JP2017014154A - Hyaluronic acid production promoter containing urolithins - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel hyaluronic acid production promoter containing urolithins. SOLUTION: A hyaluronic acid production promoter 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.) [Selection diagram] Fig. 1

Description

  The present invention relates to a hyaluronic acid production promoter containing urolithins.

Glycoproteins and substrates such as proteoglycans exist between dermal fibers and dermal fibroblasts. Proteoglycan is a macromolecule having a molecular weight of 10 ⁵ to 10 ⁶ or more in which a glycoprotein and a mucopolysaccharide such as glycosaminoglycan are combined. Glycosaminoglycan in the dermis is mainly composed of hyaluronic acid or dermatan sulfate. Acid is the main matrix component in the dermis. Hyaluronic acid plays an important role in cell protection, nutrient transport, tissue moisture retention, flexibility maintenance, lubricity maintenance, and the like. The amount of hyaluronic acid in the living body decreases due to aging and pathological conditions. In addition, a decrease in the amount of hyaluronic acid in the living body due to the action of hyaluronidase or the like decreases the moisturizing power of cells and causes symptoms such as dryness, rough skin, spots and wrinkles.

  Hyaluronidase is an enzyme that hydrolyzes hyaluronic acid and is widely distributed in animal tissues. It exists in semen of higher animals, snake venom, pneumococci and streptococci. During fertilization, it is said that the zona pellucida containing hyaluronic acid covering the egg cell surface is removed to help the invasion of sperm and to facilitate the invasion of pathogenic bacteria.

  Hyaluronidase inhibitors have been developed for the purpose of suppressing the degradation of hyaluronic acid by hyaluronidase. The hyaluronidase inhibitor can be expected to have the effect of preventing or improving the above symptoms by maintaining the amount of hyaluronic acid in the living body. Extracts from natural products, for example, effective use of seaweeds and waste combs that are cheap and present in large quantities, hyaluronidase inhibitors using sulfated polysaccharides of seaweed-derived natural polysaccharides as raw materials (Patent Documents 1 and 2), Hyaluronidase inhibitor (Patent Document 3) containing an alga-derived component as an active ingredient, Hyaluronidase activity inhibitor (Patent Document 4) containing tea polyphenols extracted from tea used for drinking as an active ingredient, low A hyaluronidase inhibitor containing molecularized psyllium seed gum as an active ingredient has been developed (Patent Document 5).

  However, various factors are related to the decrease in the amount of hyaluronic acid, and even if the action of hyaluronidase is inhibited, the amount of hyaluronic acid cannot always be maintained. Further, even if hyaluronidase is inhibited, there is no effect of increasing the amount of hyaluronic acid, and no substantial improvement is achieved. That is, in order to improve the skin functional deterioration, it is necessary to promote the biosynthesis of hyaluronic acid in the dermis layer, and thereby a hyaluronic acid production promoter that can prevent wrinkles and sagging of the skin has been desired.

  As hyaluronic acid production promoters, extracts obtained from macaques, canlanified boswellia genus frankincense, sandalwood family sandalwood genus sandalwood, rose family rose genus damask rose, perilla family mannenro rosemary are disclosed (Patent Document 6, 7). There is also a report that a lipocalin family protein or a lipocalin family protein degradation product obtained by degrading a lipocalin family protein increases the amount of hyaluronic acid produced (Patent Document 8).

On the other hand, it is known that a substance called urolithin exists. Urolithins represented by urolithin A are known as ellagic acid metabolites derived from ellagitannins contained in pomegranate, raspberry, blackberry, cloudberry, strawberry, walnut and the like. It is known that ellagitannins are classified into hydrolyzable tannins, and when ingested, they are hydrolyzed and converted to ellagic acid. Such ellagitannins and ellagic acid have very low intestinal absorption in the body, but when they are ingested, they are known to be further metabolized by the human colonic microflora and converted to urolithins. The urolithins thus produced are one of the most important compounds in the living body. In recent years, the intestinal bacteria have been identified as Gordonibacter urolithinfaciens (Non-patent Document 1).

  After ingesting ellagitannin and ellagic acid, it has been reported in rats and humans that urolithin A is the main metabolite, and it has been reported that urolithin A has anti-inflammatory and anti-cancer effects. Patent Document 9 describes urolithins such as urolithin A and urolithin B, and an effective amount of urolithin for treating or preventing symptoms selected from obesity, metabolic rate decrease, metabolic syndrome, and the like. Contains foods. Patent Document 10 describes that urolithins inhibit the activity of hyaluronic acid-degrading enzyme (hyaluronidase).

  Thus, there are many findings regarding the relationship between hyaluronic acid and the skin, and the effect of urolithin inhibiting the function of hyaluronidase is known by enzyme tests, but urolithins have a hyaluronic acid production promoting effect, And it is not known to have a moisturizing effect.

JP 2008-44912 A JP 2013-10700 A JP 2014-19668 A JP-A-6-9391 JP2012-193134A JP 2007-51091 A JP 2013-23437 A Japanese Patent Laid-Open No. 2015-38 JP-T-2014-501764 Indian Patent No. 200400392

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 hyaluronic acid production promoter containing urolithins.

As a result of searching for a novel hyaluronic acid production promoter, the present inventors have found that urolithins have a hyaluronic acid production promoting effect and have completed the present invention. That is, the present invention is as follows.
<1>
Hyaluronic acid production promoter containing urolithins represented by the following general formula (1).

(Wherein R1, R2, R3, R4, R5, and R6 each represent a hydroxyl group, a hydrogen atom, or a methoxy group, and at least one of R1, R2, R3, R4, R5, and R6 is It is a hydroxyl group.)
<2>
A humectant containing the hyaluronic acid production promoter according to <1>.
<3>
The hyaluronic acid production promoter according to <1>, wherein the urolithin is urolithin A represented by the following formula (2).

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

  According to the present invention, a hyaluronic acid production promoter containing urolithins can be provided as a novel hyaluronic acid production promoter.

It is a graph which shows the relationship between the urolithin A density | concentration and the hyaluronic acid production rate in one embodiment of this invention.

The present invention is a first embodiment according to a hyaluronic acid production promoter containing urolithins,
A second embodiment relating to a humectant containing the hyaluronic acid production promoter is included.

<1. Hyaluronic acid production promoter containing urolithins>
The first embodiment of the present invention is a hyaluronic acid production promoter containing urolithins represented by the following general formula (1).

(Urolithins)
Although the urolithins in this embodiment are not specifically limited, The structure is a substance represented by the said General formula (1). In addition, as shown in Table 1, urolithins are represented by R1-R6 in the chemical formula, and urolithin A, urolithin B, urolithin C, urolithin D, urolithin E, urolithin M3, urolithin M4, urolithin M5, urolithin M6, urolithin M7, and Examples include isouroritin A.

  Among these, since the hyaluronic acid production promoting effect is high, urolithin A, urolithin B, urolithin C, and urolithin D are preferable, and urolithin A is more preferable.

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

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

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

  Alternatively, punicalagin, a kind of ellagitannin, may be extracted from plants and hydrolyzed into ellagic acid, or ellagic acid may be extracted and converted to urolithins using microorganisms.

The kind of plant is not particularly limited, and examples include pomegranate, raspberry, blackberry, cloudberry, boysenberry, strawberry, walnut, and ginger. Of these, pomegranate, boysenberry and genokosho are preferred, and pomegranate is more preferred because of its high content of ellagitannin and / or ellagic acid.
Any one of these plants may be used, or two or more thereof may be used in combination. Moreover, the extraction method and extraction conditions from this plant are not specifically limited, What is necessary is just to follow a conventional method. For example, a known extraction method such as water extraction, hot water extraction, hot water extraction, alcohol extraction, supercritical extraction or the like can be used.

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

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

The method for converting ellagic acid to 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. .

  Although the obtained urolithins can be used as they are, they may be dried and used in a powder form. Moreover, you may refine | purify, a concentration process, etc. to the obtained urolithins as needed. As the purification treatment, treatment such as filtration or adsorption or decolorization using an ion exchange resin or activated carbon column can be performed. As the concentration treatment, a conventional method such as an evaporator can be used.

  In addition, the obtained urolithins (or purified product or concentrate) are subjected to a freeze-drying process, and powdered by spray-drying by adding excipients such as dextrin, corn starch, and gum arabic. You may powder according to well-known methods, such as a method. Further, it may be used after being dissolved in pure water, ethanol or the like as required.

(Hyaluronic acid production promoter)
This embodiment is a hyaluronic acid production promoter containing the urolithins described above. The hyaluronic acid production promoter according to this embodiment may contain one or more of the above-described urolithins.

The hyaluronic acid production promoter according to this embodiment promotes the production of hyaluronic acid.
For example, from the viewpoint of moisturizing, the stratum corneum in the outermost layer of the skin plays a role of maintaining homeostasis in the body, and dry skin is likely to occur due to a decrease in the water retention function of the stratum corneum. For this water retention, keratinocyte lipids, sebum, and natural moisturizing factor (NMF) are important, and if the production of hyaluronic acid, one of NMF, is promoted, a moisturizing effect is realized as a result. .
For this reason, the hyaluronic acid production promoter according to this embodiment is preferably used for moisturizing applications.

  The hyaluronic acid production promoter according to this embodiment may contain urolithins alone, but in addition to urolithins, known excipients, fragrances, colorants, emulsifiers, stabilizers, thickeners, enzymes , Preservatives, lubricants, surfactants, disintegrants, disintegration inhibitors, binders, absorption enhancers, adsorbents, moisturizers, solubilizers, preservatives, flavoring agents, sweeteners, etc. It can mix | blend as needed in the range which does not impair the effect of.

  The content of urolithins relative to the total amount of hyaluronic acid production promoter is not particularly limited as long as the desired effect according to this embodiment is exhibited, but the total amount of urolithins is usually 0.0001 to 10% by mass, preferably It is 0.001-1 mass%, More preferably, it is 0.01-0.1 mass%.

<2. Moisturizer>
The second embodiment of the present invention is a humectant containing the hyaluronic acid production promoter.
The moisturizer according to this embodiment may contain the above-described hyaluronic acid production promoter alone, but in addition to the above components, known excipients, fragrances, colorants, emulsifiers, stabilizers, thickeners. Enzymes, preservatives, lubricants, surfactants, disintegrants, disintegration inhibitors, binders, absorption enhancers, adsorbents, moisturizers, solubilizers, preservatives, flavoring agents, sweeteners, etc. It can mix | blend as needed in the range which does not impair the effect of embodiment.

  The content of the hyaluronic acid production promoter with respect to the total amount of the humectant is not particularly limited as long as the desired effect according to this embodiment is achieved, but the total amount of urolithins is usually 0.0001 to 10% by mass, preferably It is 0.001-1 mass%, More preferably, it is 0.01-0.1 mass%.

  The hyaluronic acid production promoter according to the first embodiment or the humectant according to the second embodiment can be used as a material for cosmetics, pharmaceuticals, foods, and the like according to the embodiment.

<3. Cosmetics>
When the hyaluronic acid production promoter according to the first embodiment or the moisturizer according to the second embodiment is used as a cosmetic material, the hyaluronic acid production promoter or moisturizer is used as an aqueous solution, lotion, spray solution, suspension. Liquids such as turbid liquids and emulsions; solids such as powders, granules and blocks; semi-solids such as creams and pastes; and gels and other desired dosage forms can be prepared. Such cosmetics include facial cleansers, milks, creams, gels, essences (beauty serums), basic cosmetics such as 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 hyaluronic acid production promoter according to the first embodiment or the moisturizer according to the second embodiment can be produced according to a conventional method. Moreover, the compounding quantity of the hyaluronic acid production promoter which concerns on 1st embodiment to cosmetics, or the moisturizer which concerns on 2nd embodiment, a compounding method, and a compounding time can be selected suitably. Furthermore, it can be enclosed in appropriate containers, such as a bottle, a bag, a can, a spray can, a spray container, a box, and a pack, as needed.

  When the hyaluronic acid production promoter according to the first embodiment or the moisturizer according to the second embodiment is used as a cosmetic material, the hyaluronic acid production promoter according to the first embodiment or the The content of the humectant according to the second embodiment is not particularly limited as long as the desired effect of each embodiment is exhibited, but is generally 0.0001 to 10% by mass, preferably 0 as the total amount of urolithins. 0.001 to 1% by mass, and more preferably 0.01 to 0.1% by mass.

When the hyaluronic acid production promoter according to the first embodiment or the humectant according to the second embodiment is used as a cosmetic material, it can be used by appropriately adding known components that are usually used.
For example, anionic surfactants (fatty acid soaps, sulfonate type anionic surfactants, sulfate ester type anionic surfactants, phosphate ester type anionic surfactants, acylmethyl taurine salts, monoalkyl phosphates , Acyl glutamate, isethionate, etc.), cationic surfactant (amine salt type cationic surfactant, quaternary ammonium type cationic surfactant (tetraalkylammonium type, pyridinium type)), nonionic Surfactant (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 Recall, polyoxyethylene polyoxypropylene 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) , Natural surfactants such as fluorosurfactants and silicone surfactants, synthetic surfactants,
Sodium alginate, propylene glycol alginate, gum arabic, xanthan gum, pectin, tragacanth, sodium carboxymethylcellulose, methylcellulose, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, cationized cellulose, cationized dextran, cationized dextrin, chitosan, Water-soluble polymers such as cationized vinylpyrrolidone polymer, N, N-dimethyl-3,5-methylenepiperidinium chloride polymer, milk protein, soybean protein, gelatin, egg protein, sodium caseinate, whey protein,
Ginkgo biloba, pearl oyster, carrot, shikoppi, caika, inchko, yashajitsu, licorice fraction, gokahi, sempukuka, hikai, yuzuuriha, chamomile, maronier, escin, terminaria, ruscogenin, butcher bloom, cola, guarana, mate, coffee, Cacao, Plectrantus, Tandin, Bisnaga, Silymarin, Leucocyanin, Hypericum Grass, Bear Goose, Perilla, Ogon, Keigai, Rosemary, Sage, Thyme, Artemisia, Paramecium, Prunus , Plant components such as Toki, Senkyu, Chimbu, Kanokosou, Bakushi, Spruce, Glaze, safflower, camellia, Bukkuri, mint
Succinic acid, fumaric acid, citric acid, pyruvic acid, 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 E, active ingredients such as oligopeptides, tranexamic acid esters, polyhydric alcohols, amino acids, mucopolysaccharides, proteins, biological extracts, fermentation metabolites, polysaccharides, plant extracts, humectants such as phospholipids, ceramides,
Fats and oils (soybean oil, nutka oil, jojoba oil, avocado oil, almond oil, cacao oil, olive oil, sesame oil, persic oil, castor oil, coconut oil, mink oil, beef fat, pork fat, and other natural fats and oils Hydrogenated hardened oil and synthetic triglycerides such as myristic acid glyceride and 2-ethylhexanoic acid glyceride, diglyceride etc.), waxes (carnauba wax, whale wax, beeswax, lanolin etc.), hydrocarbons (liquid paraffin, Petrolatum, paraffin, microcrystalline wax, ceresin, squalane, pristane, 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, Alcohol, stearyl alcohol, oleyl alcohol, cholesterol, 2-hexyldecanol, etc.), esters (cetyl octoate, myristyl lactate, cetyl lactate, isopropyl myristate, myristyl myristate, isopropyl palmitate, isopropyl adipate, butyl stearate, Decyl oleate, Colesteel isostearate, etc., essential oils (mint oil, jasmine oil, cypress brain oil, cypress oil, spruce oil, ryu oil, turpentine oil, cinnamon oil, bergamot oil, mandarin oil, shibu 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, Cineol, Eugenol, Citral, Citronellal, Borne Lumpur, linalool, geraniol, camphor, thymol, spilanthol, pinene, limonene, terpene compounds), fats and oils such as silicone oils (emollient component),
Sodium carbonate, sodium bicarbonate, sodium sesquicarbonate, borax, sodium sulfate, 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, silicic anhydride,
Yellow No. 4, Blue No. 1, Yellow No. 202, pigments such as chlorophyll, riboflavin, safflower, crocin, anthraquinone,
Fragrances,
Polymers such as acrylic resin, styrene resin, epoxy resin, nylon, polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate resin, polytetrafluoroethane, copolymers of these polymers, silicic acid, calcium silicate, natural aluminum silicate , Fine powders such as synthetic aluminum silicate, zeolite, titanium oxide, talc, kaolin, mica, bentonite,
Sulfur, Yunohana, mineral sand, mica powder, neutral white clay, rice cake, fungicide, preservative,
And other ingredients necessary for the preparation.

<Pharmaceutical>
When the hyaluronic acid production promoter according to the first embodiment or the moisturizing agent according to the second embodiment is used as a raw material for pharmaceuticals, the dosage form is the disease to be prevented or treated, the mode of use of the pharmaceutical, the route of administration It can be selected according to the like. Examples include tablets, coated tablets, pills, capsules, granules, powders, solutions, suspensions, emulsions, syrups, injections, suppositories, dip agents, decoction, tinctures and the like. These various preparations are prepared according to conventional methods as necessary with respect to the active ingredient, such as fillers, extenders, excipients, binders, humectants, disintegrants, surfactants, lubricants, coloring agents, flavoring agents. The pharmaceutical composition can be formulated using known adjuvants that can be usually used in the pharmaceutical preparation technical field, such as solubilizing agents, suspension agents, and coating agents. Moreover, you may contain a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals in this pharmaceutical formulation.

  When used as a material for the hyaluronic acid production promoter according to the first embodiment or the moisturizer according to the second embodiment, the hyaluronic acid production promoter according to the first embodiment or the second embodiment with respect to the total amount of the pharmaceutical product The content of the humectant according to the present invention 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 10% by mass, preferably 0.001 to 1. It is mass%, More preferably, it is 0.01-0.1 mass%.

<Food>
When the hyaluronic acid production promoter according to the first embodiment or the moisturizer 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, diseases It can be used as food for consumers, food additives, etc. As the form of food, soft drinks, milk, pudding, jelly, rice cake, gum, gummi, yogurt, chocolate, containing the hyaluronic acid production promoter according to the first embodiment or the moisturizer according to the second embodiment, Examples include soup, cookies, snacks, ice cream, popsicles, bread, cakes, cream puffs, ham, meat sauce, curry, stew, cheese, butter, dressing and the like.

  The hyaluronic acid production promoter according to the first embodiment or the humectant according to the second embodiment is water, protein, carbohydrate, lipid, vitamins, minerals, organic acid, organic base, fruit juice, flavors, etc. Can be used as the main component. Examples of the protein include whole milk powder, skim milk powder, partially skim milk powder, casein, soybean protein, chicken egg protein, meat protein, and other animal and vegetable proteins, and their hydrolysates and butter. Examples of the saccharide include saccharides, processed starch (in addition to dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like. Examples of lipids include lard, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, hydrogenated oil, and vegetable oils such as transesterified oil. 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, choline. And minerals include, for example, calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and whey minerals. Examples of the organic acid include malic acid, citric acid, lactic acid, and tartaric acid. Two or more of these components may be used in combination, or a synthetic product and / or a food containing a large amount thereof may be used.

The food containing the hyaluronic acid production promoter according to the first embodiment or the humectant according to the second embodiment can be produced according to a conventional method. Moreover, the compounding quantity of the hyaluronic acid production promoter which concerns on 1st embodiment to a foodstuff, or the moisturizer which concerns on 2nd embodiment, a blending method, and a blending time can be selected suitably. Furthermore, it can be enclosed in appropriate containers, such as a bottle, a bag, a can, a box, and a pack, as needed.
When the hyaluronic acid production promoter according to the first embodiment or the humectant according to the second embodiment is used as a food material, the hyaluronic acid production promoter according to the first embodiment or the second The content of the humectant according to the embodiment is not particularly limited as long as the desired effect according to each embodiment is exhibited, but is generally 0.0001 to 10% by mass, preferably 0.001 as the total amount of urolithins. It is -1 mass%, More preferably, it is 0.01-0.1 mass%.

  The cosmetics, pharmaceuticals, foods, etc. containing the hyaluronic acid production promoter according to the first embodiment or the moisturizer according to the second embodiment are used for promoting hyaluronic acid production or moisturizing. Can be sold as cosmetics, medicines, foods, etc.

  The “display” means all acts for informing the consumer of the use, and if it is a display that can recall and analogize the use, the purpose of the display, the content of the display, the display Regardless of the object, medium, etc. to be performed, all correspond to “display” in each embodiment. However, it is preferable to display in such an expression that the consumer can directly recognize the application. Specifically, the act of describing the above-mentioned use in cosmetics, medicines, foods, etc. or the packaging of the product, the thing describing the above-mentioned use in the packaging of the product or the merchandise, and delivery, transfer or delivery Exhibiting and importing, displaying advertisements related to products, price lists or transaction documents for display or distribution, or describing the above uses in information containing these contents (such as the Internet) ) The act provided by the method can be exemplified.

On the other hand, the display is preferably a display approved by the government or the like (for example, a display which is approved based on various systems determined by the government and is performed in a mode based on such approval). Display on advertising materials at sales sites such as catalogs, pamphlets, and POPs, and other documents is preferable.

  In addition, for example, if it is a food containing the hyaluronic acid production promoter according to the first embodiment or the moisturizer according to the second embodiment, health food, functional food, special-purpose food, nutritional functional food, pharmaceutical Indications such as quasi-drugs can be exemplified, and other indications approved by the Ministry of Health, Labor and Welfare, for example, foods for specific health use and indications approved by a similar system can be exemplified. Examples of the latter can include a display as a food for specified health use, a display as a condition specific food for specified health use, a display that affects the structure and function of the body, a display for reducing disease risk, etc. Speaking of the health promotion law enforcement regulations (April 30, 2003 Ministry of Health, Labor and Welfare Ordinance No. 86) labeling as food for specified health use (especially labeling the use of health), 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.

(Method for analyzing urolithin)
A 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 (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 urolithin A factor and the urolithin A concentration of the sample were calculated by the following formulas (1) and (2).

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

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

(Preparation of urolithin A)
2-Bromo-5-methoxybenzoic acid 5 g (manufactured by Wako Pure Chemical Industries, Ltd.) and aluminum chloride 15 g 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, and diethyl ether was distilled off to obtain 4.2 g of 2-bromo-5-hydroxybenzoic acid. 3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (manufactured by Tokyo Chemical Industry Co., Ltd.) were heated in 9 mL of 4M NaOH aqueous solution at 60 ° C. for 30 minutes. After adding 1.8 mL of 10% aqueous copper sulfate solution to the reaction solution, heating was further performed at 80 ° C. for 10 minutes. The produced precipitate was collected by filtration to obtain a white powder of urolithin A.

<1. Evaluation test of hyaluronic acid production promoting ability>
[Examples 1-1 to 1-3]
In order to evaluate the hyaluronic acid production promoting ability of urolithin A, the measurement was performed by the following method.
First, normal human dermal fibroblasts (Clontech) were cultured in Dulbecco's Modified Eagle medium (Life Technologies) at 37 ° C. in the presence of 5% CO ₂ until the logarithmic growth phase. Human dermal fibroblasts obtained by culture were seeded on a 96-well plate so that the cell concentration per well was 2 × 10 ³ cells / 100 μL, and cultured at 37 ° C. in the presence of 5% CO ₂ concentration for 24 hours.

  After culturing, the culture broth was removed, and 100 μL of urolithin A solution prepared with the culture broth to 0.8, 1.6 or 3.1 ppm was added to each well, and further cultured for 48 hours. Examples 1-1 to 1-3 were used. Then, this culture solution was collect | recovered and the amount of hyaluronic acid in a culture solution was measured with the hyaluronic acid measurement kit (Seikagaku Corporation) using ELISA method.

[Comparative Example 1-1]
Comparative Example 1-1 was performed in the same manner as Example 1-1 except that urolithin A was not added.

The relative value when the hyaluronic acid production amount in Comparative Example 1-1 was set to 100 was calculated, and the hyaluronic acid production rate (%) in Examples 1-1 to 1-3 was calculated. The result is shown in FIG.
The intracellular hyaluronic acid-degrading enzyme (hyaluronidase) is promoted by ultraviolet rays. Since the cell culture in this test was performed in an environment shielded from ultraviolet rays (dark room), when the relative value exceeds 100, it means that hyaluronic acid production was promoted.
From FIG. 1, it was confirmed that urolithin A promotes hyaluronic acid production in a concentration-dependent manner.

<2. Sensory test>
(1) Sensory test of cosmetic cream Based on the formulation described in Table 2, cosmetic creams of Test Product 1, Test Product 2, and Control Product 1 were produced. Specifically, it was produced as follows.
First, glycerin was added to purified water and heated to 70 ° C. to obtain an aqueous phase. On the other hand, squalane, beeswax, refined jojoba oil, glycerin monostearate, polyoxyethylene (20) sorbitan monostearate were stirred and mixed while heating to 70 ° C., and this was used as the oil phase. While stirring the aqueous phase, a 50% ethanol aqueous solution containing or not containing urolithin A was added, and then the oil phase which had been heated in advance 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, Comparative Example 2-1>
A sensory test was carried out using the cosmetic creams of test products 1 and 2 (Examples 2-1 and 2-2, respectively) and control product 1 (Comparative Example 2-1).
The panelists were seven women in their 40s who realized that their skin moisturization had decreased and “the feeling of elasticity has ceased.” After washing their face twice a day in the morning and evening, the creams of each test product were placed around the right cheek. The control 1 cream was used around the cheek for 3 weeks. Thereafter, the “elasticity” of the cheek skin surface was compared with the control product 1 by palpation. The results are shown in Table 3.

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

Claims (4)

Hyaluronic acid production promoter containing urolithins represented by the following general formula (1).

(Wherein R1, R2, R3, R4, R5, and R6 each represent a hydroxyl group, a hydrogen atom, or a methoxy group, and at least one of R1, R2, R3, R4, R5, and R6 is It is a hydroxyl group.)   A humectant containing the hyaluronic acid production promoter according to claim 1. The hyaluronic acid production promoter according to claim 1, wherein the urolithins are urolithin A represented by the following formula (2).

The humectant according to claim 2, wherein the urolithin is urolithin A represented by the following formula (2).

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