JPH11180854A - Skin preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a skin preparation for external use extremely excellent in a whitening action and capable of exhibiting its acting effect in a short time. SOLUTION: This invention relates to a skin preparation for external use containing a substance suppressing growth and/or activity of a dendritical projection of melanocyte (skin pigment cell) of, e.g. calmodulin inhibitor (naphthalenesulfonamide-based derivative, etc.), or lignin derivative, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a composition for external use on skin having an excellent skin whitening effect.

[0002]

2. Description of the Related Art There are many unclear points about the mechanism of skin pigmentation such as spots and freckles on the skin. However, in general, abnormalities of hormones and stimulation by ultraviolet rays cause excessive production of melanin pigment, It is believed to be abnormally deposited within. For the purpose of preventing or improving such pigmentation, conventionally, hydrogen peroxide, zinc peroxide, peroxides such as magnesium peroxide, or ascorbic acid, glutathione, colloidal sulfur, various natural products and the like as an active ingredient. Attempts have been made to use whitening cosmetics. However, many of these active ingredients have insufficient safety and stability, or have problems such as odor, and their effects are not necessarily sufficient.

[0003] On the other hand, in the United States and the like, hydroquinone is used as a skin bleaching agent. However, this hydroquinone is irritating and allergic. There's a problem.

[0004] Accordingly, various studies have been made to develop cosmetics having a skin whitening effect without such disadvantages. For example, as described above, pigmentation such as skin spots and freckles is considered to be caused by excessive production of melanin pigment, and tyrosinase is considered to be an important enzyme that acts on the production of melanin pigment. Studies have mainly been made on inhibiting or suppressing the action of this enzyme. As a result, a herbal extract containing mulberry bark, Kawakyu, Toki, cinnamon bark, summer hay, etc. (fragrance journal, June 1990, p.59), an external whitening agent using kojic acid and a kojic acid derivative ( JP-A-53-3
538, JP-B-56-18569, and 58
Nos. 22151, 60-9722 and 61
-60801), cosmetics containing quercetin as an active ingredient (JP-A-55-92305), and cosmetics containing quercetin fatty acid ester as an active ingredient (JP-A-5-92305).
JP-A-8-131911), cosmetics containing catechin having a polyphenol skeleton as an active ingredient (Japanese Unexamined Patent Publication No.
44375) and the like.

[0005] However, in all of these cosmetics, in actual use, the stability of the whitening component is still insufficient, or the effect is recognized at the cellular level, but the effect is sufficiently exhibited in humans. There is a problem that it is not performed, and it is not always satisfactory.

Further, the present inventors have overcome the drawbacks of such conventional skin external preparations for whitening, have excellent skin whitening effects, are high in safety, and have stability and odor. For the purpose of providing a skin external preparation without any problem, as a result of eagerly searching for those that inhibit or suppress tyrosinase activity having an important role in the production of melanin pigments, those having a polyphenol skeleton, especially ellagic acid compounds and It has been found that the alkali metal salt is excellent (Patent Registration No. 1839986).

[0007] However, as a result of further studies, even when the particularly excellent ellagic acid-based compound and its alkali metal salt are blended in a cosmetic or quasi-drug base, they can be added to ordinary external preparations. It was found that the effect was not always sufficient at the compounding concentration. As described above, it can be said that the development of a whitening agent having a sufficient effect is still limited only by studies on the production of melanin pigment such as suppressing tyrosinase activity.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide a skin external preparation which has an extremely excellent whitening effect and can exert its effect in a short time.

[0009]

According to the present invention, there is provided an external preparation for skin characterized by containing a substance that suppresses the growth and / or activity of dendrites of melanocytes.

That is, in view of the above circumstances, the present inventors have conducted research on improvement / suppression of pigmentation from a completely new viewpoint. Normal epidermis is composed of Malpighi-series cells, keratinocytes and dendritic elements, and the dendritic elements are composed of pigment cells, Langerhans cells and Merkel cells. Among them, pigment cells are called melanocytes and have dendrites (Modern Dermatology, Vol. 3, A, P6
5. Nakayama Shoten: 1982). In general, skin color is said to depend on the amount of melanin pigment in keratinocytes (epidermal cells), and this melanin pigment is produced in melanocytes (pigment cells) and migrates to keratinocytes around it. It is considered that the dendritic process of melanocytes is involved in this transition process. The dendrites are exposed to ultraviolet light or MSH (melanocyte stimulating).
hormone; melanocyte stimulating hormone), cAMP (ad
Stimulation such as enosine 3 ': 5'-cyclic monophosphate (cyclic adenosine 3': 5'-monophosphate) causes its number to increase and its length to become so-called an activated state. Was observed (K. Nakazawa, O. Damou
r, C. Collombel; Pigment Cell Research 6 406-416 (1
993)) There was no report on a substance that suppresses the function of activated dendrites or that suppresses the activation of dendrites.

Therefore, the present inventors have found that by suppressing the growth and / or activity of dendrites of melanocytes, the melanin pigments generated in melanocytes are less likely to migrate to keratinocytes, resulting in darkening of skin color. Thought that it can be prevented / improved, and as a result of intensive research,
A substance having an effect of suppressing the growth of melanocyte dendrites and / or its activity could be found. It has been found that dendritic projections of melanocytes are shortened and the number thereof is reduced when the projections return to a steady state from an activated state where the projections are long and numerous, and as a result, a whitening effect appears. Moreover, they have found that a substance that suppresses the growth and / or activity of dendrites also suppresses the production of melanin pigment. Also, in general, it is difficult to improve pigmentation when melanin migrates to the dermis, but by shortening the projections, it is possible to prevent melanin from migrating to the dermis,
The present invention has been completed.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. Examples of the substance that suppresses the growth and / or activity of dendrites of melasite, which is an active ingredient of the external composition for skin of the present invention, include a calmodulin inhibitor. Calmodulin is a calcium-binding protein having a molecular weight of about 16,000 and controls many enzyme activities including glycogen synthase and phospholipase. An example of a substance that inhibits the action of calmodulin is a naphthalenesulfonamide derivative W-5 [N- (6-Aminohexyl) -1
-Naphthalenesulfonamide], W-7 [N- (6-Aminohexy
l) -1-Chloro-Naphthalenesulfonamide) W-13 [N- (4
-Aminobutyl) -5-Chloro-Naphthalenesulfonamide)
Phenothiazine trifluoperazine, thioridazine, etc., pimozide, carmidazolium, prenyramine, vinca alkaloid, etc. can be mentioned (Hirotaka Hidaka
Shiro Kakiuchi, Calmodulin, Kodansha (1981)), but is not limited to these. These substances may be used alone or in combination.

[0013] Lignin and its derivatives may be mentioned as examples of other substances that suppress the growth and / or activity of dendrites of melasite. Lignin is
"One of the main components of woody plants such as wood, bamboo, straw, etc., a reticulated polymer compound formed by condensing constituent units having a phenylpropane skeleton" (Chemical Encyclopedia, Kyoritsu Shuppan Co., Ltd.) The derivative is a compound obtained by treating the lignin one or several times with an inorganic or organic reagent or a combination thereof. As specific examples of these, solubilized lignin include alkali lignin, Browns natural lignin, Boujolguman lignin, dioxane lignin, hydrotropic lignin, and water-insoluble lignin such as acid lignin such as sulfuric acid and hydrochloric acid, and oxidation. Examples of copper ammonia lignin, periodate lignin, and further lignin derivatives include ligninsulfonic acid, thiolignin, halogenated lignin such as chlor and bromide, carboxymethylated lignin, alcohol lignin such as methanol or ethanol or glycol, phenol lignin, Examples thereof include acylated lignin such as acetic acid and butyric acid, nitrolignin, aminolignin, and ethylene oxide adducts.

As particularly preferred substances, calmodulin inhibitors include W-5, W-7, W-13, trifluoperazine, vinca alkaloids, and lignin derivatives include ligninsulfonic acid, lignin acetate, chlorlignin, and ethylene oxide. Adducts can be mentioned.

These substances may be in the form of a plurality of derivatives or salts in one compound. Further, these substances may be used alone or in a combination of two or more.

The substance that suppresses the growth and / or activity of melanocyte dendrites used in the present invention may be synthesized or commercially available. In addition, the natural product extract may be extracted by an ordinary method or purified as necessary. Furthermore, a substance that inhibits / suppresses the activity of tyrosinase, which is an important enzyme for melanin pigment formation (abbreviated as tyrosinase inhibitor), does not necessarily inhibit the dendritic process of melanocytes, but is used in combination with a tyrosinase inhibitor. By doing
The whitening effect can be further enhanced in a short time. Examples of such tyrosinase inhibitors include ellagic acid, kojic acid, and plant extracts such as mulberry, peonies, and Toki. These tyrosinase inhibitors may be used alone or in combination of two or more, and the combination with a substance that suppresses the growth and / or activity of dendrites of melanocytes is not particularly limited. .

Although the shape of melanocytes is not necessarily constant depending on the environment in which they exist and the culture conditions, the main shapes of melanocytes are shown in FIGS. FIG. 1 shows a case where a melanocyte exhibits a bipolar state in which a stimulating factor is not added and a stimulating factor is added, and FIG. FIG. 4 shows the case where the growth and / or activity of dendrites is suppressed by the additive to exhibit a bipolar shape similar to that in FIG. 1, and FIG. Is present. In the present invention, what suppresses the growth and / or activity of dendrites of melanocytes
(A) a dendrite having a length shorter than that of melanocytes in normal skin without pigmentation or a melanocyte normally cultured without the addition of a stimulating factor, etc. Under conditions in which melanocytes are stimulated, including UV irradiation and MSH treatment, those that shorten the length of elongated dendrites, or that suppress the elongation to the length that should have grown without the addition thereof,
(C) Bipolar or vanishing radial dendrites. Further, the number of dendrites can be considered in the same manner as the length. That is, (D) the number of dendrites is less than or equal to the number of melanocyte dendrites in normal skin having no pigmentation or the like, and particularly cultured without adding any stimulating factors. Either one that reduces the number of dendrites that have increased under conditions where melanocytes are stimulated, such as ultraviolet irradiation or MSH treatment, or one that suppresses the increase to the number that would otherwise increase without the addition thereof Or something. In addition, A to C and D to E may be each alone or may be combined.

The amount of the substance that suppresses the activity of dendrites of melasite is 0.000001 to 30% (% is% by weight, the same applies hereinafter), preferably 0.001 to 10%. The compounding amount is
0.000001% is the concentration at which the effect begins to appear on the cells, while if it exceeds 30%, it is not very desirable in terms of feeling of use, irritation to skin, economy and the like. When a tyrosinase inhibitor is used in combination, the amount of the tyrosinase inhibitor is 0.000001 to 30%, and the ratio of the concentrations is not particularly limited.

The external preparation for skin of the present invention may contain, in addition to the above-mentioned essential components, various components which are usually used in the external preparation for skin as long as the effects of the present invention are not impaired. Can be blended. For example, oils, water, humectants including surfactants, alcohols, thickeners, antioxidants, sequestering agents, pH adjusters, preservatives, fragrances, pigments, ultraviolet absorbers, ultraviolet scattering agents, vitamins, Amino acids and the like can be blended.

The external preparation for skin of the present invention is a base in a wide range such as an aqueous solution, a solubilizing system, an emulsifying system, a powder dispersing system, a water-oil two-layer system, a water-oil-powder three-layer system and the like. Its use is wide-ranging in various forms, such as basic cosmetics such as creams, milky lotions, lotions, serums, and packs; makeup cosmetics such as lipsticks and foundations; pharmaceuticals such as jellies and ointments; It can be suitably used. In addition, since the compounding form, the compounding amount, and the use range are various, these preferable use amounts cannot be specified unconditionally.

[0021]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be specifically described below based on embodiments.

Example 1 Human melanocytes were seeded at 5 × 10 ³ cells / well on a 6-well plastic culture plate and incubated at 37 ° C. in the presence of 5% CO _2.
After culturing for 2 days, the medium was exchanged, and each of the substances shown in Table 1 was added. The cells were further cultured for 2 days, and the state of dendrites was observed. The observation results are shown in Table 1, and the shape of melasite is shown in FIGS.

[0023]

[Table 1]

As shown in Table 1, calmodulin inhibitors such as W-7 and lignin derivatives such as lignin sulfonic acid form a bipolar form based on dendrites which should be activated and extended radially by MSH. It can be seen that the distance is close and the elongation is suppressed.

Example 2 Human melanocytes were seeded at 5 × 10 ³ cells / well on a 6-well plastic culture plate and incubated at 37 ° C. in the presence of 5% CO _2.
After culturing for 2 days, the medium was replaced and MSH was added (A), and the cells were cultured for 2 days. The medium was replaced again, and each substance shown in Table 2 was added (B). The state of dendrites at the site was observed. Table 2 shows the observation results.

[0026]

[Table 2]

As shown in Table 2, calmodulin inhibitors such as W-7 and lignin derivatives return dendrites that have been activated by MSH and radially extended to dendrites close to the original bipolar shape, and have the same length. It can be seen that is suppressed.

Example 3 B16 melanoma cells were seeded at 1 × 10 ⁴ cells / well on a 12-well plastic culture plate, and cultured in the presence of 5% CO ₂ .
After culturing at 37 ° C. for 2 days, the medium was replaced and the substances shown in Table 3 were added, followed by further culturing for 2 days. After completion of the culture, the medium was discarded, the cells were detached from the plate with a trypsin solution, transferred to an Eppendorf tube, and collected by centrifugation. After washing with phosphate buffered saline, the color change of the cells was observed. Table 3 shows the results.

[0029]

[Table 3] (*) ±: Slight fading compared to the color of cells without addition of dendritic activity inhibitor and tyrosinase inhibitor. +: Fading. ++: Discolored considerably. +++: extremely fading.

As shown in Table 3, it can be seen that the dendritic activity-inhibiting substance, even when used alone, considerably discolors the color of B16 melanoma cells. It can be seen that when a tyrosinase inhibitor is used in combination therewith, the color of B16 melanoma cells is further remarkably faded. This indicates that the dendritic activity inhibitor suppresses not only dendritic activity but also melanin pigment productivity.

Example 4 The whitening effect as an external preparation for skin shown below was evaluated for its whitening effect. Group 1: 1.0% whitening agent in which ellagic acid was dissolved in propylene glycol as a tyrosinase activity inhibitor. Group 2: 1.0% whitening agent in which trifluoperazine was dissolved in propylene glycol. Group 3: 1.0 in which W-13 was dissolved in propylene glycol.
% Whitening Agent Group 4: 1.0% of W-7 dissolved in propylene glycol
Whitening agent Group 5: 1.0% whitening agent with vinca alkaloid dissolved in propylene glycol Group 6: 1.0% whitening agent with ligninsulfonic acid dissolved in propylene glycol Group 7: Lignin acetate dissolved in propylene glycol
1.0% whitening agent with chlorlignin dissolved in propylene glycol 1.0% whitening agent with lignin ethylene oxide adduct (EO = 1) dissolved in propylene glycol Group 10: carboxymethylated lignin with propylene 1.0% whitening agent dissolved in glycol Group 11: Whitening agent in which 0.5% each of trifluoperazine and ellagic acid are dissolved in propylene glycol

[Whitening Evaluation Method] In each group, the back body hair of 7 colored guinea pigs was shaved with a hair clipper and a shaver.
By irradiating ultraviolet rays once a day for a total of eight times, two pigmentation areas of about 2.25 cm ² were formed on the back of each guinea pig. 20 μl of test and control samples once a day, 5 times a week
Of the pigmentation once a week and use the standard color chart (Nippon Color Research Institute, "Neutral Value Sc"
ale 38 ”). Then, the brightness difference was calculated from a value converted into a Munsell value (average value) described in “Neutral Value Scale 38”. The "brightness difference" indicates how much the change in the brightness of the pigmentation approaches the skin color without pigmentation by ultraviolet irradiation, as compared to the control (only propylene glycol is applied). The evaluation is shown in Table 5 based on the results shown in Table 4 for the results at 2 weeks and 4 weeks after application.

[0033]

[Table 4] A: Excellent B: Excellent C: Good D: Invalid

[0034]

[Table 5]

As shown in Table 5, trifluoperazine, which is a dendritic activity inhibitory substance, shows a high whitening effect even when used alone. However, when ellagic acid, which is a tyrosinase inhibitor, is used in combination, the whitening effect is higher than when used alone. It can be seen that is significantly improved. Further, it can be seen that the period until the whitening effect is recognized tends to be shortened.

Example 5 An oil phase component and an aqueous phase component having the following compositions were separately separated by 70
After heating and dissolving at 0 ° C., the mixture was emulsified, and while cooling, a flavor was added on the way, and the mixture was further cooled to room temperature to prepare an emulsion.
The whitening effect of the emulsion was extremely excellent. Component Content (%) Promethazine 0.1 Squalane 5.0 Isopropyl palmitate 2.0 Cetostearyl alcohol 1.2 Glycerin monostearate 1.3 Polyethylene glycol monostearate 1.5 Propylene glycol 5.0 Octylglucoside 0. 5 Carboxyvinyl polymer (Mw = 1 million to 1.5 million) 0.1 Triisopropanolamine 0.1 Methylparaben 0.2 Purified water Balance Perfume Trace amount

Example 6 A cosmetic solution was prepared by mixing the following components.
The whitening effect of the beauty solution was extremely excellent. Ingredient Content (%) Prenyramine lactate 0.2 Ellagic acid 0.5 Glycerin 4.0 Ethanol 8.0 Carboxyvinyl polymer (Mw = 1,000,000 to 1.5,000,000) 0.2 Triethanolamine 0.12 Purified water Balance

Example 7 The oil phase component and the aqueous phase component shown below were separately dissolved by heating at 70 ° C., and the mixture was mixed and emulsified while stirring.
After cooling to room temperature, a cream was prepared. The whitening effect of the cream was extremely excellent. Ingredient Content (%) W-13 0.1 Lanolin 2.0 Sorbitan monostearate 2.0 Polyoxyethylene sorbitan monopalmitate methyl glucoside monooctyl ester 5.0 Beeswax 10.0 Squalane 15.0 Liquid paraffin 0 5.5 Oil-soluble licorice 3.0 Propylene glycol 7.0 Dipropylene glycol 0.2 Methyl paraben Balance

Example 8 An oil phase component and an aqueous phase component having the following compositions
After heating and dissolving at 0 ° C., the solution was mixed and emulsified while stirring, and cooled to room temperature to prepare a cream. The whitening effect of the cream was extremely excellent. Ingredient Content (%) Ethoxylignin 0.1 Lanolin 2.0 Sorbitan monostearate 2.0 Polyoxyethylene sorbitan monopalmitate (EO = 5) Methyl glucoside monooctyl ester 5.0 Beeswax 10.0 Squalane 15. 0 Liquid paraffin 0.5 Oil soluble licorice 3.0 Propylene glycol 7.0 Dipropylene glycol 0.2 Methyl paraben Balance Purified water Trace amount Flavor

[0040]

EFFECTS OF THE INVENTION The topical skin preparation of the present invention is a composition having an enhanced whitening effect by containing a substance that inhibits the activity of melanocyte dendrites or a substance that inhibits or inhibits tyrosinase activity. And can exhibit its whitening effect in a short time.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram of the shape of melanocytes in an inactive state (bipolar state) to which no stimulating factor is added.

FIG. 2 is an explanatory view of the shape of melanocytes in an active state (radial) to which a stimulating factor has been added.

FIG. 3 is an explanatory view of the shape of melanocytes in an inactive state (bipolar state) similar to FIG. 1 in which the growth and / or activity of dendrites is suppressed by an additive.

FIG. 4 is an explanatory diagram of the shape of melanocytes in a case where the inhibitory action of an additive is slightly relaxed (bipolar but partially radial).

Claims (1)

[Claims] 1. An external preparation for skin comprising a substance that suppresses the growth and / or activity of dendrites of melanocytes.