JPH07215837A - Skin external agent - Google Patents

Abstract

PURPOSE:To obtain a keratinization simulation-inhibiting agent high in safety, excellent in a skin roughness-improving action, and useful as an ingredient for cosmetics. CONSTITUTION:A keratinization stimulation-inhibiting agent comprises 1,2- dihydroxy-4-(2-hydroxyethyl)benzene of the formula and/or its salt. The compound is added in an amount of 0.1-10wt.% to a skin external agent. The compound is obtained by isolation from Stachys and subsequently purifying the isolated compound by a general purification method such as column chromatography, or extracting the whole grasses of the fresh or dried Stachys with a solvent, removing impurities from the extract by a filtration method, etc., removing the solvent from the obtained filtrate, and subsequently purifying the residue by the purification means.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hyperkeratosis inhibitor and a skin external preparation containing the same.

[0002]

2. Description of the Related Art The outermost layer of the epidermis is formed by stacking keratinocytes that are strongly thickened and differentiated from the cell membrane of keratinocytes, and the stacked keratinocytes protect the living body from physical or chemical damage. Has been. Therefore, since the stratum corneum has a protective function, the protective function is always kept constant by keratinization of keratinocytes and exfoliation and turn-off of keratinocytes (turnover).

[0003] However, when keratinocytes are significantly damaged or the nutritional or metabolic balance of the body is lost, keratinization is promoted, keratinocytes are excessively produced, keratin thickening occurs, and keratinization is complete. Insufficient keratinization cells that cannot be completed will accumulate in the stratum corneum, and problems such as rough skin and wrinkles will occur.

Conventionally, such hyperkeratosis has been treated symptomatically with regard to skin roughness and wrinkles, mainly in the direction of controlling the amount of water in the stratum corneum of the skin. For example, a method of suppressing evaporation of water in the stratum corneum by using an occlusive agent having a good affinity with the skin and having hydrophobicity, and a method of storing moisture in the stratum corneum, and a method of retaining moisture such as hyaluronic acid All of the methods using a high polysaccharide as a moisturizer to enhance the skin hydration effect are aimed at improving skin roughness and wrinkles by retaining water in the stratum corneum.

However, these substances have no effect on the promotion of keratinization even though the dissipation of water in the stratum corneum can be prevented to some extent. There was nothing to do.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned circumstances, and has an effect of sufficiently suppressing keratinization of the skin and improving changes in the skin condition such as skin roughness and wrinkles. It is an object of the present invention to provide a keratinization-promoting inhibitor having the above and a skin external preparation containing the same.

[0007]

[Means for Solving the Problems] In order to solve the above problems, the present inventors have screened various chemical substances with a broad keratinization-suppressing action as an index. As a result, 1,2-dihydroxy-4- shown in Structural Formula 2 was obtained.
The inventors have found that (2-hydroxyethyl) benzene has an excellent effect of suppressing hyperkeratosis, and completed the invention.

[0008]

[Chemical 2]

That is, the present invention is 1, which is shown in Structural Formula 1,
The present invention relates to a keratinization-suppressing agent consisting of 2-dihydroxy-4- (2-hydroxyethyl) benzene and / or a salt thereof and an external preparation for skin containing 0.1% by weight of 0.1%.

The present invention will be described in detail below.

1,2-Dihydroxy-4- (2-hydroxyethyl) benzene, which is a keratinization-promoting inhibitor of the present invention, was isolated from sesame, a plant of the Labiatae family. In order to obtain this substance from sesame seeds, whole grass of dried or sesame seeds is extracted with a solvent, insoluble matter is removed from this extract by filtration, etc., and the solvent is distilled off from the obtained filtrate, followed by column chromatography. It may be purified using a general purifying means such as chromatography.

At this time, the extraction may be a continuous extraction method or a batch extraction method, and may be carried out at room temperature for several days, or may be heated to a temperature near the boiling point and immersed in a solvent for several hours. It is more preferable to add stirring at this time.

The solvent used for extraction is preferably a polar solvent, for example, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as chloroform and dichloromethane, diethyl ether, isopropyl ether and the like. The ethers may be used, and these may be used alone or in combination of two or more.

In addition to 1,2-dihydroxy-4- (2-hydroxyethyl) benzene obtained as described above, salts of this compound can be used in the keratinization-promoting agent of the present invention. In this case 1,2-dihydroxy-4-
(2-hydroxyethyl) benzene and one of its salts
The seeds may be used alone, or two or more kinds selected from these may be mixed and used.

As the salt usable in the present invention, sodium obtained by reacting 1,2-dihydroxy-4- (2-hydroxyethyl) benzene with an inorganic or organic base in equal amounts is used. , Salts with alkali metals such as potassium, salts with alkaline earth metals such as calcium and magnesium, salts with amines such as ammonia and triethylamine, and salts with basic amino acids such as arginine and lysine.

The external preparation for skin of the present invention contains 0.1 to 10% by weight of the above-mentioned keratinization inhibiting agent. The keratinization-promoting inhibitor may be added to the external skin preparation as long as it is added in accordance with a conventional method, and when it is added, it is generally used as an external preparation for skin as an optional component that can be used together.
Aqueous component, oil component, powder component, surfactant, moisturizer,
Thickener, colorant, fragrance, antiseptic, antioxidant, pH adjuster,
Examples include chelating agents, ultraviolet absorbers, anti-inflammatory agents, hormones, nucleic acids, and various vitamins.

In the present invention, the compounding amount of the keratinization-promoting inhibitor is preferably 0.1 to 10% by weight. this is,
This is because if it is less than 0.1% by weight, the effect of suppressing hyperkeratosis is not sufficiently obtained, and if it exceeds 10% by weight, the effect is flat and not economical.

【Example】

Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

Example 1 Production example of keratinization-suppressing agent 10 kg of dried sesame seeds was finely chopped into 5 liters.
Of ethanol and 5 l of purified water were added, and the mixture was heated under reflux for 3 hours with stirring. Then, the extract was cooled and filtered to remove insoluble matter. The filtrate was evaporated to dryness under reduced pressure, dissolved again in purified water, passed through a column packed with Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.), and further purified water 2
This was washed by pouring l. Thereafter, 2 l of ethanol was poured to elute the adsorbed substance, which was dried under reduced pressure, and then subjected to preparative high performance liquid chromatography (manufactured by Tosoh Corp., HLC83).
7, ODS column, elution solvent: 5 → 50% acetonitrile aqueous solution, detection: UV 220 nm), and 1,2-dihydroxy-4-which is a keratinization-promoting inhibitor of the present invention.
263 mg of (2-hydroxyethyl) benzene was obtained.

Example 2 Acute toxicity Six 10 ICR mice (male, body weight 25-35 g) were intraperitoneally injected with the 10% physiological saline solution of the keratinization-suppressing agent obtained in Example 1 at 1000 mg / Kg, respectively. I made an injection.
Life or death was determined 14 days after administration, but no death was observed. From this, it is understood that the keratinization-promoting agent of the present invention has an LD ₅₀ value of 1000 mg / Kg, and is highly safe.

Example 3 Local Toxicity Local toxicity in transdermal administration was investigated using 6 Hartley white guinea pigs. That is, 2 backs of morlemot
cm squared, 10% of the hyperkeratosis inhibitor of Example 1
The aqueous solution was administered daily at 0.05 ml for 5 days. On the 6th day, the skin reaction was evaluated according to the Japanese patch test standard (Japan Dermatological Association). That is,-: no reaction, ±: suspicious positive reaction, +: positive reaction, ++: reaction with edema 4
It is a criterion of stage. As a result, all animals showed no reaction (-).

Example 4 Inhibitory effect on keratinization Since keratinization is said to occur due to accelerated cell growth, epidermal cell proliferation of the test substance, which is determined by the following method, as a parameter for the inhibitory effect on keratinization is described. It evaluated using the growth-inhibition rate with respect to a factor (EGF). That is, Eagle's minimum medium containing 10% fetal bovine serum (FBS) (10% FB
A solution containing 2.5 × 10 ⁴ fibroblasts (balb / c 3T3 cells) in 0.5 ml of S-MEM) was added to each well of a 24-well plate in an amount of 1 ml. 1% after fibroblasts become saturated in monolayer
Replace with FBS-MEM, and use 12% under 5% carbon dioxide gas at 37 ° C.
Incubated for hours. Thereafter, 50 pg of mouse-derived EGF was added to each well of this 24-well plate per well, and the keratinization-promoting inhibitor of Example 1 was added at 0.5 μg per well at n = 4, and further for 16 hours. Cultured. In addition, only the mouse-derived EGF was added to the control. Then, 0.5 μCi / 50 μl of ³ H in each hole
-Thymidine was added, and after further culturing for 8 hours, the culture solution was removed, washed with a cooled isotonic phosphate buffer solution, cold 5% trichloroacetic acid was added, and the mixture was allowed to stand for 30 minutes. The supernatant was removed from this, and the trichloroacetic acid precipitate fraction was dissolved in 0.5M sodium hydroxide solution, then neutralized with 0.5M hydrochloric acid, and a scintillator was added to this, counted by a liquid scintillation counter, and grown. The radioactivity of ³ H-thymidine incorporated with the above was measured. Here, the radioactivity values of ³ H- thymidine incorporated into cells at hyperkeratosis inhibitor coexistence of Example 1 was incorporated into the cells in the control culture medium ³ H- radioactivity value thymidine To the growth inhibition rate, and the cell growth inhibition effect of the test substance on the cell growth promoted by EGF was evaluated. The cell proliferation inhibitory rate of the keratinization-promoting inhibitor of Example 1 obtained from this was 73.1%. From this, it is found that the keratinization-promoting inhibitor of Example 1 has an excellent cell growth inhibitory effect.

Example 5 Formulation Example 1 (Emulsion) An emulsion was prepared according to the following formulation. That is, A, B, C
Was dissolved by heating at 80 ° C., B was gradually added to A with stirring, C was further added, and the mixture was cooled with stirring to obtain an emulsion. (A) Behenyl alcohol 0.5 Synthetic geyrow 2.5 Olive oil 1.5 Sorbitan monostearate 1.5 POE (20) Behenyl ether 2 Butylparaben 0.1 BHT 0.1 Liquid paraffin 3.5 3.5 Horn of Example 1 Anti-promoting agent 0.1 Stearic acid 0.5 (B) Propylene glycol 10 Methylparaben 0.2 Caustic potassium 0.1 Water 50 (C) Carbopol 0.2 Water 27.2

Example 6 Formulation Example 2 (Emulsion) An emulsion was prepared according to the following formulation. That is, A, B, C
Was dissolved by heating at 80 ° C., B was gradually added to A with stirring, C was further added, and the mixture was cooled with stirring to obtain an emulsion. (A) Behenyl alcohol 0.5 Synthetic geyrow 2.5 Olive oil 1.5 Sorbitan monostearate 1.5 POE (20) Behenyl ether 2 Butylparaben 0.1 BHT 0.1 Liquid paraffin 3.6 Corner of Example 1 Anti-promoting agent 5 Stearic acid 0.5 (B) Propylene glycol 10 Methylparaben 0.2 Caustic potassium 0.1 Water 50 (C) Carbopol 0.2 Water 22.2

Example 7 Formulation Example 3 (Emulsion) An emulsion was prepared according to the following formulation. That is, A, B, C
Was dissolved by heating at 80 ° C., B was gradually added to A with stirring, C was further added, and the mixture was cooled with stirring to obtain an emulsion. (A) Behenyl alcohol 0.5 Synthetic geyrow 2.5 Olive oil 1.5 Sorbitan monostearate 1.5 POE (20) Behenyl ether 2 Butylparaben 0.1 BHT 0.1 Liquid paraffin 3.6 Corner of Example 1 Anti-promoting agent 1 Stearic acid 0.5 (B) Propylene glycol 10 Methylparaben 0.2 Caustic potassium 0.1 Water 50 (C) Carbopol 0.2 Water 26.2

Example 8 Formulation Example 4 (Emulsion) An emulsion was prepared according to the following formulation. That is, A, B, C
Was dissolved by heating at 80 ° C., B was gradually added to A with stirring, C was further added, and the mixture was cooled with stirring to obtain an emulsion. (A) Behenyl alcohol 0.5 Synthetic geyrow 2.5 Olive oil 1.5 Sorbitan monostearate 1.5 POE (20) Behenyl ether 2 Butylparaben 0.1 BHT 0.1 Liquid paraffin 3.6 Corner of Example 1 Anti-promoting agent 5 Wrinkle improver of Example 5 5 Stearic acid 0.5 (B) Propylene glycol 10 Methylparaben 0.2 Caustic potash 0.1 Water 50 (C) Carbopol 0.2 Water 17.2

Example 9 Formulation Example 5 (Cream) A cream was prepared according to the following formulation. That is, A, B
Were dissolved by heating at 80 ° C., B was gradually added to A while stirring, and cooled to obtain a cream. (A) Behenyl alcohol 6 Olive oil 6 Hydrogenated beef tallow 2 Microcrystalline wax 6 Liquid paraffin 20 Stearic acid 4 Glyceryl monostearate 2.5 POE (20) Behenyl ether 1.5 Beeswax 2 Benzalkonium chloride 0.1 Example 1 Keratinization inhibitor 5 (B) propylene glycol 10 caustic potash 0.1 water 36.8

Example 10 Use Test A use test was conducted using the emulsion of Example 5. That is, a group of 20 female panelists suffering from rough skin (age 35-70)
, The effect of improving rough skin was examined for the emulsion of Example 10 and the emulsion of Example 5 in which the keratinization-promoting inhibitor in Example 5 was replaced with water. These emulsions were used twice a day for 30 consecutive days, and the skin condition was photographed before and after use, and the degree of improvement was judged according to the following criteria. -:
No change or deterioration, ±: Slight improvement, +: Clear improvement, ++: Significant improvement. The results are shown in Table 1. It is clear that the keratinization-promoting agent of the present invention has an effect of improving rough skin.

[0029]

[Table 1]

Example 11 Use Test The cream of Example 9 was subjected to an actual use test to confirm the effect of improving rough skin. That is, 20 female panelists (aged 40 to 65 years old) suffering from rough skin are used and divided into 2 groups of 10 persons, one group containing the cream of Example 9 and the other group containing the cream of Example 9. The cream of Comparative Example in which the hyperkeratosis inhibitor of Example 1 was replaced with olive oil was given,
I had it used twice a day for 3 months continuously. After that, the degree of improvement in rough skin was examined by a questionnaire. The results are shown in Table 2.
From this, it can be seen that the creams of Examples have improved rough skin compared to the creams of Comparative Examples. Therefore, it is clear that the keratinization-promoting agent of the present invention has an excellent effect of improving rough skin.

[0031]

[Table 2]

[0032]

INDUSTRIAL APPLICABILITY The keratinization-promoting agent of the present invention is highly useful as a component of cosmetics because it is highly safe and has an excellent effect of improving skin roughness.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Nobu Yamamoto No. 560 Kashio-cho, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. Totsuka Laboratory (72) Inventor Toshio Miyase 4-chome, Nakata, Shizuoka, Shizuoka

Claims (2)

[Claims] 1. A keratinization-promoting agent comprising 1,2-dihydroxy-4- (2-hydroxyethyl) benzene represented by Structural Formula 1 and / or a salt thereof. [Chemical 1] 2. The anti-keratinization inhibitor according to claim 1, which is 0.0
An external preparation for skin containing 1 to 10% by weight.