JP2780803B2 - External preparation for skin - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel external preparation for skin, and more particularly, to an external preparation with excellent skin whitening effect and high stability.

There are many unclear points about the mechanism of pigmentation such as skin spots and freckles on the skin.However, hormonal abnormalities and irritation by ultraviolet light cause excessive production of melanin pigment, It is thought to be an abnormal deposit.

For the purpose of preventing or improving such pigmentation, conventionally, hydrogen peroxide, zinc peroxide, peroxides such as magnesium peroxide, or ascorbic acid, glutathione,
Attempts have been made to use whitening cosmetics containing colloidal sulfur and various natural products as active ingredients. However, many of these active ingredients have insufficient safety and stability, or have problems with odor and the like, and their effects are not necessarily sufficient.

On the other hand, in the United States and the like, hydroquinone is used as a skin depigmenting agent, but this hydroquinone has irritation and allergic properties, and there is a problem in terms of safety in formulating it as an active ingredient in cosmetics. .

Problems to be Solved by the Invention The present invention overcomes the drawbacks of such conventional skin external preparations aimed at whitening, has excellent skin whitening effects, and has high safety, stability and odor. The purpose of the present invention is to provide a skin external preparation having no problem.

Means for Solving the Problems The present inventors have conducted intensive studies in order to develop a skin external preparation exhibiting a skin whitening effect without the above-mentioned disadvantages, and have first conducted an ellagic acid-based compound or its alkali. It has been found that metal salts have an excellent whitening effect and good safety (Japanese Patent Application No. 62-143507). However, in later studies, this ellagic acid-based compound and its alkali metal salts gradually discolored when stored under severe conditions for a long period of time, especially when incorporated into bases such as cosmetics and medical products, It turned out that the tendency was strong.

Therefore, the present inventors have further studied diligently, and as a result, the ellagic acid-based compound and the alkali metal salt thereof, when combined with a specific antioxidant, have good stability over time, and the antioxidant And an external preparation for skin comprising an ellagic acid-based compound and an alkali metal salt thereof, have an excellent whitening effect, and have no irritancy or sensitization, have good stability over time, and have an odor. They have found that there is no problem, and have completed the present invention based on this finding.

That is, the present invention relates to (A) at least one antioxidant selected from L-ascorbic acid and its derivatives, kojic acid and its derivatives, and ferulic acid and its derivatives; (Wherein R ₁ , R ₂ , R ₃ and R ₄ are a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, a polyoxyethylene or polyoxypropylene residue or a compound represented by the formula Which may be the same or different, and R ₅ is a hydrogen atom, a hydrogen group, or an alkoxy group having 1 to 8 carbon atoms.) An external preparation for skin comprising an ellagic acid compound and at least one selected from alkali metal salts thereof.

 Hereinafter, the present invention will be described in detail.

In the skin external preparation of the present invention, a specific antioxidant is used as the component (A). L-ascorbic acid, which is one of the antioxidants used in the present invention, is generally called vitamin C, is known as an anti-scurvy factor, and has a strong reductive action, cell respiratory action and enzyme activation. Medicine, food,
It is a highly safe antioxidant widely used in the cosmetics field. In the present invention, in addition to this L-ascorbic acid, its sodium salt and various derivatives whose stability has been improved and have recently begun to be used in the cosmetic field can also be used. Specific examples of this derivative include L-
L-ascorbic acid monoester derivatives such as ascorbic acid monostearate, L-ascorbic acid monopalmitate, L-ascorbic acid monooleate, L-ascorbic acid monophosphate ester, L-ascorbic acid-2-sulfate, L-ascorbic acid Distearate, L
-L-ascorbic acid diester derivatives such as ascorbic acid dipalmitate, L-ascorbic acid dioleate, L-ascorbic acid tristearate, L-ascorbic acid tripalmitate, L-ascorbic acid trioleate, L-ascorbic acid triphosphate and the like. L-ascorbic acid triester derivatives and their sodium salts and magnesium salts.

In the present invention, kojic acid and its derivatives can also be used as the antioxidant of the component (A). This kojic acid has a chemical name of 5-hydroxy-2-hydroxymethyl-.
4-pyrone, which is known to have an antioxidant effect. In the present invention, any of purified products obtained by fermentation extracts obtained from microorganisms such as Aspergillus, Penicillium, Acetobacter and the like and recrystallization thereof, or synthetic products, and salts thereof can also be used. be able to. This kojic acid or a salt thereof is commercially available, easily available, and as the kojic acid derivative that can be used in the present invention, a reactive derivative of one or both hydroxyl groups of kojic acid, for example, Preferred examples include fatty acid esters having 3 to 22 carbon atoms, aliphatic ethers having 3 to 22 carbon atoms, and polyoxyalkylene (C ₂ or C ₃ ) derivatives.

Furthermore, in the present invention, ferulic acid and its derivatives can also be used as the antioxidant of the component (A). This ferulic acid has a chemical name of 3-methoxy-4-hydroxycinnamic acid and is known to have an antioxidant effect. In the present invention, any of extracts of various plant components such as Agi, Shihakuhoku, Senkyu, Touki, Droom, Mokuzoku, Rifuku and the like, purified products obtained by recrystallization thereof, and synthetic products can be used. This ferulic acid is commercially available and easily available.
Examples of ferulic acid derivatives that can be used in the present invention include ethyl ferulate, which is an ester of ethyl alcohol, and γ-oryzanol, which is an ester of triterpene alcohol. In particular, γ-oryzanol is extracted from rice oil and rice germ oil, and is known to have physiological actions such as growth promoting action and microcirculation blood flow promoting action, and is also used in cosmetics as an antioxidant.

In the present invention, as the antioxidant of the component (A), one of the above-mentioned L-ascorbic acid and its derivatives, kojic acid and its derivatives, and ferulic acid and its derivatives is used.
Seeds or two or more kinds are appropriately selected and blended. The compounding amount depends on the form of the product and the frequency of use, but is usually selected in the range of 0.005 to 10% by weight, preferably 0.01 to 5% by weight based on the total amount of the external preparation for skin.

In the skin external preparation of the present invention, as the component (B), at least one selected from the ellagic acid compounds represented by the general formula (I) and alkali metal salts thereof is used. Examples of the ellagic acid-based compound include ellagic acid in which R ₁ , R ₂ , R ₃ , R ₄ and R _{5 in the} general formula (I) are all hydrogen atoms, and R ₁ , R ₂ , R ₃ and R ₄ is preferably a hydrogen atom, a methyl group or an ethyl group, and R ₅ is preferably a hydrogen atom, a hydrogen group or a methoxy group. Examples of the alkali metal salts of these ellagic acid compounds include, for example, sodium salts and potassium salts, and those in which some of the phenolic hydroxyl groups of ellagic acid have become sodium or potassium salts have poor solubility. It is preferable in that it is good.

The ellagic acid-based compound or an alkali metal salt thereof is used to adjust the lipophilicity or hydrophilicity of the external preparation for skin in order to adjust R ₁ , R ₂ , R ₃ and R _{4 in} the general formula (I). Some may be substituted with any group selected from long-chain alkyl groups having up to 20 carbon atoms, polyoxyethylene residues, polyoxypropylene residues and sugar residues represented by the formula (II). Alternatively, R ₅ may be substituted with a long-chain alkoxy group having up to 8 carbon atoms.

Specific examples of the ellagic acid-based compound and an alkali metal salt thereof include ellagic acid, 3,4-di-o-methylellagic acid,
3,3'-di-o-methylellagic acid, 3,3 ', 4-tri-o-
Methylellagic acid, 3,3 ', 4,4'-tetra-o-methyl-
5-methoxyellagic acid, 3-ethyl-4-methyl-5
Examples thereof include hydroxyellagic acid, amritoside, and alkali metal salts of these compounds.

These ellagic acid compounds are eucalyptus wood (Eucalypt
us), poisonous azalea (Koriaria japonica), radiata pine, bearberry, pomegranate, anmarok, ukyuyou, enfuyou, gaijicha, kakojuyou, miko,
Kiki, Kenjin, Kounaka, Sankyukon, Sankyuyou, Shufuboku, Senkusai, Sougenroukansou, Daihyosou, Doumouanyou, Haouben, Banseki Ryukan, Banseki Ryuh, Bossah, Moshoku, Yutaka, Kanto, Kanto, Kanto From natural products such as sokon, bansekiryuuyou, ukyubokumpi, sidokon, chinshuso, gennoshoko,
For example, it can be easily obtained by the method described in JP-B-53-14605.

The ellagic acid-based compound used in the skin external preparation of the present invention,
As described above, it is widely present in natural products, and its safety is considered to be extremely high.However, when its safety was confirmed just in case, acute toxicity, skin irritation, skin sensitization, mutagenicity In this respect, there was no practical problem, and it was confirmed that the safety was high.

In the external preparation for skin of the present invention, the ellagic acid-based compound and the alkali metal salt thereof may be used alone or in combination of two or more, and the content thereof depends on the product form and the frequency of use. Although it depends, it is usually selected in the range of 0.001 to 20% by weight, preferably 0.005 to 5% by weight based on the total amount of the external preparation for skin.

The skin external preparation of the present invention is a monosaccharide such as glucose or a basic amino acid such as arginine in order to better disperse the ellagic acid compound or an alkali metal salt thereof.
Preferably 0.001-30% by weight, more preferably 0.005-20%
% By weight, and further, if desired, various components commonly used in external preparations for skin,
For example, oils, water, humectants including surfactants, lower alcohols, thickeners, antioxidants, chelating agents, pH adjusters,
Preservatives, fragrances, dyes, ultraviolet absorbers, ultraviolet scattering agents, vitamins, amino acids and the like can be added.

Examples of the oil component include oils such as olive oil, jojoba oil, cacao butter, camellia oil, coconut oil, wood wax, grape seed oil, avocado oil, mink oil, egg yolk oil, and hardened oil, whale wax, beeswax, and lanolin. , Waxes such as carnauba wax and candelilla wax, liquid paraffin, ceresin, squalane, microcrystalline wax, paraffin wax, hydrocarbons such as petrolatum, stearic acid, oleic acid, lauric acid, myristic acid, isostearic acid, behenic acid, etc. Fatty acids, alcohols such as cetanol, stearyl alcohol, lanolin alcohol, octyldodecanol, hexyldecanol, isopropyl myristate, butyl stearate, isopropyl palmitate, octyldodecyl myristate, octyldode oleate Le, and the like esters such as cholesterol oleate.

Examples of the surfactant include anionic surfactants such as sodium stearate, sodium cetyl sulfate, polyoxyethylene lauryl ether phosphate, sodium lauryl phosphate, triethanol palmitate, sodium N-acylglutamate, and stearyl dimethylbenzyl chloride Ammonium, a chaotic surfactant such as stearyltrimethylammonium chloride, an alkylaminoethylglycine hydrochloride solution, an amphoteric surfactant such as lecithin, glyceryl monostearate, sorbitan monostearate, sucrose fatty acid ester, propylene glycol monostearate, Polyoxyethylene oleyl ether, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fat Monoethanolamide, polyoxyethylene polyoxypropylene glycol, polyoxyethylene castor oil, such as non-ionic surfactants such as polyoxyethylene lanolin.

Examples of the humectant include polyhydric alcohols such as glycerin, 1,3-butylene glycol, propylene glycol, sorbitol, polyethylene glycol and dipropylene glycol, amino acids, NMF components such as sodium lactate and sodium pyrrolidone carboxylate, hyaluronic acid, and collagen. , Mucopolysaccharides, water-soluble polymer substances such as chondroitin sulfate, etc., as lower alcohols,
For example, ethanol, isopropanol and the like, as a thickener, for example, sodium alginate, xanthan gum, aluminum silicate, quince seed extract, tragacanth gum, natural polymer substances such as starch, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, soluble starch, kaotin Semi-synthetic polymer substances such as activated cellulose, and synthetic polymer substances such as carboxyvinyl polymer and polyvinyl alcohol.

As antioxidants, for example, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate and the like, as chelating agents, for example, disodium edetate, ethanehydroxydiphosphate, pyrophosphate, hexametaphosphate, citric acid, Tartaric acid, gluconic acid, etc., as pH adjusters, for example, sodium hydroxide, triethanolamine, citric acid, sodium citrate, boric acid, borax, sodium monohydrogen phosphate, etc. Examples thereof include methyl benzoate, ethyl paraoxybenzoate, dehydroacetic acid, salicylic acid, benzoic acid, sorbic acid, and benzalkonium chloride.

Further, as an ultraviolet absorber, for example, 2-hydroxy-4-methoxybenzophenone, octyldimethylparaaminobenzoate, ethylhexylparamethoxycinnamate, and the like, and as an ultraviolet scattering agent, for example, titanium oxide, kaolin, talc, and the like, as vitamins Are, for example, vitamin A, vitamin B, vitamin D, vitamin E, vitamin F, vitamin K, vitamin P, vitamin U, carnitine, α-lipoic acid, orotic acid and derivatives thereof, and as amino acids, for example, glycine; Alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, cystine, cysteine, methionine, proline, hydroxyproline, aspartic acid, glutamic acid, arginine, histidine Such as lysine and derivatives thereof. The optional components are not limited to these.

The skin external preparation of the present invention can be prepared by appropriately mixing the essential components of the above-mentioned components (A) and (B) with these optional components, for example, lotion, cream, pack, lotion, skin milk, emulsion, It can be used as various product forms such as bath salt, body shampoo and body rinse.

Specifically, as a lotion, (A)
Component 0.01 to 2% by weight and component (B) 0.01 to 2% by weight, and optionally 2 to 10% by weight of lower alcohol, 0.5 to 1% by weight of surfactant, 3 to 7% by weight of humectant, p
A composition containing 0.05 to 0.2% by weight of an H adjuster, 80 to 95% by weight of purified water, and trace amounts of preservatives, pigments, and fragrances is used as a cream for skin, as an essential component, component (A) 0.01 to 2% by weight. And 0.01 to 2% by weight of component (B), and optionally 20 to 70% by weight of oil, 2 to 7% by weight of surfactant, 5 to 10% by weight of humectant, 11 to 73% by weight of purified water. And a composition containing a trace amount of a preservative and a fragrance, wherein the lotion contains (A) component 0.01 to 2% by weight as an essential component and (B) component 0.01 to 2% by weight, and a lower alcohol as an optional component. 5-10% by weight, surfactant 0.5-2% by weight, humectant 2-8% by weight, antioxidant 0.01-0.05% by weight, chelating agent 0.02-0.1% by weight, pH adjuster 0.1-1% by weight, purification A composition containing 77-92% by weight of water and trace amounts of preservatives, pigments, and fragrances is essential for skin milk. Component (A) is 0.01 to 2% by weight and component (B) is 0.01 to 2% by weight.
A composition containing 2% by weight and optionally containing 20 to 40% by weight of an oil, 2 to 5% by weight of a surfactant, 53 to 78% by weight of purified water, and a small amount of a preservative and a fragrance is used as an emulsion. Are (A) 0.01 to 2% by weight and (B) 0.
Contains 01 to 2% by weight, and has an oil content of 10 to 30 as an optional component.
% By weight, 1 to 5% by weight of a surfactant, 5 to 10% by weight of a humectant, 53 to 84% by weight of purified water, and a small amount of a preservative or a fragrance.

Effect of the Invention The skin external preparation of the present invention contains a specific antioxidant and an ellagic acid compound or an alkali metal salt thereof as essential components, and has a much better whitening effect than conventional ones. Has excellent safety and stability, for example, various cosmetic creams, milky lotions, lotions, serums, packs, powders, lip balms, lipsticks, under makeup, foundations, sun care, bath agents, As various product forms such as body shampoo and body rinse,
It is preferably used.

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Examples 1 to 3 and Comparative Example 1 A serum was used as a base, and an antioxidant of the kind and amount shown in Table 1 and 0.5% by weight of ellagic acid were blended in the base.
A storage test was performed at ℃ for one month. Table 1 shows the results.

Essence base Squalane 1.0% by weight Liquid paraffin 1.0 POE (15 mol) Oleyl ether 0.5 Propylene glycol 10.0 Ethanol 5.0 Xanthan gum 0.3 Fragrance Trace amount Purified water Balance As can be seen from Table 1, the serum containing ellagic acid and a specific antioxidant (Examples 1 to 3) is clearly more stable over time than the serum containing only ellagic acid (Comparative Example 1). Has been improved.

Examples 4 to 6, Comparative Examples 2 and 3 After preparing an alkali metal salt of ellagic acid by the method shown below, a cream having the composition shown in Table 2 was prepared, and the whitening effect was examined. A storage test was performed for months. Table 2 shows the results.

(1) Preparation of alkali metal salt of ellagic acid 10.0 g of commercially available ellagic acid [manufactured by Tokyo Chemical Industry Co., Ltd.] was stirred and dispersed in purified water, and then 170 g of a 1.0 N aqueous potassium hydroxide solution was added thereto. Dissolve ellagic acid,
Further, 2.0 g of activated carbon was added and stirred at room temperature for 30 minutes.
Next, this suspension was filtered under reduced pressure to obtain a reddish-brown filtrate. Then, concentrated sulfuric acid was added dropwise to adjust the pH to 7.0, and a precipitate was deposited. After centrifugation (8,000 rpm, 10 minutes), The precipitate was collected, washed with water and ethanol, and dried to obtain 10.1 g of a potassium salt of ellagic acid.

(2) Preparation of cream Potassium ellanate obtained as described above (treatment pH
7.0) was used to prepare a cream having the composition shown in Table 2. The pH of the cream was adjusted to 5.0 to 5.5 with citric acid.

(3) Effect on human pigmentation due to ultraviolet rays The forearm flexion side of 15 healthy males was covered with aluminum foil with a 1cm x 1cm square hole (5 places), and UV-B was used once a day.
Irradiation for 2-4 minutes, 3 consecutive days. From the 10th day when pigmentation occurred after irradiation and the skin color was darkest, about 20 mg of the creams of Examples 4 to 6 and Comparative Examples 2 and 3 twice a day
Applied. On the 35th day after the start of the application, the degree of pigmentation was scored according to the following criteria, and the average value (n = 15) was determined to determine the effect on pigmentation.

Pigmentation degree 0: Almost no pigmentation (very effective) 1: Slight pigmentation with unclear borders (effective) 2: Moderate pigmentation with unclear boundaries (somewhat effective) 3 : Intense pigmentation with clear boundaries (ineffective) As is clear from Table 2, a cream containing potassium ellagate and a specific antioxidant (the product of the present invention, Example 4)
6) clearly show that the aging stability is improved without impairing the effect of improving pigmentation as compared with the cream containing only potassium ellagate (Comparative Example 2).

No skin irritation or allergic reaction was observed during or after use of the cream, confirming that the safety was extremely high.

Example 7 Various skin external preparations of the present invention are shown below.

Essence 3,4-Di-o-methylellagic acid 0.15wt% L-ascorbic acid 0.3 Jojoba oil 1.0 Isostearate POE (15) glycerol 2.0 Glycerin 5.0 Ethanol 5.0 Hibiswako 105 0.5 Fragrance Fine volume Purified water Balance Lotion 1 3, 3 ', 4,4'-Tetra-o-methyl-5-methoxyellagic acid 0.1 wt% Kosic acid distearate 0.01 Glycerin 5.0 Ethanol 8.0 Perfume Minor amount Purified water Balance Lotion 2 A. Ethyl alcohol phase part Ethyl alcohol 9.0 wt% POE (60) hydrogenated castor oil 0.25 Perfume Appropriate amount B. aqueous phase potassium ellagic acid salt (treatment pH 5) 0.05 wt% ferulic acid 0.02 methylparaben 0.05 dipropylene glycol 3.0 purified water balance After dissolving Formulation A uniformly, add B The aqueous lotion was gradually added with stirring to prepare a lotion.

Emulsion 1 A. Oil phase liquid paraffin (# 70) 10.0 wt% isopropyl palmitate 3.0 glyceryl monopalmitate 0.5 stearic acid 2.0 POE (20) cetyl ether 1.0 butyl paraben 0.1 B. aqueous phase amritside 1.0 wt% γ-oryzanol 0.5 1,3-butylene glycol 4.0 Carbopol 934 0.1 Ethanol 10.0 Ethane hydroxydiphosphate 0.1 Purified water Balance C. Fragrance appropriate amount Mix and dissolve the above formulations A and B at 70 ° C, add A to B and emulsify uniformly I let it. C was further added and the mixture was cooled to prepare an emulsion.

Emulsion 2 Ellagic acid 0.25 wt% L-ascorbic acid 0.1 γ-oryzanol 0.1 Myristinic acid 1.0 Stearyl alcohol 2.5 Paraffin wax 1.0 Squalane 5.0 Glycerin monostearate 0.5 Self-emulsifying glyceryl monostearate 0.5 Polyethylene glycol 1500 1.5 Potassium hydroxide 0.1 Fragrance Fine Amount Ethyl alcohol phase Ethyl alcohol 10.0 wt% Polyvinyl alcohol 15.0 Propylene glycol 5.0 Methyl paraben 0.15 Butyl paraben 0.05 β-Glycyrrhetinic acid 0.05 B. Aqueous phase Elagic acid sodium salt (treatment pH 7) 1.0 wt% L -Sodium ascorbate 1.0 Sodium carboxymethylcellulose 3.0 POE (12) nonylphenyl ether 1.0 Purified water Balance C. Appropriate amount of perfume The above formulations A and B were mixed and uniformly heated and mixed at 70 ° C. With further cooling, C was added to prepare a pack.

Cosmetic cream A. Oil phase Liquid paraffin (# 70) 10.0 wt% Squalane 5.0 Cetanol 6.0 Beeswax 2.0 Glycerin monostearate 1.5 POE (40) Sorbitan monolaurate 2.0 Propylparaben 0.1 B. Aqueous phase Sodium ellagate 0.05 wt% Kojic acid 0.10 Glycerin 7.0 Disodium edetate 0.05 Methylparaben 0.2 Purified water Balance C. Fragrance appropriate amount After mixing and dissolving the above formulations A and B at 70 ° C, A was added to B and emulsified uniformly. Add more C,
Upon cooling, a cream was prepared.

All of the above compositions had good stability over time, had an excellent whitening effect, and had good usability and safety.

Continuation of the front page (51) Int.Cl. ⁶ identification code FI A61K 7/00 A61K 7/00 X (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 7/00-7/50

Claims (1)

(57) [Claims] (A) at least one antioxidant selected from L-ascorbic acid and its derivatives, kojic acid and its derivatives, and ferulic acid and its derivatives;
(B) General formula (Wherein R ₁ , R ₂ , R ₃ and R ₄ are a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, a polyoxyethylene or polyoxypropylene residue or a compound represented by the formula Which may be the same or different, and R ₅ is a hydrogen atom, a hydrogen group or an alkoxy group having 1 to 8 carbon atoms) An external preparation for skin comprising an ellagic acid compound and at least one selected from alkali metal salts thereof.