JP6799767B2 - Melanin production inhibitor containing urolithins - Google Patents

Description

The present invention relates to a melanin production inhibitor containing urolithins.

Skin pigmentation such as sunburn, age spots, and freckles occurs when cellular melanocytes present in epidermal cells proliferate and pigmented melanin produced in the proliferated melanocytes diffuses into adjacent cells. The mechanism of melanin production goes through a complex process that occurs inside the cell. Suppression of melanin production includes protection of the skin from ultraviolet rays, removal of singlet oxygen generated by ultraviolet rays, suppression of cytokine generation, suppression of tyrosinase activity, etc. (non-patented). Document 1). For example, various drugs that exert a whitening effect based on the suppression of melanin production as a result of inhibiting the activity of tyrosinase that oxidizes tyrosine, which is a raw material for melanin synthesis, are known (Patent Documents 1-4). ..

On the other hand, it is known that a substance called urolithin exists. Urolithins represented by urolithin A are known as ellagic acid biotransformers derived from ellagitannins contained in pomegranate, raspberry, blackberry, cloudberry, strawberry, walnut and the like. Elagitannin is classified as hydrolyzable tannin, and it is known that when ingested, it is hydrolyzed in the body and converted to ellagic acid. Although such ellagitannins and ellagic acid have very low intestinal absorption in the body, it is known that when they are ingested, they are further metabolized by the human colon microbiota and converted into urolithins. The urolithins produced in this way are one of the most important compounds in the living body. In recent years, the intestinal bacterium has been identified as Gordonibacter urolithifaciens (Non-Patent Document 2).

It has been reported in rats and humans that urolithin A is the main biotransformer after ingestion of ellagitannin and ellagic acid, and that urolithin A has anti-inflammatory and anti-cancer effects. Patent Document 5 describes urolithins such as urolithin A and urolithin B, and provides an effective amount of urolithins for the treatment or prevention of symptoms selected from obesity, decreased metabolic rate, metabolic syndrome and the like. Contains foods, etc. are listed.

In addition to these, there are findings related to the evaluation of tyrosinase inhibitory activity using the enzymatic reaction of urolithins, but the effect of suppressing melanin production has not been investigated, and urolithins have a clear inhibitory effect on melanin production. And, it is not known to have a whitening effect.

Japanese Unexamined Patent Publication No. 2004-352697 Special Table 2010-535821 Japanese Unexamined Patent Publication No. 2004-352647 Indian Patent No. 200400392 Special Table 2014-501964

FUJIFILM RESEARCH & DEVELOPMENT (No, 55-2010) Int. J. Syst. Eval. Microbiol., 64, 2346-2352 (2014)

The present invention has been made under the above circumstances, and an object of the present invention is to provide a novel melanin production inhibitor containing urolithins.

When the present inventors searched for a novel melanin production inhibitor, they found that urolithins have a melanin production inhibitory effect, and completed the present invention. That is, the present invention is as shown below.
<1>
A melanin production inhibitor containing urolithins represented by the following general formula (1).

(In the formula, R1, R2, R3, R4, R5, and R6 each represent a hydroxyl group, a hydrogen atom, or a methoxy group, and one or more of R1, R2, R3, R4, R5, and R6 are It is a hydroxyl group.)
<2>
A whitening agent containing the melanin production inhibitor according to <1>.
<3>
The melanin production inhibitor according to <1>, wherein the urolithins are urolithin A represented by the following formula (2).

<4>
The whitening agent according to <2>, wherein the urolithins are urolithin A represented by the following formula (2).

According to the present invention, as a novel melanin production inhibitor, a melanin production inhibitor containing urolithins can be provided.

It is a graph which shows the relationship between the urolithin A concentration and the melanin production rate in one Embodiment of this invention.

The present invention includes a first embodiment relating to a melanin production inhibitor containing urolithins and a second embodiment relating to a whitening agent containing the melanin production inhibitor.

<1. Melanin production inhibitor containing urolithins>
The first embodiment of the present invention is a melanin production inhibitor containing urolithins represented by the following general formula (1).

(Urolithins)
The urolithins in the present embodiment are not particularly limited, but the structure thereof is a substance represented by the above general formula (1). Further, as shown in Table 1, urolithins have urolithin A, urolithin B, urolithin C, urolithin D, urolithin E, urolithin M3, urolithin M4, urolithin M5, urolithin M6, urolithin M7, and Contains isourolithin A and the like.

Of these, urolithin A, urolithin B, urolithin C, and urolithin D are preferable, and urolithin A is more preferable, because the effect of suppressing melanin production is high.

The method for obtaining urolithins is not particularly limited, and commercially available products may be used or synthesized by chemical synthesis.

Examples of commercially available urolithins include urolithin A, urolithin B, urolithin C, and urolithin D (manufactured by Dalton Pharma).

In addition, a conventional method can be followed as a synthetic method by chemical synthesis. For example, 2-bromo-5-methoxybenzoic acid and aluminum chloride are used as raw materials for synthesis as described in Examples of the present specification. The method can be mentioned.

Alternatively, punicarazine, which is a kind of ellagitannin, may be extracted from a plant and hydrolyzed to ellagic acid, or ellagic acid may be extracted and converted into urolithins using a microorganism.

The type of plant is not particularly limited, and examples thereof include pomegranate, raspberry, blackberry, cloudberry, boysenberry, strawberry, walnut, and geranium thunbergii. Of these, pomegranate, boysenberry, and geranium thunbergii are preferable, and pomegranate is more preferable, because they contain a large amount of ellagitannin and / or ellagic acid.
Only one of these plants may be used, or two or more of these plants may be used in combination. In addition, the extraction method and extraction conditions from the plant are not particularly limited, and a conventional method may be followed. For example, known extraction methods such as water extraction, hot water extraction, hot water extraction, alcohol extraction, and supercritical extraction can be used.

When solvent extraction is performed, the solvent may be, for example, water; lower alcohols such as methanol and ethanol, and alcohols such as polyhydric alcohols such as propylene glycol and 1,3-butylene glycol (whether anhydrous or water-containing). ); Ketones such as acetone, esters such as diethyl ether, dioxane, acetonitrile and ethyl acetate, xylene and the like, preferably water, ethanol and the like. Only one of these solvents may be used, or two or more of these solvents may be used in combination.

The method for hydrolyzing the extracted ellagitannin such as punicarazine to ellagic acid is not particularly limited, and examples thereof include a method for hydrolyzing with an acid, an enzyme, and a microorganism.

The method for converting ellagic acid into urolithins using a microorganism is not particularly limited, and for example, a known method described in Food Funct., 5, 8, 1779-1784 (2014) can be used. ..

The obtained urolithins can be used as they are, but they may be dried and used in powder form. Further, if necessary, the obtained urolithins may be subjected to purification, concentration treatment or the like. As the purification treatment, treatment such as filtration or adsorption or decolorization using an ion exchange resin or an activated carbon column can be performed. Further, as the concentration treatment, a conventional method such as an evaporator can be used.

In addition, the obtained urolithins (or purified products or concentrates) are subjected to freeze-drying treatment to be pulverized, and excipients such as dextrin, cornstarch, and gum arabic are added and pulverized by spray-drying treatment. It may be pulverized according to a known method such as a method. After that, if necessary, it may be dissolved in pure water, ethanol or the like for use.

(Melanin production inhibitor)
This embodiment is a melanin production inhibitor containing the above-mentioned urolithins. The melanin production inhibitor according to the present embodiment may contain one of the above-mentioned urolithins, or may contain a plurality of them.

The melanin production inhibitor according to this embodiment suppresses melanin production. For example, from the viewpoint of whitening, the suppression of melanin production in cells suppresses browning of the skin tissue, and as a result, a whitening effect is realized. For this reason, the melanin production inhibitor according to this embodiment is preferably used for whitening purposes.

The melanin production inhibitor according to the present embodiment may contain urolithins alone, but other than urolithins, known excipients, fragrances, colorants, emulsifiers, stabilizers, thickeners, enzymes, etc. Preservatives, lubricants, surfactants, disintegrants, disintegrant inhibitors, binders, absorption promoters, adsorbents, moisturizers, solubilizers, preservatives, flavoring agents, sweeteners, etc. It can be blended as needed within a range that does not impair the effect.

The content of urolithins with respect to the total amount of the melanin production inhibitor is not particularly limited as long as the desired effect according to this embodiment is exhibited, but the total amount of urolithins is usually 0.00001 to 20% by mass, preferably 0. .0001 to 3% by mass, more preferably 0.0
It is 01 to 1% by mass.

<2. Whitening agent>
A second embodiment of the present invention is a whitening agent containing the above-mentioned melanin production inhibitor.
The whitening agent according to the present embodiment may contain the above-mentioned melanin production inhibitor alone, but in addition to the above-mentioned components, known excipients, fragrances, colorants, emulsifiers, stabilizers, thickeners, etc. Enzymes, preservatives, lubricants, surfactants, disintegrants, disintegrant inhibitors, binders, absorption promoters, adsorbents, moisturizers, solubilizers, preservatives, flavoring agents, sweeteners, etc. It can be blended as needed within a range that does not impair the effects of the embodiments.

The content of the melanin production inhibitor with respect to the total amount of the whitening agent is not particularly limited as long as the desired effect according to this embodiment is exhibited, but the total amount of urolithins is usually 0.00001 to 10% by mass, preferably 0. It is .000 to 1% by mass, more preferably 0.0003 to 1% by mass.

The melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment can be used as a material for cosmetics, pharmaceuticals, foods, etc. according to the embodiment.

<3. Cosmetics>
When the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment is used as a material for cosmetics, the melanin production inhibitor or whitening agent is used as an aqueous solution, lotion, spray solution, or suspension. And liquids such as emulsions; solids such as powders, granules and blocks; semi-solids such as creams and pastes; cosmetics in various desired dosage forms such as gels. Such cosmetics include basic cosmetics such as washing pigments, milky lotions, creams, gels, essences (beauty liquids), packs and masks, makeup cosmetics such as foundations and lipsticks, oral cosmetics, aromatic cosmetics, and hair cosmetics. It is useful as various cosmetics such as cosmetics and body cosmetics.

The cosmetic containing the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment can be produced according to a conventional method. In addition, the blending amount, blending method, and blending time of the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment in cosmetics can be appropriately selected. Further, if necessary, it can be sealed in an appropriate container such as a bottle, a bag, a can, a spray can, a spray container, a box, or a pack.

When the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment is used as a material for cosmetics, the melanin production inhibitor according to the first embodiment or the second The content of the whitening agent according to the embodiment is not particularly limited as long as the desired effect of each embodiment is exhibited, but the total amount of urolithins is usually 0.00001 to 10% by mass, preferably 0.0001. It is ~ 3% by mass, more preferably 0.0003 ~ 1% by mass.

When the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment is used as a material for cosmetics, commonly used known ingredients can be appropriately added and used.
For example, anionic surfactants (fatty soap, sulfonate-type anionic surfactants, sulfate ester-type anionic surfactants, phosphate ester-type anionic surfactants, acylmethyltaurine salts, monoalkyl phosphates. , Acylglutamate, isetionate ester salt, etc.), Cationic surfactant (amine salt type cationic surfactant, tetraammonium type cationic surfactant (tetraalkylammonium type, pyridinium type)), nonionic Surfactants (glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, tetraoleic acid polyoxyethylene sorbit, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene poly Oxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyglycerin fatty acid ester, etc.), amphoteric surfactant (imidazoline type, betaine type, amino acid type), fluorine-based surfactant , Natural and synthetic surfactants such as silicone-based surfactants,
Sodium alginate, propylene glycol alginate, arabic gum, xanthan gum, pectin, tragant, sodium carboxymethyl cellulose, methyl cellulose, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, cationized cellulose, cationized dextran, cationized dextrin, chitosan, Cationic vinylpyrrolidone polymer, N, N-dimethyl-3,5-methylenepiperidinium polymer, milk protein, soybean protein, gelatin,
Water-soluble polymers such as egg protein, sodium caseinate, and whey protein,
Ginkgo, Tsubokusa, Touyaku, Carrot, Shikoppi, Schizonepeta, Fennel, Yashajitsu, Lantobae, Gokahi, Sempukuka, Hikai, Yuzuriha, Capillary, Maronie, Essin, Terminaria, Ruscogenin, Butcher Bloom, Kora, Galana, Mate Cacao, Plectrantas, Tanjin, Bisnaga, Sirimarin, Leucocianin, Otogiri grass, Bear haze, Perilla, Ogon, Schizonepeta, Rosemary, Sage, Thyme, Yarrow, Capillary wormwood, Soujutsu, Yarrow, Perilla, Fennel, Peppermint, Peppermint , Plant components such as schizonepeta, senkyu, chinbi, valeriana, schizonepeta, perilla, schizonepeta, red flowers, irises, capillary wormwood, mint, etc.
Succinic acid, fumaric acid, citric acid, pyruvate, glucuronic acid, 2-hydroxybutyric acid, lactic acid, malic acid, tartaric acid, tartronic acid, methyl pyruvate, ethyl pyruvate, vitamin A acid, vitamin C derivative, vitamin D, vitamin Active ingredients such as E, oligopeptides, tartronic acid esters, etc.
Moisturizers such as polyhydric alcohols, amino acids, mucopolysaccharides, proteins, biological extracts, fermented metabolites, polysaccharides, plant extracts, phospholipids, ceramides, etc.
Oils and fats (soybean oil, nuka oil, jojoba oil, avocado oil, almond oil, cacao oil, olive oil, sesame oil, persic oil, castor oil, palm oil, minced oil, beef oil, pork oil and other natural oils and fats, these natural oils and fats Hardened oil obtained by hydrogenating, myristic acid glyceride, synthetic triglycerides such as 2-ethylhexanoic acid glyceride, diglycerides, etc.), waxes (carnauba wax, whale wax, beeswax, lanolin, etc.), hydrocarbons (liquid paraffin, Vaseline, paraffin, microcrystallin wax, ceresin, squalane, pristan, etc.), higher fatty acids (lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, lanolinic acid, isostearic acid, etc. ), Higher alcohols (lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, cholesterol, 2-hexyldecanol, etc.), esters (cetyl octanate, myristyl lactate, cetyl lactate, isopropyl myristate, myristyl myristate, isopropyl palmitate) , Isopropyl adipate, butyl stearate, decyl oleate, cholesteel isostearate, etc.), essential oils (hakka oil, jasmine oil, sardine brain oil, hinoki oil, peppermint oil, ryu oil, terepine oil, coconut oil, bergamot Oil, orange oil, sardine oil, pine oil, lavender oil, bay oil, clove oil, hiba oil, rose oil, eucalyptus oil, lemon oil, peppermint oil, thyme oil, rose oil, sage oil, menthol, cineole, eugenol, Oils and fats (emollient components) such as citral, citroneral, borneol, linalol, geraniol, camphor, timol, spirantol, pinen, limonene, terpene compounds, etc.), silicone oils, etc.
Sodium carbonate, sodium hydrogen carbonate, sodium sesquicarbonate, borosand, sodium sulfide, sodium sulfide, sodium nitrate, sodium thiosulfate, sodium polyphosphate, sodium phosphate, potassium chloride, potassium sulfide, calcium oxide, magnesium oxide, calcium carbonate, Inorganic salts such as magnesium carbonate,
Inorganic acids such as boric acid, metasilicic acid, and silicic anhydride,
Pigments such as Yellow No. 4, Blue No. 1, Yellow No. 202, Chlorophyll, Riboflavin, Safflower, Crocin, Anthraquinone, etc.
Fragrances,
Polymers such as acrylic resin, styrene resin, epoxy resin, nylon, polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate resin, polytetrafluoroethane, copolymers of these polymers, silicate, calcium silicate, natural aluminum silicate , Fine powder of synthetic aluminum silicate, zeolite, titanium oxide, talc, kaolin, mica, bentonite, etc.
Sulfur, Yunohana, ore sand, mica powder, neutral white clay, rice bran, fungicide, preservative,
In addition, other ingredients necessary for formulation can be mentioned.

<4. Pharmaceuticals>
When the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment is used as a material for a drug, the dosage form thereof includes a disease to be prevented or treated, a form of use of the drug, an administration route, etc. Can be selected according to. Examples thereof include tablets, coated tablets, pills, capsules, granules, powders, liquids, suspensions, emulsions, syrups, injections, suppositories, dipping agents, decoctions, tinctures and the like. These various preparations are used as a filler, a bulking agent, an excipient, a binder, a moisturizer, a disintegrant, a surfactant, a lubricant, a colorant, and a flavoring agent as needed for the main ingredient according to a conventional method. , Dissolving aids, suspending agents, coating agents and the like, can be formulated using known excipients commonly used in the pharmaceutical formulation technology field. In addition, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, or other pharmaceutical products may be contained in this pharmaceutical preparation.

When used as a material for the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment, the melanin production inhibitor according to the first embodiment or the second embodiment with respect to the total amount of the drug. The content of the whitening agent is not particularly limited as long as the desired effect according to each embodiment is exhibited, but the total amount of urolithins is usually 0.0001 to 20% by mass, preferably 0.001 to 5% by mass. It is more preferably 0.003 to 1% by mass.

<5. Food ＞
When the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment is used as a food material, in addition to general foods, foods for specified health use, dietary supplements, functional foods, sick people It can be used as a food product, food additive, etc. The form of the food includes a soft drink, milk, pudding, jelly, candy, gum, gummies, yogurt, chocolate, and soup containing the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment. , Cookies, snacks, ice cream, ice candy, bread, cakes, cream puffs, ham, meat sauce, curry, stew, cheese, butter, dressing and the like can be exemplified.

The melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment contains water, proteins, sugars, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, flavors and the like. It can be used as a main component. Examples of the protein include animal and vegetable proteins such as full-fat milk powder, skim milk powder, partially skim milk powder, casein, soybean protein, chicken egg protein, and meat protein, and hydrolysates and butters thereof. Examples of carbohydrates include sugars, modified starches (in addition to dextrin, soluble starches, British starch, oxidized starches, starch esters, starch ethers, etc.), dietary fiber and the like. Examples of the lipid include lard, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, hydrogenated oils, and vegetable fats and oils such as ester exchange oils. Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, and choline. , Folic acid and the like, and examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium and milky minerals. Examples of the organic acid include malic acid, citric acid, lactic acid, tartaric acid and the like. These ingredients may be used in combination of two or more, and synthetic products and / or foods containing a large amount thereof may be used.

The food containing the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment can be produced according to a conventional method. In addition, the blending amount, blending method, and blending time of the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment in food can be appropriately selected. Further, if necessary, it can be sealed in an appropriate container such as a bottle, a bag, a can, a box, or a pack.
When the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment is used as a material for food, the melanin production inhibitor according to the first embodiment or the second embodiment with respect to the total amount of food. The content of the whitening agent according to the above is not particularly limited as long as the desired effect according to each embodiment is exhibited, but the total amount of urolithins is usually 0.000001 to 3% by mass, preferably 0.0001 to 1. It is by mass, more preferably 0.001 to 0.3% by mass.

Indication that cosmetics, pharmaceuticals, foods, etc. containing the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment are used for suppressing melanin production or whitening. It can be sold as cosmetics, pharmaceuticals, foods, etc.

The "display" means all actions for informing the consumer of the above-mentioned use, and if the display can recall or infer the above-mentioned use, the purpose of the display, the content of the display, and the display. Regardless of the object, medium, etc., all correspond to the "indication" in each embodiment. However, it is preferable to display it in an expression that allows the consumer to directly recognize the above application. Specifically, for the act of describing the above-mentioned use on the product or product packaging related to cosmetics, pharmaceuticals, foods, etc., or for transferring, transferring or delivering the product or product packaging with the above-mentioned use described. The above-mentioned uses are described in the act of displaying and importing products, advertisements, price lists or transaction documents, or distributed, or the above-mentioned uses are described in the information containing these and electromagnetically (Internet, etc.) ) The act of providing by the method, etc. can be exemplified.

On the other hand, as the display, it is preferable that the display is approved by the government or the like (for example, the display is approved based on various systems established by the government and is performed in a manner based on such approval), and particularly packaging and containers. , Catalogs, pamphlets, POPs, and other promotional materials at sales sites, and other documents are preferable.

Further, for example, foods containing the melanin production inhibitor according to the first embodiment or the whitening agent according to the second embodiment are health foods, functional foods, special purpose foods, nutritionally functional foods, and pharmaceuticals. Labeling as an external product or the like can be exemplified, and other labeling approved by the Ministry of Health, Labor and Welfare, for example, food for specified health use, labeling approved by a system similar thereto can be exemplified. Examples of the latter include labeling as a food for specified health use, labeling as a food for specified health use as a condition, labeling to the effect that it affects the structure and function of the body, labeling for reducing the risk of illness, and the like. Speaking of which, labeling as a food for specified health use (especially labeling for health uses) stipulated in the Health Promotion Law Enforcement Regulations (April 30, 2003, Ministry of Health, Labor and Welfare Ordinance No. 86), and similar The display can be listed as a typical example.

Hereinafter, the present invention will be described in more detail with reference to specific examples, but the present invention is not limited to these examples.

(Analysis method of urolithin)
The case where urolithin A is used as an example of urolithins will be described. Analysis of urolithin A was performed using HPLC. That is, a solution prepared by dissolving urolithin A (manufactured by Dalton Farma) in an appropriate solvent was analyzed under the following HPLC conditions, and the purity (%) (A) and the peak area value (B) in HPLC were used. , The factor of urolithin A and the concentration of urolithin A in the sample were calculated by the following formulas (1) and (2).

(Urolithin A factor calculation formula)
Urolithin A factor = (B) / (Urolithin A standard solution concentration (mg / L) x (A) / 100) ... (1)
(Sample urolithin A concentration calculation formula)
Sample urolithin A concentration (mg / L) = peak area value of urolithin A in the sample /
Urolithin A factor ... (2)

(Analysis conditions)
Analytical column: Inertsil ODS-3 (250 x 4.6 mm) (manufactured by GL Sciences)
Detection wavelength: 305 nm
Mobile phase: water / acetonitrile / acetic acid = 74/25/1
Column temperature: 40 ° C
Flow velocity: 1.0 mL / min
Under the above conditions, urolithin A had a retention time of 16.5 minutes.

(Preparation of urolithin A)
5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours. After cooling, the reaction solution was transferred to ice water and extracted three times with 250 mL of diethyl ether. The obtained extract was concentrated under reduced pressure to distill off diethyl ether to obtain 4.2 g of 2-bromo-5-hydroxybenzoic acid. The obtained 2-bromo-5-hydroxybenzoic acid (3.9 g) and resorcinol (3.9 g) (manufactured by Tokyo Chemical Industry Co., Ltd.) were heated at 60 ° C. for 30 minutes in 9 mL of a 4M NaOH aqueous solution. After adding 1.8 mL of a 10% copper sulfate aqueous solution to this reaction solution, heating was further performed at 80 ° C. for 10 minutes. The resulting precipitate was collected by filtration to give a white powder of urolithin A.

<1. Evaluation test of melanin production inhibitory ability>
[Example 1]
A 3D skin model MEL-300 (Kurabo Industries) (hereinafter sometimes referred to as "skin model") is set on a 6-well plate to which EPI-100 long-term maintenance medium (Kurabo Industries) is added, and 5% CO _{In the} presence of ₂ , the cells were cultured at 37 ° C. for 18 hours. After culturing, 0.1 mL of a urolithin A solution having a final concentration of 1, 10 or 100 mg / L was added to the upper layer of the skin model, and the cells were cultured at 37 ° C. for 3 weeks in the presence of 5% CO ₂ . During culturing, ultraviolet (UV-A) irradiation with an intensity of 1 J / cm ² was performed using a UV irradiation device to induce melanin production. After culturing, the skin model was collected, 10 mM Tris-HCl buffer containing 1% SDS-EDTA was added to extract melanin in the skin model, and then the amount of melanin produced in each skin model was measured by measuring the absorbance at 475 nm. Was measured.

[Comparative Example 1]
The same as in Example 1 above was used as a control except that the urolithin A solution was not added, and used as Comparative Example 1.

A relative value was calculated when the amount of melanin produced in Comparative Example 1 was 100, and used as the melanin production rate (%) at each urolithin A concentration.

A graph showing the relationship between the urolithin A concentration and the melanin production rate is shown in FIG. As shown in FIG. 1, it was confirmed that urolithin A has a concentration-dependent inhibitory effect on melanin production.

<2. Sensory test>
(1) Sensory Test of Cosmetic Cream Based on the formulations shown in Table 2, cosmetic creams of test product 1, test product 2, and control product 1 were produced. Specifically, it was manufactured as follows.
First, glycerin was added to purified water and heated to 70 ° C., which was used as an aqueous phase. On the other hand, squalane, beeswax, refined jojoba oil, glycerin monostearate, and polyoxyethylene (20) sorbitan monostearate were stirred and mixed while heating to 70 ° C., which was used as an oil phase. While stirring the aqueous phase, a 50% ethanol aqueous solution containing or not containing urolithin A was added, and then a preheated oil phase was added dropwise. After dropping the whole amount, it was emulsified with a mixer, degassed, and cooled to obtain a cosmetic cream.

<Examples 2-1 and 2-2>
A sensory test was carried out using cosmetic creams of test products 1 and 2 (Examples 2-1 and 2-2, respectively) and a control product (Comparative Example 2-1).
The panelists are seven women in their 40s, who have a test group and a control group on the skin surface on the side of the upper arm, and use the cream of each test product in the test group and the control product 1 in the control group for home use. The tanning machine NEOTAN C-120 was irradiated with UV for 30 minutes every day, and the degree of sunburn was compared after 5 days. The results are shown in Table 3.

The present invention can be applied to formulation techniques for cosmetics, pharmaceuticals, foods and the like.

Claims (4)

A melanin production inhibitor containing urolithins represented by the following general formula (1) ( excluding those containing coenzyme Q10) .

(In the formula, R1, R2, R3, R4, R5, and R6 each represent a hydroxyl group, a hydrogen atom, or a methoxy group, and one or more of R1, R2, R3, R4, R5, and R6 are It is a hydroxyl group.) The melanin production inhibitor according to claim 1, wherein the urolithins are urolithin A represented by the following formula (2).
Cosmetics for suppressing melanin production containing urolithins represented by the following general formula (1) ( excluding those containing coenzyme Q10) .

(In the formula, R1, R2, R3, R4, R5, and R6 each represent a hydroxyl group, a hydrogen atom, or a methoxy group, and one or more of R1, R2, R3, R4, R5, and R6 are It is a hydroxyl group.) The cosmetic for suppressing melanin production according to claim 3, wherein the total amount of the urolithins is 0.00001 to 10% by mass with respect to the total amount of the cosmetic for suppressing melanin production.