoleate, Dipentaerythritol Tri-Polyhydroxystearate Examples of suitable glyceryl compounds include thrityl, tri(behenate / isostearate / eicosanedioate), polyglyceryl-10 (eicosanedioate / tetradecanedioate), bisethoxydiglycol cyclohexanedicarboxylate, bis(triethylene glycol monoethyl ether) 1,4-cyclohexanedicarboxylate, bis(diethylene glycol monoethyl ether) adipate, bis(triethylene glycol monoethyl ether) adipate, diethoxyethyl succinate, and diethylhexyl succinate.

[0091] Examples of the emulsifiers, dispersants, suspending agents, and stabilizers include polyhydric alcohols such as polyethylene glycol, propylene glycol, glycerin, and sorbitol; synthetic emulsifiers such as glycerin fatty acid esters, sucrose fatty acid esters, and polyglycerin fatty acid esters; natural emulsifiers such as lecithins, saponin, plant sterols, and milk fat globule membranes; and sodium carboxymethylcellulose, kaolin, xanthan gum, methylcellulose, tragacanth, and hydrogenated soybean phospholipid.

[0092] Examples of the sweetener include sucrose, fructose, maltose, trehalose, licorice extract, saccharin, saccharin sodium, sucralose, stevia processed sweetener, Monk fruit extract, aspartame, acesulfame potassium, erythritol, sorbitol, xylitol, maltitol, reduced starch syrup, and reduced maltose starch syrup.

[0093] Examples of the acidulant include adipic acid, itaconic acid, citric acid, potassium citrate, glucono-delta-lactone, gluconic acid, succinic acid, sodium succinate, sodium acetate, tartaric acid, sodium tartrate, carbon dioxide, lactic acid, sodium lactate, glacial acetic acid, phytic acid, fumaric acid, sodium fumarate, malic acid, and phosphoric acid.

[0094] Examples of the fruit juice include lemon juice, orange juice, berry juice, apple juice, banana juice, and the like.

[0095] The form of the composition of the present invention is not particularly limited, and examples thereof include ointments, liquids, suspensions, emulsions (milky lotions and creams), gels, liniments, lotions, patches, mists, foams, aerosols, sticks, powders, granules, tablets (including plain tablets, sugar-coated tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, troches, and film-coated tablets), detergents, soaps, solids, capsules (e.g., soft capsules), films, confectioneries (including candies, gummies, and nougat), syrups, drinks, juices, soft drinks, and tea; solids such as biscuits, tablets, granular powders, powders, and capsules; and semi-liquid forms such as pastes, jellies, soups, seasonings, and dressings. These formulations can be produced by conventional methods, for example, the methods described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition.

[0096] When the composition of the present invention is a cosmetic product, it can be used in the form of, for example, basic cosmetics such as creams, milky lotions, lotions, gels, serums, essences, facial cleansers, cleansing agents, packs, and lip balms, makeup cosmetics such as sunscreens, lipsticks, foundations, and eye colors, toiletries such as body soaps, soaps, shampoos, rinses, and conditioners, and hair cosmetics such as hair styling agents. The composition of the present invention is suitably used as an anti-aging cosmetic product that improves wrinkles and sagging.

[0097] (Lotion) When the composition of the present invention is a lotion, for example, the lotion contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the lotion is, for example, preferably 0.0005% by mass or more and 1.0% by mass or less, more preferably 0.0005% by mass or more and 0.5% by mass or less, and particularly preferably 0.001% by mass.

[0098] The lotion preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., glycerin, 1,3-butylene glycol, polyoxyalkylene alkyl glucoside, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, etc.), a thickener (e.g., xanthan gum, etc.), a preservative (e.g., methylparaben, etc.), a surfactant (e.g., PPG-13 decyltetradeceth-24, etc.), a pH adjuster (e.g., citric acid, trisodium citrate, etc.), and an ester oil (e.g., bisethoxydiglycol cyclohexane-1,4-dicarboxylate, etc.), and more preferably contains all of the above ingredients.

[0099] (Emulsion) When the composition of the present invention is an emulsion, for example, the emulsion contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the emulsion is, for example, from 0.0001% by mass to 10.0% by mass, preferably from 0.01% by mass to 5.0% by mass, more preferably from 0.1% by mass to 2.0% by mass, and particularly preferably 1.0% by mass.

[0100] The emulsion preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., diglycerin, dipropylene glycol, 1,3-propanediol, PPG-17 buteth-17, etc.), a thickener (e.g., carboxyvinyl polymer, polyvinylpyrrolidone, etc.), a base or carrier (e.g., liquid paraffin, cetanol, dimethicone, etc.), a preservative (e.g., phenoxyethanol, etc.), a surfactant (e.g., sorbitan monostearate, polysorbate 60, etc.), a pH adjuster (e.g., triethanolamine), and vitamins (e.g., triferol, etc.), and more preferably contains all of the above ingredients.

[0101] (Cream) When the composition of the present invention is a cream, for example, the cream contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the cream is, for example, from 0.0001% by mass to 10.0% by mass, preferably from 0.01% by mass to 5.0% by mass, more preferably from 0.05% by mass to 1.0% by mass, and particularly preferably 0.1% by mass.

[0102] The cream preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., glycerin, 1,3-butylene glycol, etc.), a thickener (e.g., agar, polyvinylpyrrolidone, pullulan, etc.), an oil (e.g., medium-chain fatty acid triglyceride, caprylic-capric-myristic-stearic triglyceride, meadowfoam oil, etc.), a base or carrier (e.g., cetanol, behenyl alcohol, shea butter, etc.), a preservative (e.g., sodium benzoate, phenoxyethanol, etc.), a surfactant (e.g., lipophilic glyceryl monostearate, polysorbate 60, etc.), and an emulsifier (e.g., hydrogenated soybean phospholipid, etc.), and more preferably contains all of the above ingredients.

[0103] (Gel) When the composition of the present invention is a gel, for example, the gel contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the gel is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.001% by mass or more and 1.0% by mass or less, more preferably 0.005% by mass or more and 0.1% by mass or less, and particularly preferably 0.01% by mass.

[0104] The gel preferably contains at least one optional ingredient selected from the group consisting of moisturizing ingredients (e.g., glycerin, diglycerin, dipropylene glycol, etc.), thickeners (e.g., xanthan gum, carboxyvinyl polymer, etc.), oils and fats (e.g., medium-chain fatty acid triglycerides, jojoba oil, meadowfoam oil, etc.), bases or carriers (e.g., squalane, stearyl alcohol, behenyl alcohol, etc.), preservatives (e.g., methylparaben, phenoxyethanol, etc.), surfactants (e.g., lipophilic glyceryl monostearate, etc.), and pH adjusters (e.g., sodium hydroxide, etc.), and more preferably contains all of the above ingredients.

[0105] (Sunscreen Cream) When the composition of the present invention is a sunscreen cream, for example, the sunscreen cream contains at least a specific compound, an ultraviolet absorbing component and / or an ultraviolet scattering component, and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the sunscreen cream is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.001% by mass or more and 1.0% by mass or less, more preferably 0.001% by mass or more and 0.05% by mass or less, and particularly preferably 0.005% by mass. Examples of ultraviolet absorbers include octocrylene, polysilicone-15, and 4-tert-butyl-4'-methoxydibenzoylmethane. Examples of ultraviolet scattering agents include hydrophobized titanium oxide fine particles.

[0106] The sunscreen cream preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., polyoxybutylene polyoxyethylene polyoxypropylene glyceryl ether (3B.O.) (8E.O.) (5P.O.), 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer liquid, etc.), a thickener (e.g., gellan gum, carboxyvinyl polymer, etc.), a base or carrier (e.g., triethylhexanoin, stearyl alcohol, batyl alcohol, etc.), a lubricant (e.g., methylpolysiloxane, etc.), a preservative (e.g., phenoxyethanol, etc.), a surfactant (e.g., polyoxyethylene sorbitan isostearate, glyceryl isostearate, etc.), a pH adjuster (e.g., potassium hydroxide, etc.), and a chelating agent (e.g., edetate disodium, etc.), and more preferably contains all of the above ingredients.

[0107] (Sunscreen Gel) When the composition of the present invention is a sunscreen gel, for example, the sunscreen gel contains at least a specific compound, an ultraviolet absorbing component and / or an ultraviolet scattering component, and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the sunscreen gel is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.01% by mass or more and 2.0% by mass or less, more preferably 0.1% by mass or more and 1.0% by mass or less, and particularly preferably 0.5% by mass. Examples of ultraviolet absorbers include 2-ethylhexyl paramethoxycinnamate, phenylbenzimidazole sulfonic acid, diethylaminohydroxybenzoylhexylbenzoate, bisethylhexyloxyphenol methoxyphenyl triazine, etc. Examples of ultraviolet scattering agents include hydrophobized zinc oxide fine particles, etc.

[0108] The sunscreen gel preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., 1,3-butylene glycol, pentanediol, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer liquid, etc.), a thickener (e.g., polyacrylic acid amide, hydroxypropyl cellulose, etc.), an ester oil (e.g., isononyl isononanoate, etc.), a base or carrier (e.g., liquid paraffin, stearyl alcohol, etc.), a lubricant (e.g., methylpolysiloxane, etc.), a preservative (e.g., methylparaben, phenoxyethanol, etc.), a surfactant (e.g., sorbitan monostearate, polyoxyethylene sorbitan isostearate, polyoxyethylene lauryl ether (7E.O.), etc.), an antioxidant (e.g., dibutylhydroxytoluene, etc.), and a chelating agent (e.g., edetate disodium, etc.), and more preferably contains all of the above ingredients.

[0109] (Sunscreen BB Cream) When the composition of the present invention is a sunscreen BB cream, for example, the sunscreen BB cream contains at least a specific compound, an ultraviolet absorbing component and / or an ultraviolet scattering component, and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the sunscreen BB cream is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.01% by mass or more and 2.0% by mass or less, more preferably 0.1% by mass or more and 1.0% by mass or less, and particularly preferably 0.5% by mass. Examples of ultraviolet absorbers include 4-tert-butyl-4'-methoxydibenzoylmethane and diethylaminohydroxybenzoylhexyl benzoate. Examples of ultraviolet scattering agents include hydrophobized zinc oxide fine particles, hydrophilized pigment-grade titanium oxide, hydrophilized iron oxide, and titanium mica.

[0110] The sunscreen BB cream may optionally contain moisturizing ingredients (e.g., 1,3-butylene glycol, pentanediol, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer liquid, etc.), thickeners (e.g., polyacrylic acid amide, hydroxypropyl cellulose, gellan gum, (PEG-240 / decyltetradeceth-20 / HDI) copolymer, etc.), ester oils (e.g., isononyl isononanoate, bisethoxydiglycol cyclohexanedicarboxylate, diethylhexyl succinate, etc.), bases or carriers (e.g., liquid paraffin, stearyl alcohol, cetanol, absolute ethanol, etc.), and lubricants (e.g., methylpolysiloxane It is preferable that the cosmetic composition contains at least one of an antioxidant (e.g., sorbitan monostearate, polyoxyethylene sorbitan isostearate, polyoxyethylene lauryl ether (7E.O.), glyceryl isostearate, polyethylene glycol monostearate, etc.), an antioxidant (e.g., dibutylhydroxytoluene, etc.), a chelating agent (e.g., caprylhydroxamic acid, edetate disodium, etc.), a pH adjuster (e.g., triethanolamine, etc.), and an anti-inflammatory agent (e.g., 2-ethylhexyl salicylate, etc.), and it is more preferable that the cosmetic composition contains all of the above-mentioned ingredients.

[0111] The present inventors have also found that the compound of formula (I) activates the secretion of serotonin in a human neuronal model. Serotonin is also known as the "happiness hormone," and is suggested to be involved in mental stability and skin condition.

[0112] Therefore, when the composition of the present invention is used as a cosmetic, it can be absorbed through the skin and reach serotonin-producing cells (e.g., the raphe nucleus of the brainstem) to activate the secretion of serotonin. This allows the composition of the present invention to be used as a so-called "neurocosmetics" that also provides cosmetic effects through the interaction between the skin and nerves.

[0113] (Tablets) When the composition of the present invention is in the form of a tablet, for example, the tablet contains at least a specific compound and an excipient. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in the daily dose of the tablet is, for example, 0.001 mg / day to 10.0 mg / day, preferably 0.001 mg / day to 5.0 mg / day, and more preferably 0.003 mg / day to 3.0 mg / day. Examples of excipients include maltitol and starch.

[0114] The tablet preferably contains at least one optional ingredient selected from the group consisting of a binder (e.g., crystalline cellulose, etc.) and a lubricant (e.g., calcium stearate, fine silicon dioxide, etc.), and more preferably contains all of the above ingredients.

[0115] (Soft Capsules) When the composition of the present invention is a soft capsule, for example, the soft capsule contains at least a specific compound, a base, and a coating component. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the soft capsule is, for example, 0.001 mg / day or more and 10.0 mg / day or less, preferably 0.001 mg / day or more and 3.0 mg / day or less. Examples of the base include oils and fats (e.g., vegetable oils such as safflower oil, soybean oil, sunflower oil, and olive oil). Examples of the coating component include gelatin, glycerin, etc.

[0116] The soft capsule preferably contains at least one of an emulsifier and an antioxidant (e.g., vitamin E) as an optional ingredient, and more preferably contains all of the above ingredients.

[0117] (Granules) When the composition of the present invention is in the form of granules, for example, the granules contain at least a specific compound and an excipient. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the granules is, for example, 0.001 mg / day or more and 10.0 mg / day or less, and preferably 0.001 mg / day or more and 3.0 mg / day or less. Examples of excipients include maltitol, xylitol, lactose, and modified starch.

[0118] The granules preferably contain at least one optional ingredient selected from the group consisting of a sweetener, a lubricant (calcium stearate), a base or carrier (e.g., hydroxypropyl methylcellulose, etc.), a flavoring, and a coloring (e.g., riboflavin, gardenia pigment, carotenoid pigment, etc.), and more preferably contain all of the above ingredients.

[0119] (Drinks) When the composition of the present invention is a drink, for example, the drink contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the drink is, for example, 0.001 mg / day or more and 10.0 mg / day or less, and preferably 0.001 mg / day or more and 3.0 mg / day or less.

[0120] The drink preferably contains at least one of the following optional ingredients: a sweetener (e.g., sugar, glucose, erythritol, etc.), a stabilizer (e.g., pectin, etc.), an acidulant, a flavoring, and a coloring (e.g., riboflavin, gardenia pigment, carotenoid pigment, etc.), and more preferably contains all of the above ingredients.

[0121] (Gummy Candy) When the composition of the present invention is a gummy candy, for example, the gummy candy contains at least a specific compound, sugar, starch syrup, and gelatin. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the drink is, for example, 0.001 mg / day or more and 10.0 mg / day or less, and preferably 0.001 mg / day or more and 3.0 mg / day or less.

[0122] The gummy candy preferably contains at least one of the following optional ingredients: a stabilizer (e.g., pectin), a sweetener (e.g., sorbitol), glycerin, an acidulant, a flavoring, a glazing agent, an emulsifier, an oblate, and a coloring agent, and more preferably contains all of the above ingredients.

[0123] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0124] As shown below, an in vitro test was carried out to confirm the effect of the compound represented by formula (I-1) on human skin fibroblasts.

[0125] (In vitro Test A) The compound represented by formula (I-1) was administered to human dermal fibroblasts (NHDF, manufactured by Kurabo Industries, Ltd.) in vitro by the following method, and the mRNA expression levels of type I collagen gene, elastin gene, mammalian hyaluronidase 1 gene, and MMP-1 gene were measured.

[0126] The medium used to culture human dermal fibroblasts (NHDF, manufactured by Kurabo Industries, Ltd.) was medium (A) prepared by adding 10% fetal bovine serum (manufactured by Corning Incorporated) and 1% antibiotics (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) to DMEM (Dulbecco's Modified Eagle Medium) (manufactured by Thermo Fisher Scientific Co., Ltd.). When adding the test substance, medium (B) prepared by adding 0.1% fetal bovine serum and 1% antibiotics to the DMEM was used.

[0127] First, 2 × 10 ４Cells (NHDF) were seeded onto a 24-well plate at 500 μL / well. Next, NHDF were cultured using medium (A) at 37°C under an environment of 5% carbon dioxide and 95% air. After confirming that there were no problems with cell (NHDF) growth by microscopic observation, the NHDF were cultured for an additional 24 hours (the above process is referred to as "culture procedure A"). The medium was then replaced with medium (B). The compound represented by formula (I-1) was added as a test substance to medium (B) used for this medium replacement at the test concentrations shown in Tables 1 to 4 and Figures 1 to 4. Meanwhile, a control (control) was used in which normal medium (B) without the test substance was added during the medium replacement. Thus, the cells were treated with the test substance (24 hours for the type I collagen gene, 48 hours for the elastin gene and mammalian hyaluronidase 1 gene, and 72 hours for the MMP-1 gene).

[0128] Next, the treated cells (NHDF) were collected. Total RNA was extracted from the collected cells using an extraction kit (Maxwell RSC simplyRNA Tissue Kit: manufactured by Promega) and an automatic extractor (Maxwell RSC48 Instrument: manufactured by Promega). The collected total RNA was then reverse transcribed using a reverse transcription kit (ReverTra Ace (registered trademark) qPCR RT Master Mix: manufactured by Toyobo Co., Ltd.) to synthesize cDNA. The obtained cDNA was then subjected to qPCR using a qPCR master mix (TaqMan Fast Advanced Master Mix: manufactured by ABI). The GAPDH (glyceraldehyde 3-phosphate dehydrogenase) gene was used as an internal standard. The mRNA expression levels of type I collagen, elastin, MMP-1, and mammalian hyaluronidase 1 were measured, and the mRNA expression level of the gene to be measured relative to the mRNA expression level of GAPDH (mRNA expression level of the gene to be measured / mRNA expression level of GAPDH) was evaluated.

[0129] The primers used are listed below. When measuring the mRNA expression level of mammalian hyaluronidase 1, a Taqman primer for GAPDH (internal standard) was used in combination with a Taqman primer for hyaluronidase 1. When measuring the mRNA expression levels of type I collagen, elastin, and MMP-1, a SYBR primer for GAPDH (internal standard) was used in combination with a SYBR primer for type I collagen, elastin, or MMP-1.

[0130]

[0131] The measurement results are shown in Tables 2 to 5 and Figures 1 to 4.

[0132]

[0133] As described above, it was confirmed that the compound represented by formula (I-1) activates the expression of type I collagen gene in human skin fibroblasts (FIG. 1).

[0134]

[0135] As described above, it was confirmed that the compound represented by formula (I-1) activates the expression of the elastin gene in human skin fibroblasts (FIG. 2).

[0136]

[0137] As described above, it was confirmed that the compound represented by formula (I-1) inhibits the expression of the mammalian hyaluronidase 1 gene in human skin fibroblasts (FIG. 3).

[0138]

[0139] As described above, it was confirmed that the compound represented by formula (I-1) inhibits the expression of the MMP-1 gene in human skin fibroblasts (FIG. 4).

[0140] The above tests confirmed that the specific compound has excellent effects in promoting collagen expression, promoting elastin expression, inhibiting hyaluronidase expression, promoting hyaluronic acid production, or inhibiting MMP-1 expression. Furthermore, the specific compound is considered to have excellent effects in improving skin texture, enhancing skin elasticity (including the effect of reducing skin sagging), reducing wrinkles, or anti-aging effects by regulating these extracellular matrix-related genes.

[0141] (In Vitro Test B) The same procedure as in Culturing Procedure A described in In Vitro Test A was performed. Specifically, human dermal fibroblasts (NHDF, manufactured by Kurabo Industries, Ltd.) were cultured in medium (A). The medium was then replaced. A compound represented by formula (I-1) was added as a test substance to medium (B) used for the medium replacement, at the test concentrations shown in Table 6 and Figure 5. Meanwhile, a control (control) was prepared using a normal differentiation medium without the addition of the test substance during the medium replacement. Thus, the cells (NHDF) were treated with the test substance. The cell culture supernatant was collected 48 hours after the culture for quantification of hyaluronic acid concentration, and 72 hours after the culture for quantification of MMP-1 protein secretion.

[0142] (Quantification of hyaluronic acid concentration) The hyaluronic acid concentration in the cell culture supernatant was measured by ELISA. Specifically, the hyaluronic acid concentration was quantified using the following kit according to the standard protocol included with the kit: Human, Mouse, & Rat Hyaluronan ELISA Kit (product number: DHYAL0) (manufactured by R&D Systems).

[0143] The measurement results are shown in Table 6 and FIG.

[0144]

[0145] As described above, it was confirmed that the compound represented by formula (I-1) increases the hyaluronic acid concentration in the culture supernatant of human skin fibroblasts in the range of 0.001 mM to 0.1 mM (FIG. 5).

[0146] (Quantification of MMP-1 Protein Secretion Amount) The amount of MMP-1 protein secreted in the cell culture supernatant was measured by ELISA. Specifically, the amount of MMP-1 protein secreted was quantified using the kit shown below, following the standard protocol included with the kit. Human Total MMP-1 DuoSet ELISA (product number: DY901B) (manufactured by R&D Systems).

[0147] The measurement results are shown in Table 7 and FIG.

[0148]

[0149] (In vivo Study A) A placebo-controlled, randomized, single-blind, parallel-group comparative study was conducted on Japanese women aged 35 to 59. Specifically, subjects were administered a formulation containing the hydrochloride of the compound represented by formula (I-1) at a concentration of 0.001% (formulation group, 14 subjects) or a placebo formulation not containing the hydrochloride of the compound (placebo group, 14 subjects) for 8 weeks (twice daily, morning and evening). The width of crow's feet and nasolabial folds, as well as collagen density, were quantitatively measured before application (0W), 4 weeks after application (4W), and 8 weeks after application (8W) using the following methods.

[0150] Details of the formulations used are as follows, where the numbers represent parts by mass. Water: 70.63362 Dimethicone: 11.7422 Butylene glycol (BG): 8.1 Ethanol: 5 PEG-11 methyl ether dimethicone: 1.5 Cyclopentasiloxane: 0.93 (Dimethicone / (PEG-10 / 15)) crosspolymer: 0.7578 Sodium chloride: 0.5 Phenoxyethanol: 0.305 Methylparaben: 0.2 EDTA-2Na: 0.1 Sodium citrate: 0.0758 (Dimethicone / vinyl dimethicone) crosspolymer: 0.07 TEA: 0.05 Glycerin: 0.03 Ethylhexylglycerin: 0.002 Citric acid: 0.0017 Hydrochloride of the compound represented by formula (I-1): 0.001 Potassium hydroxide: 0.00088

[0151] (Crow's feet wrinkles) The width of the crow's feet wrinkles was measured using the skin analyzer "Antera 3D ＴＭ(manufactured by Gadelius Medical Co., Ltd.) was used, and measurements were taken in accordance with the Guidelines for Evaluation of Anti-Wrinkle Products (Journal of the Japanese Society of Cosmetic Chemistry, Vol. 30, No. 4, pp. 316-332 (2006)). Note that "corner of the eye" refers to the outer corner of the eye (the point where the upper and lower eyelids meet), and corner of the eye wrinkles refer to the groove that runs linearly from the outer corner of the eye. In addition, for subjects with multiple corner of the eye wrinkles, the average width of each corner of the eye wrinkle was used as the measurement value. The measurement results are shown in Table 8 and Figure 7. For reference, images of corner of the eye wrinkles at 0W and 8W for one subject in the formulation group are shown in Figure 8.

[0152]

[0153] (Laugh lines) The width of laugh lines was measured using the skin analyzer described above. The measurement results are shown in Table 9 and Figure 9. For reference, images of laugh lines at 0W and 8W for one subject in the formulation group are shown in Figure 10.

[0154]

[0155] As is clear from Tables 8 and 9 and Figures 7 and 9, the formulation group to which the preparation containing the hydrochloride of the compound represented by formula (I-1) was applied showed a significant decrease in the width of crow's feet and the width of nasolabial folds in both intra-group comparison and inter-group comparison with the control group.

[0156] (Collagen Density) The collagen density was measured using an ultrasonic dermis imaging device "DermaLab" (manufactured by Integral Corporation) and the results are shown in Table 10 and FIG.

[0157]

[0158] As is clear from Table 10 and FIG. 11, the formulation group to which the preparation containing the compound represented by formula (I-1) was applied showed a significant improvement in collagen density in both intra-group comparison and inter-group comparison with the control group.

[0159] From the above, it is presumed that the preparation containing the specific compound shows a high effect of improving wrinkles and sagging by increasing collagen density.

[0160] (In vitro Test C) According to the following method, a human neuronal cell model (human neuroblastoma cells (SH-SY5Y)) was cultured in vitro in a medium containing a compound represented by formula (I-1) or (I-2). Then, the amount of serotonin protein secreted in the human neuroblastoma cells was measured.

[0161] The human neuroblastoma clone SH-SY5Y cell line was obtained from the American Type Culture Collection (ATCC®, Manassas, CA). The culture medium was prepared by adding 15% fetal bovine serum (FBS) (Corning), MEM non-essential amino acids (Fujifilm Wako Pure Chemical Industries, Ltd.), and 1% penicillin-streptomycin solution (Fujifilm Wako Pure Chemical Industries, Ltd.) to DMEM / F12 (Dulbecco's Modified Eagle Medium) (Thermo Fisher Scientific).

[0162] First, 4 x 10 ４ Cells (SH-SY5Y) were seeded in a 24-well plate at 500 μl / well under the conditions of 37°C, 5% CO ２ SH-SY5Y cells were cultured for 24 hours under an environment of 10% CO₂ and 95% air. Microscopic observation confirmed that the cells (SH-SY5Y) were viable. The medium was then replaced. The new medium (A) used for this medium replacement (DMEM / F12 (Dulbecco's Modified Eagle Medium) (Thermo Fisher Scientific) supplemented with 1% penicillin-streptomycin solution (Fujifilm Wako Pure Chemical Industries)) contained the test compounds at the test concentrations shown in Table 11. Meanwhile, a control medium (A) containing no test compounds was used during the medium replacement. Thus, the cells were treated with the test compounds. After 24 hours, the culture supernatant was collected.

[0163] The amount of serotonin protein secreted in the cell culture supernatant was measured by ELISA. Specifically, the serotonin protein was quantified using the kit shown below according to the standard protocol included with the kit. Serotonin kit: Serotonin ELISA kit (manufactured by Enzo Life Sciences).

[0164] The measurement results are shown in Table 11 and FIG.

[0165]

[0166] As is clear from Table 11 and Figure 12, it was revealed that the compound represented by formula (I-1) or (I-2) activates the secretion of serotonin in a human neuronal cell model. From the above, it is possible that a composition containing a specific compound may also have a positive effect on the mental state.

[0167] According to the present invention, it is possible to provide a composition having an excellent effect of improving skin texture, an effect of increasing skin elasticity (including an effect of improving skin sagging), an effect of improving wrinkles, or an anti-aging effect, and a composition having an excellent effect of promoting collagen expression, promoting elastin expression, suppressing hyaluronidase expression, promoting hyaluronic acid production, or suppressing MMP-1 expression.

Claims

1. A composition for improving skin texture, increasing skin elasticity, improving wrinkles or anti-aging, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH).

2. A composition for promoting collagen expression, promoting elastin expression, inhibiting hyaluronidase expression, promoting hyaluronic acid production, or inhibiting MMP-1 expression, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH).

3. In the formula (I), R １ represents an alkoxy group having 1 to 3 carbon atoms; R ２ and R ３ each independently represents a hydrogen atom or —CHO; ４ and R ５ each independently represents a hydrogen atom or an acyl group having from 2 to 4 carbon atoms; R ６ The composition according to claim 1 or 2, wherein represents a hydrogen atom.

4. The composition according to claim 1 or 2, wherein the compound represented by formula (I) is represented by the following formula (I-1):

5. A composition according to any one of claims 1 to 4, which is an external or oral composition.

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