JP2787404B2 - External preparation for skin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for the skin, and more particularly, to the production of a melanin which causes spots, freckles, etc., to further enhance the whitening effect and to reduce the irritation of the ultraviolet absorber. It relates to a highly topical skin external preparation.

[0002]

2. Description of the Related Art Spots and freckles and pigmentation after sunburn are the result of a marked increase in melanin production due to the activation of pigment cells present in the skin. Has become. Generally, melanin changes from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosinase biosynthesized in pigment cells, and then converts intermediates such as 5,6-dihydroxyindophenol. It is supposed to be formed after passing through.

[0003] Therefore, in order to prevent or improve skin darkness, it is necessary to prevent ultraviolet rays that cause the activation of pigment cells present in the skin, or to inhibit the melanin production process, and to further prevent melanin already produced. Can be lightly bleached. Based on this idea, various ultraviolet absorbers and whitening components have been conventionally proposed and used together. Such whitening ingredients include, for example, tyrosine
As inhibiting zease activity and suppressing melanin production,
Sulfur compounds represented by glutathione are exemplified. In addition, as a thing that light-color bleaching produced melanin,
Hydrogen peroxide, hydroquinone, arbutin, vitamin C and the like have been used.

[0004]

However, many of these conventional components have extremely poor stability in the formulation system and cause coloration and off-odor due to decomposition, and also have problems in safety. Further, the efficacy and effect at the cellular or biological level have not been sufficient. For example, it has been previously pointed out that the irritation to the skin based on the formulation of ultraviolet absorbers is a problem depending on the type and individual differences of the ultraviolet absorbers, and hydroquinone has a strong fair skin effect, but irreversible vitiligo, There are problems such as causing rash. In addition, arbutin has been pointed out with regard to cytotoxicity.

[0005] As described above, none of the conventionally used components has been practically satisfactory in terms of efficacy / effect, stability and safety. The present invention has been made in view of such circumstances, and it is an object of the present invention to provide a skin external preparation which has a whitening effect by sufficiently improving skin pigmentation and can be used safely.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have used a 4-hydroxyphenyl disaccharide or trisaccharide glycoside together with an ultraviolet absorber. And 4-hydroxyphenyl disaccharide or trisaccharide glycosides inhibit the skin irritation of ultraviolet absorbers, and furthermore have a strong whitening effect on skin due to the strong inhibitory effect on melanin production of living pigment cells. The present inventors have found that an effect is exhibited, and based on this, completed the present invention.

[0007] That is, the present invention is characterized in that it comprises an ultraviolet absorber and a 4-hydroxyphenyl disaccharide or trisaccharide glycoside represented by the following general formula: In a preferred embodiment, the content of the 4-hydroxyphenyl disaccharide or trisaccharide glycoside is 0.01 to 10% by weight based on the total amount of the base, The content of the ultraviolet absorber is 0.05 to 10% by weight based on the total amount of the base, and the disaccharide glycoside of 4-hydroxyphenyl is 4-hydroxyphenyl-D
The present invention relates to a skin external preparation which is maltoside or 4-hydroxyphenyl-D-cellobioside.

Embedded image (In the formula, R represents a disaccharide or trisaccharide residue containing pentose and / or hexose as a constituent.)

Hereinafter, the present invention will be described in detail.

The 4-hydroxyphenyl disaccharide or trisaccharide glycoside applied to the present invention is represented by the above general formula (2), wherein R is a pentose sugar. And / or a disaccharide or trisaccharide residue containing a hexasaccharide as a component. Examples of such disaccharide or trisaccharide residues include maltose, isomaltose, cellobiose, kojibiose, laminaribiose, nigerose,
Examples include disaccharide residues such as gentiobiose, trehalose, sambubiose and neohesperidose, and trisaccharide residues such as maltotriose. Regarding the binding mode in this glycoside, α-glycoside and β-glycoside can be used.

Specific examples of 4-hydroxyphenyl disaccharide or trisaccharide glycosides represented by the general formula 2 include 4-hydroxyphenyl-D-maltoside,
4-hydroxyphenyl-D-cellobioside, 4-hydroxyphenyl-D-cordiobioside, 4-hydroxyphenyl-D-laminaribioside, 4-hydroxyphenyl-D-gentiobioside, 4-hydroxyphenyl-D-trehaloside, 4-hydroxyphenyl- Examples thereof include D-neohesperidoside and 4-hydroxyphenyl-D-maltotrioside, among which 4-hydroxyphenyl-D-maltoside and 4-hydroxyphenyl- from the viewpoint of melanin production inhibitory ability and the like. The use of D-cellobioside is preferred.

Next, an outline of a method for synthesizing 4-hydroxyphenyl-β-D-maltoside among dihydroxyglycosides or trisaccharide glycosides of 4-hydroxyphenyl represented by the general formula (2) I do. Hydroquinone and β-D-maltoside octaacetate are added to a diethylene chloride solvent and reacted for 2 hours in an ice-cooled and nitrogen stream. Thereafter, the diethylene chloride layer is evaporated to dryness and fractionated by silica gel column chromatography. After isolation, it is deacetylated. 4-Hydroxyphenyl-β-D-cellobioside can also be easily produced by a similar method using β-D-cellobiose octaacetate.

In the skin external preparation of the present invention, at least one or more of the above-mentioned 4-hydroxyphenyl disaccharide glycoside or trisaccharide glycoside is preferably used in an amount of 0.1 to 100% based on the total amount of the external preparation base.
It is blended in the range of 01 to 10% by weight, more preferably 0.1 to 5% by weight. Among the external preparations for skin, in particular for the purpose of preventing and improving spots, freckles and hatredness caused by sunburn, the compounding amount is preferably 0.1% by weight or more.

When the amount is less than 0.01% by weight, the effect based on the inhibitory effect on melanin production is reduced, and when the amount exceeds 10% by weight, the effect is hardly changed. Does not need to exceed 10% by weight.

Next, similarly, the ultraviolet absorber used in the external preparation for skin of the present invention may be any ultraviolet absorber conventionally applied to external preparations for skin, and typical compounds of such ultraviolet absorbers Is as follows.

(1) Benzoic acid type ultraviolet absorbers paraaminobenzoic acid, monoglycerin paraaminobenzoate, ethyl N, N-dipropoxyparaaminobenzoate,
Ethyl N, N-diethoxyparaaminobenzoate, N, N
-Butyl dimethyl paraaminobenzoate, amyl N, N-dimethylparaaminobenzoate, octyl N, N-dimethylparaaminobenzoate, etc.

(2) Anthranilic acid ultraviolet absorbers, such as homomenthyl-N-acetylanthranilate

(3) Salicylic acid ultraviolet absorbers: amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate, dipropylene glycol salicylate, etc.

(4) Cinnamic acid ultraviolet absorbers isoferulic acid, ferulic acid, caffeic acid, octylcinnamic acid, ethyl-4-isopropylcinnamic acid, methyl-
2,5-diisopropylcinnamic acid, propyl-p-methoxycinnamic acid, isopropyl-p-methoxycinnamic acid,
Isoamyl-p-methoxycinnamic acid, octyl-p-methoxycinnamic acid (2-ethylhexyl-p-methoxycinnamic acid), 2-ethoxyethyl-p-methoxycinnamic acid, cyclohexyl-p-methoxycinnamic acid , Ethyl-
α-cyano-β-phenylcinnamic acid, 2-ethylhexyl-α-cyano-β-phenylcinnamic acid, glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamic acid, diparamethoxycinnamic acid mono- Glyceryl 2-ethylhexanoate, etc.

(5) Benzophenone UV absorber 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-
Sodium methoxybenzophenone sulfonate (sodium oxybenzon sulfonate), 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4-
Methoxybenzophenone, 2,2'-4,4'-tetrahydroxybenzophenone, 2,2'-dihydroxy-
Sodium 4,4'-dimethoxybenzophenone sulfonate, 4-phenylbenzophenone, 4-hydroxy-3-carboxybenzophenone, etc.

(6) Other UV absorbers urocanic acid, ethyl urocanate, 3- (4'-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor, 2- (2-hydroxy -5
-Methylphenyl) benzotriazole, 2,2'-hydroxy-5-methylbenzoxazole, 2,2'-hydroxy-5-methylphenylbenzotriazole,
-(2'-hydroxy-5'-t-octylphenyl)
Benzotriazole, 4-methoxy-4'-t-butyldibenzoylmethane, etc.

In the skin external preparation of the present invention, the above-mentioned ultraviolet absorber is preferably 0.05 to 1 based on the total amount of the external preparation base.
0% by weight, more preferably 0.5 to 8% by weight. If the amount is too small, sunburn cannot be prevented, and the whitening effect of the dihydroxy or trisaccharide glycoside of 4-hydroxyphenyl tends to be offset, which is not preferable. If it is too much, the stability of the external preparation for skin tends to be impaired, which is not preferable. The relative ratio between the blending amount of the UV absorber and the blending amount of the 4-hydroxyphenyl disaccharide or trisaccharide glycoside is not particularly limited. In order to suppress this, it is preferable to add 0.1 to 60 parts by weight of 4-hydroxyphenyl disaccharide or trisaccharide glycoside to 1 part by weight of the ultraviolet absorbent.

The external preparation for skin of the present invention includes, in addition to the above-mentioned active ingredients, various components generally used in pharmaceuticals, cosmetics, etc., ie, aqueous components, oil components, powder components, surfactants, humectants, Thickener, coloring agent, fragrance, antioxidant, PH
Agents such as regulators, chelating agents, preservatives, or anti-inflammatory agents, and other whitening ingredients can be included.

Particularly, whitening agents include, for example, pantethein-s-sulfonic acid, magnesium phosphate ascorbic acid, arbutin, codic acid, linoleic acid and the like.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and is usually used for pharmaceuticals, quasi-drugs, cosmetics, etc., for example, ointments, creams, emulsions, lotions, and the like.
Dosage forms such as packs and bath agents are included.

The following are examples of various experiments conducted to evaluate how useful the combined use of the 4-hydroxyphenyl disaccharide glycoside and the trisaccharide glycoside according to the present invention with an ultraviolet absorber is as follows. The present invention will be described in more detail with reference to

EXPERIMENTAL EXAMPLE 1 Cytotoxic Effect on Pigment Cells and Inhibitory Effect on Melanin Production 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ). Using MEM medium in the presence of 5% carbon dioxide, 37
The cells were cultured under the condition of ° C. Two days later, the test samples were given a concentration of 0 (control), 25, 50, 75, 100 in the medium.
It was adjusted to be μmol and cultured for further 4 days.

After completion of the culture, the medium was removed, washed with an equilibrated phosphate buffered saline (PBS), and then trypsin and EDTA were removed.
The cells were detached from the flask using the containing medium, collected in a glass centrifuge tube, and collected by centrifugation. After the obtained cells were washed once with PBS, a certain amount of PBS was added, the cells were mixed by flushing, a certain amount of the cell suspension was taken, the number of cells was counted with a Coulter counter, and The cell number ratio at the sample concentration was calculated. The remaining suspension was collected after centrifugation again, and the whiteness of the precipitate was visually observed according to the following criteria. Table 1 shows the results.

(Evaluation criteria)-: Equivalent to the solvent control +: Whitening weaker than the solvent control ++: Clearly whitening compared to the solvent control

[0029]

[Table 1]

As is clear from the results shown in Table 1, 4-hydroxyphenyl-β-D-maltoside according to the present invention,
4-Hydroxyphenyl-β-D-cellobioside is
Compared to a solvent control (control), it was demonstrated to have an effect of significantly suppressing melanin production in pigment cells. It was also shown that the inhibitory concentration was lower than that of arbutin (4-hydroxyphenyl-β-D-glucoside), which is a conventional product, and that it had a strong melanin production inhibitory action. Furthermore, the lethal concentration for cells was shifted to a higher concentration as compared with hydroquinone and arbutin, and reduction in cytotoxicity was clearly observed.

EXPERIMENTAL EXAMPLE 2 Stimulant Inhibitory Effect of Ultraviolet Absorber A group of six healthy male and female Hartley guinea pigs weighing 350-500 g was used. The entire back skin was shaved with an electric clipper, and 1 hour after shaving, sodium 2-hydroxy-4-methoxybenzophenone-5-sulfonate (H
^10-5 %, ^10-3 %, ^10-1 %, 1%, 5% of MBS)
Each of the saline suspensions was injected intradermally on one side of the midline. Further, each of them has 4-hydroxyphenyl-β-D
A sample obtained by adding 5 × 10 ⁻³ % of maltoside (HPM) and dissolving the sample was subjected to HMB symmetrically with respect to the site where the sample was administered and the midline.
0.05 ml intradermal injection was performed on the other side so that the same S concentration was obtained. The skin reaction at the intradermal injection site 24 hours after the intradermal injection was evaluated according to the following observation criteria,
Table 2 shows the average of the evaluation values.

[0032]

[0033]

[Table 2]

As shown in the results in Table 2, 4-hydroxyphenyl-β-D-maltoside was converted to 2-hydroxy-4-methoxybenzophenone-5, an ultraviolet absorber.
When used in combination with sodium sulfonate, the irritation of the ultraviolet absorber to the skin was clearly suppressed.

Experimental Example 3 Actual use test 1 3% of 2-hydroxy-4-methoxybenzophenone and 4-hydroxyphenyl-β-D- shown in Example 1 described later.
Cream of the Invention Containing 0.5% Maltoside and Example 1
And a control cream in which 4-hydroxyphenyl-β-D-maltoside in the water was replaced with water.
A group of 0 women suffering from black and white, spots and freckles was continuously used for 3 months to evaluate the improvement effect. Table 3 shows the results.

[0036]

[Table 3]

As is clear from the results in Table 3, the product of the present invention containing 4-hydroxyphenyl-β-D-maltoside was significantly different from the control product containing no 4-hydroxyphenyl-β-D-maltoside. It has been proved to have an effective effect of improving effective black and white, spots and freckles. Incidentally, no unfavorable reaction on the skin was observed at the application site of the product of the present invention.

Experimental Example 4 Actual use test 2 4% of p-methoxycinnamic acid-2-ethylhexyl ester and 4-hydroxyphenyl-β- shown in Example 5 below.
Emulsion of the present invention containing 1% of D-maltoside and the emulsion of a control product in which 4-hydroxyphenyl-β-D-maltoside in Example 5 was replaced with water were used as a group of 20 women aged 20 to 50 years. A total of 40 people were used for one week from 7 to 8 months, and after one week, the presence or absence of skin irritation (crispness) and the degree of appearance during the use period were determined according to the following evaluation criteria investigated. Table 4 shows the results.

(Evaluation criteria)-: No crispness was recognized at all. ±: Slight crispness was recognized. +: Crispness was recognized. ++: Strong crispness was recognized.

[0040]

[Table 4]

As shown in the results in Table 4, the product of the present invention containing 4-hydroxyphenyl-β-D-maltoside was
It was clearly demonstrated that the control product without 4-hydroxyphenyl-β-D-maltoside suppressed the skin irritation caused by the ultraviolet absorbent.

[0042]

Examples of the present invention will be described below. In addition, the compounding ratio in an Example is a weight part.

Example 1 Oil-in-water cream (A) POE (30) cetyl ether 2 glycerin monostearate 10 liquid paraffin 10 petrolatum 4 cetanol 5 2-hydroxy-4-methoxybenzophenone 3 γ-tocophero- 0.05 BHT 0.01 butyl paraben 0.1 (B) propylene glycol 10 mucin 0.1 collagen hydrolyzate 0.3 water-soluble thymus extract 0.2 4-hydroxyphenyl-β-D-maltoside 0 5.5 Purified water 54.54 (C) Fragrance 0.2 (Production method) According to each component of (A), heat to 80 ° C.
Combine the components of (B) and heat to 80 ° C. The prescription of (A) is added to the prescription of (B) and stirred to emulsify. Thereafter, (C) is added and cooled.

Example 2 Oil-in-water cream (A) POE (30) Cetyl ether 2 Glycerin monostearate 10 Liquid paraffin 10 Vaseline 4 Cetanol 5 Glycosphingolipid 0.1 δ Tocopherol 0.05 2 -Ethylhexyl paradimethylaminobenzoate 34-methoxy-4'-t-butyldibenzoylmethane 1 glycyrrhetinic acid 0.1 titanium oxide 1 BHT 0.01 butylparaben 0.1 (B) mulberry bark extract 0.1 toki extract 0 .1 Calcium pantethein-s-sulfonate 1 Hydroquinone-β-D-cellobioside 1 Propylene glycol 10 Purified water 51.34 (C) Fragrance 0.1 (Production method) Combine with each component of (A) and heat to 80 ° C. .
Combine the components of (B) and heat to 80 ° C. The prescription of (A) is added to the prescription of (B) and stirred to emulsify. Thereafter, (C) is added and cooled.

Example 3 Emulsion (A) Synthetic gay wax 2.5 Cetanol 1 Squalane 4 Stearic acid 1 Polyethylene glycol monostearate (25EO) 2.2 Glycerin monostearate 0.5 Sterol glucoside 0.1 2-Ethylhexyl paradimethyl Aminobenzoate 2 Sodium isoferrate 1 Allantoin 0.1 Zinc oxide 1 Butylparaben 0.1 γ-Tocopherol 0.05 Rosemary extract 0.01 Disodium edetate 0.2 (B) 1,3-butylene glycol 3 Propylene glycol 7 Malonie extract 0.1 Xanthan gum 0.1 Caustic potash 0.2 Magnesium phosphate ascorbic acid 1 Arbutin 2 Chitin hydrolyzate 0.2 4-Hydroxyphenyl-β-D-cellobioside 3 Purification Water 67.54 (C) Fragrance 0.1 (Production method) Dissolve (A) and (B) at 70 ° C. while stirring each. (A) is added to (B), preliminarily emulsified, and uniformly emulsified by a homomixer. After emulsification, (C) is added, and the mixture is cooled to 30 ° C. while stirring.

Example 4 Emulsion (A) Synthetic gay wax 1.5 Cetanol 0.5 Liquid paraffin 5 Polyethylene glycol monostearate (25EO) 2 Glycerin monostearate 0.4 p-Methoxycinnamic acid-2-ethylhexyl ester 4 Titanium oxide 0.5 Butylparaben 0.1 γ-Tocopherol 0.05 BHT 0.01 (B) 1,3-butylene glycol 3 Propylene glycol 5 Carboxyvinyl polymer 0.3 Sodium hyaluronate 0.1 Royal jelly 0.3 Ogon Extract 0.2 4-Hydroxyphenyl-β-D-maltoside 1 Purified water 75.9 (C) Fragrance 0.14 (Production method) Dissolve (A) and (B) at 70 ° C. while stirring each. (A) is added to (B), preliminarily emulsified, and uniformly emulsified by a homomixer. After emulsification, (C) is added, and the mixture is cooled to 30 ° C. while stirring.

Example 5 Lotion (A) POE (20) Sorbitan Monolaurate 1.5 POE (20) Lauryl Ester 0.5 Ethanol 10 p-Methoxycinnamic acid-2-ethylhexyl ester 3 Sodium Isoferulate 0. 2 Stearyl glycyrrhetinate 0.5 γ-Tocopherol 0.02 Fragrance 0.1 (B) Glycerin 5 Propylene glycol 4 Citric acid 0.15 Sodium citrate 0.1 Magnesium phosphate ascorbic acid 3 Placenta extract 0.1 Cow Blood deproteinizing extract 0.1 4-Hydroxyphenyl-β-D-maltoside 3 Dye 0.1 Purified water 68.63 (Production method) Combine the components of (A) and dissolve at room temperature.
On the other hand, each component of (B) was also dissolved at room temperature, and this was dissolved in (A)
Solubilize in addition to prescription.

Example 6 Lotion (A) POE (20) Sorbitan Monolan Phosphate 1.5 POE (20) Lauryl Ester 0.5 Ethanol 8 2-Ethylhexylparadimethylaminobenzoate 24 4-Methoxy-4′-t-buty Rudibenzoylmethane 3 γ-oryzanol 0.3 γ-tocopherol 0.02 (B) glycerin 5 1,3-butylene glycol 4 citric acid 0.15 sodium citrate 0.1 ethinyl estradiol 0.001 gennoshoco extract 0.1 serine 0.1 4-Hydroxyphenyl-β-D-cellobioside 0.5 Dye 0.1 Purified water 74.629 (Production method) The components of (A) are combined and dissolved at room temperature.
On the other hand, each component of (B) was also dissolved at room temperature, and this was dissolved in (A)
Solubilize in addition to prescription.

Example 7 Packing material (A) Polyvinyl alcohol 15 Purified water 40 Bisabolol 0.5 Vitamin A acid 0.2 γ-Tocopherol 0.02 Sodium isoferrate 0.1 Titanium oxide 10 (B) Ethano 1,4-butylene glycol 4 polyoxyethylene (8) polyoxypropylene glycol (55) 3 peony extract 0.3 aloe extract 0.4 tonin extract 0.3 4-hydroxyphenyl-β-D- Maltoside 0.5 Purified water 21.68 (Production method) (A) is dispersed and dissolved at room temperature. To this (B)
And dissolve uniformly.

[0050]

According to the present invention, it is possible to provide an external preparation for skin which is excellent in whitening effect and high in stability and safety. The topical skin preparation of the present invention can be used for preventing, improving, and treating local pigmentation such as spots, freckles, and sunburn, and systemic pigmentation such as Addison's disease. In addition, since it is excellent in safety such as suppressing skin irritation of the ultraviolet absorber, it can be used continuously for a long period of time.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takayuki Katagiri 560 Paula-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Totsuka Research Laboratory (72) Koji Yokoyama 560 Paula-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Kasei Kogyo Co., Ltd., Totsuka Laboratory (72) Inventor Tadashi Suzuki Kanagawa Prefecture, Yokohama City, Totsuka-ku, Kashio-cho 560 Paula Kasei Kogyo Co., Ltd. (72) Inventor Tomomi Kato, Kanagawa Prefecture, Yokohama-shi Totsuka-ku, Kashio-cho, 560 Paula (72) Inventor Hiroyuki Nakano 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Totsuka Laboratory (56) References JP-A-6-92858 (JP, A) JP Sho 61-200906 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 7/00-7/50

Claims (4)

(57) [Claims] 1. An external preparation for skin comprising an ultraviolet absorbent and a 4-hydroxyphenyl disaccharide or trisaccharide glycoside represented by the general formula (1). Embedded image (In the formula, R represents a disaccharide or trisaccharide residue containing pentose and / or hexose as a constituent.) 2. The content of the 4-hydroxyphenyl disaccharide or trisaccharide glycoside is 0.0% based on the total amount of the base.
The external preparation for skin according to claim 1, which is 1 to 10% by weight. 3. The external preparation for skin according to claim 1, wherein the content of the ultraviolet absorbent is 0.05 to 10% by weight based on the total amount of the base. 4. The disaccharide glycoside of 4-hydroxyphenyl is 4-hydroxyphenyl-D-maltoside or 4hydroxyphenyl.
The skin external preparation according to any one of claims 1 to 3, which is -hydroxyphenyl-D-cellobioside.