JP5132095B2 - Emulsion dosage form for external use on skin - Google Patents

Description

  The present invention relates to a skin external preparation, and more particularly, to a skin external preparation suitable for stably retaining a resorcinol derivative having a cyclic or branched alkyl group at the 4-position having a whitening effect and / or a salt thereof.

  4-Alkylresorcinols having an alkyl group introduced at the 4-position have an excellent inhibitory effect on melanin production, and 4-n-butylresorcinol has already been used in cosmetics as an active ingredient of quasi drugs. ing. In order to improve the transdermal absorbability of this product, an attempt was made to convert the alkyl group at the 4-position, and 4-cyclopentylresorcinol, 4-cyclohexylresorcinol (for example, Patent Document 1, Patent Document 2, Patent Document 3). Resorcinol derivatives having a branched alkyl group such as 4- (1-methylpropyl) resorcinol and 4- (1-methylbutyl) resorcinol have been developed (for example, patent documents) 4, see Patent Document 5). These compounds are expected to be useful active ingredients with improved transdermal absorbability, although their melanin production-suppressing action is reduced, but the stability in the preparation is impaired compared with that of linear alkyl groups. Therefore, it has been desired to develop a formulation technique that ensures this stability.

  On the other hand, since a water-in-oil emulsion has an oily component in the continuous phase, it has higher moisturizing properties due to the blocking effect and superior percutaneous absorbability of the oily active ingredient compared to an oil-in-water emulsion. doing. On the other hand, as a feeling of use, it has an oily and heavy defect. As a method of overcoming these disadvantages and taking advantage of the advantages of water-in-oil emulsions, various attempts have been made to produce high-in-water water-in-oil emulsions, and organic modifications such as dimethyl distearyl ammonium chloride-modified hectorite. Techniques for producing high-in-water water-in-oil emulsions using clay minerals have been developed (see, for example, Patent Document 6, Patent Document 7, and Patent Document 8). However, there is no known technique for blending such a high internal phase oil-in-water emulsifier with a resorcinol derivative having a cyclic or branched alkyl group at the 4-position and / or a salt thereof. In the dosage form, it has not been known at all that the resorcinol derivative having a cyclic or branched alkyl group at the 4-position and / or the stability thereof is improved.

JP 2005-527534 Gazette JP 2005-526093 A Japanese Patent Laid-Open No. 11-152203 JP 2006-124358 A JP 2006-124357 A JP 2005-255623 A JP 2004-292373 A JP 2001-58937 A Lille, J .; Bitter, L. A .; Peiner, V. Trudy-Nauchono-Issledovatel 'skii Institut Slantsev (1969), No. 18, 127-34

  The present invention has been made under such circumstances, and an object of the present invention is to provide a dosage form that improves the stability of a resorcinol derivative having a cyclic or branched alkyl group at the 4-position.

In view of such a situation, the present inventors sought for a dosage form that improves the stability of a resorcinol derivative having a cyclic or branched alkyl group at the 4-position, and as a result of earnest research efforts, It was found that the water-in-oil emulsifier form of minerals has such characteristics, and the invention has been completed. That is, the present invention is as follows.
(1) A skin external preparation in the form of a water- in- oil emulsifier comprising 1) a resorcinol derivative having a cyclic or branched alkyl group at the 4-position and / or a salt thereof; and 2) an organically modified clay mineral. .
(2) The external preparation for skin according to (1), wherein the resorcinol derivative having cyclic or branched alkyl at the 4-position is 4-cyclohexylresorcinol.
(3) The skin external preparation according to (1) or (2), wherein the organically modified clay mineral is an organically modified hectorite.
( 4 ) The skin external preparation according to any one of (1) to ( 3 ), further comprising an ultraviolet absorber.

  According to the present invention, it is possible to provide a dosage form that improves the stability of a resorcinol derivative having a cyclic or branched alkyl group at the 4-position.

(1) Organically modified clay mineral 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 an organically modified clay mineral as an essential component. Here, organic modification means that a part or all of the properties of an organic compound is made into a clay mineral by causing a part of the organic compound to form a strong or loose bond via a covalent bond or an ionic bond. This means that it is imparted to minerals. Examples of such modifications include a method of binding a quaternary amine group and an anion portion of a clay mineral, and a method of binding a carboxyl group and a cation portion of a clay mineral. A method of combining the group and the anion portion of the clay mineral is particularly preferable.

  Although it does not necessarily limit as a compound which has a quaternary amino group which modifies a clay mineral, The compound called quaternium is illustrated. Quotanium is a low molecular weight substituted quaternary ammonium salt, and is preferably a cosmetic raw material registered in International Standard Cosmetic Ingredients (INCI). Furthermore, the compound having a quaternary amino group that modifies the clay mineral is preferably a quaternium compound contained in a conventional external skin preparation among quaternium compounds. Preferred examples of the quaternium compound used in conventional external preparations for skin include stearyl trimethyl ammonium chloride and dimethyl distearyl ammonium chloride. Stearyl trimethyl ammonium chloride, dimethyl distearyl ammonium chloride and the like are preferable because they can form a stable water-in-oil emulsion structure together with clay minerals.

  On the other hand, as a clay mineral (unmodified clay mineral) modified with a compound having a quaternary amino group, any clay mineral contained in a conventional external preparation for skin can be used without particular limitation. Preferred clay minerals contained in conventional skin external preparations include smectite-type hectorite, bentonite and montmorillonite; kaolinite; illite; marine clay mineral (sea mud); desert rose clay mineral; Among these, bentonite, hectorite, montmorillonite or kaolinite which can stabilize the water-in-oil emulsion structure is preferably exemplified.

An example of a method for producing a clay mineral modified with a compound having a quaternary amino group contained in the external preparation for skin of the present invention will be described below.
The unmodified clay mineral is dispersed in a dispersion medium. The dispersant is preferably an aqueous solvent, and may be water. A compound having a quaternary amino group is further added to the dispersion containing the dispersed unmodified clay mineral and stirred well. The compound having a quaternary amino group may be added after being dissolved in water. The amount of the compound having a quaternary amino group to be added is preferably 0.1 to 20% by mass, and more preferably 0.5 to 15% by mass with respect to the amount of the dispersed unmodified clay mineral. This is because by taking such a configuration, a preferable feeling of use is exhibited in the emulsification system. After stirring, the dispersoid is filtered, dehydrated and dried to obtain the modified clay mineral in the present invention. Or the modified clay mineral in this invention can also be obtained by removing a dispersing agent by concentrating under reduced pressure without filtering a dispersoid, and making it dry. The obtained modified clay mineral is preferably pulverized to a desired size (preferably having a particle size of 1 to 1000 μm) and contained in the skin external preparation of the present invention.

  The modified clay mineral in the present invention can be prepared and used as described above, but a commercially available one can also be used. Some modified clay minerals on the market are used as external preparations for skin such as cosmetics. Preferable examples of commercially available modified clay minerals include dimethyl distearyl ammonium modified hectorite sold under the name “Benton 38V” by Elementis.

  In the skin external preparation of this invention, this component is contained preferably 0.5-10 mass%, More preferably, 1-5 mass% is contained. Such an ingredient acts as an emulsifier in the above-mentioned content range to form a high internal phase water-in-oil emulsifier form.

(2) A resorcinol derivative having a cyclic or branched alkyl group at the 4-position, which is an essential component of the external preparation for skin of the present invention, a resorcinol derivative having a cyclic or branched alkyl group at the 4-position and / or Or the salt is contained as an essential component, It is characterized by the above-mentioned. Examples of such resorcinol derivatives include 4-cyclopentylresorcinol, 4-cyclohexylresorcinol, 4-isooctylresorcinol, 4-amylresorcinol, 4-isoamylresorcinol, 4-isobutylresorcinol, 4-tarsha Libutylresorcinol, 4- (1-methylpropyl) resorcinol, 4- (1-methylbutyl) resorcinol, 4- (1-ethylpropyl) resorcinol, 4- (1-ethyl-2-methylpropyl) resorcinol, 4- (1-isopropyl-2-methylpropyl) resorcinol, 4- (1-dimethyl-3-methylbutyl) resorcinol, 4- (1-butylpentyl) resorcinol, 4- (1-isobutyl-3-methylbutyl) resorcinol, 4-i Resorcinol derivatives having a cyclic or branched alkyl group having 3 to 20 carbon atoms such as stearyl resorcinol in 4-position can be suitably exemplified. Among these, preferred are those having a cyclic alkyl group, preferably 4-cyclopropylresorcinol having low toxicity, and those having a branched alkyl group are those having a good balance between effect and toxicity. 1-methylpropyl) resorcinol or 4- (1-methylbutyl) resorcinol is preferred. In terms of the remarkable effect of the present invention, 4- (1-ethylpropyl) resorcinol or 4- (1-isopropyl-2-methylpropyl) resorcinol is preferable because significant stability improvement can be obtained. A method for producing such 4-alkylresorcinol and / or a salt thereof is already known. (See, for example, Lille, J .; Bitter, LA; Peiner, V. Trudy-Nauchono-Issledovatel 'skii Institut Slantsev (1969), No. 18, 127-34) That is, resorcin and the corresponding carboxylic acid are zinc chloride And a method of condensing with resorcinol and the corresponding alcohol at a high temperature of 200 to 400 ° C. For example, if an isooctyl group or an isostearyl group is to be introduced, resorcin and isooctanoic acid or isostearic acid may be condensed in the presence of zinc chloride, cyclopentyl alcohol, cyclohexyl alcohol, 2-ethylhexanol, isoamyl alcohol, amyl When alcohol, isobutyl alcohol, and tertiary butyl alcohol are condensed with resorcin at 200 to 300 ° C., 4-cyclopentylresorcinol, 4-cyclohexylresorcinol, 4-isooctylresorcinol, 4-amylresorcinol, 4-isoamyl Resorcinol, 4-isobutylresorcinol, 4-tertiarybutylresorcinol, etc. are obtained. Further, when an alkyl group having a methyl group at the 1-position is introduced, the methods described in Patent Document 4 and Patent Document 5 may be followed, and acetophenone can be reacted with a Grignard reagent derived from propyl chloride or butyl chloride. For example, 4- (1-methylpropyl) resorcinol, 4- (1-methylbutyl) resorcinol, and 4-isostearylresorcinol are obtained. Similarly, when an ethyl group is introduced at the 1-position, the desired derivative can be obtained by catalytic reduction of 2 ′, 4′-dihydroxypropiophenone as a starting material and the remaining hydroxyl group using palladium as a catalyst. This method is also described in Patent Document 5. The introduction of another alkyl group having a branch at the 1-position can also be obtained by conducting a Grignard reaction using 4-isobutyrylresorcinol or the like as a starting material, and if necessary, a catalytic reduction reaction using palladium as a catalyst.

  In the external preparation for skin of the present invention, such a 4-substituted alkylresorcinol can be contained in the form of a salt. These salts can be used without any particular limitation as long as they are used in skin external preparations, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts. Preferred examples include organic amine salts such as ammonium salt, triethylamine salt, triethanolamine salt, and monoethanolamine salt, and basic amino acid salts such as lysine salt and alginate.

  In the external preparation for skin of the present invention, the preferable content of the 4-substituted alkylresorcinol and a salt thereof is not particularly limited as long as it is an amount that exhibits a melanin production inhibitory action, and is a total amount, with respect to the total amount of external skin preparation, It is 0.05-5 mass%, More preferably, it is 0.1-1 mass%.

(3) The skin external preparation of this invention The skin external preparation of this invention contains the said essential component, It is characterized by the above-mentioned. Dosage forms, Ru water-in-oil emulsifier type Der by taking advantage of features of the organic modified clay mineral must be agreed Sunari min. Here, the water-in-oil emulsifier form is defined as a general term for emulsions in which the continuous phase of the outermost phase is the oil phase, and not only the water-in-oil emulsifier form, but oil-in-water emulsified drops are distributed in the oil. It also includes complex emulsions. When incorporated in such a dosage form, the resorcinol derivative having a cyclic or branched alkyl group at the 4-position and / or the salt thereof has the same stability as the resorcinol derivative having a linear alkyl group at the 4-position. To increase.

In order to improve the stability of such a resorcinol derivative having a cyclic or branched alkyl group at the 4-position and / or a salt thereof, it is more preferable that an ultraviolet absorbent coexist in the external preparation for skin of the present invention. Examples of such UV absorbers, for example, Pas Raamino benzoic acid (hereinafter, abbreviated as PABA), PABA monoglycerol ester, N, N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester, N, N- Benzoic acid UV absorbers such as dimethyl PABA ethyl ester, N, N-dimethyl PABA butyl ester, N, N-dimethyl PABA methyl ester, anthranilic acid UV absorbers such as homomenthyl-N-acetylanthranilate, amyl salicylate Salicylic acid UV absorbers such as menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate, octylcinnamate, ethyl-4-isopropyl Pilcinnamate, methyl-2,5-diisopropylcinnamate, ethyl-2,4-diisopropylcinnamate, methyl-2,4-diisopropylcinnamate, propyl-p-methoxycinnamate, isopropyl-p-methoxycinnamate, Isoamyl-p-methoxycinnamate, octyl-p-methoxycinnamate (2-ethylhexyl-p-methoxycinnamate), 2-ethoxyethyl-p-methoxycinnamate, cyclohexyl-p-methoxycinnamate, ethyl-α- Cyano-β-phenylcinnamate, 2-ethylhexyl-α-cyano-β-phenylcinnamate, glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamate, methyl bis (trimethylsiloxane) silyl trimethoxycinnamate Cinnamic acid UV absorbers such as sopentyl, 3- (4′-methylbenzylidene) -d, 1-camphor, 3-benzylidene-d, 1-camphor, urocanic acid, urocanic acid ethyl ester, 2-phenyl-5 Methylbenzoxazole, 2,2′-hydroxy-5-methylphenylbenzotriazole, 2- (2′-hydroxy-5′-t-octylphenyl) benzotriazole, 2- (2′-hydroxy-5′-methyl) Phenylbenzotriazole, dibenzalazine, dianisoylmethane, 4-methoxy-4'-t-butyldibenzoylmethane, 5- (3,3-dimethyl-2-norbornylidene) -3-pentan-2-one, 2-cyano- Examples include 2-ethylhexyl 3,3-diphenyl acrylate, etc. Particularly preferable is 4- (t-butyl). ) -4-Methoxydibenzoylmethane. The preferable content of such an ultraviolet absorber is 0.1 to 5% by mass.

The external preparation for skin of the present invention can contain, in addition to such components, optional components that are usually used in external preparations for skin. Examples of such optional ingredients include 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, and hardened coconut oil. Oil, wax, oils such as beeswax, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax; , 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 Linear polysiloxanes such as oxane and diphenylpolysiloxane; cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and 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; Anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether of alkyl sulfates; Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyltaurine; sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (eg, glyceryl monostearate), propylene glycol fatty acid esters (eg, propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid ester Tells (POE-glycerol monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl) Ethers, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), Nonionic surfactants such as sucrose fatty acid ester and alkyl glucoside; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene Polyhydric alcohols such as recall, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol; sodium pyrrolidonecarboxylate Moisturizing ingredients such as lactic acid and sodium lactate; powders such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate, etc. whose surface may be treated Body, the surface may be treated, inorganic pigments such as bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide; surface may be treated, mica Pearl agents such as titanium, fish phosphorus foil, bismuth oxychloride; red 202 which may be raked, red Color 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 No., green 201, purple 201, red 204, etc .; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; lower alcohols such as ethanol and isopropanol; Vitamin A such as vitamin A or a derivative thereof, vitamin B ₆ hydrochloride, vitamin B ₆ tripalmitate, vitamin B ₆ dioctanoate, vitamin B ₂ or a derivative thereof, vitamin B ₁₂ , vitamin B ₁₅ or a derivative thereof; α-tocopherol , Β-tocopherol, γ-tocopherol, vitamin E such as vitamin E acetate, Min D, vitamin H, pantothenic acid, pantethine, vitamins etc. pyrroloquinoline quinone and the like; and antibacterial agents such as phenoxyethanol preferred examples.

The external preparation for skin of the present invention can be produced by treating the above components according to a conventional method. The external preparation for skin of the present invention produced as described above is applied to cosmetics including quasi-drugs, external preparations for skin or general items for external use, but 4 - alkyl-substituted resorcinol and / or a salt thereof. It is particularly preferred to be applied to cosmetics that can easily utilize the excellent melanin production inhibitory action.

  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.

<Reference example>
The stability of aqueous solutions of resorcinol derivatives in which the 4-position hydrogen atom was substituted with an alkyl group was compared. That is, 0.5% aqueous solutions of various 4-alkylresorcinols were prepared, stored at 40 ° C. for 1 month, and 4-alkylresorcinol was quantified by HPLC. HPLC conditions were as follows: Column: ODS 4.6 mm × 150 mm, column temperature: 40 ° C., detection: absorption at 230 nm in ultraviolet region, mobile phase: 25% acetonitrile in 15 mM tetrabutylammonium bromide , added 15 mM phosphate buffer (pH 6.5) The flow rate was 1 ml / min. The quantitative value after storage was divided by the quantitative value immediately after production, and a value obtained by multiplying by 100 was obtained as the residual rate. The results are shown in Table 1. From this, it is understood that when a branched alkyl group or a cyclic alkyl group is employed as the alkyl group, the stability is lowered.

Based on the above stability data, a formulation study was conducted to improve the stability. As water-in-oil emulsion formulations, emulsifiers form an organic modified hectorite (Formulation 1: Table 2), emulsifier type using polyglycerol fatty acid ester (formulation 2: Table 3) and oil in water emulsifier type (Formulation 3: Table 4 ) And stored at 40 ° C. for 1 month, and the residual rate was similarly determined. The results are shown in Table 5. From this, a very good residual rate was shown in the water-in-oil emulsifier form using organically modified hectorite.

<Production Method of Formulation 1>
The ingredients of (a) and (b) are heated to 80 ° C. and kneaded to form a gel. C is added to dissolve in this, and the mixture is gradually added with emulsification with stirring and emulsified, followed by cooling with stirring. .

<Production Method of Formulation 2>
The components of (a) were kneaded well to form a white gel, and after adding and diluting to this, the temperature was adjusted to 80 ° C., and the components of (c) that had been adjusted to 80 ° C. in advance were stirred. Slowly add, add ni and immediately cool with stirring.

<Production Method of Formulation 3>
Warm each of the components (a), (b) and (c) at 80 ° C., gradually add (b) to emulsify the mixture while stirring, further add (c) to neutralize while continuing to stir, add (d) and immediately cool with stirring.

  In the same manner as Preparation 1, Preparations 4 to 13 in the form of a water-in-oil emulsifier were prepared according to the following formulation. These were stored at 40 ° C. for 1 month, and the residual rate was determined. The results are shown in Table 7. From this, it can be seen that the same effect as in the preparation 1 is observed.

  A preparation 14 was prepared according to the following prescription in the same manner as the preparation 1, and stored at 40 ° C. for 1 month. The residual rate was determined to be 97.1%. From this, it is understood that it is preferable that the ultraviolet absorber coexists.

  The present invention can be applied to external preparations for skin such as cosmetics.

Claims (4)

1. A skin external preparation in the form of a water- in- oil emulsifier comprising 1) a resorcinol derivative having a cyclic or branched alkyl group at the 4-position and / or a salt thereof; and 2) an organically modified clay mineral. The external preparation for skin according to claim 1, wherein the resorcinol derivative having cyclic or branched alkyl at the 4-position is 4-cyclohexylresorcinol. The skin external preparation according to claim 1 or 2, wherein the organically modified clay mineral is an organically modified hectorite. Furthermore, the skin external preparation of any one of Claims 1-3 characterized by containing a ultraviolet absorber.