JPH08269074A - New ascorbic acid derivative and cosmetic containing the same - Google Patents

Abstract

PURPOSE: To obtain a new ascorbic acid derivative excellent in solubility to water, etc., and useful as an ingredient of cosmetics capable of preventing e.g. dermal wrinkles due to aging by light. CONSTITUTION: This new ascorbic acid derivative is a compound of formula I (R<1> and R<2> are each H, an alkyl, etc.; X is H, Na, K, Ca, etc.; Y is H, Na, K, Ca, etc.) (e.g. potassium 5,6-O-benzylidene ascorbate phosphate) and is obtained by reaction of the hydroxyl groups on the 5 and 6 sites of ascorbic acid with a methylidene derivative (e.g. benzylidene dimethylacetal) followed by reaction with phosphorus oxychloride.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel ascorbic acid derivative and cosmetics containing the same.

[0002]

2. Description of the Related Art Generally, aging of the skin is a physiological phenomenon caused by the mutual effects of aging-related physiological aging and photoaging due to exposure to sunlight (ultraviolet rays). The relationship between photoaging and wrinkles, spots and tarmi on the skin is emphasized. For damage to the skin by UV rays, UV-
Although many DNA damages, erythema, and secondary blackening caused by B (290 to 320 nm) have been reported, recently, UV-A (320 to 400) in the long wavelength region of ultraviolet rays has been reported.
(nm) has attracted attention. UV-A is U
This is because it has been found that 10 times as much energy as V-B reaches the surface of the earth and reaches deep inside the dermis, causing large wrinkles and tarmi on the skin. (Bissett, dlet.al:
Photoaging of Skin by UVA, "Biological Responses t
o Ultraviolet A Radiation "P181-188, Valdenmar Publ
(ishing Company, 1992)

Conventionally, in order to prevent the skin from being damaged by these ultraviolet rays, cosmetics containing various kinds of ultraviolet absorbing, scattering and shielding substances such as titanium oxide, zinc oxide, paramethoxycinnamic acid ester, paraaminobenzoic acid ester and the like. (Sunscreen, Sunprotect cosmetics) have been developed and are in use. However, even if these cosmetics are used, it is difficult to protect the skin from overwhelming sun exposure.

Thus, from the UV rays that have not penetrated into the skin without being cut off by the cosmetics present on the skin surface, especially from UV-A that has reached deep inside the dermis, the target cells are in the vicinity thereof. Various drugs for the purpose of protecting or repairing damaged cells have been studied.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and its purpose is to provide a novel substance having good safety and stability and an excellent photoaging-preventing effect. Further, it is an object of the present invention to provide a cosmetic having excellent skin-beautifying effects by preventing and improving skin wrinkles, tarmi, etc. due to photoaging by blending the same.

[0006]

[Means for Solving the Problems] In view of the present situation, as a result of intensive studies, the present inventors found that the following general formula (1):
The ascorbic acid derivative shown in (2) is excellent in the effect of preventing photoaging, and the cosmetic containing the ascorbic acid derivative is effective in preventing and improving wrinkles and tarmi due to photoaging, and is excellent in the skin beautiful effect. I found out that

[0007]

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[Chemical 6]

That is, the present invention is a novel derivative of ascorbic acid, which is a cosmetic containing the same.

The ascorbic acid derivative of the present invention and the cosmetics containing the same will be described in detail below.

The ascorbic acid derivative of the present invention is generally obtained by a method of reacting the hydroxyl groups at the 5th and 6th positions of ascorbic acid and araboascorbic acid with a methylidene derivative and further reacting with phosphorus oxychloride. . It is also possible to react the ascorbic acid derivative thus obtained with an alkaline compound and use it as a salt. Examples of the methylidene derivative used in this reaction include benzylidene dimethyl acetal, benzylidene diethyl acetal, cyclohexylidene dimethyl acetal, ethoxybenzylidene dimethyl acetal and the like.

Further, the ascorbic acid derivative of the present invention has excellent water solubility, is extremely stable, and does not cause discoloration, odor, decomposition and inactivation over time even when formulated into a preparation, and thus can be used in various dosage forms. In contrast, it can be blended stably and easily.

The ascorbic acid derivative of the present invention will be described below with reference to examples.

[0013]

Example 1 Synthesis of Potassium Phosphate 5,6-O-benzylidene ascorbate 100 g of L-ascorbic acid, 100 g of benzylidene dimethyl acetal and 1 g of P-toluenesulfonic acid as a reaction catalyst were dissolved in 500 ml of dimethylformamide,
The reaction was carried out while heating at 60 ° C. The by-product methanol was removed by distillation under reduced pressure every 30 minutes during the reaction. After 6 hours, the solvent was distilled off under reduced pressure, and the obtained viscous substance was subjected to liquid-liquid partition three times with ethyl acetate and water to give 5,6-O-benzylideneascorbic acid crystals in a yield of 75%. Obtained.
Obtained 5,6-O-benzylidene ascorbic acid 50
g was dissolved in 500 ml of a 15% pyridine-water mixed solvent,
Phosphorus oxychloride (43.6 g) and aqueous potassium hydroxide solution were added to adjust the pH to 12 to 13, and the mixture was reacted at -5 ° C for 3 hours. After completion of the reaction, the solvent pyridine-water was distilled off under reduced pressure, and then potassium 5,6-O-benzylidene ascorbate phosphate was purified using a silica gel column with methanol as an eluent. After distilling off methanol, recrystallization was performed using acetone to obtain potassium 5,6-O-benzylidene ascorbyl phosphate. (Final yield 53.6%)
The H-NMR data of the obtained potassium phosphate of 5,6-O-benzylidene ascorbate was as follows.

1 H-NMR (solvent: DMSO: D ₂ O = 1: 1) 7.482 ppm 5H (single line) Aromatic ring 5.860, 5.772 ppm 1H (double line) 4th-position methine 4.531 ~ 4.072ppm 4H (Multiple line) Methine at 5th position, Methylene at 6th position, Methine at benzylidene

[0015]

Example 2 Synthesis of 5,6-O-benzylidene ascorbic acid sodium phosphate 100 g of L-ascorbic acid, 100 g of benzylidene dimethyl acetal and 1 g of P-toluenesulfonic acid as a reaction catalyst were dissolved in 500 ml of dimethylformamide,
The reaction was carried out while heating at 60 ° C. The by-product methanol was removed by distillation under reduced pressure every 30 minutes during the reaction. After 6 hours, the solvent was distilled off under reduced pressure, and the obtained viscous substance was subjected to liquid-liquid partition three times with ethyl acetate and water to give 5,6-O-benzylideneascorbic acid crystals in a yield of 75%. Obtained.
Obtained 5,6-O-benzylidene ascorbic acid 50
g was dissolved in 500 ml of a 15% pyridine-water mixed solvent,
Phosphorus oxychloride (43.6 g) and aqueous sodium hydroxide solution were added to adjust the pH to 12 to 13, and the mixture was reacted at -5 ° C for 3 hours. After completion of the reaction, the solvent pyridine-water was distilled off under reduced pressure, and sodium 5,6-O-benzylidene ascorbyl phosphate was purified using a silica gel column with methanol as an eluent. After distilling off methanol, recrystallization was performed using acetone to obtain sodium 5,6-O-benzylidene ascorbyl phosphate. (Final yield 58.
4%)

[0016]

Example 3 Synthesis of 5,6-O-benzylidene ascorbic acid magnesium phosphate 100 g of L-ascorbic acid, 100 g of benzylidene dimethyl acetal and 1 g of P-toluenesulfonic acid as a reaction catalyst were dissolved in 500 ml of dimethylformamide,
The reaction was carried out while heating at 60 ° C. The by-product methanol was removed by distillation under reduced pressure every 30 minutes during the reaction. After 6 hours, the solvent was distilled off under reduced pressure, and the obtained viscous substance was subjected to liquid-liquid partition three times with ethyl acetate and water to give 5,6-O-benzylideneascorbic acid crystals in a yield of 75%. Obtained.
Obtained 5,6-O-benzylidene ascorbic acid 50
g was dissolved in 500 ml of a 15% pyridine-water mixed solvent,
Phosphorus oxychloride (43.6 g) and magnesium chloride were added to adjust the pH to 12 to 13, and the mixture was reacted at -5 ° C for 3 hours. After completion of the reaction, the solvent pyridine-water was distilled off under reduced pressure, and then 5,6-O-benzylidene ascorbic acid magnesium phosphate was purified using a silica gel column with methanol as an eluent. After distilling off methanol, recrystallization was performed using acetone to obtain 5,6-O-benzylidene ascorbic acid magnesium phosphate. (Final yield 45.
2%)

[0017]

Example 4 Synthesis of Potassium Phosphate 5,6-O-Paramethoxybenzylidene Ascorbate 100 g of L-ascorbic acid, 100 g of paramethoxybenzylidene dimethyl acetal and 1 g of P-toluenesulfonic acid as a reaction catalyst were dissolved in 500 ml of dimethylformamide. The reaction was carried out while heating at 60 ° C. The by-product methanol was removed by distillation under reduced pressure every 30 minutes during the reaction. After 6 hours, the solvent was distilled off by vacuum distillation, and the obtained viscous substance was subjected to liquid-liquid partition three times with ethyl acetate and water.
Crystals of 5,6-O-paramethoxybenzylidene ascorbic acid were obtained in a yield of 75%. 50 g of the obtained 5,6-O-paramethoxybenzylidene ascorbic acid was dissolved in 500 ml of a 15% pyridine-water mixed solvent, and 43.6 g of phosphorus oxychloride and an aqueous potassium hydroxide solution were added to adjust the pH to 1
It was adjusted to 2 to 13 and reacted at -5 ° C for 3 hours. After completion of the reaction, the solvent pyridine-water was distilled off under reduced pressure, and then methanol was used as an eluent and a silica gel column was used for 5, 6
The -O-paramethoxybenzylidene ascorbate potassium phosphate was purified. After distilling off methanol, the residue was recrystallized from acetone to obtain potassium 5,6-O-paramethoxybenzylidene ascorbate phosphate. (Final yield 49.6%)

The skin cosmetic composition of the present invention contains the ascorbic acid derivative of the present invention in an amount of usually 0.001 based on the total amount of the cosmetic composition.
10 to 10% by weight, preferably 0.01 to 5% by weight. When the compounding amount of the ascorbic acid derivative of the present invention with respect to the cosmetic is less than 0.001% by weight, the skin-beautifying effect for improving the skin condition such as wrinkles and tarmi may not be sufficiently obtained. Even if the amount used exceeds the amount by weight, it is difficult to expect an effect commensurate with the increase.

The dosage form of the cosmetic of the present invention is not particularly limited, but specific examples include creams, emulsions, oils, lotions, packs and ointments.
From the viewpoint of transdermal absorbability, creams, emulsions, oils and the like are particularly preferable. These skin cosmetics can be produced by the same method as that for ordinary skin cosmetics except that the ascorbic acid derivative of the present invention is blended.

In addition to the cosmetics of the present invention, hydrocarbons such as liquid paraffin, petrolatum, squalane, etc., which are usually applied to skin cosmetics, isopropyl myristate, synthetic whale wax, jojoba oil, carna. Esters such as uba wax, animal and vegetable oils such as olive oil and beef tallow, higher alcohols such as cetanol and stearyl alcohol, higher fatty acids such as stearic acid and oleic acid, anionic surfactants such as sodium lauryl sulfate and alkylsulfosuccinate. Cationic surfactants such as quaternary alkyl amine salts, fatty acid monoglycerides, nonionic surfactants such as polyoxyethylene hydrogenated castor oil, amphoteric surfactants such as alkyl betaines, polyhydric alcohols such as glycerin and propylene glycol. , Lower alcohol such as ethanol, propanol, etc. Preservatives such as alcohols, parabens and chlorhexidine gluconate, antioxidants such as vitamin E and butylhydroxytoluene, thickeners such as gum arabic and carboxyvinyl polymers, moisturizers such as polyethylene glycol, citrate , PH adjusting agents such as acetate,
Titanium oxide, silica gel, powders such as talc, fragrances, pigments, hyaluronic acid, placenta extract, ginseng extract, sterol glycosides, etc. .

In addition to the ascorbic acid derivative of the present invention, the cosmetic composition of the present invention also protects the skin from ultraviolet rays such as para-aminobenzoic acid derivatives and benzophenone derivatives, and β-carotene and superoxide desmutase. You may mix | blend the chemical | medical agent etc. which protect or it has the repair | restoration effect of the skin damaged by ultraviolet rays.

Here, the ascorbic acid derivatives obtained in Examples 1 to 4 were used to evaluate the stability over time, the action of suppressing the photo (ultraviolet) aging reaction, and the action of suppressing the erythema of ultraviolet rays.

<Stability test with time> The derivatives of Examples 1 to 4 were used as 0.1% aqueous solutions of pH 4, 6, and 9, and the generation of odor and the coloration were observed over time when left at 60 ° C for 1 week. The results obtained are shown in Table 1.

[0024]

[Table 1]

<Photoaging Reaction Inhibition Test> (Sample) (a) 300 mg of the derivative of Example 1 was diluted with 100 parts of diluent solvent.
Dissolved in ml. (B) 300 mg of the derivative of Example 2 was added to 100 parts of the diluent solvent.
Dissolved in ml. (C) 300 mg of the derivative of Example 3 was added to 100 parts of the diluent solvent.
Dissolved in ml. (D) 300 mg of the derivative of Example 4 was added to 100 parts of the diluent solvent.
Dissolved in ml. (E) 300 mg of magnesium ascorbyl phosphate,
What was dissolved in 100 ml of diluent solvent. (F) Diluent solvent (equal mixture of propylene glycol and ethanol). (Method) 6 groups of 5 hairless mice (9 to 10 weeks old, female) were prepared as experimental animals, and their back skin was irradiated with UV-A 5 times weekly for 6 months once a day. . Toshiba BLB lamp is used as a light source, and 7 m to cut UV-B.
A m-thick plate glass was attached between the animal and the lamp. The irradiation energy amount was 14 to 28 mJ / cm ² / day,
The amount of energy was gradually increased every month. One hour before the UV-A irradiation, samples (a) to (f) were applied to each group of hairless mice, and 50 μl of each sample was uniformly applied to the entire back of the animal. After 6 months, the photoaging reaction generated on the skin was visually evaluated according to the following criteria. (Judgment Criteria) 0: Light-skinned pink color and tajiwa are observed. 1: The skin color turned pale and Tajiwa disappeared. 2: The skin color was moderately pale, and Tajiwawa disappeared,
Weak nodules and large wrinkles and tarmi are observed. 3: The skin color was intensely pale, the white wrinkles disappeared, strong nodules, and strong wrinkles and tarmi were observed.

The average value of the scores of 5 animals was obtained, and the inhibition rate was calculated using the following formula. Table 2 shows the results.

[0027]

## EQU1 ## Inhibition rate = 100 × (average value of control group−average value of sample administration group) / average value of control group

[0028]

[Table 2]

From these results, it was found that the ascorbic acid derivative of the present invention has an effect of suppressing the UV-A photoaging reaction of hairless mice. <Ultraviolet Erythema Suppression Test> (Sample) (a) 300 mg of the derivative of Example 1 was diluted with 100 parts of a diluent solvent.
Dissolved in ml. (B) 300 mg of the derivative of Example 2 was added to 100 parts of the diluent solvent.
Dissolved in ml. (C) 300 mg of the derivative of Example 3 was added to 100 parts of the diluent solvent.
Dissolved in ml. (D) 300 mg of the derivative of Example 4 was added to 100 parts of the diluent solvent.
Dissolved in ml. (E) 300 mg of magnesium ascorbyl phosphate,
What was dissolved in 100 ml of diluent solvent. (F) Diluent solvent (equal mixture of propylene glycol and ethanol). (Method) Six groups of 6 Hartley guinea pigs (weight 700-900 g, male) were prepared as experimental animals.
The back was removed and shaved beforehand. To prevent the ultraviolet rays from hitting other than the irradiated area, a wide bandage with 6 small holes of 1.5 × 1.5 cm (3 in parallel on the left and right) was placed on the hair removal area, and ultraviolet rays were irradiated from above. did. Toshiba FL3 as the light source
0-SE was used. Irradiation energy amount is 768 mJ / c
It was set to m ² . After 24 hours, a uniform erythema reaction was observed at the above 6 sites. The sample was administered once before and three times after the ultraviolet irradiation. A single dose was 10 μl / site. The erythema reaction 24 hours after UV irradiation was evaluated according to the following criteria. (Judgment Criteria) 0: No skin reaction is observed. 1: Weak or erythema with unclear boundaries is observed. 2: Moderate erythema with unclear boundaries is observed. 3: Severe unclear erythema (sometimes accompanied by edema) is observed.

The average of the scores of 6 animals was determined, and the inhibition rate of the erythema of ultraviolet rays by each photoaging agent was determined in the same manner as in Experimental Example 1 above. The results are shown in Table 3.

[0031]

[Table 3]

As is clear from the above results, the photoaging inhibitor of the present invention comprising an ascorbic acid derivative exhibited a remarkable inhibitory effect on UV erythema of Hartley guinea pigs.

Next, based on the above results, how the whitening of the cosmetic composition containing the novel ascorbic acid derivative of the present invention
In order to demonstrate whether or not the skin-beautifying effect is excellent, an actual use test was conducted using the cosmetics shown in Examples 5 and 6 below, and the efficacy was confirmed. As comparative products, Examples 5 and 6 described later were used.
The cosmetics prepared by replacing the ascorbic acid derivative in Example 2 with magnesium ascorbate phosphate were used.

<Actual Use Test> 40 healthy adult women in Japan having dry skin, wrinkles and tarmi on the face were panelists, 1 group was 10 persons, and the face of group A was the product of the present invention. 5 lotion, B group with comparative lotion, C group face with emulsion of Example 6 which is the product of the present invention, D group with comparative emulsion. I had it used for a month. Three months after the start of use, each of the evaluation items for rough skin and wrinkles was evaluated self-evaluated for the improved condition or the condition of natural deterioration based on the following criteria. The results are shown in Table 4. (Evaluation Criteria) 3: There was a marked improvement. 2: It improved considerably. 1: Somewhat improved. 0: No change. -1: Natural deterioration.

[0035]

[Table 4]

As shown in the results of Table 4, the cosmetics of the present invention gave good results over all the evaluation items as compared with the cosmetics of the comparative products, and in particular, the rough skin and wrinkles were remarkably improved. It was demonstrated that the aesthetic appearance was improved and the skin-beautifying effect was excellent. It was also confirmed at the same time that the cosmetic of the present invention can be safely used without any subjective or objective symptoms on the skin during use.

Examples of cosmetics containing the ascorbic acid derivative of the present invention are shown below, but the present invention is not limited to these examples. The mixing ratio is parts by weight.

Example 5. Lotion (A) Ethanol 15 1,3-butylene glycol 2 Polyoxyethylene (50) hydrogenated castor oil 1 (B) Ethylparaben 0.05 Perfume 0.05 Citric acid 0.1 Sodium citrate 0.15 Example 1 Derivative of 0.5 Purified water 81.15 (Production method) The components of (A) are combined and dissolved at room temperature. On the other hand, each component (B) is also dissolved at room temperature, and this is added to the component (A) to solubilize it.

Example 6. Emulsion (A) Polyoxyethylene (20) hydrogenated castor oil 1.5 Coconut oil fatty acid monoglyceride 1 Oleic acid triglyceride 7.5 (B) Glycerin 2.5 Derivative of Example 2 0.5 Purified water 86.8 (C) Fragrance 0.2 (Manufacturing method) Combine with each component of (A), mix by heating, and 70 ° C.
And The respective components of (B) are combined and mixed by heating at 70 ° C., the component (A) is added to this and emulsified, and (C) is added while cooling.

Example 7. Cream (A) Vaseline 18 Cetanol 8 Polyoxyethylene (20) oleyl ether 1.4 Sorbitan monostearate 0.8 (B) Ethylparaben 0.3 Derivative of Example 3 0.1 Purified water 71.2 (C) Fragrance 0.2 (Manufacturing method) Combine with each component of (A), mix by heating, and 70 ° C.
And The components of (B) are combined and mixed by heating at 70 ° C, the component (B) is added to the component (A) to emulsify, the mixture is cooled to 35 ° C, and the component (C) is added.

Example 8. Cream (A) POE (30) Cetyl ether 2 Glycerin monostearate 10 Liquid paraffin 10 Vaseline 4 Cetanol 5 γ Tocopherol 0.05 BHT 0.01 2-Hydroxy-4-methoxybenzophenone 0.5 Butylparaben 0.2 ( B) Derivative of Example 4 5 Purified water 63.24 (Production method) The components of (A) are combined and heated to 80 ° C.
The component (B) is heated to 80 ° C. The component (B) is added to the component (A), the mixture is stirred and emulsified, and then cooled to 35 ° C.

Example 9. Emulsion (A) Synthetic Geyrow 2.5 Cetanol 1 Squalane 4 Stearic acid 1 Polyethylene glycol monostearate (25EO) 2.2 Glycerin monostearate 0.5 Butylparaben 0.1 γ-tocopherol 0.05 BHT 0.01 4 -(1,1-Dimethylethyl) -4'-methoxy-dibenzoylmethane 0.5 (B) 1,3-butylene glycol 3 propylene glycol 7 xanthan gum 0.1 carboxyvinyl polymer 0.2 potassium hydroxide 0.2 Example 1 1. Purified water 76.64 (Production method) Components (A) and (B) are dissolved with stirring at 70 ° C. The component (A) is added to the component (B), preliminarily emulsified, uniformly emulsified with a homomixer, and after emulsification, cooled to 30 ° C. with stirring.

Example 10. Lotion (A) POE (20) sorbitan monolaurate 1.5 POE (20) lauryl ether 0.5 ethanol 10 γ-tocopherol 0.02 (B) glycerin 5 sodium isoferurate 0.5 citric acid 0.15 citric acid Sodium acid 0.1 Derivative of Example 2 3 Purified water 79.23 (Production method) The components of (A) are combined and dissolved at room temperature. On the other hand, each component of (B) is also dissolved at room temperature and added to the component (A) to be solubilized.

[0044]

EFFECTS OF THE INVENTION According to the present invention, a novel ascorbic acid derivative having excellent water solubility and stability over time is provided, and further, it is highly safe and has effective photoaging resistance, and is safe without harmful effects on the skin. It is possible to provide a cosmetic that can be used for.

[Chemical 7]

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Claims (10)

[Claims] 1. An ascorbic acid derivative represented by the following general formula (1). 2. An ascorbic acid derivative represented by the following general formula (2). 3. An ascorbic acid derivative represented by the following general formula (3). 4. An ascorbic acid derivative represented by the following general formula (4). 5. The ascorbic acid derivative according to claim 3, wherein R is H and X is an alkali metal or an alkaline earth metal. 6. The ascorbic acid derivative according to claim 3, wherein R is H, X is K, and Y is H. 7. The ascorbic acid derivative according to claim 3, wherein the substituents are R for H, X for Na, and Y for H. 8. The ascorbic acid derivative according to claim 3, wherein R is H, X is 1 / 2Mg, and Y is H. 9. A cosmetic containing at least one ascorbic acid derivative according to claim 1. 10. One or more of the ascorbic acid derivative according to any one of claims 1 to 8 with respect to the total amount of cosmetics.
Cosmetics prepared by blending 01 to 10% by weight. Embedded image Embedded image Embedded image [Chemical 4]