WO2007148804A1 - Composition capable of promoting the production of hyaluronic acid - Google Patents

Abstract

Disclosed is a novel composition capable of remarkably promoting the production of hyaluronic acid. The composition comprises (A) at least one member selected from the group consisting of retinol and a derivative thereof and (B) at least one member selected from the group consisting of a peptide represented by Leu-Glu-His-Ala (Formula I), a derivative thereof and a salt of the peptide or the derivative. Alternatively, the composition comprises (A) at least one member selected from the group consisting of retinol and a derivative thereof and (B) at least one member selected from the group consisting of a peptide having the conservative substitution, deletion and/or addition of at least one amino acid residue in the amino acid sequence: Leu-Glu-His-Ala (Formula I) and capable of promoting the production of hyaluronic acid in a cell, a derivative thereof and a salt of the peptide or the derivative.

Description

 Specification

 Composition having hyaluronic acid production promoting ability

 Technical field

 [0001] The present invention relates to a useful novel composition having hyaluronic acid production-promoting ability and a related invention.

 Background

 Conventionally, it has been known that connective tissues of animals contain collagen, hyaluronic acid, elastin, chondroitin sulfate, heparan sulfate, dermatan sulfate, laminin and the like as main components. Of these, hyaluronic acid plays an important role in connective tissues as described below.

 [0003] Hyaluronic acid is a kind of acidic mucopolysaccharide present in skin, cartilage, joint fluid, umbilical cord, ophthalmic vitreous and other connective tissues. Hyaluronic acid is known to play a variety of roles in the body.For example, hyaluronic acid has a function of acting as a cushion in joints and repairing worn cartilage as the main component of joint fluid. It is known. Hyaluronic acid is also known to have an anti-inflammatory effect in vivo.

 [0004] Furthermore, in the skin epidermis, hyaluronic acid is widely distributed from the basal layer to the granular layer, supports the structure of the epidermal extracellular space, and transports nutrients such as waste products from the epidermal basal layer to the horny layer. It is known to be involved and act as a trigger to promote epidermal cell turnover. It is also known that hyaluronic acid has a strong water-holding action that can hold about 6 L of water in as little as 1 lg, and has the role of holding water in the cell gap by this action. Hyaluronic acid is known to gradually decrease with aging, and this reducing power can lead to the formation of skin tartarmi, reduced skin elasticity and firmness, or skin aging such as skin dryness and rough skin. It is a cause.

[0005] For the reasons described above, the power that is desired to supplement and increase the amount of hyaluronic acid that has decreased due to aging, etc. Since hyaluronic acid is a high molecular compound, the external force of the skin It is not easy to supply to. Therefore, in order to supply hyaluronic acid in vivo (for example, between epidermal cells) etc., the biosynthesis of hyaluronic acid in vivo is promoted. Progress is said to be important.

 [0006] Various hyaluronic acid synthesis promoting substances have been found in order to improve the state caused by the decrease in hyaluronic acid. For example, aloe extract, okra extract, water-soluble 1,3-Dalcan derivative, yeast extract (Patent Document 1), seaweed extract belonging to the genus Coleoptera (Patent Document 2), lavender extract ( Known are Patent Document 3), extracts of seaweeds belonging to the genus Davilia (Patent Document 4), retinoic acid, and the like.

 Patent Document 1: JP 2004-051533 A

 Patent Document 2: JP 2000-136147 A

 Patent Document 3: Japanese Patent Laid-Open No. 10-182402

 Patent Document 4: Japanese Patent Laid-Open No. 09-176036

 Disclosure of the invention

 Problems to be solved by the invention

[0007] In view of the importance of the role played by hyaluronic acid in the living body as described above, development of a further useful new composition having a remarkable hyaluronic acid production promoting ability is desired. The present invention is directed to providing a useful new composition having a remarkable ability to promote the production of hyaluronic acid in view of the conventional problems that are encouraging. Another object of the present invention is to provide a method for promoting hyaluronic acid production in cells.

 Means for solving the problem

[0008] As a result of intensive studies to solve the above problems, the present inventors have used retinols in combination with specific peptides having a specific amino acid sequence, thereby using retinols alone. In addition, the present inventors have found that the ability to promote hyaluronic acid production in cells is remarkably promoted, and have completed the present invention.

Accordingly, the present invention provides the following.

 (1) (A) at least one selected from the group consisting of retinol and derivatives thereof, and (B) a peptide represented by Leu-Glu-His-Ala (formula I), a derivative thereof and a salt thereof. A composition containing at least one selected from the group described above.

(2) (A) at least one selected from the group consisting of retinol and its derivatives, and (B) a conservative arrangement of one or more amino acids in the amino acid sequence of Leu-Glu-His-Ala (formula I) A composition comprising at least one selected from the group consisting of peptides having derivatives, deletions and z or additions, and having the ability to promote hyaluronic acid production in cells, derivatives thereof, and salts thereof.

 (3) The composition according to item (2), wherein the peptide has an amino acid length of 3 to 10 residues.

(4) The composition according to any one of items (1) to (3), which can be used to promote hyaluronic acid production in cells.

 (5) The composition according to any one of items (1) to (4), which is a composition for external use.

 (6) (A) at least one selected from the group consisting of retinol and derivatives thereof, and (B) a peptide represented by Leu-Glu-His-Ala (formula I), a derivative thereof and a salt thereof. A method for promoting hyaluronic acid production in a cell using at least one selected from the group described above.

 (7) A conservative substitution of one or more amino acids in the amino acid sequence of (B) Leu-Glu-His-Ala (formula I) with (A) at least one selected from the group consisting of retinol and its derivatives. And hyaluronic acid production in cells using at least one selected from the group consisting of a peptide having a deletion, Z or addition and having the ability to promote hyaluronic acid production in cells, derivatives thereof, and salts thereof how to.

 (8) For the production of a composition for promoting hyaluronic acid production in cells, (A) at least one selected from the group consisting of retinol and its derivatives, and (B) Leu- Glu His— Ala ( Use with at least one selected from the group consisting of peptides represented by formula I), derivatives thereof, and salts thereof.

 (9) For the production of a composition for promoting hyaluronic acid production in cells, (A) at least one selected from the group consisting of retinol and its derivatives, and (B) Leu- Glu His -Ala ( A peptide having a conservative substitution, deletion and Z or addition of one or more amino acids in the amino acid sequence of formula (I), and an ability to promote hyaluronic acid production in cells, its derivatives, and salts thereof Use with at least one selected from the group consisting of The invention's effect

The present invention provides a useful novel composition having a remarkable ability to promote hyaluronic acid production. The composition of the present invention is used to promote hyaluronic acid production in cells For example, the composition can be beneficially used as an anti-itch composition, an anti-tarmi composition, a composition for preventing or treating joint disorders, a composition for preventing or treating inflammatory diseases, and the like. Furthermore, the present invention also provides a method for promoting hyaluronic acid production in cells.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail. It should be understood that the terms used in this specification are used in the meaning normally used in the art unless otherwise specified.

 [0012] The present invention includes (A) at least one selected from the group consisting of retinol and derivatives thereof, and (B) a peptide represented by Leu-Glu-His-Ala (formula I), a derivative thereof, and a derivative thereof. It is a composition containing at least one selected from the group consisting of salt power.

 [0013] The present invention also relates to (A) at least one selected from the group consisting of retinol and derivatives thereof, and (B) one or more amino acids in the amino acid sequence of Leu-Glu-His-Ala (formula I). A composition comprising at least one selected from the group consisting of peptides having conservative substitutions, deletions and Z or additions, and having the ability to promote hyaluronic acid production in cells, derivatives thereof, and salts thereof .

 [0014] Retinol and its derivatives used in the present invention (hereinafter sometimes collectively referred to as "retinols" in the present specification) are used in the fields of pharmaceuticals, quasi drugs, cosmetics or foods. If it can be used, it will not be specifically limited.

 [0015] Retinol derivatives include: retinoic acid; retinal; retinol, retinoic acid, or an isomer of retinal; an ester derivative of retinol or its isomer; an ether derivative of retinoic acid or its isomer; a retinoic acid or its isomer; Ester derivatives; epoxy derivatives of retinol, retinoic acid, retinal or their isomers; derivatives of retinoic acid, retinoic acid, retinal or their isomers with elimination of hydrogen atoms or addition of hydrogen atoms; .

[0016] Examples of isomers of retinol, retinoic acid, or retinal include geometric isomers (cis-to-lance isomers, or E, Z isomers), and the positions and number of double bonds and their steric structures are particularly limited. Not. Specific examples of retinal, retinoic acid, or retinal isomers include retinol

, Retinoic acid or retinal, all-trans form, 13 cis form, 11-cis form, 9 cis form, 7 cis form, 7, 9 di-cis form, 7, 13 di-cis form, 11, 13 di-cis Body, 9, 13 di-cis body, 9, 11, 13 tri-cis body and the like. Among these isomers, the all-trans isomer or the all-trans isomer, in which the 13-cis isomer is preferred, are particularly preferred

[0017] Examples of ester derivatives of retinol or its isomer include esters of retinol or its isomer with acids such as aliphatic carboxylic acids and aromatic carboxylic acids.

 [0018] Examples of the aliphatic carboxylic acid include saturated or unsaturated aliphatic carboxylic acids having 1 to 22 carbon atoms, preferably saturated or unsaturated aliphatic carboxylic acids having 2 to 18 carbon atoms. Specific examples include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, hexanoic acid, heptanoic acid, octanoic acid, octylic acid, nonanoic acid, decanoic acid, undecanoic acid, Lauric acid, myristic acid, pentadecanoic acid, palmitic acid, isopalmitic acid, heptadecanoic acid, stearic acid, isostearic acid, behenic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, undecylenic acid, myristoleic acid , Aliphatic monocarboxylic acids such as palmitoleic acid, oleic acid, ricinolenic acid, linoleic acid, linolenic acid, arachidonic acid, icosapentaenoic acid, docosahexaenoic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid; , Malonic acid, succinic acid, dartaric acid, adipic acid, Aliphatic dicarboxylic acids such as phosphoric acid, suberic acid, azelaic acid, sebacic acid, fumaric acid, maleic acid or their monoesters (eg, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl) And retinoic acid and the like. In addition, the aliphatic carboxylic acid may be substituted. Examples of the substituent include an alkoxy group having 1 to 6 carbon atoms (e.g., a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, s butoxy group). Group, t-butoxy group, isobutoxy group, pentyloxy group, hexyloxy group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), amino group, hydroxy group and the like.

Examples of aromatic carboxylic acids include aromatic carboxylic acids having 7 to 12 carbon atoms. Or an aromatic carboxylic acid having 7 to 10 carbon atoms. Specific examples include aromatic monocarboxylic acids such as benzoic acid, naphthoic acid and cinnamic acid; aromatic dicarboxylic acids such as phthalic acid, isophthalic acid and terephthalic acid; In addition, the aromatic carboxylic acid may be substituted, and the substituent is, for example, an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group). T-butyl group, isobutyl group, pentyl group, hexyl group, etc.), alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, s butoxy group, t Butoxy group, isobutyloxy group, pentyloxy group, hexyloxy group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), amino group, hydroxy group and the like.

[0019] Specific examples of the ester derivative of retinol or its isomer include retinol acetate, retinol propionate, retinol butyrate, retinol pivalate, retinol heptanoate, retinol octylate, retinol nonanoate, retinol laurate, myristic Acid retinol, retinol palmitate, retinol stearate, retinol heptadecanoate, retinol oleate, retinol linolenate, retinol linoleate, retinol cyclopentanecarboxylate, retinol succinate, L-retinol lactate, etc. The body is mentioned.

 [0020] Examples of the ether derivative of retinol or its isomer include those in which the hydrogen atom of the hydroxy group of retinol or its isomer is substituted with an alkyl group, an alkenyl group, an aryl group, a sugar residue, or the like.

 As an alkyl group, a C1-C22 alkyl group is mentioned, Preferably it is a C1-C6 alkyl group. Specific examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, sbutyl group, tbutyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group. Group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, otadecyl group and the like.

Examples of the alkenyl group include alkenyl groups having 2 to 12 carbon atoms, preferably alkenyl groups having 2 to 6 carbon atoms. Specific examples include a vinyl group, a allyl group, a buture group (eg, 1-buture, 2-buture) and the like. These alkyl groups and alkenyl groups may be substituted! The substituents may be alkoxy groups having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group). , S-butoxy group, t-butoxy group, isobutyloxy group, pentyloxy group, hexyloxy group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), amino group, hydroxy group, Examples thereof include an oxo group and a phenyl group.

 Examples of aryl groups include aryl groups having 6 to 12 carbon atoms. Specific examples include phenyl group, naphthyl group-naphthyl group, 2-naphthyl group) and the like. The aryl group may be substituted, and the substituent is, for example, an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sbutyl group). , T-butyl group, isobutyl group, pentyl group, hexyl group, etc.), alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, s butoxy group, t-butoxy group, isobutyloxy group, pentyloxy group, hexyloxy group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), amino group, hydroxy group and the like.

Examples of sugar residues include monosaccharide residues and oligosaccharide residues. Specific examples of the monosaccharide residue include glucose residue, fructose residue, galactose residue, mannose residue, talose residue, idose residue, altrose residue, allose residue, growth residue, xylose. Residues, ribose residues, arabinose residues, rhamnose residues, fucose residues, glucuronic acid residues and the like. Examples of oligosaccharide residues include oligosaccharide residues composed of 2 to 10 monosaccharides. Examples of the constituent monosaccharides of oligosaccharide residues include glucose, fructose, galactose, mannose, talose, idose, ananolose, garose, growth, xylose, ribose, arabinose, rhamnose, fucose, glucuronic acid, etc. Or they may be different. The hydrogen atom of the hydroxy group of the sugar residue may be substituted. Examples of the substituent include an acyl group having 1 to 7 carbon atoms (e.g., formyl group, acetyl group, propiol group, ptylyl group, isoptylyl group). , Valeryl group, isovaleryl group, bivaloyl group, etc.), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sbutyl group, tbutyl group, isobutyl group, Pentyl group, hexyl group, etc.). [0022] Specific examples of ether derivatives of retinol or its isomer include 15-deoxy-15-methoxyretinol, 15-deoxy-15-ethoxyretinol, O- (j8-D-darcopyranosyl) retinol, O- (β-D group Chronopyranosyl) retinol, Ο— (β D maltosyl) retinol and the isomers thereof.

 [0023] Examples of ester derivatives of retinoic acid or its isomers include esters of retinoic acid with aliphatic or aromatic alcohols, tocopherols and the like.

 Examples of the aliphatic alcohol include an aliphatic alcohol having 1 to 22 carbon atoms, and an aliphatic alcohol having 1 to 18 carbon atoms is preferable. Specific examples include methanol, ethanol, propanol, isopropanol, butanol, sbutanol, t-butanol, isobutanol, pentanol, hexanol and the like. Aliphatic alcohols may be substituted, and the substituents include alkoxy groups having 1 to 6 carbon atoms (e.g., methoxy groups, ethoxy groups, n propoxy groups, isopropoxy groups, n butoxy groups, s Butoxy group, t-butoxy group, isobutyloxy group, n-pentyloxy group, n-hexyloxy group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), amino group, phenyl group Etc.

 Examples of the aromatic alcohol include aromatic alcohols having 6 to 12 carbon atoms, and specific examples include benzyl alcohol, 1-phenylethyl alcohol, 2-phenyl alcohol, and the like. In addition, aromatic alcohols that may be substituted include alkyl groups having 1 to 6 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s Butyl group, t-butyl group, isobutyl group, n pentyl group, n-hexyl group, etc.), alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n —Butoxy group, s-butoxy group, t-butoxy group, isobutoxy group, n-pentyloxy group, n-hexyloxy group, etc., halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) ), Amino group, hydroxy group and the like.

 Examples of tocopherols include α-tocopherol, j8-tocopherol, δ tocopherol and the like.

[0024] Specific examples of ester derivatives of retinoic acid or its isomer include retinoic acid These isomers include chill, retinoic acid ethyl, α-tocopheryl retinoate, β-tocopheryl retinoate, and δ-tocopheryl retinoate.

 [0025] The epoxy derivatives of retinol, retinoic acid, retinal or their isomers include those in which the double bond of retinol, retinoic acid, retinal or their isomers is epoxidized. The position and number are not particularly limited. Moreover, the epoxy derivatives of retinol, retinoic acid, retinal or their isomers may be further esterified or etherified, respectively.

 Specific examples include 5,6-dihydro-5,6-epoxyretinol, 5,6-epoxy-5,6-dihydroretinol acetate, 5,8 dihydro-5,8 epoxyretinol, 11,14 epoxy 11,14-dihydro Retinol, 5, 6; 11, 14-diepoxy 5, 6, 11, 14-tetrahydroretinol, 5, 6 dihydro-5, 6 epoxy retinoic acid and the isomers thereof

 [0026] In the derivative from which hydrogen atoms of retinol, retinoic acid, retinal or their isomers are eliminated, the position and number of the hydrogen atoms to be eliminated are not particularly limited. In addition, in the retinoic acid, retinoic acid, retinal, or a derivative in which a hydrogen atom is added to the isomer, the position and number of the hydrogen atom to be added are not particularly limited. In addition, the derivatives of retinol, retinoic acid, retinal or their isomers from which a hydrogen atom is eliminated or a hydrogen atom is added may be further esterified or etherified, respectively.

 Specific examples include 3,4-didehydroretinol, 7,8-didehydroretinol, 7,8-didehydroretinol acetate, 5,6-dihydroretinol acetate, 5,6-dihydroretinol, 3,4 didehydro. Examples thereof include retinal, 5,6-dihydroretinal, 7,8-dihydroretinal, 9,10 dihydroretinal, 3,4 didehydroretinoic acid, and the isomers thereof.

[0027] The retinol derivative of the present invention may further have a substituent, and the position of substitution and the number of substituents are not particularly limited. Examples of the substituent include alkyl groups having 1 to 6 carbon atoms (eg, methyl group, ethyl group, η propyl group, isopropyl group, η butyl group, s butyl group, t butyl group, isobutyl group, n pentyl group, n —Hexyl group, etc.), C 1-6 alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n Butoxy group, s-butoxy group, t-butoxy group, isobutyloxy group, n-pentyloxy group, n-hexyloxy group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) , Amino group, hydroxy group, carboxy group, oxo group and the like.

 [0028] The retinol derivative may be a salt. As such a salt, a pharmacologically physiologically acceptable salt is preferable. Specific examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts; alkanolamine salts such as monoethanolamine salts; .

 [0029] In the present invention, preferably, all-trans retinol, retinol acetate, retinol palmitate, or δ tocopheryl retinoate is used as retinol and derivatives thereof.

[0030] In the present invention, the above retinol and derivatives thereof may be used alone or in a mixture of two or more. Further, for example, in the present invention, as retinol and derivatives thereof, fatty oils obtained from marine animal tissues containing retinol and derivatives thereof, extracts (such as vitamin coconut oil), and the like can also be used.

 [0031] The amount of retinol compounded in the composition of the present invention is not particularly limited as long as the effect of the present invention can be achieved, but is usually 0.1 IU to 5 million IU, more preferably 50 IU per lOOg of the composition. ˜1.5 million IU, more preferably 300 IU to 1 million IU, 1000 IU to 500,000 IU.

 [0032] Here, IU is an international unit relating to the amount of fat-soluble vitamins such as vitamin A, as can be generally understood by those skilled in the art. For example, retinol corresponds to 1 IU = approximately 0.30 g retinol, retinol acetate corresponds to 1 IU = approximately 0.34 g retinol acetate, and retinol palmitate has 1 IU = approximately 0.55 g. Corresponds to retinol palmitate and, in the case of δ-tocopheryl retinoate, corresponds to 1 IU = about 0.72 g of δ-tocopheryl retinoate.

[0033] The present invention further includes at least one selected from the group consisting of a peptide represented by Leu-Glu-His-Ala (formula I), a derivative thereof, and a salt power thereof, or Leu-Glu-His-Ala. A peptide having conservative substitution, deletion and Z or addition of one or more amino acids in the amino acid sequence of (formula I), and the ability to promote hyaluronic acid production in cells, At least one selected from the group consisting of derivatives and their salt strength is used [hereinafter, these may be collectively referred to as “specific peptides” t hereinafter].

 In the present specification, the term “peptide derivative” means, for example, that a peptide is acetylated, palmitoylated, myristylated, amidated, acrylated, dansylated, pyotinylated, phosphoric acid, Succinylation, alkylation, benzyloxycarbonylation, formylation, nitration, sulfonated, aldehyded, cyclized, glycosylated, monomethylated, dimethylated, trimethylated, guaylated Amidinized, maleylated, trifluoroacetylated, force rubamylylated, tri-tropylated, nitrotropylated, or acetoacetylylated derivatives. Among these, palmitoirui is preferred because it is expected to have high cell penetration, and N-terminal acetylation, C-terminal amidation, and C-terminal methylation will degrade peptides from the end. It is preferable because it is expected to be resistant to exopeptidase and have high stability in the living body.

 [0035] In the present specification, a salt of a peptide or a derivative thereof includes any pharmacologically acceptable salt (including an inorganic salt and an organic salt) of a peptide or a derivative thereof, for example, Sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, hydrochloride salt, sulfate salt, nitrate salt, organic acid salt (acetate salt, kenate salt, maleate salt, malic acid) Salt, oxalate, lactate, succinate, fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, etc.). Umu salts, hydrochlorides, sulfates and acetates, more preferably ammonium salts and acetates.

 In the present specification, the term “conservative substitution of amino acids” refers to substitution between amino acids in each group of Table 1 below.

[0037] [Table 1] Acidic amino acids aspartic acid (D), glutamic acid (E) basic amino acids arginine (R), lysine (K), histidine

 (H)

 Hydrophilic amino acids Serine (S), Threonine (T), Asparagine (N), Gluyumin (Q)

 Hydrophobic amino acid tributophan (W), phenylalanine

 (F), Parin (V), Leucine (L), Isoguchi Icine (I), Methionine (M), Proline (P), Alanine (A)

 Aromatic amino acids tyrosine (Y), tributophane (W), phenylalanine (F)

 Hydroxyami serine (S), leonine (T)

 No acid

 Sulfur-containing amino acid cystine (C), cystine, methionine

 (M)

 Small amino acid glycine (G), alanine (A), cerine

 (S), Methionine (M), Threonine (T)

[0038] Of these, preferred conservative substitutions of amino acids include substitution between aspartic acid (D) and glutamic acid (E), arginine (R), lysine (K) and histidine (H). Substitution between tryptophan (W) and phenylalanin (F), substitution between phenylalanine (F) and parin (V), leucine (L) and isoleucine (I) And alanine (A), and a substitution between glycine (G) and alanine (A).

 [0039] A conservative substitution of one or more amino acids preferably refers to a conservative substitution of one or several amino acids, more preferably 1 to 3, more preferably 1 to 2, even more preferably. Is a conservative substitution of one amino acid! /

 [0040] The deletion of one or more amino acids is preferably a deletion of one amino acid.

 [0041] The addition of one or more amino acids is preferably 1 to 6, more preferably 1 to 4, even more preferably 1 to 3, even more preferably 1 to 2, even more preferably. This means a caroten with one amino acid.

[0042] In Leu—Glu—His—Ala (in this specification, the peptide sequence may be indicated by a single letter abbreviation of the amino acid, for example, the peptide may be referred to as LEHA). Peptides with conservative substitutions, deletions and Z or additions include, for example, those containing one or more amino acid conservative substitutions in the LEHA sequence (e.g., IEHA, L DHA, LDKA, LEKA, etc.), LEHA sequences containing one or more amino acid deletions (eg LEH, EHA, LHA, LEA, etc.), and LEHA sequences with one or more amino acids added (For example, LEHAW ゝ LEHAF, LEHAV, LEHAL, LEHAI, LEHAM, LEHAG ゝ LEHAS, LEHAT ゝ ALEHA ゝ GLEHA, SLEHA, MLEHA, TLE HA, FLEHA, GLEHAL, DLEHAL, QLEHAK, SLEHAD ゝ QLEHAR ゝ EF LEPE, LEHAW , HLEHAAS, LEHASVD, etc.) 1S. Among these, preferred peptides include IEHA, LDHA, LD KA, LEKA, LEH, LEHAF, FLEHA, GLEHAL, DLEHAL, QLEHAK, SL EHAD ゝ QLEHAR, EFLEHA ゝ LEHAW ゝ DPELEHA ゝ HLEHAAS ゝ LEHA SVD, and more. LEKA, LDHA, LEH and LEHAF are preferred.

 [0043] Further, for example, a peptide having a conservative amino acid substitution and an attachment in a LEHA peptide is not particularly limited, but IEHAF, LDHAF, LDKAF, LEKAF and the like are preferable examples.

 [0044] In the present specification, the term "having the ability to promote hyaluronic acid production in cells" means that when a test substance is allowed to act on cells, the test substance is not allowed to act on cells, as compared with the case, This means that the amount of hyaluronic acid produced in the cell is increased. In a particular embodiment, the cell in the term means a keratinocyte, and in a particular embodiment means an epidermal keratinocyte.

 [0045] The peptides used in the present invention can be prepared by methods known in the art. For example, the peptide of the present invention may be synthesized by a chemical synthesis method (eg, a solid phase method (eg, Fmoc method), a liquid phase method, etc.) or may be produced by a method such as gene recombinant expression. Good. The amino acid constituting the peptide of the present invention may be L-form or D-form. Power is preferably L-form.

 [0046] Furthermore, the peptide of the present invention can also be prepared by cleaving a peptide having the amino acid sequence strength of the protein containing the target amino acid sequence and the target amino acid sequence capability by a known means such as protease treatment. . For example, the protein containing LEHA sequence includes the proteins shown in Table 2 below.

[0047] [Table 2] Origin organism Protein name Sequence including LEHA sequence

 Point

 Carrot β- ^ ructofuranosidase 12-15 residues LPSRDLEHASSYTP

(Daucus carota) (EC3.2.1.26) isozyme I class

 3 precursor, soluble

 卜 Mato 3β-hydroxylase 134-137 residues IFQSPLfHA QLWP

(Lycopersicon

 esculentum)

 Potato Chaperonin-60 beta subunit 560-563 residues VVRCCLBWASVAK

(Sofanum tuberosum) precursor

 Rice Putative chaperonin 60 beta 562-565 residues VVRCCLEHAASVAK

(Oryza sativa)

 Soybean glycinin G3 precursor 228-231 residues FAPEaEHAFVVDR

(Glycine max)

 Kidney bean Serine threonine kinase 334-337 residues EVEVQLEHALSMQE (Phaseolus vulgaris) homolog COK-4

 Cassava Flavonol 3-0-168-171 residues PQVEILEHAALQVF (^ anihot escufenta) glucosyltransferase '(EC

 2.4.1.91) (UDP-glucose

 flavonoid 3—0-glucosyltransferase 7)

 (Fragment)

 Peach MADS6 93-96 residues TGSWTLEHAKLKAR

(Prunus persica)

 Strawberry UDP-glucose 304-307 residues EIANALEHAQHRFL

(r-ragaria x ananassa) glucosyltransferase

 Murasaki Kyoji Hyperpolarization— activated 406-409 residues VAINQLEHAHWWEQ (otrongylocentrotus (Ih) channel

 purpuratus no

 Kajame Homeoprotein LjEMX 193-196 residues SQLLRLEHAFEKNH

(Lethenteron

 japonicum)

 Nguyen Paramyosin 618-621 residues DARSLLEHAERARK

(nytilus

 In consideration of the sequence specificity of the protease, the person skilled in the art appropriately selects an appropriate protease from the protein amino acid sequence containing the target amino acid sequence in order to cut out the peptide consisting of the target amino acid sequence. obtain. For example, in order to excise the LE HA sequence from the carrot-derived sequence, thermolysin (derived from Bacillus thermoproteolyticus) and chymotrypsin (derived from Cushion knee) can be used. In addition, for example, in order to excise the LEHA sequence from the potato-derived sequence, protease M “Amano” G (derived from Aspergillus oryzae: manufactured by Amano Enzym Co., Ltd.) and the aforementioned thermolysin can be used. For example, the LEHA sequence is cut out from the rice-derived sequence.

Ye Zhou (Rule 26) For this purpose, the protease M “Amano” G and the thermolysin are used in combination. In addition, for example, in order to cut out the above-mentioned soybean-derived alignment ability LEHA sequence, the above thermolysin may be used. In addition, for example, in order to excise the LEHA sequence from the above-described bean-derived sequence, the above-mentioned chymotrypsin and the above-mentioned morimoricin may be used in combination. In addition, for example, in order to excise the LEHA sequence from the cassava-derived sequence, the chymotrypsin and the thermolysin are used in combination. In addition, for example, in order to cut out the above-described arrangement ability LE HA sequence derived from the chayame, trypsin (derived from porcine spleen) and the aforementioned thermolysin may be used in combination. The combination of the protein containing the target amino acid sequence and the protease is not limited to the above combination, but a preferable combination includes a combination of soybean protein and thermolysin.

[0049] The reaction conditions used when the protein is hydrolyzed with protease are not particularly limited, and can be appropriately selected by those skilled in the art according to common general technical knowledge. For example, when using a commercially available protease, the reaction conditions can be selected according to the instructions for use. In general, reaction temperatures of 30-80 ° C, preferably 40-70 ° C, more preferably 50-60 ° C may be used. In general, reaction times of 2 to 30 hours, preferably 3 to 24 hours, more preferably 10 to 20 hours, particularly preferably 12 to 18 hours may be used. The reaction pH is preferably close to the optimum pH of the protease used. As a means for stopping the reaction, a known means without particular limitation can be used. Examples of such means include heat treatment such as heating at 85 ° C. for 15 minutes and heating at 100 ° C. for 5 minutes.

[0050] After hydrolysis with protease, the target peptide can be obtained by purification by means known in the art. As such known means, for example, strongly acidic ion exchange resin octadecyl silica (ODS) resin can be used. For example, the peptide of interest can be purified by adsorbing the aqueous peptide solution after protease treatment to ODS resin and eluting it with an organic solvent of any concentration (eg, acetonitrile). Alternatively, for example, an aqueous peptide solution after protease treatment is adsorbed on a strong acid ion exchange resin, and an eluate having a salt concentration of about 0.18 M to 0.25 M (eg, salt The target peptide can be purified by elution with an eluent having a salt concentration of about 0.20M to 0.23M, such as sodium chloride or potassium chloride.

[0051] As described above, a peptide obtained by hydrolyzing a natural protein with a protease is more advantageous in terms of cost than a case where it is produced by a chemical synthesis method. Furthermore, peptides obtained by hydrolyzing natural proteins with protease are considered safer for the living body. Therefore, the peptide obtained in this way can be suitably used for inner-moon β-agents, foods, sensitive skin cosmetics, feeds, and the like that require higher safety for application to living bodies.

 [0052] Derivatives of the peptide of the present invention are known in the art according to a solid phase synthesis method by Fmoc method (A. Carpino, GYHan, J. Am. Chem. Soc, 92, 5748 (1970)), etc. It can be made by a method.

 [0053] The salts of the peptides of the present invention can also be prepared by those skilled in the art by any method known in the art.

 In the present invention, the specific peptides as described above may be used alone or in any combination of two or more.

[0055] The amount of the specific peptide compounded in the composition of the present invention is not particularly limited as long as the effect of the present invention can be achieved, but it is usually about 0.0001 to 70% by weight with respect to the entire composition. Good. Particularly when present composition is a topical composition, Yogu be the amount is less for example, 0.00001 to 5 wt _^0/0, more preferably <is 0.0001 to 1 weight _^0/0, Even more preferably, 0.0001-0.1% by weight, particularly preferably 0.0001-0.1% by weight, the sufficient effect of the present invention can be obtained.

 [0056] In one embodiment, the composition of the present invention has the above-mentioned specific peptide strength, for example, 0.05% by weight or more, preferably 0.08% by weight or more, more preferably 0.1% by weight or more, Preferably, it can be prepared by blending so that it is refined so that it may become 0.12 weight% or more, and it may become the said compounding quantity.

[0057] Further, the mixing ratio of the specific peptides and retinols in the composition of the present invention is not particularly limited as long as the effect of the present invention can be achieved, but usually, IX 10 ^_81 1 per 100 g of the specific peptides; X 10 ⁸ IU, preferably 1 X 10 ^_7 11; to 1 X 10 ⁷ IU, more preferably 1 X 10 " ⁶ 1 U to l X 10 ⁶ IU, more preferably 1 X 10 ^_5 Il; to 1 X 10 ⁵ IU, particularly preferably 1 X 10 " ⁴ IU to 1 X 10 ^_3 IU.

[0058] In addition to the retinols and specific peptides as described above, the composition of the present invention may be used for the purpose of enhancing or supplementing the action of retinols or specific peptides, or other useful for the composition of the present application. Whitening ingredients, anti-inflammatory ingredients, antibacterial ingredients, cell activation ingredients, astringent ingredients, antioxidant ingredients, anti-acne components, collagen and other biological component synthesis promoting ingredients, blood circulation promoting ingredients, moisturizing ingredients In addition, various components such as anti-aging components can be used alone or in combination of two or more. Preferably whitening component, anti-inflammatory component

, An antibacterial component, a cell activation component, an astringent component, an antioxidant component, an anti-aging component or a moisturizing component. These components are not particularly limited as long as they can be used in the fields of pharmaceuticals, quasi drugs, foods, and cosmetics, and arbitrary components can be appropriately selected and used.

 [0059] Examples of the whitening component include placenta; arbutin; kojic acid; ellagic acid; phytic acid; lucinol; chamomile ET, vitamins such as pantothenic acid or derivatives thereof. Of these, preferred are pantothenic acid or its derivatives, ellagic acid, and phytic acid. These whitening components may be used alone or in combination of two or more.

[0060] Plant components having a whitening effect that may be used as a whitening component include: Iris (Iris), almond, aloe, yew, oolong tea, age, ogon, oulen, ogitirisou, odricosou, seaweed, Katsukon, Gardenia, Kujin, Chlorella, Gobaishi, Wheat, Rice, Rice haiga, Oryzanol, Rice bran, Saishin, Salamander, Perilla, Peacock, Senkiyu, Sakuhakuhi, Soybean, Natto, Tea, Toki, Tokinsen, Ninyu, Hamamelis , Benipana, Buttonpi, Bokupinin, Amethyst, Acaciak, Acebi ヮ rabi, Inumaki, Enoki, Oyster (Diospyros kaki), Cattle, Black bean, Gentiana, Genzin, Salsa, Syagen, Shokuma, Jiu-Uro, Sage, Zenko, Daikon, Dodge, Cook Ingredients derived from plants such as shihagi, toshin, diggi, parsley, holly, hops, mulbahagi, tiyouji, licorice and the like can be mentioned. Preferably, Iris (Iris), Aloe, Ichiyo, Oolong tea, Eiji, Ogon, Oulen, Otogirisou, Odorikosou, Seaweed, Katsukon, Gardenia, Kujin, Gobaishi, Wheat, Rice, Rice bran, Saishin, Salamander, Perilla, Shatayak , Nukiyu, Sohakuhi, Tea, Toki, Tokinkin Power, Hamelis, Bebana, Buttonpi, Kyokinin, Amethyst, Acacia, Enoki, Oyster (Diospyros kaki), Kisage, Black Bean, Gentian, Salsa, Saingen, Jiuyou, Sage, It is a component derived from plants of Zenko, Japanese radish, Dodge, Amberjack, Toshin, Futaki, Parsley, Holly, Hop, Chiyoji and Kanzo, and more preferably Iris (Iris), Aloe, Ichiyo, Eiji, Ogon, O Wren, Hypericum, Gardenia, Kujin, Rice, Rice bran, Saishin, Shatayak, Senkiyu, Sohakuhi, Tea, Toki, Tokinsen, Hamamelis, Benipana, Buttonpi, Amethyst, Sensaku, Enoki, Oyster (Diospyros kaki) Japanese radish, wedge, parsley, ho Flop, and a plant-derived component of the force Nzou and Yokuinin. When these plant components are used in the composition of the present invention, the form of the plant component is not particularly limited, but it can usually be used in the form of plant extracts (plant extracts), essential oils and the like. The parentheses in the above plant components are the scientific name, alias or herbal name of the plant.

 [0061] When the above-mentioned whitening component is used, the proportion to be added to the present composition is preferably 0.0003 to 10% by weight, more preferably 0.01 to 5% by weight.

[0062] When a plant component having a whitening effect is used as a whitening component, one or two or more types can be used in any combination depending on the purpose. When using the plant components as whitening component, the mixing ratio of the present composition is an extract terms, such as extracts or essential oils, usually from 0.00001 to 20 weight _^0/0, preferably <is 0.0001 to 15 weight _^0/0, more preferably <is a 0.0 01 to 10% by weight.

 [0063] Anti-inflammatory components include allantoin, calamine, glycyrrhizic acid or derivatives thereof, dallicylretinoic acid or derivatives thereof, zinc oxide, guaiazulene, tocopherol acetate, pyridoxine hydrochloride, menthol, camphor, turpentine oil, indomethacin, salicylic acid or derivatives thereof, etc. Is mentioned. Preferred are allantoin, glycyrrhizic acid or a derivative thereof, glycyrrhetinic acid or a derivative thereof, guaizlene, or menthol.

 [0064] When the anti-inflammatory component is used, the proportion of the anti-inflammatory component is preferably 0.003 to 10% by weight, more preferably 0.01 to 5% by weight.

[0065] Antibacterial components include chlorhexidine, salicylic acid, benzalkonium chloride, acrylol, ethanol, benzethonium chloride, cresol, darconic acid and its derivatives, Pydonod, potassium iodide, iodine, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101, photosensitizer 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyl diaminoglycine hydrochloride, etc. It is done. Preferably, salt benzalkonium, benzethonium chloride, darconic acid and its derivatives, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101, photosensitizer 201, paraben, phenoxyethanol, 1, Examples include 2-pentanediol and alkyl diaminoglycine hydrochloride. More preferred are salt benzalkonium, darconic acid and derivatives thereof, benzethonium chloride, and isopropylmethylphenol.

 [0066] When the antibacterial component is used, the proportion of the composition of the present application is preferably 0.0003 to 10% by weight, more preferably 0.01 to 5% by weight.

 [0067] Cell activation components include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid: vitamins such as thymine, riboflavin, pyridoxine hydrochloride and pantothenic acids: α-hydroxy acids such as glycolic acid and lactic acid : Tannin, flavonoid, saponin, allantoin, photosensitizer 301 and the like. Preferred are amino acids such as γ-aminobutyric acid and ε-aminocaproic acid: vitamins such as thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acids.

 [0068] When the above-described cell activation component is used, the proportion to be added to the composition of the present application is preferably 0.

0003-10 a weight _^0/0, more preferably from 0.01 to 5 weight ^_0/0.

 [0069] Convergence components include metal salts such as myo-non, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, zinc sulfate, and aluminum potassium sulfate; Mention may be made of acids. Preferred are myoban, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, potassium ammonium sulfate and tannic acid.

 [0070] When the astringent component is used, the proportion to be added to the composition of the present application is usually 0.0003 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.01 to 5% by weight.

[0071] Antioxidant components include butylhydroxyl-sol, dibutylhydroxytoluene, sodium bisulfite, erythorbic acid and salts thereof, flavonoids, dartathione, glutathione peroxidase, glutathione-S-transferase, catalase, super And monooxide dismutase, thioredoxin, taurine, thiotaurine, hypotaurine and the like. Preferred are thiotaurine, hypotaurine, thioredoxin, and flavonoids.

 [0072] When the antioxidant component is used, the proportion to be added to the composition of the present application is usually 0.00001 to 10% by weight, preferably 0.0001 to 5% by weight, more preferably 0.001 to 5% by weight.

 [0073] Examples of the anti-aging ingredient include pangamic acid, strength rice, ursolic acid, turmeric extract, sphingosine derivative, carbene, kainic acid, N-methyl L-serine, mevalonolataton and the like. Preferably, it is force rice.

 [0074] When the anti-aging component is used, the proportion of the composition of the present application is preferably 0.003 to 10% by weight, more preferably 0.01 to 5% by weight.

 [0075] Examples of moisturizing ingredients include alanine, serine, leucine, isoleucine, threonine, glycine, proline, hydroxyproline, gnolecosamine, theanine and the like; glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol Which polyhydric alcohols; Sugar alcohols such as sorbitol; Phospholipids such as lecithin and hydrogenated lecithin; Mucopolysaccharides such as propylene glycol hyaluronate, heparin and chondroitin; NMF-derived components such as lactic acid, sodium pyrrolidonecarboxylate and urea Can be mentioned. Preferred are alanine, serine, glycine, proline, hydroxyproline, gnolecosamine, theanine, collagen, collagen peptide, glycerin, 1,3-butylene glycol, hydrogenated lecithin, propylene glycol hyaluronate, heparin, chondroitin, Lactic acid, sodium pyrrolidonecarboxylate.

[0076] When using a humectant, as the proportion in the present compositions, usually from 0.1 to 10 wt%, preferably 0.5 to 7.5 wt _^0/0, more preferably from 0.5 to 5 % By weight.

[0077] In addition to the above components, the composition of the present invention suitably contains components usually used in the fields of pharmaceuticals, quasi drugs, cosmetics, and foods, depending on the use or dosage form of the composition. May be. The components that can be blended are not particularly limited. For example, amino acids, alcohols, polyhydric alcohols, saccharides, gums, polysaccharides and other high molecular compounds, surfactants, solubilizing components, fats and oils, Percutaneous absorption promoting component, antiseptic, antibacterial, bactericidal agent, PH adjusting agent, Chelating agents, antioxidants, enzyme components, binders, disintegrating agents, lubricants, fluidizing agents, cooling agents, minerals, cell activators, nutrient tonics, excipients, thickeners, stability Agents, preservatives, tonicity agents, dispersants, adsorbents, disintegration aids, wetting agents or wetting regulators, moisture-proofing agents, coloring agents, flavoring agents or fragrances, fragrances, reducing agents, solubilizing agents, Examples include solubilizers, foaming agents, thickeners or thickeners, solvents, bases, emulsifiers, plasticizers, buffers, and brighteners. In particular, by adding surfactants, soluble ingredients or oils and fats, the stability of retinols in the preparation can be increased, and when the composition is for external use, the feeling of use of the preparation is further improved. Can be made. Further, when the composition of the invention is a composition for external use, it is preferable to further blend a transdermal absorption promoting component.

The surfactants used here include polyoxyethylene (hereinafter referred to as POE) -octyldecyl alcohol, POE—branched alkyl ethers such as POE-2-decyltetradecyl alcohol; POE oryl alcohol ether and POE cetyl alcohol. POE-alkyl ethers such as ethers; sorbitan esters such as sorbitan monooleate, sonorebitan monoisostearate and sorbitan monolaurate; POE sorbitan monooleate, POE—sorbitan monoisostearate, and POE sorbitan POE sorbitan esters such as monolaurate; glycerol fatty acid esters such as glycerol monooleate, glycerin monostearate, and glycerol monomyristate; PO E—glycerol monosoleate, POE glycerol monostearate POE-glycerin fatty acid esters such as POE glycerin monomyristate; POE-dihydrocholesterol esters, POE hydrogenated castor oil, and POE hydrogenated castor oil fatty acid esters such as POE hydrogenated castor oil isostearate; POE octylphenol ether, etc. POE—alkyl aryl ethers; glycerin alkyl ethers such as monoisostearyl glyceryl ether and monomyristyl daryl ether ether; POE—POE glycerin alkyl ethers such as monostearyl glyceryl ether and POE monomyristyl daryl ether ether; Various nonionic surfactants such as polyglycerin fatty acid esters such as glyceryl monostearate, decaglyceryl decastearate, decaglyceryl decaisostearate, and diglyceryl diisostearate: Or naturally derived surface activity such as lecithin, hydrogenated lecithin, saponin, surfatatin sodium, cholesterol, bile acids, etc. A sex agent etc. can be illustrated. These surfactants can be used alone or in any combination of two or more! /.

 [0079] When a surfactant is used, the blending ratio in the composition of the present application is not particularly limited as long as it does not hinder the effects of the present invention, and usually 0.01 to 30% by weight in the composition of the present application. It can be appropriately selected and used in such a range that it is contained in a percentage. From the viewpoint of the stability of the active ingredient in the composition of the present application, the range is preferably from 0.1 to 20% by weight, more preferably from 0.5 to 10% by weight.

 [0080] Examples of the soluble koji component include lower alcohols such as ethanol, polyhydric alcohols such as glycerin and ethylene glycol, hydrogenated soybean phospholipid, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene lanolin alcohol, Examples include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sterol, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, and polyoxyethylene alkylphenol ether. Preferably, ethanol, glycerin, ethylene glycol, diethylene glycol, dipropylene glycol, hydrogenated soybean phospholipid, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene lanolin alcohol, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil And polyoxyethylene alkyl ether, more preferably ethanol, glycerin, ethylene glycol, diethylene glycol, dipropylene glycol, and hydrogenated soybean phospholipid. These soluble ingredients can be used alone or in any combination of two or more.

 [0081] When these solubilizing components are used, the blending ratio in the composition of the present application is not particularly limited as long as the effects of the present invention are not hindered. It can be appropriately selected and used within a range such that it is contained in a proportion of 70% by weight. From the viewpoint of the stability of the active ingredient in the present application product, the range is preferably 0.1 to 50% by weight, more preferably 0.1 to 30% by weight.

[0082] Examples of fats and oils include synthetic fats and oils such as medium chain fatty acid triglycerides; soybean oil, rice oil, rapeseed oil, cottonseed oil, sesame oil, safflower oil, castor oil, olive oil, cacao oil, coconut oil, castor oil Oil, palm oil, flax oil, perilla oil, shea oil, monkey oil, palm oil, tree wax, jojoba oil, gray Vegetable oils such as pseed oil and apogado oil; animal oils such as mink oil, egg yolk oil, beef tallow, milk fat, and pork fat; waxes such as beeswax, whale wax, lanolin, carnaupalou, candelillaro; liquid paraffin, squalene, squalane , Microcrystalline wax, ceresin wax, hydrocarbons such as raffin wax, petrolatum; natural and synthetic fatty acids such as lauric acid, myristic acid, stearic acid, oleic acid, isostearic acid, behenic acid; cetanol, stearyl alcohol Natural and synthetic higher alcohols such as hexyl decanol, octyl decanol, lauryl alcohol; isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, octyldodecyl oleate, cholesterol oleate, etc. Ether or ethers; silicone oil, and the like. These fats and oils may be used alone or in any combination of two or more.

[0083] When these fats and oils are used, the blending ratio in the composition of the present application is not particularly limited as long as the effects of the present invention are not hindered. It can be appropriately selected and used within the range of 70% by weight. From the viewpoint of the stability of the active ingredient in the composition of the present application, it is preferably 0.1 to 60% by weight, more preferably 0.1 to 50% by weight.

[0084] The composition of the present invention can take a dosage form usually used for pharmaceuticals, quasi-drugs, cosmetics or foods depending on the use, and is usually a solid, semi-solid or liquid. is there. Specifically, tablets (including intraoral quick disintegrating tablets, chewable tablets, effervescent tablets, troches, jelly-like drops, etc.), pills, granules, fine granules, powders, hard capsules, soft capsules The capsules, dry syrups, liquids (including drinks, suspensions, syrups), gels, ribosomes, extracts, tinctures, lemonades, ointments, jellys, etc. Can do. If necessary, other solvents, commonly used bases, etc. may be blended to form a paste, mousse, jewel, liquid, emulsion, cream, sheet (base material support), aerosol Can be prepared in various desired forms such as

[0085] These dosage forms can be produced by ordinary methods in the art. For example, in the case of a semi-solid preparation, the above-mentioned optional components are blended and mixed as necessary in combination with the above-mentioned retinols and specific peptides, and if necessary, other solvents and commonly used external use Prepared in various desired forms such as paste, mousse, jelly, liquid, emulsion, cream, sheet (substrate support), aerosol, spray, etc. by blending the composition base, etc. can do.

 [0086] The composition of the present invention is not particularly limited as long as the effects of the present invention are achieved. For example, pharmaceuticals, quasi-drugs, foods [confectionery, health foods, nutritional supplements (balance nutritional foods, supplements, etc.) )), Nutritional functional foods, foods for specified health use, etc.) and cosmetics such as foundations, lipsticks, mascaras, eye shadows, eyeliners, eyebrows and beauty nails Basic cosmetics such as emulsions, creams, lotions, oils and packs; cleansing agents such as facial cleansers, cleansings, body cleansing agents, and bath preparations.

 [0087] The composition of the present invention may be used as an internal composition or an external composition, but is preferably used as an external composition.

[0088] Since the composition of the present invention has a remarkable ability to promote hyaluronic acid production, it can be suitably used to promote hyaluronic acid production in cells. For example, the composition of the present invention is

, Compositions for the treatment or prevention of various disorders (such as rheumatism, arthritis, osteoarthritis, joint disorders such as osteoarthritis, inflammatory disorders, etc.) associated with reduction or degeneration of hyaluronic acid, prevention or treatment of cosmetic problems Composition for preventing skin wrinkles or talmi due to UV exposure, aging, etc. and Z or improving composition, prevention of skin elasticity or resistance, decrease It can be suitably used as a composition for improvement.

 [0089] The present invention further provides a method for promoting hyaluronic acid production in cells using (A) retinols and (B) specific peptides as described above. In one embodiment, the method of the present invention may include a step of applying (A) retinols and (B) specific peptides to the skin.

[0090] In the method of the present invention, (A) retinols and (B) specific peptides may be the same as those used in the aforementioned composition. The amount of (A) retinols and (B) specific peptides used may be more than the effective amount that provides the effect of promoting hyaluronic acid production in cells. [0091] The present invention further provides a composition for the production of a composition for promoting hyaluronic acid production in a cell, and preferably for use as a composition for external use as described above (A) Provide the use of retinols and (B) specific peptides.

 [0092] (A) Retinols and (B) specific peptides may be the same as those used in the aforementioned composition. The amount of (A) retinol and (B) specific peptide used should be the same as the content in the yarn and the composition.

 Example

 [0093] Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited to these examples.

[0094] Example 1

 Preparation of LEHA peptide

 Peptides were synthesized by a solid phase synthesis method by Fmoc method using an automatic peptide synthesizer (manufactured by Shimadzu Corporation: PSSM8). Subsequently, LEHA peptide was obtained by removing unreacted material by preparative HPLC for purification.

 Reverse phase high performance liquid chromatography for analysis [column: μ Bondaspher e 5 μ C18-100A (inner diameter: 3.9mm, length: 150mm) manufactured by Waters

 Mobile phase: solvent A (0.1% trifluoroacetic acid) and solvent B (0.1% trifluoroacetic acid, 90% acetonitrile) (0 min (solvent B = 12%) 20 min (solvent B = 17%)); Flow rate: 1 mlZ min; Detection method: Absorbance at wavelength 220] showed a single sharp peak at 12.8 min with a purity of 99%.

[0095] Example 2

 Hyaluronic acid production assay in epidermal keratinocytes

Human normal epidermal keratinocytes (NHEKZB-3, Kurashiki Boseki Co., Ltd.) were cultured in 48-well culture plates. More specifically, the cells were seeded at a density of 0.8 × 10 ⁴ cells Zwell and cultured at 37 ° C. in an environment of 5% carbon dioxide and 95% air for 4 days. As a culture solution, HuMedia KG-2 (manufactured by Kurashiki Boseki Co., Ltd.) was used at 400 μL per well. Thereafter, the culture solution was removed, and the test drug shown in Table 3 below was replaced with a 4001 medium dissolved at each concentration and cultured. On the other hand, neither retinol nor LEHA peptide A medium supplemented with 400 μL of non-added medium was used as a control. After culturing for 2 days, the culture solution was collected, and the concentration of hyaluronic acid secreted in the culture solution was quantified by enzyme-linked immunoassay (hyaluronic acid measurement kit; manufactured by Seikagaku Corporation). Based on the quantification results, the amount of hyaluronic acid in each test culture was calculated with the amount of hyaluronic acid in the control culture as 100%. The results are summarized in Table 3.

 [Table 3]

[0097] From these results, it was found that hyaluronic acid production was significantly increased in cells cultured in a culture medium containing both retinol and LEHA peptide, compared to when cultured in a culture medium containing retinol alone. It was demonstrated that the ability to promote hyaluronic acid production can be dramatically enhanced.

 It was also recognized that the hyaluronic acid production promoting effect obtained by combining retinol and LEHA peptide was synergistic.

[0098] Further, the number of viable cells was counted by WST-1 method for the cells after collecting the culture solution. More specifically, the medium was changed to that added with WST-1 reagent at a rate of 10 μΐ in 4001 medium, and after incubation for 45 minutes, 200 μΐ of the supernatant was taken and the absorbance was measured. As a result, it was confirmed that the number of living cells was not significantly decreased by culturing in a culture medium containing both retinol and LEHA peptide, and that it could be used safely for the living body.

 [0099] Formulation examples are given below, but the present invention is not limited to these examples.

[0100] Formulation Example 1: Emulsion

 [Ingredient] [Ratio]

 All-trans retinol 0.07g

Replacement invitation (Rule 26) LEHA peptide 0. Olg squalene 2. Og Soybean oil 0.6 g Liquid paraffin 5. Og Cetanolol 0.5 g Glycerolinole monostearate 2. Og

 POE (25) Cetyl ether 2. Og Glycerin 4. Og

 1,3-butylene glycol 6. Og

 .

pH adjuster

 Yuri

Preservative appropriate amount

Perfume

Purified water

 100.0g Formulation Example 2: Cream

 [Components] [Ratio] Retinol palmitate 0.14 g

LEHA peptide 0. 05g Vaseline 1. Og squalane 5. Og castor oil 0. lg liquid paraffin 10. Og stearic acid 1.5 g stearyl alcohol 2. Og glycerinole monostearate 2. Og

POE (20) cetyl ether 3. Og Glycerin 6. Og

1,3-butylene glycol 8. Og pH adjuster appropriate amount preservative appropriate amount perfume appropriate weight purified water appropriate amount

 100. Og

[0102] Formulation Example 3: Cream

 [Components] [Ratio] δ Tocopheryl retinoate 0.lg

LEHA peptide 0.2 g glycerin 6. Og tri (caprylic acid Z force purine) glyceryl 0.9 g canoleboxini vinylol polymer 0.8 g polyoxyethylene cetyl ether 3.5 g glyceryl monostearate 3.5 g cetanol 3. Og pH adjuster Suitable amount Preservative Appropriate amount Fragrance Dried amount Purified ice Suitable amount

 100. Og

[0103] Formulation Example 4: Tablets for internal use (in 1 tablet)

 [Ingredients] [Ratio] All-trans-retinol 0.05 mg

LEHA Peptide 5. Omg Vitamin Bl 1. Omg Vitamin B2 0.5 mg Fragrance 0. 625mg

 Sweetener 0.625mg

 Sucrose fatty acid ester 3.75mg

 Manoleto Tonole 113. 45mg

 125. Omg

 Formulation Example 5: Cream

 [Ingredient] [Ratio]

 δ Tocopherino Retinoate 0.25 g

 LEHA peptide 0.2 g

 Glycerin 6. Og

 Tri (forced prillic acid Z-forced purinate) glyceryl 2.25g

 Canoleboxyvininole polymer 0.8g

 Polyoxyethylene cetyl ether 3.5g

 3.5 g of glyceryl monostearate

 Cetanore 3. Og pH adjuster

 Preservative appropriate amount

 Perfume

 Purified water

 100. Og

 Industrial applicability

 [0105] The composition of the present invention can be used as an anti-pruritic composition, an anti-tarmi composition, a composition for preventing or treating joint disorders, a composition for preventing or treating inflammatory diseases, and the like. it can

Sequence listing free text

[0106] SEQ ID NO: 1 is a peptide that can be used in the present invention.

SEQ ID NO: 2 is a peptide that can be used in the present invention. SEQ ID NO: 3 is a peptide that can be used in the present invention. SEQ ID NO: 4 is a peptide that can be used in the present invention.

Claims

The scope of the claims

 [1] (A) at least one selected from the group consisting of retinol and derivatives thereof;

 (B) Leu—Glu—His—Ala (at least one selected from the group consisting of peptides represented by the formula (I), derivatives thereof and their salt strength)

 A composition containing

 [2] (A) at least one selected from the group consisting of retinol and derivatives thereof;

 (B) a peptide having a conservative substitution, deletion and Z or addition of one or more amino acids in the amino acid sequence of Leu-Glu-His-Ala (formula I) and an ability to promote hyaluronic acid production in cells, At least one selected from the group consisting of derivatives thereof and salts thereof

 A composition containing

 [3] The composition according to claim 2, wherein the peptide has an amino acid length of 3 to 10 residues.

 [4] The claim 1 that can be used to promote hyaluronic acid production in cells.

The composition according to any one of the items 3 to 3.

[5] The composition according to any one of claims 1 to 4, which is a composition for external use.