KR20060111186A - External agent for the skin - Google Patents

Abstract

An external agent for the skin is provided to improve use feeling, reduce sticky feeling, moisturize the skin, improve the coarseness of the skin, and promote skin penetration of humectant. The external agent for the skin contains one spiculisporic acid derivative selected from ester of spiculisporic acid and polyhydroxy compound or its salt, or ester of 3-hydroxy-1,3,4-tetradecane tricarboxylic acid that is prepared by opening the ring of spiculisporic acid and polyhydroxy compound or its salt, wherein the polyhydroxy compound is one selected from glycerin, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, octaglycerin, nonaglycerin and decaglycerin, one saccharide selected from inositol, lactose, sucrose, glucose, fructose, xylitol, mannitol, maltitol, sorbitol and pentaerythritol, or one glycol selected from ethylene glycol, propyleneglycol, 1,3-butyleneglycol, 1,4-butyleneglycol and hexyleneglycol; and the amount of spiculisporic acid derivative is 0.01-70 wt.%. The skin external composition for promoting the transdermal absorption of hydrophilic drugs comprises the spiculisporic acid and the hydrophilic drugs, wherein the hydrophilic drug is humectant such as glycerin.

Description

Skin external preparations {EXTERNAL AGENT FOR THE SKIN}

The present invention relates to esters of 4,5-dicarboxy-4-pentadecanoide (hereinafter referred to as "spiculisporic acid") with polyhydroxy compounds and their salts as external skin preparations, especially as active ingredients. And an external preparation for skin comprising an ester of 3-hydroxy-1,3,4-tetradecane tricarboxylic acid and a polyhydroxy compound which is ring-opened spiculispolic acid, and a spiculispolic acid derivative which is a salt thereof will be.

In order to maintain healthy skin, the maintenance of moisture is indispensable, and many external skin preparations for the purpose of moisturizing have been developed. In addition, as a feeling of use of the external preparation for skin, there is a demand for smoothness and no sticky feeling.

Studies on moisturizing agents are actively conducted, for example, glycerin, which is used for various purposes such as a lotion or an emulsion. The glycerin has the effect of improving the roughness of the skin in addition to the moisturizing effect.

However, the glycerin must be increased in order to exhibit a moisturizing effect and an improvement on skin roughening, and as a result, the emulsification system becomes unstable, poor in usability, or dried by sebum when applied to the skin. There are problems such as poor familiarity with the skin.

As moisturizers other than glycerin, polyols such as 1,3-butylene glycol, propylene glycol, polyethylene glycol, sorbitol and xylitol are known. However, these polyols have a lower feeling of use, for example, stickiness compared to glycerin, but have a low moisturizing effect or a roughening effect on the skin, and when applied to the skin such as glycerin, it is dried by sebum. There are problems such as poor familiarity with the skin.

On the other hand, Japanese Patent Laid-Open No. 10-259112 discloses (poly) ethylene glycol dialkyl ether having a good feeling and having a skin care effect. However, the (poly) ethylene glycol dialkyl ether is an oil-based base, and can exhibit an effect of barrier function and suppression of transdermal moisture loss by forming a hydrophobic coating as oil, but having low water solubility and having a function as a moisturizing agent itself. no.

It is an object of the present invention to provide an external preparation for skin with excellent moisturizing effect and an effect of improving skin roughness.

The present invention relates to esters of 4,5-dicarboxy-4-pentadecanoide (I) represented by the following general formula (1) with a polyhydroxy compound and salts thereof, or 3-hydroxy ring-opened spiculic acid; It is an external preparation for skin comprising at least one component of -1,3,4-tetradecane tricarboxylic acid (II) and a polyhydroxy compound and its spiculic acid derivative.

In addition to the moisturizing effect and the effect of improving the roughness of the skin, the spiculosporic acid derivative has a stickiness improving effect and a percutaneous absorption promoting effect.

When the specific topical spiculispolic acid derivative is blended into the external preparation for skin, there is no feeling of use, particularly smoothness and no stickiness, and at the same time, it has an effect of improving the moisturizing effect and roughening of the skin. In addition, when used together with a moisturizing agent such as glycerin, the spiculosporic acid derivative is further promoted percutaneous absorption of the moisturizing agent, which significantly improves the moisturizing effect and the roughening of the skin, and also improves the stickiness due to the moisturizing agent . It has been found that the sculisporic acid derivatives exhibit a transdermal absorption promoting effect corresponding to a whitening agent such as arbutin, thus completing the present invention.

In the present invention, the external skin agent is characterized in that it contains a spiculosporic acid derivative.

In one embodiment of the external preparation of the present invention, it is particularly preferable to blend 0.01 to 70% by weight of the above-mentioned spiculispolic acid derivative.

In one embodiment, the moisturizing agent in the present invention comprises the above spiculispolic acid derivatives.

In one embodiment, the improving agent for skin roughness in the present invention comprises the above spiculic acid.

In one embodiment, the stickiness improving agent in the present invention comprises the above spiculic acid.

In one embodiment, the percutaneous absorption enhancer in the present invention comprises the above spiculispolic acid derivative.

In addition, the topical skin preparation of the present invention includes the above spiculosporic acid derivative and a hydrophilic agent, while the spiculosporic acid derivative is a transdermal absorption accelerator of a hydrophilic drug.

In one embodiment, it is preferred that the hydrophilic agent is a moisturizing agent, and more preferably the moisturizing agent is glycerin.

In one embodiment, it is particularly preferred that the hydrophilic agent is at least one selected from hydroquinone derivatives or ascorbic acid derivatives.

In one embodiment, the transdermal absorption control agent in the present invention comprises the above-mentioned sculispolic acid derivative.

According to the present invention, it is preferable that 1 mole or 2 moles of glycerin and diglycerin are esterified as a polyhydroxy compound with respect to 1 mole of spiculic acid, and the spiculic acid poly represented by the following formula (2) Monoglycerol monospirulic phosphate (I), monodiglycerol monospirulic phosphate (II) which is a hydroxy ester, monoglycerol dispirulic phosphate (III), or monodiglycerol dispirulic formate (VI) And the external preparation for skin containing the salt thereof.

Characterized spiculisporic acid in the present invention is a penicillium spiculisporium by microbial reactions based on glucose ( Penicillium spiculisporium , As a metabolite of ATCC 16071), it is a mass-produced substance in high yield, and is excellent in safety and biodegradability, and is a substance having various interfacial properties by moderately neutralizing it from a polybasic acid type surfactant. The 3-hydroxy-1,3,4-tetradecane tricarboxylic acid of the present invention is a substance which can be obtained by neutralizing with an acid after adding excess sodium hydroxide to the above spiculosic acid and warming it.

In the present invention, the polyhydroxy compound is a polyhydric alcohol having two or more hydroxyl groups in the molecule. Polyglycerols including glycerin, diglycerine, triglycerine and the like, preferably glycerin having 3 to 30 carbon atoms; Or inositol, lactose, sucrose, glucose, fructose, fructose, xylitol, mannitol, maltitol, sorbitol, pentaerythritol sugars, including (pentaerythritol); And glycols containing ethylene glycol, propylene glycol, 1, 3- butylene glycol, 1, 4- butylene glycol, hexylene glycol, etc. can be illustrated.

The spiculosporic acid derivative of the present invention can be produced by a known method. For example, spicrycryspric acid or 3-hydroxy-1,3,4-tetradecane tricarboxylic acid and a polyhydroxy compound are introduced into the reactor at an arbitrary ratio, and the reaction temperature is 110 ° C to 170 ° C and the reaction pressure. It can obtain by making it react under reduced pressure or normal pressure of 50 mmHg or less. Although there is no limitation on the number of moles of reaction in esterification of spiculosic acid or 3-hydroxy-1,3,4-tetradecane tricarboxylic acid with a polyhydroxy compound, Preferably it is polyhydroxy compound 1 To moles are 1 mole or 2 moles of spiculosic acid or 3-hydroxy-1,3,4-tetradecane tricarboxylic acid. You may use a spiculispolic acid derivative in combination of 2 or more type.

In the external preparation for skin of the present invention, the blending amount of the spiculosporic acid derivative is not particularly limited, but is usually about 0.01 to 70% by weight, preferably about 0.5 to 40% by weight. When it is less than 0.01 weight%, the expression of the effect by mixing may not be enough, and when it exceeds 70 weight%, you may feel stickiness after use.

In the present invention, when used in combination with an external preparation for skin, the spiculosporic acid derivative exhibits a moisturizing effect and an effect of improving roughness of the skin. Moreover, when mix | blending other moisturizing agents, such as glycerin, the effect which suppresses stickiness was confirmed. Examples of the moisturizing agent are glycerin, 1,3-butylene glycol, polyethylene glycol, propylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfuric acid, hyaluronic acid, hycouronic acid sulfate, caronine Tricholic acid, Athero collagen, cholesteryl 12-hydroxystearate, sodium lactate, bile acid salt, dl-fatiro Lidon carbonate (di-pyrrolidone carboxylate), short-chain soluble collagen, diglycerol (EO) PO adduct, etc. are mentioned.

In the present invention, the spiculosporic acid derivative also has an effect of promoting keratin permeability of other moisturizing agents. Therefore, by using the spiculosporic acid derivative and other moisturizers together in the external skin preparation, it is possible to obtain an extremely high moisturizing effect and skin roughening improvement effect by the synergistic effect. Examples of such moisturizing agents include those described above, but glycerin is particularly preferred.

Although the compounding quantity of a moisturizer is not specifically limited, Preferably it is 0.001-20.00 weight% in skin external preparations, More preferably, it is 0.1-10.0 weight%.

In addition, in the present invention, the spiculosporic acid derivative also has an action of promoting keratin permeability against hydrophilic agents other than moisturizers, for example, whitening agents such as arbutin.

The skin external preparation of this invention is adjusted by mix | blending said essential component with an existing skin external preparation base. The external skin preparations of the present invention include surfactants, oils, polyhydric alcohols, lower alcohols, thickeners, and the like, which are usually used as external preparations for skin, such as cosmetics and pharmaceuticals, in addition to the essential components described above, as necessary without impairing the effects of the present invention. It can be mix | blended suitably with the cosmetics comprised from a ultraviolet absorber, a scattering agent, an antibacterial preservative, antioxidant, a chelating agent, an organic acid, a chemical | medical agent, a natural extract, a pH adjuster, a fragrance | flavor, a pigment | dye, and water.

Specific examples of such components are as follows.

As surfactant, Polyoxyethylene alkyl ether, such as polyoxyethylene octyl dodecyl alcohol, polyoxyethylene-2-decyl tetradecyl ether, polyoxyethylene oleyl ether, polyoxyethylene cetyl ether; Sorbitan esters such as sorbitan monooleate, sorbitan monoisostearate and sorbitan monolaurate; Polyoxyethylene sorbitan esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monoisostearate and polyoxyethylene sorbitan monolaurate; Glycerin fatty acid esters such as glycerin monooleate, glycerin monostearate and glycerin monomyristate; Polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glycerin monooleate, polyoxyethylene glycerin monostearate, polyoxyethylene glycerin monomyristate and the like; Polyoxyethylene cured castor oil fatty acid esters such as polyoxyethylene dihydrocholester ester, polyoxyethylene cured castor oil and polyoxyethylene cured castor oil isostearate; Polyoxyethylene alkyl aryl ethers such as polyoxyethylene octylphenyl ether; Glycerin alkyl ethers such as monoisostearyl glyceryl ether and monomyristyl glyceryl ether; Polyoxyethylene glycerin alkyl ethers such as polyoxyethylene monostealylglyceryl ether and polyoxyethylene monomyristyl glyceryl ether; Nonionic surfactants such as polyglycerol fatty acid esters such as diglyceryl monostearate, decaglyceryl decastearate, decaglyceryl decaistearate, and diglyceryl diisostearate; And salts such as potassium, sodium, diethanol amine, triethanol amine, and amino acids of higher fatty acids such as myristic acid, stearic acid, palmitic acid, behenic acid, iso stearic acid and oleic acid, the alkali salts of ethercarboxylic acids, N-acyl amino acids Anionic surfactants such as salts, N-acyl salconates and higher alkyl sulfonates; And cationic surfactants such as alkyl amine salts, polyamines, amino alcohol fatty acid organic silicone resins, and alkyl quaternary ammonium salts, or amphoteric surfactants such as lecithin and betaine derivatives.

Macadamia nut oil, corn oil, rapeseed oil, sunflower seed oil, castor oil, olive oil, cacao oil Cocoa oil, Camellia oil, Palm oil, Jojoba oil, Grape seed oil, Avocado oil, Rice bran oil, Evening primrose oil, soy bean oil, cotton seed oil, sesame oil, sesame oil, safflower oil, palm oil, perilla herb oil, shea butter Fats and oils; Animal fats and oils, such as mink oil and egg yolk oil; Rows such as Beeswax, Spermaceti, Lanolin, Carnauba wax, and Candelilla wax; Hydrocarbons such as liquid paraffin, squalene, microcrystalline wax, ceresin wax, paraffin wax, and petrolatum; Natural and synthetic fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, oleic acid, linolenic acid, linoleic acid, hydroxystearic acid, etc. Ryu; Natural and higher alcohols such as cetanol, stearyl alcohol, hexasildecanol, octyldecanol, and lauryl alcohol; And esters such as isopropyl myristic acid, isopropyl palmitic acid, isopropyl stearic acid, octyl dodecyl myristic acid, octyl dodecyl oleic acid, 2-ethyl hexanoic acid glycerol and cholesterol oleate.

As a polyhydric alcohol, Polyglycerol, such as ethylene glycol, polyethylene glycol, propylene glycol, 1, 3- butylene glycol, 1, 4- butylene glycol, dipropylene glycol, glycerin, diglycerol, triglycerol, tetraglycerine; Glucose, maltose, maltitose, sucrose, fructose, xylitol, sorbitol, maltotriose, erythritol, and the like; Polar oils such as diethylene glycol monopropyl ether, polyoxyethylene polyoxypropylene pentaerythritol ether, polyoxypropylene butyl ether and ethyl linoleate; And other silicone oils.

Thickeners include sodium alginate, Xantan Gum, aluminum silicate, Quince seed Gum, Arabic Gum, Tragacanth Gum, starch, collagen, sodium hyaluronate Natural polymer materials such as; Semisynthetic polymer materials such as methyl cellulose, hydroxy ethyl cellulose, carboxymethyl cellulose, soluble starch, cationic cellulose; And synthetic polymer materials such as carboxyvinyl polymer and polyvinyl alcohol.

Ultraviolet absorbers include p-aminobenzoic acid, isopropyl p-methoxycinnamate, butyl methoxy benzoyl methane and glyceryl mono 2-ethylhexanoyl-di-paramethoxy benzo Phenone (Glyceryl 2-ethylhexyl Di-p-benzophenone), Digaloyl trioleate, 2,2'-hydroxy-methoxybenzophenone (2,2'-Hydroxy-4-methoxybenzophenone ), Ethyl 4-bishydroxypropylaminobenzoate (Ethyl 4- [N, N-di (2-hydroxypropyl) amino] benzoate), 2-ethylhexyl-2-cyano 3,3'-diphenyl acryl Ethyl Hexyl, 2-Ethylhexyl Salicylate, Glyceryl Paraaminobenzoate, Homomenthyl Salicylate, Methyl Ortho-Aminobenzoate, 2-Hydrate Roxy-4-methoxybenzophenone, amirparadimethylaminobenzo And 2-phenylbenzoimidazole 5-sulfonic acid, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, and the like.

Antibacterial and preservatives include Benzoate, Salicylate, Sorbate, Dehydroacetate, Parahydroxy Benzoate, 2,4,4'-trichloro- 2'-hydroxy diphenyl ether, 3,4,4'-trichlorocarbanilide (3,4,4'-Trichlorocarbanilide), benzalkonium chloride, hinokitiol, resorcinol, Ethanol and the like.

Antioxidants include tocopherol, butylhydroxyanisole, dibutyl hydroxy toluene, nordihydroguaiaretic acid, propy gallate, and phytic acid. have.

Examples of the chelating agent include sodium edetate, sodium citrate, and the like.

Organic acids include N-Acyl sarcosinate (e.g. sodium laurylylmethyl sacosinate), glutathione, citric acid, malic acid, malic acid, tartaric acid, lactic acid (Lactic acid) etc. are mentioned.

Nicotinamide, Benzyl nicotinate, γ-Oryzanol, Allantoin, Glycyrrhizinate, Glycyrrhezinic acid ) And derivatives thereof, Bisabolol, Eucarlyptol, Thymol, Inositol, Saponin (Carrot saponin, Sponge gourd saponin, Mukurossi saponin, Pantothenyl ethyl ether, Ethynylestradiol, Tranexamic acid, Sepharanine, etc. are mentioned.

Natural extracts include Rumex japonicus Houtt. , Ginseng Sophora flavescens , Nuphar, Orange, Sage, Yarrow, Mallow flowers, Cnidium officinale , Gentiana scabra var.buergeri, thyme , Angelica acutiloba Kitagawa , Bitter Orange Peel , Bach ( Allantoin ), Horsetail , Sponge Gourd et al, Horse Chestnut , beomuigwi (Saxifrage), arnica (mountain tobacco), lily (lily), mugwort (mugwort), peony root (peony Root), aloe (Aloe), gardenia (gardenia), painter tree (Chamae cyparis pisifera) an organic solvent, etc. Extracts extracted with alcohol, polyhydric alcohol, water, aqueous alcohol, and the like.

In addition, it can be suitably formulated into cosmetics composed of absorbent powders such as starch obtained from corn, potato, etc., silicic anhydride, talc, kaolin, magnesium aluminum silicate, calcium alginate, and porous pigments.

In addition, the whitening skin external preparation of the present invention is applied to skin such as cosmetics, quasi-drugs, as well as cosmetics such as makeup cosmetics such as foundation, eyeliner and bathing cosmetics, as well as basic cosmetics such as lotion, emulsion, cream and pack. It can include everything.

Thus, the formulations are also based on aqueous solutions, solubilizing systems (e.g., lotions), emulsifying systems (e.g., emulsions, creams, etc.), powder dispersion systems, emulsion systems, gels, ointments, water-oil two-layer systems, water -It can take a wide range such as an oil-powder three-step.

Hereinafter, although an Example and an experimental example are demonstrated in this invention, the scope of the present invention is not limited to such an Example and an experimental example.

In this invention, conductance was evaluated about each 10% aqueous solution of various moisturizing agents. The evaluation method is as follows.

The skin conductance before and after application | coating 30 minutes, 60 minutes, and 120 minutes was measured using the forearm part of 10 panelists, and the moisturizing effect was evaluated from this change rate. Usually, the change rate of skin conductance is calculated | required by the following formula (1), and it is possible to examine the influence on the water absorption of water each layer, and water retention. If this rate of change is small, it can be said that there is an increase in moisture in each layer and the moisturizing effect is high.

Conductance change rate = (conductance before application) / (conductance after application)

The evaluation criteria of "the test by conductance measurement" are as follows.

◎: Average of conductance change rate of ten panels: 0 or more and less than 0.1

○: Average of conductance change rate of ten panels: 0.1 or more and less than 0.2

(Triangle | delta): The average of the conductance change rates of ten panels: 0.2 or more and less than 0.5

X: Average of conductance change rate of ten panels: 0.5 or more

compound  30 minutes later 60 minutes later 120 minutes later Purified water △ × × glycerin ◎ ○ ○ 1,3-butylene glycol △ △ △ Spiculisporic acid △ △ × Monoglycerol monospiculosporate ◎ ◎ ◎ Monodiglycerol monospiculosporate ◎ ◎ ◎ Monoglycerol Dispicules Forate ◎ ◎ ◎ Monodiglycerol disiculfosforate ◎ ◎ ◎

From the results shown in Table 1, it was evident that the spiculosporic acid derivatives were excellent in moisturizing properties as compared with general moisturizing agents such as glycerin or 1,3-butylene glycol.

Next, the spiculosporic acid derivative was adjusted, and the evaluation as an external preparation for skin was performed using the basic composition for a test as follows.

Examples 1-4 (production of a skin external preparation)

The external preparation for skin of the composition shown in following Table 2 (active-weight-% display, 100% of total amount) was prepared by the general method, and sensory evaluation was carried out by ten expert panelists. The evaluation method is as follows.

(a) skin smoothness

The actual use test was done about the smoothness of the skin during use and after use.

Evaluation criteria are as follows.

◎: 8 or more professional panelists say that the skin is smooth during and after use.

(Circle): 6 or more and less than 8 professional panelists say that skin is smooth during use and after use.

(Triangle | delta): Three or more professional panelists say that skin is smooth during use and after use.

X: Less than 3 professional panelists say that the skin is smooth during and after use.

(b) no stickiness on the skin

A practical use test was conducted for the absence of stickiness on the skin during use and after use.

Evaluation criteria are as follows.

◎: More than 8 professional panelists say that the skin is not sticky during and after use.

(Circle): It is said that more than 6 and less than 8 expert panelists are non-sticky in use and after use.

(Triangle | delta): It is said that 3 or more and less than 6 professional panelists are non-sticky in use and after use.

X: Less than 3 professional panelists say that the skin is non-sticky during and after use.

(c) moisturizing effect

The actual use test was done about the presence or absence of the moisturizing effect feeling after 120 minutes of use.

Evaluation criteria are as follows.

◎: It is said that more than eight professional panelists have a moisturizing effect.

(Circle): It is said that more than six professional panelists have less than eight people, and there is a moisturizing effect.

(Triangle | delta): It is said that three or more professional panelists have less than six, and there exists a moisturizing effect.

X: Less than three professional panelists seem to have a moisturizing effect.

(d) Skin roughness improvement effect test

The test method applied another lotion to the cheeks of right and left for 1 week, and judged on the next day after the end of the period.

Evaluation criteria are as follows.

(Double-circle): It is said that roughness of skin improves more than 8 professional panelists.

(Circle): It is said that skin roughness improves more than six expert panelists and less than eight.

(Triangle | delta): It is said that skin roughness improves by three or more professional panelists and less than six.

X: It is said that roughness of skin improves in less than three professional panelists.

(e) skin irritation test

The test method performed the obstruction patch for 24 hours in the inner side of a brachi, and computed the average value on the following references | standards after that.

0: No difference is recognized.

1: A little red color is recognized.

2: Red is recognized.

3: Redness and rash are recognized.

Evaluation criteria are as follows.

(Double-circle): Average value of ten professional panelists: More than 0 and less than 0.1

○: Average of 10 professional panelists: More than 0.1 and less than 0.15

(Triangle | delta): Average value of ten professional panelists: More than 0.15 Less than 0.2

X: Average of 10 professional panelists: 0.2 or more

From the results shown in Table 2, the external skin preparations (Examples 1 to 4) of the present invention are excellent in smoothness and non-stickiness compared to the composition of the comparative example, while having excellent effects such as moisturizing effect and skin roughening effect. there was. In other words, spiculosporic acid derivatives and glycerin have a moisturizing effect and skin roughening effect on their own, but in combination with other moisturizers, the moisturizing effect and skin roughening effect are synergistically improved. .

Furthermore, in the present invention, it was found that the spiculosporic acid derivatives have an effect of improving the stickiness seen in moisturizers such as glycerin. That is, the stickiness resulting from glycerin etc. is recognized with respect to the comparative example 1 which does not mix | blend a spiculosporic acid derivative. In addition to this, the addition of spiculosporic acid derivatives not only suppresses the sticky feeling, but also improves the stickiness caused by other moisturizers.

Comparative example Example One 2 One 2 3 4 glycerin 5.0 5.0 5.0 5.0 5.0 5.0 1,3-butylene glycol 5.0 5.0 5.0 5.0 5.0 5.0 Nicotinic acid amide 0.3 0.3 0.3 0.3 0.3 0.3 Pyrrolidone Sodium Carbonate 0.5 0.5 0.5 0.5 0.5 0.5 Spiculisporic acid 5.0 Monoglycerol monospiculosporate 5.0 Monodiglycerol monospiculosporate 5.0 Monoglycerol Dispicules Forate 5.0 Monodiglycerol disiculfosforate 5.0 antiseptic 0.3 0.3 0.3 0.3 0.3 0.3 pH regulator Amount made to pH 6.5 Purified water Remaining amount made to 100% by weight Skin smoothness △ ○ ◎ ◎ ◎ ◎ No stickiness on the skin × ○ ◎ ◎ ◎ ◎ Moisturizing effect △ × ◎ ◎ ◎ ◎ Skin roughness improvement effect test △ △ ◎ ◎ ◎ ◎ Skin irritation test × ○ ◎ ◎ ◎ ◎

Examples 5-8 (Manufacture of external skin preparations)

The external preparation for skin of the composition (active component weight% display, 100% of total amount) shown in following Table 3 was prepared by the general method, and the conductance evaluation and the keratin permeation promoting action test were done.

The test method is as follows.

The test was performed by the tape stripping method. Tape stripping method is a method of obtaining the drug concentration in each layer by peeling each layer with a tape after applying the drug, and is a method generally used as a means of estimating the amount of drug absorption of human skin. Specifically, the permeability of glycerin was examined from the glycerin recovery amount in each layer which was operated by the procedure of the following 1-7 and peeled off with the tape. The test was carried out by five panels and evaluated by the average value.

1. Soap the inside of your forearm.

2. Apply the sample to the inside of the forearm so that it is 20 ml / 20 cm ² .

3. Leave for 4 hours.

4. Soap the inside of your forearm.

5. Strip with 8 layers of each layer tape.

6. Extract glycerin with ion-exchanged water from the tape.

7. Quantify glycerin in HPLC.

As shown in Table 3 below, incorporating the spiculosporic acid derivative (Examples 5 to 8) compared to the control of the spiculosporic acid derivative-free blending (Comparative Example 3), the amount of penetration of glycerin into each layer was increased. have. From the above, it has been suggested that the spiculosporic acid derivatives promote transdermal absorption for moisturizing agents such as glycerin.

Comparative example Example 3 5 6 7 8 glycerin 10.0 10.0 10.0 10.0 10.0 Monoglycerol monospiculosporate 5.0 Monodiglycerol monospiculosporate 5.0 Monoglycerol Dispicules Forate 5.0 Monodiglycerol disiculfosforate 5.0 pH regulator Amount made to pH 6.5 Purified water Remaining amount made to 100% by weight Conductance measurement evaluation × ◎ ◎ ◎ ◎ Glycerin Recovery (μg) 90.5 125.8 115.3 145.6 130.1

Examples 9-12

In addition, the same study was conducted using arbutin (hydroquinone-β-D-glycopyranoside) in order to investigate the effect of the spiculosporic acid derivative on hydrophilic agents other than the moisturizing agent. The test method is in accordance with the test method for promoting keratin penetration promotion. The sample used and the result are shown in Table 4 below.

Comparative example Example 4 9 10 11 12 Arbutin 6.0 6.0 6.0 6.0 6.0 glycerin 10.0 10.0 10.0 10.0 10.0 Monoglycerol monospiculosporate 10.0 Monodiglycerol monospiculosporate 10.0 Monoglycerol Dispicules Forate 10.0 Monodiglycerol disiculfosforate 10.0 pH regulator Amount made to pH 6.5 Purified water Remaining amount made to 100% by weight Arbutin recovery (μg) 0.9 4.2 4.0 4.9 4.7 Glycerin Recovery (μg) 129.9 159.3 156.5 170.2 165.6

As shown in Table 4, compared with the control of the non-spirulic acid derivative combination (Comparative Example 4), the infiltration amount of both arbutin and glycerin increased in each layer when the spirulic acid derivative was blended (Examples 9 to 12). Doing.

From the above, it has been suggested that the spiculosporic acid derivatives promote transdermal absorption even for whitening agents such as arbutin.

Although the functional group exerting the percutaneous absorption promoting effect of the spiculosporic acid derivatives of the present invention is not clear, the spiculosporic acid derivatives of the present invention lower the affinity between hydrophilic agents such as humectants and whitening agents and bases. It is speculated that it is promoting transdermal absorption.

That is, theoretically, the greater the activity in the drug base, the greater the skin penetration rate of the drug. Therefore, in the region below the saturated solubility of the drug, the difference in the value of the solubility parameter between the drug and the agent is widened. It is possible to enlarge distribution to skin by reducing the affinity of.

As a characteristic of the spiculosporic acid derivative of this invention, what has high water solubility and also high fat solubility is mentioned. This dissolution property is derived from the chemical structure of the spiculosic acid derivative. As described above, the aqueous base having both water solubility and fat solubility has a function capable of greatly changing the solubility parameter of the base by blending with the aqueous base, and at the same time, few have excellent performance as a base for external skin preparations.

Therefore, the addition of such spiculosporic acid derivatives to the aqueous base greatly changes the solubility parameter of the base, which significantly lowers the affinity of the base with a hydrophilic agent such as a humectant, and consequently increases the keratin permeability. . Therefore, when a hydrophilic drug, such as a humectant, is water-soluble and penetrates the skin and exerts an effect, for example, a water-soluble vitamin, an amino acid, or a whitening agent, the effect can be expected to be improved. A drug that can be expected to promote transdermal absorption is preferably a high hydrophilic agent, but is not limited thereto. Water / octanol partition coefficient which is a polarity coefficient which is easy to distribute water and water-soluble substances to octanol. When (logP value) is set as one index, 0 or less is effective, and more preferably -1 or less. For example, hydroquinone glycosides and derivatives, ascorbic acid and its derivatives, salicylic acid derivatives, etc. are mentioned as a water-soluble agent of logP value -1.0 or less.

On the other hand, for fat-soluble drugs having relatively high keratin permeability, on the contrary, it is thought that it is possible to suppress transdermal absorption by compounding the spiculosporic acid derivative. For example, if a fat-soluble drug is solubilized or dispersed in an aqueous base, the difference in solubility parameter between the base and the drug is reduced by the addition of the spiculispolic acid derivative, which increases the affinity between the drug and the base, resulting in keratin permeability. Suppressed. Therefore, for fat-soluble drugs such as antiseptics and ultraviolet absorbents, which preferably do not penetrate the skin as much as possible, the suppression of transdermal absorption can be expected by the formulation of spiculispolic acid derivatives. The agent that can be expected to suppress transdermal absorption is not limited to this, but a water / octanol partition coefficient (logP value) of 0.5 or more is effective, and more preferably 1.0 or more. Examples of the fat-soluble agent having a logP value of 1.0 or more include methyl paraben, ethyl paraben, butyl paraben, propyl paraben, phenoxy ethanol, and octyl methoxycinname.

As described above, the spiculosporic acid derivative of the present invention can exhibit transdermal absorption-promoting action against hydrophilic agents such as humectants and whitening agents by blending in an aqueous base. On the other hand, for fat-soluble drugs such as antiseptics and ultraviolet absorbers, transdermal absorption inhibitory effect is expected. In addition, it can be inferred that spiculispolic acid derivatives have an opposite effect in these oily bases. Therefore, the spiculosporic acid derivative of the present invention can function as a transdermal absorption control agent.

The spiculosporic acid derivative of the present invention can adjust its properties by the number and ratio of spiculosporic acid and a polyhydroxy compound, which also has the advantage that the titration can be easily controlled according to the target drug.

Hereinafter, although a very suitable example of the external preparation for skin in this invention is demonstrated, the scope of the present invention is not limited to such an Example.

Example 13 lotion

The composition (active component weight% display, 100% of total amount) shown in following Table 5 was prepared by the general method, and the lotion was obtained. The obtained lotion was excellent in smoothness, and was not sticky, and also the moisturizing effect and skin roughening improvement effect were confirmed.

Furtherance Compounding amount Monoglyceryl Monospiric phosphate glycerin 1,3-butylene glycol Nicotinic acid amide Pyrrolidone sodium carbonate ε-amino caproic acid preservative pH adjuster Purified water 3.0 5.0 5.0 0.3 0.5 0.1 0.2 pH 6.5 Make up 100% by weight

Example 14 Latex

Phase I, the oily component of the following Table 6, was heated to about 75 ° C. to uniformly dissolve, and was heated to 75 ° C. for phase II to uniformly dissolve. Then, the solution of phase I was added and emulsified while stirring with a homo mixer, followed by stirring. It cooled to 40 degreeC and obtained the emulsion. The obtained latex was found to be excellent in smoothness, non-sticky, and at the same time have a moisturizing effect and skin roughening effect.

I phase Furtherance Compounding amount Squalene Myristic Octyl Dodecyl Cetanol Preservative 7.0 3.0 2.0 0.1

Phase II

Furtherance Compounding amount Monodiglyceryl Monospirulfosporate Glycerin Xanthan Gum Pyrrolidone Sodium Carbonate Preservative pH Adjuster 5.0 5.0 0.2 1.0 0.2 pH 6.5 Make up 100% by weight

Example 15 Cream

The phase I oil, which is an oil phase component of the following Table 7, was uniformly dissolved by heating to about 75 ° C., and the phase II was also uniformly dissolved by heating to 75 ° C., and then emulsified by adding a solution of phase I while stirring with a homomixer, followed by stirring. It cooled to 40 degreeC and obtained the cream. The obtained cream was found to be excellent in smoothness, non-stickiness, and at the same time have a moisturizing effect and skin roughening effect.

I phase Furtherance Compounding amount Squalene jojoba oil glyceryl tri-2-ethylhexanoate stearic acid behenyl alcohol preservative 12.0 3.0 5.0 5.0 3.0 0.1

Phase II

Furtherance Compounding amount Monoglyceryl disiculfosporate glycerin 1,3-butylene glycol sodium hyaluronate sodium pyrrolidone sodium carbonate preservative pH adjuster purified water 8.0 10.0 5.0 1.0 1.0 0.2 Amount to make pH 6.5 Remaining amount to make 100% by weight

Example 16 O / W Emulsifying Sunscreen

The oily phase component of phase I of the following Table 8 is mixed, and it melt | dissolves at 80 degreeC, and the aqueous phase component of phase II is heated and disperse | distributed at 70-75 degreeC. Phase I is gradually added and mixed with stirring to phase II and emulsified using a homo mixer. It cooled to 30 degreeC, stirring an emulsion, and obtained the O / W emulsion type sunscreen agent. It was confirmed that the obtained O / W emulsified sunscreen agent was excellent in smoothness, excellent in stickiness, and at the same time had a moisturizing effect and a skin roughening effect.

I phase Furtherance Compounding amount Liquid paraffin isostearic acid behenic acid cetanol dimethyl polysiloxane paramethoxycapylate octyl preservative 7.0 1.0 1.0 1.5 2.0 3.0 0.1

Phase II

Furtherance Compounding amount Monodiglyceryl Disiculfosfolate Polyethylene Glycol 1000 Dipropylene Glycol Titanium Dioxide Powder Carboxyvinyl Polymer Polymer Pyrrolidone Sodium Carbonate Preservative pH Adjuster Purified Water 4.0 5.0 5.0 2.0 1.0 0.1 0.2 pH 6.5 Make up 100% by weight

Example 17 W / O Emulsifying Sunscreen

After phase I of Table 9 is sufficiently swollen, phase II is added, followed by heating and mixing to disperse and dissolve sufficiently. The dispersion is maintained at 70 ° C., and the solution in which the phase III is mixed is gradually added and emulsified with a homo mixer. It cooled to 30 degreeC, stirring an emulsion, and obtained the W / O emulsion type sunscreen. The obtained W / O emulsified sunscreen agent was confirmed to have excellent smoothness, no stickiness, and at the same time have a moisturizing effect and skin roughening effect.

I phase Furtherance Compounding amount Monoglyceryl Disiculfosfolate Ethyl Cellulose Ethanol 3.0 0.5 5.0

Phase II

Furtherance Compounding amount Octoxy paracyl octylate (silica methoxyphosphoric acid) coating titanium oxide di 2-ethylhexyl succinate (Di (2-ethylhexyl) succinate) 5.0 6.0 22.0

Ⅲ phase

Furtherance Compounding amount Carboxymethyl Cellulose Preservative pH Adjuster Purified Water 1.0 0.3 pH 6.5 Volume 100% by weight

The skin external preparation of the present invention is formulated with a spiculispolic acid derivative, which is excellent in use feel, especially smoothness and non-stickiness, and at the same time has a moisturizing effect and skin roughening effect. When other moisturizers are used in combination, the spiculosporic acid derivative promotes keratin permeability of the moisturizer, significantly improving the moisturizing effect and roughening effect of the skin, and also promotes percutaneous absorption for whitening agents and the like.

Claims (14)

Esters of spiculispolic acid with a polyhydroxy compound and salts thereof, or esters of 3-hydroxy-1,3,4-tetradecane tricarboxylic acid with a polyhydroxy compound, ring-opening spiculispolic acid, and A composition for external application for skin, comprising at least one component among spiculispolic acid derivatives which are salts thereof. The composition according to claim 1, wherein the polyhydroxy compound is at least one selected from polyglycerols including glycerin, diglycerine, triglycerine and the like. The composition according to claim 1, wherein the polyhydroxy compound is at least one selected from the group consisting of inositol, lactose, sucrose, glucose, fructose, xylitol, mannitol, maltitol, sorbitol and pentaerythritol. The polyhydroxy compound according to claim 1, wherein the polyhydroxy compound is at least one selected from glycols including ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, hexylene glycol, and the like. Composition. The composition according to claim 1, wherein 0.01% to 70% by weight of the above spiculispolic acid derivative is blended. Moisturizing composition comprising a spiculosporic acid derivative. Composition for improving rough skin comprising spicullispoic acid derivatives. A composition for improving stickiness comprising spiculispolic acid derivatives. Percutaneous absorption promoting composition comprising a spiculosporic acid derivative. A composition for regulating transdermal absorption comprising spiculispolic acid derivatives. A composition for external application for skin, comprising a spiculosporic acid derivative and a hydrophilic agent, wherein the spiculosporic acid derivative is a transdermal absorption accelerator of a hydrophilic agent. 12. The composition of claim 11, wherein the hydrophilic agent is a humectant. 13. The composition of claim 12 wherein the humectant is glycerin. 12. The composition of claim 11, wherein the hydrophilic agent is at least one selected from hydroquinone derivatives or ascorbic acid derivatives.