JPH06157274A - Melanogenesis suppressing agent and skin external preparation - Google Patents

Abstract

PURPOSE:To obtain a melanogenesis suppressing agent and a skin external preparation having practical stability and safety and improving and treating effects on chromatosis. CONSTITUTION:The skin external preparation is obtained by blending N-(4- methylsuccimide-n-butyl)-p-cumaramide or/and its salt as an active ingredient of a melanogenesis suppressing agent in an amount of 0.01-10wt.% based on total amount of skin external preparation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a melanin production inhibitor and a skin external preparation, and more specifically, a melanin production inhibitor containing N- (4-methylsuccinimido-n-butyl) -p-coumaramide as an active ingredient, and An external preparation for skin is provided.

[0002]

2. Description of the Related Art Pigmentation after spots, freckles and sunburn is a result of markedly enhanced melanin production due to activation of pigment cells present in the skin, and is one of the troubles of the middle-aged and old-aged skin. Has become. Generally, melanin is considered to be formed by the action of the enzyme tyrosinase biosynthesized in pigment cells, changing from tyrosine to dopa and from dopa to dopaquinone, and then via intermediates such as 5,6-dihydroxyindophenol. ing.

Therefore, in order to prevent or improve the darkness of the skin, it is considered to inhibit the melanin production process or to bleach already produced melanin. Based on such an idea, various whitening components have been conventionally proposed.

[0004] For example, as a substance that inhibits the melanin production process, a substance that suppresses tyrosinase activity, such as a sulfur compound represented by glutathione, can be mentioned (for example, JP-A-63-24631). Further, hydrogen peroxide, hydroquinone, arbutin, ascorbic acid or the like has been used as a substance for lightly bleaching already produced melanin.

[0005]

However, these whitening ingredients are extremely poor in stability in the formulation system, cause discoloration due to decomposition, give off an offensive odor, and have insufficient efficacy at the cell or biological level. There was such a problem. Further, although hydroquinone has a strong whitening effect, it has safety problems such as causing irreversible white spots and rashes. Furthermore, concerns have been pointed out regarding arbutin in terms of cytotoxicity.

[0006] As described above, none of the whitening components used hitherto has been practically satisfactory in terms of efficacy, stability, and safety. The present invention has been made in view of the above circumstances, and in order to overcome the above problems, practical stability, safety, and melanin production having an effect of improving and treating skin pigmentation disease. An object is to provide an inhibitor and an external preparation for skin.

[0007]

Means for Solving the Problems The present inventors have conducted extensive studies to solve the above problems, and as a result, N- (4-methylsuccinimido-n-butyl) -p-coumaramide and salts thereof,
It has a strong inhibitory effect on the melanin production of living pigment cells, and found that it exhibits an excellent skin-whitening effect and is also excellent in stability and safety,
The present invention has been completed.

That is, the present invention provides a melanin production inhibitor containing N- (4-methylsuccinimide-n-butyl) -p-coumaramide or / and a salt thereof as an active ingredient, and a melanin production inhibitor for external use. 0.01 to 1 based on the total amount of the agent
A skin external preparation containing 0% by weight. Hereinafter, the present invention will be described in detail.

<1> N- (4-methylsuccinimido-n-butyl) -p-coumaramide used in the present invention The melanin production inhibitor and the external preparation for skin of the present invention are N- (4 -Methylsuccinimide-n-butyl) -p-coumaramide or / and a salt thereof as an active ingredient.

[0010]

[Chemical 1]

N- (4-methylsuccinimide-n-butyl) -p-coumaramide was isolated from the bulb of Lilyum ligare,
The structure has been determined, and can be isolated from the bulb of Lilyum ligare by a commonly used purification means such as column chromatography using an XAD column or an ODS column.

Also, chemical synthesis can be easily performed. For example,
1,4-Diaminobutane was reacted with 4-methylsuccinic anhydride to synthesize 1-amino-4-succinimidobutane, and 4-hydroxycinnamic acid in which phenolic hydroxyl groups were protected with urethane groups and DCC (dicyclohexylcarbohydrate) were synthesized. Disimid)
It can be easily produced by condensing with a condensing agent such as the above and then deprotecting. Then, by recrystallizing from alcohol, needle crystals having a melting point of 185 ° C. can be easily purified.

<2> Melanin production inhibitor and external preparation for skin of the present invention The melanin production inhibitor of the present invention comprises the above-mentioned N- (4-methylsuccinimido-n-butyl) -p-coumaramide or / and a salt thereof. Contains as an active ingredient. The salt may be any physiologically acceptable salt, and examples thereof include sodium salt, potassium salt and ammonium salt. These can be used alone or as an arbitrary mixture.

The external preparation for skin of the present invention preferably contains the melanin production inhibitor in an amount of 0.01 to 1 with respect to the total amount of the external preparation.
0% by weight, more preferably 0.1 to 5% by weight. Among the external preparations for skin, especially for those for the purpose of preventing and improving stains, freckles, and color darkening due to sunburn, the blending amount is preferably 0.1% by weight or more.

If the blending amount is less than 0.01%, the effect based on the melanin production inhibitory action is reduced. On the other hand, an amount exceeding 10% by weight may be used, but the effect will reach the ceiling.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and it is usually used for medicines, quasi drugs, cosmetics and the like, for example, ointments, creams, emulsions, lotions,
The dosage forms include packs and bath agents.

In addition to the above-mentioned active ingredients, the external preparation for skin of the present invention includes various bases and drugs generally used in pharmaceuticals, cosmetics, etc., such as an aqueous component, an oil component, a powder component, a surfactant, Moisturizers, thickeners, colorants, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, UV protectants,
Anti-inflammatory agents, other whitening ingredients, etc. can be added.
Among these, whitening ingredients include, for example, pantotheine-
Examples include s-sulfonic acid, isoferric acid, ascorbic acid magnesium phosphate, arbutin, kojic acid, and linoleic acid.

[0018]

The function of N- (4-methylsuccinimido-n-butyl) -p-coumaramide used in the present invention will be described below with reference to various experimental examples.

<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 ) and Eagle MEM containing 10% serum. Using a medium, in the presence of 5% carbon dioxide, 3
Cultured at 7 ° C. After 2 days of culturing, each sample of N- (4-methylsuccinimido-n-butyl) -p-coumaramide, hydroquinone, and arbutin was adjusted to 0 (control), 25, 50, 75, 100 μmol at the concentration in the medium. And added for 4 days.

After completion of the culture, the medium is removed and the inside of the flask is washed with equilibrium phosphate buffered saline (PBS), and then the cells are detached from the flask using trypsin and EDTA-containing medium, collected in a glass centrifuge tube and centrifuged. The cells were collected by separation. The obtained cells were washed once with PBS, and then a fixed amount of PBS was added to suspend the cells by flushing. Then, a fixed amount of this cell suspension was taken and the number of cells was counted with a Coulter counter. .

For each sample, the ratio of the number of cells at each concentration when the control was 100 was calculated. Also,
The remaining suspension was centrifuged again and collected, and the whiteness of the precipitate was visually observed according to the following criteria. The results are shown in Table 1.

(Evaluation Criteria) −: Equivalent to control +: Whitening to a lesser extent than control ++: Clearly whitening from control

[0023]

[Table 1]

Next, the amount of melanin in the cells was measured, and the melanin production suppression rate was examined. To the precipitate obtained above, 1N sodium hydroxide was added and dissolved by heating. After cooling, chloroform was added and the mixture was centrifuged again. 400 nm of the obtained supernatant
The absorbance was measured and the amount of melanin was determined using a calibration curve prepared in advance using synthetic melanin. The melanin amount was calculated as the amount per 10 ⁴ cells. Also,
The inhibition rate was calculated by the following formula. The results are shown in Table 2.

Inhibition rate (%) = (Melanin amount of control product−Melanin amount of test sample added product) × 100 / (Melanin amount of control product)

[0026]

[Table 2]

As is clear from the above results, N- (4-methylsuccinimido-n-butyl) -p-coumaramide used in the present invention has an action of significantly suppressing melanin production in pigment cells. Was demonstrated (Table 2). Further, it is recognized that the cell growth inhibitory action is weak and the cytotoxicity is low as compared with hydroquinone and arbutin (4-hydroxyphenyl-β-D-glucoside) which have been conventionally used as a whitening component (Table 2). <2> Inhibition of pigmentation by UV rays The back skin of brown guinea pigs (7 animals) was shaved and shaved with an electric hair clipper and shaver, and this area was cut at 1.5 x 1.5.
A black cloth with a total of 6 cm irradiation windows on the left and right sides is covered, and the FL20S / E30 lamp is used as a light source from above this cloth.
Ultraviolet rays of mW / cm ² / sec were irradiated for 4 minutes and 20 seconds.

This operation was performed once a day for 3 consecutive days. From the day after the end of irradiation, 2,3-dihydroxypropyl ferulate was added to 0 (control), 0.3%,
0.02 ml of a sample solution dissolved in propylene glycol / ethanol (3: 1) to be 0.5% 1
The application was continued for a total of 20 days. On the 21st day from the start of the experiment, the degree of pigmentation in the treated area was visually determined according to the following criteria. The results are shown in Table 3 as an average value.

(Criteria) 0: No pigmentation 0.5: Weak pigmentation with indistinct borders 1: Pigmentation with weak demarcation 2: Moderate pigmentation with definite borders 3: Definite intensity Pigmentation

[0030]

[Table 3]

As is clear from this result, when applied to the skin, ferulic acid-2,3-dihydroxypropyl suppressed the melanin production by ultraviolet rays at a concentration of at least 0.3%.

From the above experimental results, it can be seen that the ferulic acid-2,3-dihydroxypropyl used in the present invention has an excellent melanin production inhibitory action and a small cell growth inhibitory action.

[0033]

EXAMPLES Examples of the present invention will be shown below. The mixing ratio in the examples is parts by weight.

[0034]

Example 1 Oil-in-water cream As an external preparation for skin of the present invention, an example of an oil-in-water cream will be described. The components of Tables 4A and B are mixed and heated to 80 ° C. The formulation of A is added with the formulation of B, and the mixture is stirred and emulsified, and then cooled.

[0035]

[Table 4]

[0036]

Example 2 Emulsion Next, an example of emulsion will be described. After dissolving the components of Tables 5A and 5B at 70 ° C. with stirring, the prescription of A is added to the prescription of B and preliminarily emulsified, and uniformly emulsified with a homomixer. Then, it is cooled to 30 ° C. with stirring.

[0037]

[Table 5]

[0038]

[Embodiment 3] Lotion Next, an example of a lotion will be described. The ingredients of Table 6A 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 formulation of A to solubilize it.

[0039]

[Table 6]

[0040]

[Fourth Embodiment] Packing Charge An example of a packing charge will be described. Each component of Table 7A is dispersed and dissolved at room temperature. Each component of B is added to this and it melt | dissolves uniformly.

[0041]

[Table 7]

<Evaluation of skin external preparation of the present invention> The effect of the skin external preparation of the present invention was evaluated by a practical use test. N- (4-methylsuccinimido-n-butyl) -obtained in Example 1
The cream of the present invention containing 0.5% of p-coumaramide and the cream of Comparative Example in which N- (4-methylsuccinimido-n-butyl) -p-coumaramide in Example 1 was replaced with water. , A statistically equivalent group of 40 females suffering from black-skin, spots, and freckles were used continuously for 3 months, and the improvement effect was evaluated. The results are shown in Table 8
Shown in.

[0043]

[Table 8]

As is clear from this result, the product of the present invention containing N- (4-methylsuccinimido-n-butyl) -p-coumaramide is N- (4-methylsuccinimido-n-butyl) -p -It was proved to have a markedly effective effect of improving color blacks, stains and freckles as compared to the comparative example containing no comalamide.
No unfavorable reaction on the skin was observed at the site to which the product of the present invention was applied.

[0045]

According to the present invention, it is possible to provide a melanin production inhibitor and a skin external preparation which are excellent in whitening effect, and which are highly stable and safe. The external preparation for skin of the present invention can be used for the prevention, amelioration, and treatment of local pigmentation diseases such as spots, freckles, and dark skin due to sunburn, and systemic pigmentation diseases such as Addison's disease. Moreover, it has excellent safety and can be used for a long period of time.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location // A61K 7/42 7252-4C C07D 207/404 8314-4C (72) Inventor Yutaka Sashida Tokyo 3-20-7 Nanyodai, Hachioji

Claims (2)

[Claims] 1. N- (4-methylsuccinimide-n-butyl) -p-
A melanin production inhibitor containing coumaramide or / and a salt thereof as an active ingredient. 2. The melanin production inhibitor according to claim 1,
An external preparation for skin containing 0.01 to 10% by weight based on the total amount of the external preparation.