JP3344660B2 - External preparation for skin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an α-hydroxyacetic acid,
Α- selected from lactic acid, tartaric acid, citric acid and malic acid
Hydroxy acid and tocopherol are diester bonds or
An anti-inflammatory agent and a wound healing agent that is effective for preventing skin aging, improving skin roughness, etc. by synergistic effects of dermal cell growth promotion and anti-oxidation by compounding a derivative linked via a phosphodiester bond. Skin external preparations useful as skin cosmetics and the like.

[0002]

2. Description of the Related Art Recently, in the field of skin external preparations, many studies have been made to activate skin cells themselves and activate skin functions themselves, thereby improving skin symptoms and producing an anti-inflammatory effect or a wound healing effect. . Conventionally, various substances such as hormones, vitamins, γ-oryzanol, saponin and other crude drug extracts, placenta extracts, plant lectins, mushroom extracts, and animal-derived proteins have been used as such external preparations for skin. Was.

Further, we have previously found and disclosed that α-hydroxyacetic acid acts on and activates dermal fibroblasts (Japanese Patent Application No. 3-30109).
0). Since then, the proliferation action of α-hydroxy acids on dermal cells has been known.

[0004]

However, the above-mentioned skin activators are limited in use due to the side effect, or have insufficient action and effect, and must be used in a large amount. And there was a problem such as. In addition, in the case of plant and animal-derived substances, there is also a problem that quality control is particularly difficult, it is difficult to receive a stable skin activator, and when it is added to a skin external preparation, it is easily deactivated. .

[0005] Although α-hydroxy acid is a very useful skin activator, α-hydroxyacetic acid and lactic acid, which have particularly strong effects, are water-soluble.
The affinity for the skin was weak, it was difficult to be absorbed percutaneously, and a sufficient effect could not be exhibited.

[0006] The present invention solves the above-mentioned problems, and is an anti-inflammatory agent, a wound treatment agent, and the like which are effective in preventing skin aging, improving skin roughness, and the like.
The present invention relates to a skin external preparation useful as a skin cosmetic or the like.

[0007]

In order to solve the above problems, we have modified α-hydroxy acids,
An attempt was made to increase its biocompatibility and improve transdermal absorption.

[0008] Vitamin E group compounds, which are fat-soluble vitamins, themselves exhibit antioxidant effects, and when applied to the skin,
It has the effect of suppressing the production of lipid peroxide in the skin, thereby preventing aging of the skin. We use α-hydroxyacetic acid, lactic acid, tartaric acid, citric acid,
Tocopherol was bonded to the hydroxyl group of the α-hydroxy acid selected from coronic acid via dicarboxylic acid, phosphoric acid or the like to impart lipophilicity and enhance transdermal absorption.
At this time, α-hydroxyacetic acid, lactic acid, tartaric acid, citric acid
The carboxyl group of the α-hydroxy acid selected from acids and malic acids is preferably alkylated in advance by an ester bond with an aliphatic alcohol or the like in order to improve lipophilicity.

[0009] α-hydroxyacetic acid, milk used in the present invention
Acid selected from acid, tartaric acid, citric acid and malic acid
The droxy acid and the tocopherol form a diester bond or phos
Derivatives linked via a homodiester bond are, as described above, α-hydroxyacetic acid, lactic acid, tartaric acid,
Phosphate, alpha-hydroxy acids and bets selected from malic acid
Copherol can be obtained by diester bond or phosphodiester bond with dicarboxylic acid or phosphoric acid. The alpha-hydroxy acids, alpha-hydroxy acid, lactic acid, tartaric acid, citric acid, malic acid, preparative
Examples of coferol include α-, β-, γ-, and δ-tocopherols.

The dicarboxylic acid includes malonic acid, succinic acid, glutaric acid, adipic acid and the like. Protecting one of the two carboxyl groups of these dicarboxylic acids,
An ester bond is formed with tocopherol by a conventional method. Then, the remaining and removing the protective group of carboxyl group, alpha-hydroxy acid carboxyl groups were alkylated like, milk
Acid selected from acid, tartaric acid, citric acid and malic acid
The ester reaction with droxy acid is carried out, and α-
Hydroxyacetic acid, lactic acid, tartaric acid, citric acid, malic acid
Α-hydroxy acid selected from
Linked via an ester bond or a phosphodiester bond
Derivatives are obtained.

An α-hydroxy acid- tocopherol bond complex via a phosphodiester bond with phosphoric acid can be synthesized as follows. That is, a tocopherol, and a halophosphate esterifying agent of phosphoryl chloride are reacted in the presence of a non-reactive solvent deoxidizer such as benzene, a carboxyl group and the resulting product was alkylated like α -Hydroxyacetic acid, lactic acid, sake
Α-hydroxy selected from folic acid, citric acid and malic acid
React with silicic acid . The reaction can proceed in a solvent such as tetrahydrofuran in the presence of a deoxidizing agent.

The α-hydroxy prepared as described above
Selected from acetic acid, lactic acid, tartaric acid, citric acid, malic acid
Α-hydroxy acid and tocopherol form a diester bond
Induction linked via union or phosphodiester bond
The skin external preparation according to the present invention is obtained by adding the body to an ordinary skin external preparation base or cosmetic base.

[0013]

When the external preparation for skin according to the present invention is applied to the skin, α-hydroxyacetic acid, milk formulated as an active ingredient
Acid selected from acid, tartaric acid, citric acid and malic acid
Droxyic acid and tocopherol are diester linked or
Derivatives linked via a Suhojiesuteru bond bets
Due to the fat solubility of coferol , it has a good affinity for the skin and shows good transdermal absorption. The primarily in the dermis, esterases in the skin, phosphodiesterase, an enzyme phosphatase etc., bonds, phosphodiester bonds are hydrolyzed, alpha-human
From droxyacetic acid, lactic acid, tartaric acid, citric acid and malic acid
It is divided into the selected α-hydroxy acid and the tocopherol compound. α-hydroxyacetic acid, lactic acid, tartaric acid, que
Α-hydroxy acid selected from malic acid and malic acid acts on fibroblasts of the dermis to promote this proliferation and activate skin cells. On the other hand, tocopherol traps free radicals in the skin, breaks down peroxides, prevents peroxidation of skin lipids, and prevents skin aging caused by peroxidation of skin lipids.

[0014] Thus, in the external skin preparation according to the present invention, a skin cell activation action of α- hydroxy acid, Tokofe
The skin aging prevention effect by the roll 's inhibition of lipid peroxide production is synergistic, resulting in a synergistic skin improvement effect, which is an excellent effect in preventing skin aging such as inflammation and wound healing, improving skin roughness, wrinkles and sagging Show.

[0015]

EXAMPLES Further, the features of the present invention will be described in detail with reference to examples. First, Table 1 shows the formulation of an O / W emulsion ointment type skin external preparation as Example 1. In each of the following examples, lactic acid and phosphodiester of α-tocopherol were used as the α-hydroxy acid / vitamin E group compound binding complex. In Table 1, (1)-
The oil phase component of (5) is mixed and dissolved to make uniform, and heated to 75 ° C. On the other hand, the aqueous phase components (6), (7) and (10) are mixed and dissolved and heated to 75 ° C. Then, the oil phase component was added to the water phase component to emulsify, and after cooling, (8) and (9) were added at 50 ° C.
Mix.

[Table 1]

Next, Table 2 shows the formulation of skin lotion as Example 2. In Table 2, the components (1) to (7) were mixed with (9),
Dissolve to homogeneity, add (8) and mix, then (9) reduce the total amount to 1
00% by weight.

[Table 2]

Next, the formulation of the emulsion for skin as Example 3 is shown in Table 3. In Table 3, the oil phase components (1) to (6) are mixed and dissolved to make uniform, and heated to 75 ° C. On the other hand, (7), (8), (1
The aqueous phase components (0) and (13) are mixed and dissolved, and heated to 75 ° C. Pre-emulsifying by adding an oil phase component to the above water phase component,
After adding (9) to this, it is emulsified uniformly with a homomixer. Thereafter, the mixture was cooled, and the pH was adjusted by adding (11) to 50.
Add (12) at ℃ and mix.

[Table 3]

Finally, Table 4 shows the formulation of a skin cream as Example 4. In Table 4, the oil phase components (1) to (8) are mixed and dissolved to make uniform, and heated to 75 ° C. On the other hand, (9),
The aqueous phase components (10) and (12) are mixed and dissolved, and heated to 75 ° C. Then, after the oil phase component is added to the water phase component and preliminarily emulsified, the mixture is uniformly emulsified by a homomixer. Thereafter, the mixture is cooled, (11) is added and mixed at 50 ° C.

[Table 4]

[0019]

In order to demonstrate the effects of the present invention, the following tests were conducted for each of the above Examples. Here, in Example 1, lactic acid and α-tocopherol were used in place of the phosphodiester of α-tocopherol in Comparative Example 1,
Comparative Example 2 was prepared using lactic acid, and Comparative Example 3 was prepared by simply mixing 5.0% by weight of lactic acid and α-tocopherol. In the second, third, and fourth embodiments,
Comparative Example 4 using lactic acid, α-tocopherol, lactic acid and 5.0% by weight of α-tocopherol instead of lactic acid and α-tocopherol phosphodiester, respectively,
Comparative Example 5 and Comparative Example 6 were set. In each comparative example, lactic acid was added to the aqueous phase and α-tocopherol was added to the oil phase, and prepared in the same manner as in each example.

(1) Wound healing effect and anti-inflammatory effect For each of Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3, 10 mice each of which artificially generated a wound or inflammation were used,
Each sample was applied to a wound site or an inflamed site in an amount of 0.5 g seven times a day. On the seventh day, observe the condition of the wound or inflammation site,
The wound healing status was evaluated in three stages of "complete healing", "almost healing" and "incomplete healing", and the anti-inflammatory effect was evaluated in three stages of "effective", "slightly effective" and "ineffective" . The results are shown in Table 5 in terms of the number of mice obtained for each evaluation.

[Table 5]

From Table 5, in the group to which Example 1 was applied, complete healing of the wound was observed in all mice, and the anti-inflammatory effect was evaluated as effective in all cases. In contrast, in the Comparative Example 1 application group containing only α-tocopherol, the wound healing was incomplete in all cases, and the anti-inflammatory effect was evaluated as slightly effective in 6 out of 10 cases. No effect was observed in four cases. In the Comparative Example 2 application group containing only lactic acid, wound healing was observed in all cases, but complete healing was observed in 2 cases.
Stayed the example. With respect to the anti-inflammatory effect, efficacy was observed in all cases, but it was judged to be slightly effective in 4 cases. In the comparative example 3 application group in which lactic acid and α-tocopherol were simply blended, the wound healing and anti-inflammatory effect were considerably good, but the complete healing was observed in 4 cases, and the effective anti-inflammatory effect was recognized. Had only seven cases.

(2) Effect of improving skin roughness Each of Examples 2 to 4 and Comparative Examples 4 to 6 was used for one month by blinds for 20 months each having skin roughness symptoms, and the improvement of skin roughness symptoms was evaluated. . The evaluation was performed in five stages of "improvement", "slight improvement", "no change", "slight deterioration", and "deterioration". The results are shown in Table 6 by the number of panelists who gave each evaluation.

[Table 6]

As is clear from Table 6, in the group using Example 2, almost all panelists tended to improve the rough skin symptoms, and none of the panelists answered that the rough skin symptoms were not improved. In contrast, in the group using Comparative Example 4 in which only lactic acid was blended, almost all panelists showed an improvement tendency, but 35% of panelists answered that they were completely improved. In the use groups of Example 3 and Example 4, almost all panelists recognized improvement of the rough skin symptoms. On the other hand, in the group using Comparative Example 5 containing only α-tocopherol, no change in symptoms was observed, and lactic acid and α
-In the group using Comparative Example 6 in which only tocopherol was simply blended, all the subjects tended to improve the symptoms of rough skin, but only 55% of the panelists answered that they were completely improved.

(3) Antiaging Effect of Skin Aging Examples 2 to 4 and Comparative Examples 4 to 6 were blinded to 20 panelists, each in their 50s to 60s, who were worried about skin deterioration. They were used for one month and evaluated for improvement of skin aging symptoms. Improvement of skin aging symptoms includes prevention of wrinkles, skin sticking, and skin texture as evaluation items .
For the former, three of "valid", "slightly valid", and "invalid"
At the stage, the latter two are “good”, “somewhat good”,
The evaluation was made in three stages of “no change”. The results are shown in Table 7 by the number of panelists who gave each evaluation.

[Table 7]

In Table 7, in Example 2 use group, 60
% Of panelists rated it effective in preventing wrinkles, and none said it was ineffective. Everyone said that skin beam was good, and 75% of panelists were good about skin texture.
We evaluated as good . On the other hand, in the group using Comparative Example 4 containing only lactic acid, almost all the items were effective, but 25% answered that they were effective in preventing wrinkles.
%, 55% answered good about skin abrasion, and 40% answered good about skin texture. In Examples 3 and 4, 80 to 85% of panelists evaluated that wrinkle prevention was effective, all answered that skin stiffness was good, and panel texture exceeded 90%. Answered that it was good. In contrast, in the group using Comparative Example 5 containing only α-tocopherol, panelists evaluated as effective or good evaluated slightly less than 10% in all the evaluation items, and 20 to 30% evaluated somewhat effective or slightly good. However, the rest were evaluated as invalid or unchanged. In the group using Comparative Example 6 in which lactic acid and α-tocopherol were simply blended, all the panelists recognized an effective anti-aging effect on the skin, but 40% answered that they were effective in preventing wrinkles, Only 65% and 50% answered good about skin abrasion and skin texture, respectively.

As described above, the external preparation for skin, which is an example of the present invention, has a superior wound healing effect as compared with the comparative example containing only lactic acid or α-tocopherol or the comparative example using these alone. An anti-inflammatory effect was observed. In addition, the skin cosmetics of the examples of the present invention had excellent effects of improving rough skin symptoms and preventing skin aging as compared with the comparative examples. Therefore, in the present invention, α
-Hydroxyacetic acid, lactic acid, tartaric acid, citric acid, malic acid
Α-Hydroxy acid and tocopherol, which are selected from the group consisting of a single agent or a combination of the two, are clearly superior to wound healing, anti-inflammatory, skin aging prevention and skin condition improving effects. Can be done.

Further, α-hydroxyacetic acid, lactic acid, tartaric acid, citric acid,
Α-hydroxy acid selected from malic acid and tocopher
Roll is via diester bond or phosphodiester bond
Derivatives are stable in various forms of skin external preparations and skin cosmetics, have good percutaneous absorbability, and have α-hydroxyacetic acid, lactic acid, tartaric acid, citric acid,
Α-hydroxy acid and tocophero selected from ngolic acid
Since the compound exhibits very high activity due to the synergistic effect of each action of the compound, it may be added in a small amount, and no undesired effects such as skin irritation and side effects did not occur.

Therefore, according to the present invention, it is possible to provide a skin external preparation excellent in skin aging prevention, skin roughness improvement, wound healing effect, anti-inflammatory effect, etc. by activating skin cells and suppressing the production of lipid peroxide. Was.

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-5-112422 (JP, A) JP-A-4-99772 (JP, A) JP-A-59-219295 (JP, A) JP-A-4-112 270212 (JP, A) JP-A-1-265015 (JP, A) JP-A-5-505393 (JP, A) International Publication No. 92/7544 (WO, A1) (58) Fields investigated (Int. Cl. ⁷⁾ A61K 7/00-7/50

Claims (2)

(57) [Claims] (1) α-hydroxyacetic acid, lactic acid, tartaric acid,
Α-hydroxy acid selected from citric acid and malic acid
And tocopherol is a diester bond or phosphodies
Comprising a derivative linked via a ter bond ,
External preparation for skin. Wherein, wherein the skin external preparation is a cosmetic, a skin external preparation according to claim 1.