JPH07206661A - External preparation for skin - Google Patents

Abstract

PURPOSE:To obtain an external preparation for skin effective for activating metabolism of skin, increasing elasticity of skin, protecting skin and retaining water, comprising a protein and a decomposition product of protein and an ester of gentisic acid and tranexamic acid and its salt. CONSTITUTION:This external preparation for skin contains 0.01-20wt.% of a protein and a decomposition product of protein (e.g. casein or collagen) and 0.001-20 wt.% of an ester of gentisic acid and tranexamic acid of the formula and its salt (e.g. 2-(trans-4-aminomethylcyclohexylcarbonyloxy)-5-hydroxybenzoic acid). The external preparation for skin can be pharmaceutically prepared into a dosage form such as a solution base, a solubilized base, an emulsion base, a powder dispersion base, a water-double layer base, a water-oil-powder three layer base and can be used as an external preparation for skin for facial use such as toilet lotion, milky lotion, cream and pack, an external preparation for skin for body use and an external preparation for skin for hair use such as hair tonic, hair cream, shampoo, hair rinse, etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a new external preparation for skin, which aims to activate skin metabolism, increase skin elasticity, protect skin and retain water. It is intended to provide a skin external preparation having an effect.

[0002]

2. Description of the Related Art When a skin is histologically analyzed, it is said that collagen fibers and elastic fibers form a mesh in the dermis, which gives elasticity and tensile strength of the skin. In recent years, collagen and elastin obtained by solubilizing these fibers obtained from animals by scientific treatment or extracting soluble fiber molecules from these fibers have been incorporated into skin external preparations as skin protection and moisturizers. Came. From the same point of view, gelatin, casein,
Blending of soy protein etc. has also been proposed.

[0003]

However, when these proteins are added alone to the external preparation for skin, the expected action and effect thereof are not yet sufficient, and therefore the stability of the external preparation for skin is increased by increasing the amount of addition. It had drawbacks such as adverse effects and stickiness.

In view of the above circumstances, the inventors of the present invention have conducted diligent research and, as a result, conducted one or more kinds selected from the group consisting of proteins and proteolytic products, and specific gentisic acid and tranexamic acid ester and salts thereof. The external preparation for skin mixed with one or more selected from the group consisting of consists of synergistically increasing the water retention, smoothing the skin, and imparting appropriate "moisturizing" and "swelling". The present invention has been completed based on the findings and this finding.

[0005]

[Means for Solving the Problems] That is, claim 1 of the present invention provides one or more kinds selected from the group consisting of proteins and proteolytic products, and gentisic acid and tranexam represented by the following general formula 2. The external preparation for skin is characterized by being blended with one or more kinds selected from the group consisting of an acid ester and a salt thereof.

[Chemical 2]

According to a second aspect of the present invention, in the external preparation for skin according to the first aspect, the ester form of gentisic acid and tranexamic acid and its salt are 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5- A skin external preparation characterized by being hydroxybenzoic acid and a salt thereof. A third aspect of the present invention is the external preparation for skin according to claim 1 or 2, wherein the compounding amount of one or more selected from the group consisting of gentisic acid and tranexamic acid esters and salts thereof is 0.001 of the total amount
The external preparation for skin is characterized in that it is -20% by weight. A fourth aspect of the present invention is the external preparation for skin according to any one of claims 1 and 2, wherein the compounding amount of one or two or more kinds selected from the group consisting of gentisic acid and tranexamic acid esters and salts thereof is The external preparation for skin is characterized in that the total amount is 0.1 to 7% by weight. A fifth aspect of the present invention is the external preparation for skin according to any one of claims 1 to 4, wherein the compounding amount of one or two or more kinds selected from the group consisting of proteins and proteolytic products is 0.01 to the total amount of the external preparation for skin. 20% by weight of the external preparation for skin. A sixth aspect of the present invention is the external preparation for skin according to any one of claims 1 to 4, wherein the compounding amount of one or two or more kinds selected from the group consisting of proteins and protein degradation products is 0.01 to the total amount of the external preparation for skin.
The external preparation for skin is characterized by being 10% by weight.
A seventh aspect of the present invention is the external preparation for skin according to the first to sixth aspects, wherein the compounding ratio of one or more kinds selected from the group consisting of gentisic acid-tranexamic acid esters and salts thereof is protein and protein. 0.1-60 with respect to 1 part by weight of one or more selected from the group consisting of decomposition products
The external preparation for skin is characterized by being parts by weight.

The structure of the present invention will be described in detail below. Proteins and protein degradation products used in the present invention, soybean protein, wheat protein, glutelin, glucagon, collagen,
Gelatin, elastin, egg white lysozyme, amylase,
Fipurinogen, myosin, enolase, chymotrypsinogen, histone, fish meat protein, apidine, pepsin, globulin, casein, succinylated casein, and salts thereof.

The external preparation for skin of the present invention is appropriately selected and blended with one or more of these. The amount of the protein and the proteolytic product blended is 0.0 in the external preparation for skin of the present invention.
It is 1 to 20% by weight, preferably 0.01 to 10% by weight. If the blending amount is less than 0.01%, the moisturizing effect on the skin is unlikely to appear, and even if it is added over 20%, no increase in the effect can be expected substantially, and problems such as stickiness may occur, which is not preferable.

The ester of gentisic acid and tranexamic acid and salts thereof according to the present invention can be synthesized, for example, by the following method. That is, gentisic acid ester of tranexamic acid is produced by reacting traneticamic acid or its reactive derivative with gentisic acid. As the reactive derivative of tranexamic acid, acid chloride, acid halide such as acid bromide, mixed acid anhydride and the like are preferable. When the tranexamic acid is reacted as it is, it is preferable to coexist a condensing agent such as dicyclohexylcarbodiimide. Alternatively, the amino group of tranexamic acid may be protected with an appropriate protecting group such as a benzyloxycarbonyl group, and the protecting group may be eliminated by catalytic reduction after esterification. Further, the carboxyl group of gentisic acid and / or one phenolic hydroxyl group may be protected with an appropriate protecting group such as benzyl group, and the esterified ester may be removed by catalytic reduction or the like. .

The compound of the present invention produced as described above is an inorganic acid salt such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, or acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid or citric acid, as desired. , An organic acid salt such as methanesulfonic acid and p-toluenesulfonic acid, or a sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt and the like.

Specific examples of the substance name are 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid and 2- (trans-4-).
Aminomethylcyclohexylcarbonyloxy) -5-
Hydroxybenzoic acid hydrochloride, sodium 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoate, 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid, 5- ( Examples include trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid hydrochloride, potassium 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoate, and the like. From the standpoints of synergistically increasing the water retention, making the skin smooth, and imparting appropriate "moisturizing" and "swelling", 2- (trans-4-
Aminomethylcyclohexylcarbonyloxy) -5-
Hydroxybenzoic acid and its salts are preferred.

The blending amount of the gentisic acid and tranexamic acid ester and its salt to be blended in the external preparation for skin according to the present invention is not particularly limited, but generally 0.001 to 0.001 to the total amount of the external preparation for skin. 20% by weight, preferably 0.1
˜7% by weight. If the content is less than 0.001% by weight, the skin metabolism of the external preparation for skin is activated, the elasticity of the skin is increased, and the effect of excellent protection of skin and water retention tends to be poor. If the amount is more than 20% by weight, an increase in the effect cannot be expected substantially, and it tends to be difficult to compound it in the external skin preparation. There is no particular limitation on the relative ratio between the amount of the gentisic acid and tranexamic acid ester and its salt and the amount of the above-mentioned protein and protein hydrolyzate, but it also activates the metabolism of the skin and improves the elasticity of the skin. In order to improve skin protection and moisture retention, 0.1 to 60 parts by weight of gentisic acid and tranexamic acid ester and salts thereof should be added to 1 part by weight of protein and protein degradation product. Is preferred.

In addition to the above essential components, the external preparation for skin of the present invention may optionally contain other components usually used in the fields of medicine and cosmetics such as sodium salt of ethylenediaminetetraacetic acid (EDTA) and citric acid. sodium,
Sequestering agents such as sodium metaphosphate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), propyl gallate, -α-tocopherol and other antioxidants, surfactants, UV absorbers, fragrances, water, Alcohols such as ethanol and isopropanol, thickeners, colorants, powders, drugs, organic acids such as citric acid and malic acid, inorganic acids such as phosphoric acid, and the like can be added. Of course, these components must be used within a qualitative and quantitative range that does not impair the effects of the present invention. The dosage form of the external preparation for skin of the present invention is arbitrary, a solution system,
Solubilization system, emulsion system, powder dispersion system, water-two-layer system, water-oil-
Any dosage form such as a powder three-layer system may be used. Further, the application of the external preparation for skin of the present invention is also optional, such as lotion, emulsion,
Skin or topical skin preparations such as creams and packs, hair tonics, hair creams, shampoos,
It can be used as an external preparation for the skin of hair such as hair rinse.

[0014]

EXAMPLES Next, the present invention will be specifically described with reference to Examples and Comparative Examples. The present invention is not limited to this. The blending amount is% by weight. First, a synthetic example of an ester of gentisic acid and tranexamic acid and a salt thereof according to the present invention will be described in detail.

Synthesis Example 1 Benzyloxycarbonyl protected form of tranexamic acid (trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylic acid) Benzyloxycarbonyl of tranexamic acid (6.3 g, 40 mmol) in 10% aqueous sodium hydroxide solution (16 ml). Chloride
(8.2 g, 48 mmol), 10% aqueous sodium hydroxide solution (20 ml)
Was sequentially added dropwise with stirring under ice cooling. After stirring for 1 hour under ice cooling, hydrochloric acid was added to acidify the reaction system, and the crystals were collected by filtration. Recrystallization from benzene-petroleum ether gave a protected benzyloxycarbonyl derivative of tranexamic acid (10.7 g, yield 92%). Melting point 114-116 ° C

Synthesis Example 2 Dibenzyl protected form of gentisic acid (5-benzyloxy-2-hydroxybenzoic acid benzyl ester) Gentisic acid (10 g, 65 mmol) was added to benzyl bromide (20 ml, 130 mmol) in acetone at room temperature in the presence of potassium carbonate. )
React for 10 hours with silica gel column for purification.
A dibenzyl protected form of gentisic acid (14.0 g, yield 83%) was obtained. Melting point 68.5-69.0 ° C

Synthetic Example 3 Protected ester of gentisic acid and tranexamic acid (5-benzyloxy-2- (trans-4-benzyloxycarbonylaminomethylcyclohexylcarbonyloxy) benzoic acid benzyl ester) trans-4-benzyloxy Carbonylaminomethylcyclohexanecarboxylic acid (4.4 g, 15 mmol) was added to thionyl chloride (5 ml) and reacted at 40 ° C for 30 minutes, and then petroleum ether (50 ml) was added to the reaction system to precipitate white crystals. I filtered it. A solution of the white crystals in dry benzene (50 ml) was stirred at room temperature to dissolve 5-benzyloxy-2-hydroxybenzoic acid benzyl ester (3.75 g, 14.5 mmol) and triethylamine (1.63 g, 16 mmol) in dry benzene (60 ml). ) Was gradually added dropwise, and the mixture was further stirred for 4 hours.
After the triethylamine hydrochloride precipitated in the reaction system was filtered off, the product was separated and purified on a silica gel column to give a protected ester of gentisic acid and tranexamic acid (4.02 g, yield 52
%) Was obtained. Melting point 118.5-119 ° C

Synthesis Example 4 Esters of gentisic acid and tranexamic acid (2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid) 5-benzyloxy-2- (trans-4-benzyloxycarbonyl) Aminomethylcyclohexylcarbonyloxy) benzoic acid benzyl ester (1.07 g, 2 mmol) was dissolved in acetic acid (100 ml), 10% palladium carbon (100 mg) was added, and catalytic reduction was performed at room temperature and atmospheric pressure. After the theoretical amount of hydrogen was absorbed, the catalyst was removed by filtration, the reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ether to give gentisic acid and tranexamic acid ester as white crystals (438 mg, yield 100%). Obtained. Melting point 196 ~ 198.5 ℃

Synthetic Example 5 Ester hydrochloride of gentisic acid and tranexamic acid (2- (4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid hydrochloride) 2- (4-aminomethylcyclohexylcarbonyloxy) -5- Hydroxybenzoic acid (500 mg) was crystallized from 9% hydrochloric acid acetic acid solution-ether and recrystallized from ethanol-ether to give the ester hydrochloride of gentisic acid and tranexamic acid as white crystals (420 mg, yield 72%). Obtained. Melting point 246.5 to 248.5 ° C. ¹ H-NMR (DMSO-d _6, TMS, ppm) δ 1.01 to 2.51 (m, 10H, cyclohexane ring) δ 2.66 (d, 2H, J = 6.8 Hz, −C) H ₂ NH
₂ ) δ6.91 (d, 1H, J = 8.5Hz, benzene ring H)
-3) δ 6.98 (dd, 1H, J = 2.9 and 8.5 Hz,
Benzene ring H-4) δ7.28 (d, 1H, J = 2.9 Hz, benzene ring H)
-6) δ8.05 (bs, 3H, -N H 3 + Cl -) δ9.75 (bs, 1H, -O H) δ12.74 (bs, 1H, -COO H) 13 C-NMR (DMSO- d6 _, TMS, ppm) δ27.6 (cyclohexane ring C-3, C-5) δ28.6 (cyclohexane ring C-2, C-6) δ34.9 (cyclohexane ring C-4) δ42.0 (cyclohexane) ring C-1) δ44.1 (- C H 2 NH 2) δ117.0 ( benzene ring C-6) δ120.0 (benzene ring C-4) δ124.4 (benzene ring C-3) δ124.6 ( benzene ring C-1) δ142.0 (benzene ring C-2) δ154.8 (benzene ring C-5) δ165.6 (ester C = O) δ173.7 (- C OOH) elemental analysis C ₁₅ H ₁₉ Calculated value as NO ₅ · HCl (%) C: 54.63 , H: 6.11, N: 4.25,
Cl: 10.75 Measured value (%) C: 54.62, H: 6.12, N: 4.22,
Cl: 10.72

Synthesis Examples 6 to 8 The following compounds were synthesized according to the methods of Synthesis Examples 2 to 5.

Synthesis Example 6 2,5-Dihydroxy-benzoic acid benzyl ester Melting point 101.5-103.0 ° C

Synthesis Example 7 5- (trans-4-benzyloxycarbonylaminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid benzyl ester Melting point 110-111 ° C

Synthesis Example 8 5- (4-Aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid hydrochloride Melting point 181 to 185 ° C. ¹ H-NMR (DMSO-d _6, TMS, ppm) δ 1.02 to 2.55 (M, 10H, cyclohexane ring) δ 2.68 (t, 2H, J = 5.9Hz, -CH ₂ NH
₂ ) δ 6.98 (d, 1H, J = 8.8Hz, benzene ring H)
-3) δ 7.25 (dd, 1H, J = 2.9 and 8.8Hz,
Benzene ring H-4) δ7.47 (d, 1H, J = 2.9 Hz, benzene ring H)
-6) δ8.11 (bs, 3H, -N H 3 + Cl - Calculated) Elemental analysis _{C 15 H 19 NO 5 · HCl} (%) C: 54.63, H: 6.11, N: 4.25,
Cl: 10.75 actual value (%) C: 54.64, H: 6.08, N: 4.22,
Cl: 10.78

Example 1 Lotion A lotion was prepared by a conventional method according to the prescription. Ethanol 8.0 Sodium 2-pyrrolidone-5-carboxylate 2.0 Polyoxyethylene (20 mol) oleyl alcohol ether 1.8 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid hydrochloride 0.1 Collagen 0.5 Pullulan 0.05 Jojoba oil 0.5 Caustic potash 0.015 EDTA-3Na 0.01 Perfume 0.1 Ion-exchanged water Residual amount

Example 2 Cream A cream was produced by a conventional method according to the following formulation. 1,3-butylene glycol 5.0 polyethylene glycol 4000 1.0 glycerin 2.0 squalane 20.0 petrolatum 5.0 cetostearyl alcohol 3.0 polyoxyethylene (20 mol) oleyl alcohol ether 1.5 glyceryl monostea Rate 1.5 2- (trans-4-aminomethylcyclohexyl carbonyloxy) -5-hydroxybenzoic acid hydrochloride 20.0 Elastin 10.0 Sodium lactate 2.0 Xanthan gum (Keltrol® trade name) 0.05 Methylparaben 0. 1 Ethylparaben 0.2 Caustic potassium 0.01 EDTA-3Na 0.01 Perfume 0.2 Ion-exchanged water Residual amount

Example 3 Emulsion An emulsion was prepared by a conventional method according to the following formulation. Glycerin 2.0 Squalane 5.0 Vaseline 1.0 Cetostearyl alcohol 0.3 Polyoxyethylene (20 mol) oleyl alcohol ether 1.5 Glyceryl monooleate 1.5 2- (trans-4-aminomethylcyclohexyl carbonyloxy ) -5-Hydroxybenzoic acid hydrochloride 7.0 Sodium polyacrate 0.03 Ethylparaben 0.2 Gelatin 7.0 Caustic potassium 0.1 EDTA-3Na 0.03 Fragrance 0.2 Ion-exchanged water Residual amount

Example 4 Pack A pack was produced by a conventional method according to the following formulation. Propylene glycol 2.0 Polyethylene glycol 4000 3.0 Glycerin 15.0 Ethanol 10.0 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid hydrochloride 15.0 Polyvinyl alcohol 10.0 Olive oil 3 0.0 Lactic acid 1.0 Casein 10.0 Carboxymethylcellulose 0.07 Methylparaben 0.1 Ethylparaben 0.1 Caustic potassium 0.02 EDTA-3Na 0.01 Perfume 0.1 Ion-exchanged water Residual amount

Example 5 Hair Cream A hair cream was produced by a conventional method according to the following formulation. Beeswax 3.0 Vaseline 15.0 Liquid paraffin 42.0 Polyoxyethylene (5 mol) stearic acid ester 3.0 Polyoxyethylene (6 mol) oleyl alcohol ether 2.0 Polyoxyethylene (6 mol) cetyl alcohol ether 1 0.0 5- (trans-4-aminomethylcyclohexyl carbonyloxy) -2-hydroxybenzoic acid hydrochloride 7.0 Elastin 5.0 Purified water Residual fragrance Suitable amount Preservative Suitable amount

The effects of the present invention were tested by a usage test. In the use test, 30 women were divided into 3 groups, respectively, and used as a panel. To the first group, the lotion of Example 1 was added.
The cream of Example 2 was used in the second group, and Example 3 was used in the third group.
The emulsion was tested for use. It was carried out by applying an appropriate amount of the cosmetics after washing the face to the face twice a day in the morning and at night for two weeks. The evaluation evaluated the effectiveness of the following three items.

[0030]

[Table 1]

[0031]

[Table 2]

[0032]

[Table 3]

As is clear from Tables 1 to 3, the cosmetics of the present invention can give the skin moisture, firmness and moisture of the next morning. Also, in the pack of Example 4 obtained in the present invention, in the same effect use test as that performed in Examples 1 to 3, the moisture of the skin, the firmness of the skin and the moisture of the next morning were felt.

[0034]

EFFECTS OF THE INVENTION One or more selected from the group consisting of proteins and protein degradation products according to the present invention, and one or more selected from the group consisting of gentisic acid and tranexamic acid esters and salts thereof. An external preparation for skin that contains revitalizes the metabolism of the skin, increases the elasticity of the skin,
It is a highly safe external preparation for skin that synergistically increases the water-retaining property of the skin, makes the skin smooth, and imparts appropriate "moisturizing" and "swelling".

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yuki Shibata, 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Inside Shiseido Daiichi Research Center, Inc. Address Shiseido Daiichi Research Center (72) Inventor Kenji Kitamura 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Incorporated Shiseido Daiichi Research Center (72) Inventor Iwamoto Naka Kohoku-ku, Yokohama-shi, Kanagawa 1050 Shinba-cho Shiseido Daiichi Research Center, a stock company

Claims (7)

[Claims] 1. One or more selected from the group consisting of proteins and proteolytic products, and one selected from the group consisting of gentisic acid-tranexamic acid esters represented by the following general formula 1 and salts thereof. Or, an external preparation for skin characterized by being blended with two or more kinds. [Chemical 1] 2. The external skin preparation according to claim 1, wherein the ester of gentisic acid and tranexamic acid and a salt thereof are 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid and a salt thereof. An external preparation for skin characterized by being 3. The external preparation for skin according to claim 1 or 2, wherein one or more kinds selected from the group consisting of esters of gentisic acid and tranexamic acid and salts thereof are contained in the total amount of the external preparation for skin. A skin external preparation characterized by being 0.001 to 20% by weight. 4. The external preparation for skin according to claim 1, wherein one or two or more kinds selected from the group consisting of esters of gentisic acid and tranexamic acid and salts thereof are contained in the total amount of the external preparation for skin. The external preparation for skin is characterized by being 1 to 7% by weight. 5. The external preparation for skin according to any one of claims 1 to 4, wherein the compounding amount of one or more selected from the group consisting of proteins and proteolytic products is 0.01 to the total amount of the external preparation for skin.
20% by weight of external preparation for skin. 6. The external preparation for skin according to claim 1, wherein the compounding amount of one or two or more kinds selected from the group consisting of proteins and proteolytic products is 0.01 to the total amount of the external preparation for skin.
An external preparation for skin, which is 10% by weight. 7. The external skin preparation according to any one of claims 1 to 6, wherein the compounding ratio of one or more selected from the group consisting of gentisic acid / tranexamic acid esters and salts thereof is higher than that of protein and protein hydrolyzate. The external preparation for skin, which is 0.1 to 60 parts by weight with respect to 1 part by weight of one or more selected from the group consisting of