JP2009073806A - Insulin-like growth factor-1 secretagogue - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an IGF-1 secretagogue without problems such as skin irritation and effective such as for: inhibition of skin crease by increased skin elasticity; amelioration of skin sag; and hair growth. <P>SOLUTION: The insulin-like growth factor-1 secretagogue is characterized by containing a saccharide and/or sialic acid without binding to protein, or without containing sericin. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an insulin-like growth factor-1 secretion promoter containing sialic acid.

  Sialic acid is a family name generically referring to substances in which the amino group or hydroxy group of neuraminic acid is substituted, and is naturally N-acetylneuraminic acid that is acetylated at the 5-position. There are many (N-acetylneuraminic acid; NeuAc), followed by N-glycolylneuraminic acid (NeuGc) modified with glycolic acid. Sialic acid is an acidic amino sugar that can be obtained from glycolipids and glycoproteins of living organisms. In addition to simple substances in vivo, it is present as a component of complex carbohydrates at the end of oligosaccharides on the surface of cell membranes. It has important biological functions.

  Conventionally, as an active ingredient for the prevention and improvement of skin wrinkles and sagging, and for the purpose of giving elasticity and tension to the skin, the axilla extract obtained by extracting the axilla with water or water-containing organic solvent as an active ingredient Containing cosmetics are known (Patent Documents 1 and 2), and as cosmetics for the purpose of imparting hygroscopicity and moisture retention to the skin, contains at least two components of sericin and saccharides Cosmetics are known (Patent Document 3). In the axillary extract, which is a component of the former cosmetic, sialic acid is present in the form of a glycoprotein in which at least a part of the protein and at least a part of the carbohydrate are bound. As free sialic acid, Does not exist. In addition, as a saccharide that is one component of the latter cosmetic, Patent Document 3 uses D-glucose, lactose, maltotriose, and the like, and sialic acid is also exemplified. It is only used in combination with sericin, not sialic acid alone.

  On the other hand, insulin-like growth factor-1 (hereinafter sometimes abbreviated as IGF-1) is a peptide hormone having a molecular weight of about 7500 having a structure and action very similar to insulin. Yes (see Non-Patent Document 1), actively promoting the differentiation of cells, helping cell proliferation, etc., actively maintaining the cells in a healthy state (see Non-Patent Documents 2 and 3), and preventing the progression of aging ( Non-patent document 4), and known to have a hair-growth effect (see patent document 4). However, there is no mention that sialic acid promotes the secretion of IGF-1, and there is no description suggesting the relationship between sialic acid and IGF-1.

Japanese Patent Laid-Open No. 9-301819 International Publication No. 99/22709 Pamphlet JP 2001-64148 A Japanese Patent Publication No. 4-60567 Goodman Gilman's Pharmacology Book [Lower] Pharmacotherapy Basics and Clinic-10th Edition-; Chapter 61 Pharmacology of Insulin, Oral Hypoglycemic Drugs and Pancreatic Endocrine 2003, p2144 Translation: Shuji Takafumi, Hideomi Fukuda, Akiaki Akaike Tokyo Issued by Yodogawa Shoten Conn KJ and six others, The Journal of Biological Chemistry (J. Biol. Chem.) 1996, 271, 46, p. 28853-28860 Braham C and 4 others, Dermatology, 2002, 20th, 4th, p. 325-329 Robenoff R, 8 outside, The American Journal of Medicine (Am. J. Med.), 2003, Vol. 115, No. 6, p. 501-502

  The present invention solves problems such as skin irritation, and is a novel insulin-like growth factor-1 (hereinafter referred to as IGF) having effects such as suppression of skin wrinkles due to increased skin elasticity, reduction of skin sagging, and hair growth. -1)) An object is to provide a secretagogue.

  As a result of intensive studies to solve the above problems, the inventors of the present invention applied to a skin of a mouse that has been applied with a skin external preparation containing sialic acid not bound to sugar and / or protein and not containing sericin. When applied, it was found that insulin-like growth factor-1 in the skin was remarkably increased, and further research was carried out based on this finding to complete the present invention.

That is, the present invention
[1] An insulin-like growth factor-1 secretion promoter characterized by containing sialic acid not bound to sugar and / or protein and not containing sericin,
[2] The insulin-like growth factor-1 secretion promoter according to the above [1], wherein the sialic acid not bound to sugar and / or protein is N-acetylneuraminic acid,
[3] The insulin-like growth factor-1 secretion promoter according to [2] above, containing N-acetylneuraminic acid in an amount of 0.00001% by mass to 10.0% by mass,
[4] Insulin-like growth factor-1 secretion promoter according to [1] or [2], which promotes differentiation, proliferation and / or stromal substance production function of skin fibroblasts,
[5] Promotion of insulin-like growth factor-1 secretion according to [4] above, wherein the interstitial substance is one or more selected from the group consisting of skin collagen, elastin and hyaluronic acid Agent,
[6] Insulin-like growth factor-1 secretion promoter according to any one of [1] to [5], which is an external preparation for skin,
[7] 5 masses of one or more compounds selected from the group consisting of nonionic surfactants, amphoteric surfactants and cationic surfactants with respect to the total insulin-like growth factor-1 secretion promoter % To 30% by mass or less, The insulin-like growth factor-1 secretion promoter according to any one of [1] to [6],
[8] The nonionic surfactant is polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether, and Insulin-like growth factor-1 secretion promoter according to [7] above, which contains one or more compounds selected from polyoxyethylene sorbite fatty acid esters,
[9] The amphoteric surfactant contains one or more compounds selected from alkylbetaines, alkylamidobetaines, alkyldimethylaminoacetic acid betaines, sulfobetaines and imidazoline-type betaines. 7], an insulin-like growth factor-1 secretion promoter,
[10] The insulin according to [7], wherein the cationic surfactant contains one or more compounds selected from alkyltrimethylammonium salts, amidoamines, and alkyldimethylbenzylammonium salts. A growth factor-1 secretion promoter,
[11] Any one of [1] to [10] above, which is a liquid, suspension, emulsion, cream, ointment, gel, liniment, lotion, poultice, or pack. The insulin-like growth factor-1 secretion promoter according to any one of [1] to [11], which is an insulin-like growth factor-1 secretion promoter according to [12].

  By administering the IGF-1 secretion promoter of the present invention, the effect of improving skin roughness and wrinkles, and the effect of hair restoration and hair growth can be exhibited.

  The sialic acid used in the present invention is in a free form that is not bound to sugar or protein (hereinafter, sialic acid in the present specification refers to a form that is not bound to sugar or protein). For example, N-acetylneuraminic acid, N-glycolylneuraminic acid, deaminoneuraminic acid, 2,3-dehydroneuraminic acid, N-acetyl-2,7-anhydroneuraminic acid, etc. Can be mentioned.

  Sialic acid used in the present invention can be produced by a conventional method. For example, N-acetylneuraminic acid can be produced by an enzymatic method. Specifically, N-acetylneuraminic acid can be produced by subjecting N-acetylglucosamine and sodium pyruvate to an enzymatic synthesis reaction with N-acetylneuraminate lyase.

  The compounding amount of N-acetylneuraminic acid in the IGF-1 secretion promoter of the present invention is usually about 0.00001% by mass to 10.0% by mass, preferably about 0.0001% by mass to 1.0% by mass. % Or less, more preferably about 0.001 mass% or more and 0.1 mass% or less.

  The IGF-1 secretion promoter in the present invention is preferably used as a skin external preparation. Preferred examples of the external preparation for skin include pharmaceuticals or quasi-drugs such as liquids (including aerosol type tonics), suspensions, emulsions, creams, ointments, gels, liniments, lotions or poultices. It is done. Skin external preparations include, for example, lotion, cosmetic emulsion, cosmetic cream, cosmetic gel, cosmetic lotion, pack, aerosol, foundation, facial cleanser, body soap, hand cream, shampoo, rinse, hairdressing. Cosmetics such as skin care products such as cosmetics and hair restorers or makeup products are also included. The pH of the external preparation for skin is preferably about 2 to 10, more preferably about 3 to 7, and particularly preferably about 3 to 5.

The dose of the IGF-1 secretion promoter of the present invention varies depending on the sex, age, health condition, etc. of the person who takes it, but it cannot be said unconditionally, but when applied locally, depending on the skin area to be administered, Typically, it is desirable to have about 1 to 1000 mg, preferably about 10 to 500 mg, more preferably about 50 to 100 mg per day for an application site area of about 1 cm ² , thereby The desired effect is obtained. The administration dose may be applied once or several times per day.

  The IGF-1 secretion promoter of the present invention can promote the secretion of IGF-1 in the skin. IGF-1 is a growth factor that is similar in structure and action to insulin, and promotes the differentiation, proliferation, and stromal substance production functions of cells, particularly fibroblasts, in tissues, particularly skin. Examples of the interstitial substance include skin collagen, elastin and hyaluronic acid. When differentiation and proliferation of the fibroblasts are activated, a large amount of collagen, elastin, and hyaluronic acid are produced. Collagen and elastin are fibers that occupy most of the dermis and have the function of maintaining the elasticity of the skin. Hyaluronic acid has strong water-containing power and gives skin tension. If fibroblasts produce a large amount of these interstitial substances, the skin becomes tight and wrinkles can be reduced.

  The IGF-1 secretion promoter of the present invention preferably contains a nonionic surfactant, an amphoteric surfactant or a cationic surfactant. These surfactants can be used by appropriately selecting one kind or two or more kinds. By incorporating these surfactants into the IGF-1 secretion promoter, penetration into the skin is promoted. As a result, IGF-1 secretion is promoted at the site to which the IGF-1 secretion promoter of the present invention is applied.

  Nonionic surfactants include, for example, alkyl glucoside (for example, butyl glucoside, decyl glucoside, lauryl glucoside, myristyl glucoside, cetostearyl glucoside, etc.), propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene fatty acid Ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene alkylphenyl ether, polyoxyethylene hydrogenated castor Oil, polyoxyethylene sterol, polyoxyethylene alkyl ether, poly Polyoxypropylene alkyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycols, and fatty acid alkanolamides. As said alkyl, a C1-C20 linear, branched or cyclic alkyl group is mentioned. Specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, cyclopentyl group, cyclopentylmethyl group, hexyl group, cyclohexyl group, cyclohexyl Examples include a methyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, and an eicosyl group.

  Examples of amphoteric surfactants include betaine types (for example, alkylbetaines such as decylbetaine, cetylbetaine, and palm oil alkylbetaine; amide methylbetaine laurate, amidemethylbetaine myristate, amidemethylbetaine palmitate, amidepropylbetaine laurate) Alkyl amide betaines such as amide propyl betaine cocoate; alkyl dimethyl amino acetate betaines such as lauryl dimethylamino acetate betaine, stearyl dimethyl amino acetate betaine, coconut oil fatty acid amidopropyl dimethylamino acetate betaine; lauryl hydroxysulfo betaine, coconut oil fatty acid dimethyl Sulfopropyl betaine, coconut oil fatty acid aminomethylsulfopropyl betaine, myristylaminomethyldimethylsulfopropyl betaine, lauryl Sulfobetaines such as nomethyl-bis- (2-hydroxyethyl) -sulfopropylbetaine; 2-coconut oil fatty acid acyl-N-carboxyethyl-N-hydroxyethylimidazolinium betaine, 2-alkyl-N-carboxymethyl-N -Imidazoline type betaines such as hydroxyethyl imidazolinium betaine), glycine type (for example, dialkyldiaminoethylglycine, alkyldimethylbenzylglycine), amino acid type (amide amino acid salt) and the like. As said alkyl, a C1-C20 linear, branched or cyclic alkyl group is mentioned.

  Examples of the cationic surfactant include alkyltrimethylammonium salts (for example, behenyltrimethylammonium chloride, cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, etc.), amidoamines (for example, dimethylaminopropylamide stearate), alkyldimethylbenzylammonium salts. (For example, distearyl dimethyl benzyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride) etc. are mentioned. As said alkyl, a C1-C20 linear, branched or cyclic alkyl group is mentioned.

  Examples of the anionic surfactant include N-acyl amino acid salt, alkyl ether carboxylate, fatty acid soap, alkyl phosphate, polyoxyethylene alkyl ether phosphate, N-acyl taurine salt, alkyl sulfate, polyoxy Examples thereof include ethylene alkyl ether sulfate, sulfosuccinate and sarcosine salt. As said alkyl, a C1-C20 linear, branched or cyclic alkyl group is mentioned.

  The blending amount of the surfactant varies depending on the surfactant used, but is about 1% by mass or more, preferably about 5% by mass or more, more preferably about 10%, based on the whole IGF-1 secretion promoter. It is at least mass%. The upper limit of these surfactants is about 30% by mass, although it varies depending on the surfactant used.

  In the IGF-1 secretion promoter of the present invention, the blending ratio of sialic acid and surfactant varies depending on the surfactant used, but usually about 100 to 100 surfactants per 1 part by mass of sialic acid. 3000 parts by mass, preferably about 500 to 2000 parts by mass. Examples of the IGF-1 secretion promoter having the above blending ratio include, for example, a preparation containing about 0.001% by mass to 0.1% by mass of sialic acid and about 5% by mass to 20% by mass of polyoxyethylene hydrogenated castor oil. Etc.

  The IGF-1 secretion promoter of the present invention further includes other components generally used in cosmetics, such as polymer compounds (for example, cationized cellulose, hydroxylated cellulose, etc.), solvents (for example, purified water). , Physiological saline, isopropanol, glycerin, ethanol, 1,3 butylene glycol, propylene glycol, macrogol 400, etc.), moisturizer (eg, sodium hyaluronate, sodium chondroitin sulfate, diisostearyl malate, glycerin, propylene glycol, Dipropylene glycol, etc.), suspending agent / thickening agent (eg gum arabic, xanthan gum, carmellose, carmellose sodium, carmellose calcium, hydroxypropylcellulose, hydroxypropylmethylcellulose, popidone, methyl Rulose, aluminum monostearate, etc.), hydrocarbons (eg, liquid paraffin, liquid isoparaffin, petrolatum, squalane, etc.), fatty oils (eg, medium chain fatty acid triglycerides (eg, glyceryl tri-2-ethylhexanoate, triethylhexanoin, etc.) ), Synthetic oil such as hard fat, olive oil, soybean oil, rapeseed oil, hydrogenated palm oil, peanut oil, safflower oil, nuka oil, sesame oil, camellia oil, corn oil, menthol oil, coconut oil, squalane, etc. Hardened oil, etc.), antioxidants (eg, acetic acid, lactic acid, malic acid, citric acid, tartaric acid or vitamin C), ultraviolet absorbers (eg, cinnamic acid, p-methoxycinnamic acid, 2,4-diisopropoxy) Cinnamic acid, octyl methoxycinnamate, oxybenzone, anisic acid, salicylic acid, Azole carboxylic acid, aminobenzoic acid, dimethylaminobenzoic acid, ferulic acid or t-butylmethoxydibenzoylmethane), antioxidant (eg, DL-α-tocopherol acetate, α-tocopherol, etc.), emulsion stabilizer (eg, Cetyl alcohol, cetostearyl alcohol, trisodium citrate, etc.), anti-dandruff agents (eg salicylic acid, zinc pyrithione, benzalkonium chloride etc.), fragrances (eg l-menthol etc.), other pearlizing agents, chelating agents, An antiseptic, a coloring agent, etc. can be mix | blended according to the objective.

  Hereinafter, the present invention will be described using examples and test examples, but the present invention is not limited thereto.

[Example 1]
While heating, cetostearyl glucoside, cetostearyl alcohol, hydrogenated palm oil, triethylhexanoin, tri (caprylic / capric) glyceryl, squalane, and preservative were mixed and dissolved as oil phase components. Separately, xanthan gum, 1,3-butylene glycol, ethanol, sodium hyaluronate, and malic acid were mixed and dispersed in purified water as an aqueous phase component while heating. The oil phase was added to the aqueous phase with stirring and emulsified, and then cooled with stirring. In the middle, a solution prepared by dissolving N-acetylneuraminic acid in purified water was added, and a cream was prepared with the blending amounts shown in Table 1 below.

[Example 2]
DL-α-tocopherol acetate, l-menthol, polyoxyethylene oleyl ether, glycerin, and ethanol were dissolved and mixed as oil phase components while heating, and then poured into hot water. Separately, salicylic acid, citric acid, trisodium citrate, and N-acetylneuraminic acid were dissolved in purified water, and in addition to the hot water, a liquid (aerosol type tonic) was obtained in the amount shown in Table 2 below. .

[Example 3]
Liquid isoparaffin, liquid paraffin, isostearoyl dimer linoleate polyglyceryl-2, diisostearyl malate, polyoxyethylene oleyl ether, pentaerythrityl tetraisostearate, polyglyceryl diisostearate, (behenic acid / Eicosanedioic acid) glyceryl, glycerin and preservative were dissolved and mixed. Thereto, a solution obtained by dissolving N-acetylneuraminic acid in purified water was added to obtain a gel (lip gloss) in the blending amounts shown in Table 3 below.

[Test Example 1]
(Test method)
8 weeks old C57BL-6 male mice (3 cases per group) were intraperitoneally administered with ketalal (100 mg / kg) and xylazine (10 mg / kg) to anesthetize the mice, and shaving cream on the back skin of the mice After applying, the hair was removed using a razor. Test cream (cream with N-acetylneuraminic acid of Example 1 0.005 mass%, 0.01 mass%, 0.05 mass%) or control (N-acetylneuramin of Example 1) The acid-free cream agent) was applied to the back skin after hair removal 10 minutes in an amount of 100 mg per cm ² . Mouse skin (epidermis and dermis) at the application site was collected 30 minutes after application of the test cream or control. The collected mouse epidermis and dermis (1 cm ² each) were frozen in liquid nitrogen, homogenated with 1N acetic acid, and stored at −80 ° C. until IGF-1 measurement. The amount of IGF-1 in the frozen and stored homogenate was measured by the EIA method using an IGF-1 measurement kit (ACTIVE registered trademark, Rat IGF-1 EIA; manufactured by Cosmo Bio Inc.). The results are shown in FIG. In the figure, * indicates that there was a significant difference at a significance level of 1%.

(Discussion)
As apparent from FIG. 1, the amount of IGF-1 in the mouse skin coated with the cream containing N-acetylneuraminic acid was significantly increased relative to the amount of IGF-1 in the skin coated with the control. It was confirmed that secretion of 1 was promoted.

[Test Example 2]
11 female panelists from the age of 20 to 66 years old apply lip gloss containing 0.01% of N-acetylneuraminic acid of Example 3 to a lip gloss of 20 mg, about 3 times a day. This was continued for 20 days. The results from the start of use until the 20th are shown in Table 4 below.

  As is apparent from Table 4, when lip gloss containing 0.01% by mass of N-acetylneuraminic acid was applied, it was confirmed that the dryness, wrinkles and elasticity of the skin were improved.

[Test Example 3]
The amount of N-acetylneuraminic acid 0.01% of Example 1 to 10 female panelists in their 20s and 30s was 100 mg per dose, once a day, after face washing, before going to bed, This was applied to the hand and continued for 4 weeks. Before the application and 4 weeks after the start of use, the skin elasticity recovery rate is measured using a cut meter (manufactured by Integral Co., Ltd.), and the elasticity recovery rate before sample application is subtracted from the elasticity recovery rate after sample application. The average of each panel was evaluated. The results are shown in FIG. The elastic recovery rate is calculated as follows.
Elasticity recovery rate (%) = [(extension length−non-retraction length) / extension length] × 100
However, in the above formula, the height of the skin stretched by the negative pressure suction is defined as the stretch length (unit: mm), and the height of the skin that does not return after the negative pressure is released is not retracted (unit: mm) And

  As apparent from FIG. 2, it was confirmed that the elasticity of the skin was improved when a cream containing 0.01% by mass of N-acetylneuraminic acid was applied.

[Test Example 4]
Apply a liquid formulation containing 0.01% of N-acetylneuraminic acid of Example 2 to 10 thin male panel members in their 20s to 40s once a day before going to bed. The hair condition before and after 3 months was compared. As a result, 9 out of 10 improvements were observed in terms of hair loss, thinning of the thinned hair, or increased hair in the thinned hair. The state before the start of application of a panel and after 3 months is shown in FIG.
From the above results, it was confirmed that there was a significant effect on hair growth when a solution containing 0.01% by mass of N-acetylneuraminic acid was applied.

  INDUSTRIAL APPLICABILITY The present invention is useful as an insulin-like growth factor-1 secretion promoter that exhibits an effect of suppressing skin wrinkles due to an increase in skin elasticity, an effect of reducing skin sagging, and a hair growth effect.

FIG. 1 shows the amount (level) of IGF-1 in the mouse skin of Test Example 1. FIG. 2 shows the average elasticity recovery rate of women in their 20s and 30s using a cream containing N-acetylneuraminic acid. FIG. 3 shows the results of Test Example 4. The left figure shows before application, and the right figure shows 3 months after the start of application.

Claims (12)

  An insulin-like growth factor-1 secretion promoter characterized by containing sialic acid not bound to sugar and / or protein and not containing sericin.   The insulin-like growth factor-1 secretion promoter according to claim 1, wherein the sialic acid not bound to the sugar and / or protein is N-acetylneuraminic acid.   The insulin-like growth factor-1 secretion promoter according to claim 2, comprising N-acetylneuraminic acid in an amount of 0.00001 mass% to 10.0 mass%.   The insulin-like growth factor-1 secretion promoter according to any one of claims 1 to 3, which promotes differentiation, proliferation and / or stromal substance production function of skin fibroblasts.   The insulin-like growth factor-1 secretion promoter according to claim 4, wherein the interstitial substance is one or more selected from the group consisting of skin collagen, elastin and hyaluronic acid.   It is a skin external preparation, The insulin-like growth factor-1 secretion promoter in any one of Claims 1-5.   One or more compounds selected from the group consisting of nonionic surfactants, amphoteric surfactants and cationic surfactants are used in an amount of 5% by mass or more and 30% by mass or more based on the total insulin-like growth factor-1 secretion promoter. The insulin-like growth factor-1 secretion promoter according to any one of claims 1 to 6, which is contained in an amount of mass% or less.   Nonionic surfactants include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether and polyoxyethylene. The insulin-like growth factor-1 secretion promoter according to claim 7, comprising one or more compounds selected from sorbite fatty acid esters.   The amphoteric surfactant contains one or more compounds selected from alkylbetaines, alkylamidobetaines, alkyldimethylaminoacetic acid betaines, sulfobetaines, and imidazoline-type betaines. Of insulin-like growth factor-1 secretion promoter.   The insulin-like growth factor- according to claim 7, wherein the cationic surfactant contains one or more compounds selected from alkyltrimethylammonium salts, amidoamines, and alkyldimethylbenzylammonium salts. 1 secretion promoter.   The insulin-like growth factor according to any one of claims 1 to 10, which is a liquid, suspension, emulsion, cream, ointment, gel, liniment, lotion, poultice or pack. -1 secretion promoter.   The insulin-like growth factor-1 secretion promoter according to any one of claims 1 to 3, which is a hair growth agent.