JP2007045768A - Neutralized and stabilized skin care preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new means for stabilizing a structure formed by a component contributing to the formation of the structure of the preparation. <P>SOLUTION: The skin care preparation comprises lysylglutamic acid and/or its salt. The preparation further comprises an ionizable component contributing to the formation of the structure of the preparation. The ionizable component contributing to the formation of the structure of the preparation is preferably selected from fatty acid soap, anionic surfactant, amphoteric surfactant, cationic surfactant, carboxyvinyl polymer which may be modified with an alkyl group, alginic acid, carboxymethyl cellulose, and clay mineral which may be modified with an organic compound. The content of the lysylglutamic acid and its salt is preferably ≥10 μM. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an external preparation for skin such as cosmetics.

  In cosmetics and skin external medicine, the act of applying a skin external preparation on the skin is inevitably involved in its use. In such an application, the most important thing is to apply a formulation in order to prevent the topical skin preparation from dripping or spreading to unnecessary parts. A structure such as a structure is formed in a pharmaceutical manner to maintain a viscosity suitable for use and maintain usability. Such a structure formation often uses an ionic cross-linking structure, and for this purpose, components having various ionization properties and contributing to the formation of the structure of the preparation are blended. As an ingredient that contributes to the formation of such an ionizable formulation structure, it may be modified with a fatty acid soap, an anionic surfactant, an amphoteric surfactant, a cationic surfactant, or an alkyl group. Representative components include carboxyvinyl polymer, alginic acid, carboxymethylcellulose, and clay minerals that may be organically modified.

  The structure formed by the components that contribute to the formation of the structure of the drug product having these ionization properties is relatively stable. However, since it depends on the ionic cross-linking structure, it becomes unstable due to the presence of an electrolyte or the like. There are many things. In many cases, the electrolyte affecting the structure is an active ingredient essential for the preparation. (For example, refer to Patent Document 1) From such a viewpoint, efforts have been made to stabilize the structure with components that contribute to the formation of the structure of the preparation having ionization properties. Such efforts include, for example, a method of coexisting an ionizable mucopolysaccharide (see, for example, Patent Document 2), and a method of solidifying an oil phase in a emulsion with a component having high consistency such as wax ( For example, refer to Patent Document 3), stabilization of the structure by using a plurality of combinations of components having ionizing properties and contributing to the formation of the structure of the preparation (for example, refer to Patent Document 4). However, although these methods can reduce the degree of viscosity change, they do not have a sufficient effect. That is, it can be said that development of a new means for stabilizing the structure formed by components that contribute to the formation of the structure of the preparation is desired.

  On the other hand, lysylglutamic acid is a known compound, but it is not known at all to incorporate this into a skin external preparation. A technique for adding glutamyl lysine (epsilon-N- (gamma-glutamyl) lysine), which is an approximate compound, to cosmetics for the purpose of moisturizing is known (see, for example, Patent Document 5 and Patent Document 6). It is not known at all that lysylglutamic acid is contained in a skin external preparation for the purpose of stabilizing the structure, and that such a compound has a stabilizing effect on the structure.

JP 2003-12696 A JP-A-11-180821 Japanese National Patent Publication No. 11-505822 JP 2000-143436 A JP 2001-2552 A JP-A-5-301814

  The present invention has been made under such circumstances, and an object thereof is to provide a means for stabilizing a structure formed by components that contribute to the formation of a new structure of a preparation.

In view of such a situation, the present inventors sought lysylglutamic acid as a result of earnest research efforts seeking a new means for stabilizing the structure formed by components that contribute to the formation of the structure of the drug product. It has been found that such a structure can be stabilized by adding to the system, and the present invention has been completed. That is, the present invention is as follows.
(1) An external preparation for skin comprising lysylglutamic acid and / or a salt thereof.
(2) The external preparation for skin according to (1), further comprising an ionizing property and a component contributing to the formation of the structure of the preparation.
(3) The external preparation for skin according to (2), wherein the component having ionizing properties and contributing to the formation of the structure of the preparation is any of the following components.
(Ingredients that contribute to the formation of ionizing pharmaceutical structures)
Fatty acid soaps, anionic surfactants, amphoteric surfactants, cationic surfactants, carboxyvinyl polymers that may be modified with alkyl groups, alginic acid, carboxymethylcellulose, and clay minerals that may be organically modified.
(4) The external preparation for skin according to any one of (1) to (3), wherein the content of lysylglutamic acid and a salt thereof is at least 10 μM.
(5) The skin external preparation according to any one of (1) to (4), further comprising dipotassium glycyrrhizinate and / or stearyl glycyrrhetinate.
(6) The external preparation for skin according to (5), which is a quasi-drug having an anti-inflammatory effect.

  ADVANTAGE OF THE INVENTION According to this invention, the structure stabilization means formed with the component which contributes to formation of the structure of a new formulation can be provided.

(1) Lysylglutamic acid which is an essential component of the external preparation for skin of the present invention The external preparation for skin of the present invention is characterized by containing lysylglutamic acid and / or a salt thereof. The salt of this substance is not particularly limited as long as it is physiologically acceptable, and the amino group is salted with an acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or the carboxyl group is alkali metal or alkaline earth. An alkali salt can be formed with a metal, an organic amine, or the like. Lysylglutamic acid is a dipeptide in which the carboxyl group of lysine and the amino group of glutamic acid are amide-bonded, and the lysine and glutamic acid can be taken in either L-form or D-form, but those in which both lysine and glutamic acid are in L-form are particularly preferred. Such a peptide can be produced according to a conventional method. That is, the non-reactive terminal amino group and carboxyl group are protected with FMOC (fluorenylmethoxycarbonyl) group or nitrobenzyl group, if desired, and then the unprotected amino group and carboxyl group are synthesized with a peptide such as DCC. The peptide of the present invention can be synthesized by condensing with a reagent and then deprotecting.

(Production example)
Two amino groups of 5 g of L-lysine were protected with a BOC group to form 1,4-bis- (N-BOC) lysine, and two carboxyl groups of 5 g of L-glutamic acid were separately protected with a benzyl group. , 5-Dibenzylglutamic acid with 200 ml of methylene chloride as a solvent, and stirred for 48 hours at room temperature in the presence of 5 g of DCC. The insoluble matter was removed by filtration and concentrated under reduced pressure, followed by silica gel column chromatography (elution solvent; chloroform: methanol). = 100: 0 → 70: 30), after which the benzyl group and the BOC group were deprotected to obtain 0.9 g of lysylglutamic acid.

  In the external preparation for skin of the present invention, the lysylglutamic acid has an action of stabilizing the structure of the system. In order to exhibit such an action, lysylglutamic acid and a salt thereof must be present at least 10 μM in the external preparation for skin, and more preferably 0.0001 to 1% by mass. This is because if the amount is too small, the system structure stabilizing action may not be obtained, and if the amount is too large, precipitation may occur.

(2) External preparation for skin of the present invention The external preparation for skin of the present invention is characterized by containing lysylglutamic acid and / or a salt thereof as an essential component. The external preparation for skin of the present invention is not particularly limited as long as it is externally administered to the skin, and examples thereof include cosmetics including quasi-drugs, external preparations for skin, and general-purpose items for external use. Of these, particularly preferred are quasi drugs, and it is particularly preferable to apply them to quasi drugs that have an anti-inflammatory effect. This is because dipotassium glycyrrhizinate, which is an active ingredient for such action, is a component that easily breaks the structure of the system by the electrolyte, and the effect of the present invention is particularly remarkable in the presence of dipotassium glycyrrhizinate. The content of dipotassium glycyrrhizinate is preferably 0.01 to 0.2% by mass. The mass of such a component is preferably at least 10 times the amount of lysylglutamic acid.

  In addition, since the gist of the present invention is the stabilization of the structure formed by the components that contribute to the formation of the structure of the preparation having ionization properties, the external preparation for skin of the present invention has the ionizing property of the preparation. It is preferable to contain a component that contributes to the formation of the structure. Examples of such components include fatty acid soaps such as sodium stearate, potassium laurate, and triethanolamine palmitate, anionic surfactants such as potassium lauryl sulfate and triethanolamine ether of alkyl sulfate, and imidazoline-based amphoteric surfactants. Agents (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyl taurine Agents, cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide, carboxyvinyl polymer, alkyl acrylate / acrylic acid copolymer, alkyl methacrylate / alkyl methacrylate Clay minerals such as carboxy vinyl polymer, alginic acid, carboxymethyl cellulose, montmorillonite, saponite, hectorite, etc. which may be modified with alkyl groups such as limer, dodecyltrimethylammonium chloride, myristyltrimethylammonium chloride, cetyltrimethylammonium chloride , Stearyltrimethylammonium chloride, alkyltrimethylammonium chloride, behenyltrimethylammonium chloride, myristyldimethylethylammonium chloride, cetyldimethylethylammonium chloride, stearyldimethylethylammonium chloride, alkyldimethylethylammonium chloride, behenyldimethylethylammonium chloride, myristyldiethylmethyl Ammonium chloride, cetyldiethylmethylammonium chloride, stearyldiethylmethylammonium chloride, alkyldiethylmethylammonium chloride, behenyldiethylmethylammonium chloride, benzyldimethylmyristylammonium chloride, benzyldimethylcetylammonium chloride, benzyldimethylstearylammonium chloride, benzyldimethylbehenylammonium chloride Organically modified clay minerals such as organically modified clay minerals modified with cationic surfactants such as benzylmethylethylcetylammonium chloride, benzylmethylethylstearylammonium chloride, distearyldimethylammonium chloride, dibehenyldihydroxyethylammonium chloride Good clay minerals etc. Can be illustrated. These preferable contents are 0.01-10 mass%, and it is preferable that this content is 10-10000 times the sum of the mass of the said lysyl glutamic acid and its salt.

  The skin external preparation of the present invention can contain any component that is usually used in a skin external preparation in addition to the above-described components. Such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, hydrogenated coconut oil Oil, wax, oil such as beeswax, canola wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum , Hydrocarbons such as microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol, isostearyl Higher alcohols such as alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, malic acid Diisostearyl, di-2-ethylhexanoic acid ethylene glycol, dicaprate neopentyl glycol, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, tri Synthetic ester oils such as trimethylolpropane isostearate and pentane erythritol tetra-2-ethylhexanoate; dimethylpolysiloxane, methylphenylpoly Chain polysiloxanes such as Loxane and diphenylpolysiloxane; Cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexanesiloxane; amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, Oil agents such as silicone oils such as modified polysiloxanes such as fluorine-modified polysiloxanes; sorbitan fatty acid esters (such as sorbitan monostearate and sorbitan sesquioleate), glycerin fatty acids (such as glyceryl monostearate), and propylene glycol fatty acid esters (Propylene glycol monostearate, etc.), hydrogenated castor oil derivative, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan) Monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbite monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol) Monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyl) Tetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), sucrose fatty acid ester, alkylglucosi Nonionic surfactants such as polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, Polyhydric alcohols such as 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol; moisturizing ingredients such as lactic acid and sodium lactate; surface treated mica, talc, Powders such as kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic anhydride (silica), aluminum oxide, barium sulfate; surface may be treated, bengara, yellow iron oxide, black iron oxide, oxidized Cobalt, ultramarine, bitumen, titanium oxide, zinc oxide inorganic Materials: pearl agents such as titanium mica, fish phosphorus foil, bismuth oxychloride, etc. whose surface may be treated; red 202, red 228, red 226, yellow 4 that may be raked , Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1, Green 201, Purple 201, Red Organic dyes such as No. 204; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; paraaminobenzoic acid UV absorbers; anthranilic acid UV absorbers; salicylic acid UV absorbers Cinnamic acid UV absorbers; Benzophenone UV absorbers; Sugar UV absorbers; 2- (2′-hydroxy-5′-t-octylfe) Nyl) benzotriazole, UV absorbers such as 4-methoxy-4'-t-butyldibenzoylmethane; lower alcohols such as ethanol and isopropanol; vitamin A or derivatives thereof, vitamin B6 hydrochloride, vitamin B6 tripalmitate Vitamin B6 such as vitamin B6 dioctanoate, vitamin B2 or a derivative thereof, vitamin B12, vitamin B15 or a derivative thereof; vitamin E such as α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate, vitamin D, Preferable examples include vitamins such as vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone and the like; and antibacterial agents such as phenoxyethanol.

  The skin external preparation of this invention can be manufactured by processing the said essential component, a preferable component, and an arbitrary component in accordance with a conventional method. The preparation of the external preparation for skin of the present invention is not particularly limited as long as it is a dosage form used in cosmetics including the above quasi-drugs, external preparations for skin, miscellaneous items for external use, such as lotions and emulsions. Preferred examples include dosage forms such as creams, high-viscosity essences, and detergents.

  Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

  In accordance with the formulation shown below, a cosmetic preparation (quasi-drug that promoted anti-inflammatory action), which is an external preparation for skin of the present invention, was prepared. That is, the component (a) is stirred to obtain a uniformly dispersed state, gradually added under stirring to the mixture, diluted, added with neutralization under stirring, neutralized, and used as a high-viscosity lotion according to the present invention. A cosmetic 1 was obtained.

Icarboxyvinyl polymer 0.1% by mass
"Carbopol 1382" 0.1% by mass
(Alkyl-modified carboxyvinyl polymer; manufactured by Goodrich)
1,3-butanediol 5% by mass
1,2-pentanediol 3% by mass
B 0.1% lysylglutamic acid aqueous solution 0.1% by mass
Phenoxyethanol 0.5% by mass
1% dipotassium glycyrrhizinate aqueous solution 5% by mass
80% by mass of water
C Potassium hydroxide 0.1% by mass
6.2% by mass of water

  After manufacturing cosmetic 1 and storing at 20 ° C for 1 day, measuring the viscosity, storing at 50 ° C for 1 week, storing at 20 ° C for 1 day, making a constant weight, measuring the viscosity again, Tested. Comparative Example 1 in which lysylglutamic acid of cosmetic 1 was replaced with water was also tested for stability. The results are shown in Table 1. From this, it can be seen that the addition of lysylglutamic acid stabilizes the gel structure of the aqueous gel formed by the carboxyvinyl polymer and the alkyl-modified carboxyvinyl polymer.

  In accordance with the following formulation, a stabilized foundation was formed by forming a structure with fatty acid soap. That is, the components (a) and (b) are each heated to 80 ° C., and the component (c) is dispersed with a disper and then emulsified by gradually adding to the mixture with stirring, and then cooled by stirring. Suncare milk (Cosmetic 2; a quasi-drug that promoted anti-inflammatory action) was obtained.

Isqualane 2% by mass
Neopentyl glycol diisostearate 18% by mass
Cetanol 1% by mass
Stearic acid monoglyceride 1.2% by mass
POE (20) sorbitan sesquistearate 1.8% by mass
POE (45) stearate 1% by mass
Stearic acid 1% by mass
1,3-butanediol 5% by mass
Phenoxyethanol 0.5% by mass
1,2-pentanediol 2.5% by mass
Triethanolamine 1% by mass
0.1% lysylglutamic acid aqueous solution 0.1% by mass
1% dipotassium glycyrrhizinate aqueous solution 5% by mass
39.9% by mass of water
C Titanium dioxide 10 mass%
Zinc oxide 4% by mass
Talc 6% by mass

  After the cosmetic 2 is manufactured, it is stored at 20 ° C. for 1 day, and after measuring the viscosity, it is stored at 50 ° C. for 1 week, stored at 20 ° C. for 1 day, made constant, and then the viscosity is measured again. Tested. Comparative Example 2 in which lysylglutamic acid in cosmetic 2 was replaced with water was also tested for stability. The results are shown in Table 2. This shows that lysylglutamic acid has improved the stability of the structure made by fatty acid triethanolamine soap.

  In accordance with the formulation shown below, cosmetic 3 (milky lotion; quasi-drug that promotes anti-inflammatory action), which is an external preparation for skin of the present invention, was prepared. In other words, the ingredients (a), (b), and (c) are heated, dissolved and dispersed at 80 ° C., and then gradually added to (a) with stirring. It cooled and the cosmetics 3 were obtained.

Sodium Ialginate 0.2% by mass
Glycerin 8% by mass
1,3-butanediol 8% by mass
Methylparaben 0.2% by mass
Water 59% by mass
1% dipotassium glycyrrhizinate aqueous solution 5% by mass
0.1% lysylglutamic acid aqueous solution 0.1% by mass
Havehenic acid 1% by mass
Stearyl palmitate 2% by mass
Solid paraffin 2% by mass
Cetyl alcohol 2.5% by mass
Vaseline 1% by mass
Squalane 10% by mass
Dimethicone 1% by mass

  Store the cosmetic 3 at 20 ° C. for 1 day after manufacturing, measure the viscosity, store at 50 ° C. for 1 week, store at 20 ° C. for 1 day, make a constant weight, measure the viscosity again, and improve the stability. Tested. Comparative Example 3 in which the lysylglutamic acid in cosmetic 3 was replaced with water was also tested for stability. The results are shown in Table 3. This shows that lysylglutamic acid has improved the stability of the structure formed by sodium alginate.

  Cosmetics 4 (water-in-oil emulsified cream; quasi-drug that promoted anti-inflammatory action), which is an external preparation for skin of the present invention, was prepared according to the formulation shown below. That is, the components of A, B, C, D, E and F were heated at 80 ° C., A was gradually added to B with stirring, and C was further added to prepare an intermediate emulsion. F was added to the mixture to make it uniform, and this was added to the mixture under stirring to form a gel. The intermediate emulsion was gradually added to the gel with stirring, and the mixture was cooled with stirring to obtain a cosmetic 4 in the form of an oil-in-water oil emulsifier.

Ibehenic acid 0.4% by mass
Stearic acid 0.15% by mass
Glycerin 4.5% by mass
10% aqueous potassium hydroxide 0.45 mass%
Water 2.9% by mass
Robehenyl alcohol 0.5 mass%
Stearyl alcohol 0.3% by mass
Squalane 4.5 mass%
Phenoxyethanol 0.15% by mass
1,3-butanediol 4.5% by mass
16.55% by mass of water
1% dipotassium glycyrrhizinate aqueous solution 5% by mass
0.1% lysylglutamic acid aqueous solution 0.1% by mass
D "Benton 38" 2.5 mass%
(Distearyldimethylammonium chloride-treated montmorillonite: National Red)
Sucrose monostearate 4% by mass
Squalane 3.5 wt%
Cyclomethicone 23% by mass
Lanolin 1% by mass
Hoglycerin 20% by mass
Methylsiloxane network polymer 2% by mass
Phenoxyethanol 0.15% by mass
Undecylenic acid monoglyceride 2% by mass
Sodium helginate (high purity product) 0.2% by mass
1.65% by weight of water

  After the cosmetic 4 is manufactured, it is stored at 20 ° C. for one day, and after measuring the viscosity, it is stored at 50 ° C. for one week, stored at 20 ° C. for one day, made constant, and then the viscosity is measured again. Tested. Comparative Example 4 in which lysylglutamic acid in cosmetic 4 was replaced with water was also tested for stability. The results are shown in Table 4. This shows that lysylglutamic acid has improved the stability of the structure formed by sodium alginate and organically modified clay minerals.

  The present invention can be suitably applied to quasi drugs.

Claims (6)

A skin external preparation characterized by containing lysylglutamic acid and / or a salt thereof. Furthermore, the skin external preparation of Claim 1 containing the component which contributes to formation of the structure of a formulation which has ionization property. The external preparation for skin according to claim 2, wherein the component contributing to the formation of the structure of the preparation having ionization properties is any of the following components.
(Ingredients that contribute to the formation of ionizing pharmaceutical structures)
Fatty acid soaps, anionic surfactants, amphoteric surfactants, cationic surfactants, carboxyvinyl polymers that may be modified with alkyl groups, alginic acid, carboxymethylcellulose, and clay minerals that may be organically modified. The external preparation for skin according to any one of claims 1 to 3, wherein the content of lysylglutamic acid and a salt thereof is at least 10 µM. The skin external preparation according to any one of claims 1 to 4, further comprising dipotassium glycyrrhizinate and / or stearyl glycyrrhetinate. The external preparation for skin according to claim 5, which is a quasi-drug having an anti-inflammatory effect.