JPH1171231A - Skin whitening agent and skin whitening cosmetic - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin whitening agent excellent in prevention/suppression of fleckle development clue to ultraviolet radiation exposure, and useful in formulation in cosmetics or medicines, by including bakuchiol, a new tyrosinase inhibitor. SOLUTION: This skin whitening agent is obtained by including 0.005-5.0 wt.% of bakuchiol afforded by removing furocoumarin derivatives and flavonoids through purification treatment (e.g. using a silica gel column, synthetic polymer adsorbent column) of an organic solvent extract from pref. the seeds of Psoralea corylifolis L., and, as necessary, other skin whitening agent(s), medicinal ingredient(s), and physiologically active substance(s)(e.g. progesterone, corticosterone).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel whitening agent and a cosmetic having a whitening effect.

[0002]

2. Description of the Related Art Coloring, darkening, spots and freckles of human skin may be caused by internal factors such as abnormal secretion of hormones and metabolic disorders, but rather directly or directly by ultraviolet rays derived from sunlight. It is overwhelmingly often caused by indirect stimulation and activation of melanocytes. That is,
The coloration of the skin and the increase of spots and freckles are promoted by the passing of the black pigment / melanin abnormally produced by the activation of melanocytes to the epidermal cells or intensively storing in specific parts of the skin.

[0003] As a means for preventing skin coloration, spots, freckles, etc. from increasing due to the mechanism described above and maintaining white skin, a substance that inhibits the activity of an enzyme or tyrosinase, which is conventionally strongly involved in melanin production in melanocytes, has been proposed. Use has been studied and vitamin C and its derivatives, kojic acid, hydroquinone, arbutin, ellagic acid and the like have been confirmed as effective substances.

[0004] However, these drugs are not satisfactory because they may irritate the skin or cause allergies, and may not have sufficient heat and light stability and storage stability. Was.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to suppress and prevent the increase of skin coloring, spots, freckles, etc. due to ultraviolet rays and to have excellent storage stability, and to provide cosmetics, pharmaceuticals, quasi-drugs, etc. An object of the present invention is to find a novel tyrosinase inhibitor that can be easily incorporated into plant components having high safety, and to provide it as a whitening agent and a whitening cosmetic.

[0006]

Means for Solving the Problems The whitening agent of the present invention which has succeeded in achieving the above object contains bactiol, which is a kind of monotenpene phenol derivative, as an active ingredient. Bactiol is a colorless oily compound at room temperature having the structure shown below. It is soluble in ethanol, methanol, acetone, chloroform, methylene chloride, ethyl acetate, etc., but hardly soluble in water.

[0007]

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[0008] Bactiol, which is an active ingredient of the whitening agent and the whitening cosmetic of the present invention, has an effect of inhibiting the activity of tyrosinase involved in the synthesis of the black pigment melanin, thereby suppressing the production of melanin and thus a whitening effect. Is shown.

[0009] Bactiols can be synthesized chemically, but legumes, Dutch bean (Psoralea cor
ylifolia L.), which is used as a crude drug under the name of "bone fat" and can be extracted and used with the above-mentioned solvent.

[0010] However, the osseous fat contains photocoumarin derivatives (for example, psoralen and isopsoralen) which have a photosensitizing effect and cause allergies, and these are extracted together with bactiol. It is desirable to remove the extract during the purification process so as not to be mixed.

[0011] Bone cartilage fat also includes flavonoids such as babakin, babakinin, isobabacin and the like, which are known to have a tyrosinase activity inhibitory action. Since these flavonoids are extracted together with bakuchiol, they can be used as a whitening agent component as they are. However, since they are coloring substances, the use of the whitening agent may be limited, and therefore, they are also removed in the purification step. It is desirable.

The whitening agent of the present invention containing bactiol as an active ingredient, when it is a solid preparation, includes sugars such as cellulose and dextrin; sugar alcohols such as sorbitol and mannitol; and other anhydrous sodium sulfate, sodium hydrogen carbonate, and kaolin. , Clay and other inorganic compounds as excipients, and in the case of liquids, ethanol, propylene glycol,
By appropriately mixing alcohols such as 1,3-butylene glycol and various oils such as vegetable oils and fats, mineral oils and waxes as solvents, the formulation operation becomes easy and the preparations become easy to use.

[0013] The whitening agent of the present invention can be applied to the skin by applying, spraying, or any other method, a drug, various quasi-drugs,
When added to cosmetics and the like, it can be used for prevention of skin blackening and erythema. A preferable addition amount is 0.005 to 5.0% by weight as bakuchiol. In this case, if necessary, other whitening agents, other optional medicinal ingredients, physiologically active substances, and the like can be added.

Examples of physiologically active substances which can be contained in cosmetics in combination with the whitening agent of the present invention include progesterone, corticosterone, hydrocortisone, and the like.
17β-estradiol, ethinylestradiol,
Hormones such as estrone; mucopolysaccharides such as hyaluronic acid, dermatan sulfate, keratan sulfate, chondroitin, heparin, chondroitin sulfates, chitin, chitosan;
Complex lipids such as glycerophospholipids, sphingolipids, glyceroglycolipids, and glycosphingolipids; superoxide dismutase, catalase, β-carotene, oil-soluble licorice extract, glabridine, lycochalcone A, baicalin, baicalein, ginkgo extract, and soybean extract Substances, kujin extract, hamamelis extract and other substances having an active oxygen scavenging action; substances having an anti-inflammatory action such as allantoin, guaiazulene, kama azulene, stearylepsilonaminocaproic acid, indomethacin, zinc oxide; arnica extract, intinko Extract, squirrel extract, oak extract, chamomile extract, liquorice extract (aqueous extract), hawthorn extract, sicon extract,
Peonies extract, peanut extract, peanut extract, birch extract, horse chestnut seed extract, calendula extract, sapling extract, rosemary extract, sawberry grass extract, mugwort extract, yokuninin extract, Plant extracts having anti-inflammatory and anti-allergic activities, such as aloe extract, dirt extract, senkyu extract, psycho extract, boufu extract, yokinin extract, and loofah extract; collagen, hydrolyzed collagen, elastin, vitronectin , Fibronectin, placenta extract, royal jelly, animal extract such as conchiolin hydrolyzate; retinol, retinal, retinoic acid, pantothenic acid, panthenol, riboflavin, pyridoxine, tocopherol, ascorbic acid, folic acid, nicotinic acid Vitamins; nucleic acids and their bases; amino acids; cholesterols; plant sterols; lipoproteins; microorganism-derived products such as fermented products of bifidobacteria, fermented products of lactic acid bacteria, yeast extracts, and litchi mycelium extracts; glycyrrhizin Glycyrrhetinic acid derivatives such as acid, glycyrrhetinic acid and stearyl glycyrrhetinic acid;
organic acids such as α-hydroxy acids; and the like.

Examples of whitening cosmetics containing bakuchiol include solutions, ointments, emulsions, packs, haptics, and the like.
Any dosage form is possible, such as dusting agents, soaps, creams, rinses, baths, and the like. There are no restrictions on the auxiliaries used in the production thereof, and various animal and plant fats and oils, waxes, higher fatty acids, mineral oils, alcohols such as ethanol, glycerin, and 1,3-butylene glycol, surfactants, and thickeners Agent,
Any of the commonly used auxiliaries such as antioxidants, preservatives, fragrances, coloring agents and the like can be used.

[0016]

【Example】

Example 1 Extraction and purification of bakuchiol 1 kg of osseous fat is immersed in 10 liters of absolute ethanol.
Heat under reflux for 2 hours. Thereafter, the mixture was filtered, and the residue was immersed again in 10 liters of absolute ethanol and treated similarly. The extracts obtained by the above two treatments were combined, concentrated and dried under reduced pressure to obtain 140.8 g of an extract.

The extract was combined with 500 ml of water and 5 parts of chloroform.
After adding 00 ml, a chloroform layer was obtained by liquid-liquid countercurrent distribution. 500 ml of chloroform was further added to the aqueous layer,
The same treatment was performed twice. The chloroform layers were combined, concentrated under reduced pressure and dried to obtain 127.2 g of an extract (hereinafter, this extract is referred to as extract A).

The whole amount of the extract A was put on a 4 liter silica gel column, and 7 liters of a mixed solvent of hexane: ethyl acetate = 2: 1 was passed. The passing solution was concentrated under reduced pressure to obtain 30.4 g of a solid. (Hereinafter, this is referred to as extract B. Flavonoids extracted together with bactiol were removed by the purification so far.)

28.7 g of the extract B was placed on a 5 liter silica gel column, and 5 liters of a mixed solvent of hexane: ethyl acetate = 7: 1 was passed through the column, followed by washing the column (the furocoumarin derivative extracted together with bactiol was used here). Until purification). Subsequently, 5 L of a mixed solvent of hexane: ethyl acetate = 6: 1 was passed through, and the passed solution was concentrated under reduced pressure to obtain a pale brown oily bakuchiol fraction of 8.6.
g was obtained (hereinafter, this is referred to as a bakuchiol fraction).

Example 2 Extraction and purification of bactiol 200 g of osseous fat was immersed in 2 liters of a 90% by weight aqueous ethanol solution and heated under reflux for 2 hours. After filtration, the residue was again immersed in 2 liters of a 90% by weight aqueous ethanol solution, and operated in the same manner. The obtained extracts were combined and concentrated under reduced pressure to obtain 37.3 g of an extract. To this extract was added 500 ml of a 50% by weight aqueous solution of ethanol, and the mixture was sufficiently stirred and dissolved, and then filtered using diatomaceous earth as a filter aid to obtain a clear liquid. This is used as a synthetic polymer adsorbent (Diaion HP-
20; product of Mitsubishi Chemical Corporation) was passed through a column filled with 500 ml at SV = 1, and then the column was washed with 2.5 liters of a 50% by weight aqueous ethanol solution (furocmarin derivatives and flavonoids extracted together with bactiol) Was removed by the purification so far.)

Thereafter, 3 liters of an 85% by weight aqueous ethanol solution was passed through the column, and the passed solution was concentrated under reduced pressure.
A brown paste was obtained (yield 8.3 g; hereinafter, referred to as bakuchiol fraction).

The extract and bactiol fraction of each of the above examples were subjected to quantitative analysis of bactiol and psoralen by high performance liquid chromatography. Table 1 shows the analysis results.

[0023]

Table 1 Bactiol content ( % by weight ) Psoralen content (% by weight) Extract A 23.5 0.72 Extract B 61.2 No detectable Bactiol fraction 91.3 No detectable Bactiol fraction 78 .9 Not detected

A part of the bactiol fraction was further purified to obtain a purified bactiol having a purity of 99.8%.

Example 1 The bactiol fraction and purified bactiol obtained in each of the above examples were examined for their inhibitory activity on tyrosinase by the following test methods. Table 2 shows the results.

Tyrosinase inhibitory activity test method: 0.05%
0.5 ml of a sample solution obtained by dissolving the sample in a tyrosine solution, a tyrosinase solution [a tyrosinase preparation manufactured by Sigma (titer: 3,40
0 unit / mg) solution with a concentration of 60 μg / ml] 0.7 ml, and 1/1
Mix 1.8 ml of 5M phosphate buffer (pH 6.8),
In 1 hour of reaction, measuring absorbance A ₁ in 475 nm. The absorbance A ₁ is proportional to the concentration of a series of coloring components such as melanin generated from tyrosine. The same operation was performed for the case where no sample was added, and the absorbance A _{0 at} 475 nm was measured.
Is measured, and the tyrosinase inhibition rate is calculated from the following equation. Tyrosinase inhibition rate (%) = (1−A ₁ / A ₀ ) × 100

The above-mentioned inhibition rate is measured by changing the sample concentration of the sample solution in a stepwise manner, and the sample concentration at which the inhibition rate is 50% is determined by an interpolation method, and is displayed as IC ₅₀ .

[0028]

[Table 2]

Example 2 A cream of the present invention using the above bactiol fraction as a whitening agent and a control product of the same composition except that the bakuchiol fraction was not added were prepared by a conventional method (numerical values are% by weight). .

[0030]A (the present invention) B (control product)  Surfactant A (* 1) 3.5 3.5 Surfactant B (* 2) 1.5 1.5 Liquid paraffin 25.0 25.0 Whale wax 5.0 5.0 Lanolin 5.0 5.0 0 Cetanol 2.0 2.0 Paraoxybenzoic acid ester 0.1 0.1 Glycerin 3.0 3.0 Carboxyvinyl polymer (* 3) 5.0 5.0 Vactiol fraction 0.1 0 Purified water Remaining Remaining amount * 1: Self-emulsifying glyceryl monostearate * 2: Sorbitan monostearate * 3: 1% aqueous solution

Next, the creams A and B were tested for whitening effect by the following method.

Test method: The back of a brown guinea pig was dehaired,
Oxoralen of 0.1% is applied there, and after 30 minutes, P
Irradiate with UVA at 1 J / cm ² . A part of the area irradiated with PUVA is divided into three sections of 2 cm × 2 cm, and one of the creams A and B is used in two of the sections.
It is applied immediately after irradiation and 12 hours after. Nothing is applied to one section. 24 hours after irradiation, the concentration of the resulting erythema is determined by visual observation. Further, in the PUVA-irradiated area, a part where pigmentation was observed after one week in a part not used in the erythema suppression effect confirmation test was divided into three sections of 2 cm × 2 cm, and the creams A and B were divided into two sections. Is applied once every morning and evening for 7 consecutive days (nothing is applied to one section). Seven days after the start of the application of the cream, the degree of increase in the coloring due to the pigmentation in each section is compared by visual observation, and the extent to which the pigmentation that progresses even after the start of the cream application is suppressed by the cream is determined.

The test results were as follows. Erythema inhibitory effect: No application ≤ cream B≪ cream A Pigmentation inhibitory effect: no application ≤ cream B≪ cream A

Example 3 The following raw materials were uniformly emulsified by a conventional method for producing an emulsion.
An emulsion having a whitening effect was produced (values are% by weight of the product). Stearic acid 2.0 Cetanol 1.5 Vaseline 3.0 Lanolin alcohol 2.0 Liquid paraffin 10.0 Polyoxyethylene monooleate 2.0 1.3-butylene glycol 3.0 Glycerin 2.0 Triethanolamine 1.0 Polyethylene glycol 2000 2.0 Paraoxybenzoate 0.1 Bactiol fraction 0.05 Stearyl glycyrrhizinate 0.1 Perfume 0.1 Purified water Remaining

As a control, an emulsion having the same composition except that the bactiol fraction was not used was prepared.

The above examples of the present invention and the control were tested for use on human skin by the following method. Table 3 shows the test results.

Test Method: Healthy subjects 15 between 20 and 45 years old
Names were selected and left and right upper arms were exposed to direct sunlight for two hours a day for two consecutive days. Thereafter, twice daily in the morning and evening, the product of the present invention was applied to a given section of the left-arm sunlight-irradiated section, and a control product was applied to a given section of the right-arm sunlight-irradiated section for one month (during this period, the test site was not exposed to direct sunlight). And covered with clothes.). Thereafter, the section where the emulsion was applied and the surrounding area where no emulsion was applied were compared by visual observation, and the effect of the emulsion on inhibiting pigmentation was evaluated according to the following criteria.

A: Almost no pigmentation. ：: Pigmentation is considerably less than the non-coated part. Δ: Pigmentation was slightly less than in the uncoated part. X: There is no difference in pigmentation as compared with the uncoated portion.

[0039]

[Table 3] ◎ ○ △ × Product of the present invention 13 2 0 0 Control product 0 1 8 6

The product of the present invention containing bakuchiol was clearly excellent in the effect of inhibiting pigmentation. In addition, no subject complained of skin irritation such as itching or symptoms such as allergy due to continuous application for one month, and no abnormal appearance of the skin on the application surface was observed at all.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tomoko Imoto 14703-10 Mukotocho, Onomichi-shi, Hiroshima Maruzen Pharmaceutical Co., Ltd. (72) Inventor Shizuko Kataoka 14703-10 Mukotocho, Onomichi-shi, Hiroshima Maruzen Pharmaceutical Co., Ltd. Inside

Claims (3)

[Claims] 1. A whitening agent comprising bakuchiol as an active ingredient. 2. A whitening agent comprising, as an active ingredient, a tyrosinase inhibitor obtained by subjecting an organic solvent extract of osseous fat containing bactiol to a purification treatment for removing a flocoumarin derivative and flavonoids. 3. A whitening cosmetic comprising the whitening agent according to claim 1 or 2.