EPIDERMAL KERATINOCYTE PROLIFERATION PROMOTER AND EXTERNAL SKIN APPLICATION FOR PROMOTING EPIDERMAL KERATINOCYTE PROLIFERATION

Abstract

To provide an epidermal keratinocyte growth stimulator that has a high effect of stimulating epidermal keratinocyte growth and is highly safe, and an external preparation for skin that has a high effect of stimulating epidermal keratinocyte growth and is highly safe.SOLUTION: A epidermal keratinocyte growth stimulator contains nicotinamide in combination with at least one selected from the group consisting of Paeonia lactiflora extract, Golden Silk extract, Morinda citrifolia fruit juice, Alpinia speciosa extract, pearl protein hydrolysate, Isodon japonicus extract, Ganoderma lucidum (Fr).Karst. extract, and oil-soluble Glycyrrhiza extract.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an epidermal keratinocyte proliferation promoter and an external preparation for skin. [Background technology]

[0002] The epidermis, which functions to mitigate external stimuli and control the loss of body components such as water, is composed of a four-layer structure starting from the basal layer at the bottom, followed by the spinous layer, granular layer, and stratum corneum. Most of the cells in each layer are keratinocytes differentiated from the basal layer. Keratinocytes that divide and proliferate in the basal layer differentiate into keratinocytes as they pass through the spinous layer and granular layer, forming the stratum corneum composed of keratin protein fibers with strong cross-linking, and finally falling off from the stratum corneum as scum. This stratum corneum is present in the outermost shell of the skin and serves as a physical barrier against stimuli from the outside world. To provide this barrier function, the skin repeats a cycle (keratinization) from when keratinocytes are produced in the basal layer until they become scum and fall off, usually in a four-week cycle, and the metabolism of the epidermis is carried out.

[0003] However, when the skin is exposed to external factors such as ultraviolet rays, extremely dry air, excessive skin washing, smoking, etc., or when the skin ages, the activity and proliferation ability of epidermal cells declines, and the turnover rate of the epidermis slows down, causing differentiation failure such as thinning of the epidermis and thickening of the stratum corneum. As a result, the skin's moisturizing function and elasticity decline, abnormal peeling of the stratum corneum occurs, and the skin ages, causing changes such as wrinkles, dullness, loss of texture, and decreased elasticity.

[0004] Therefore, if the proliferation of keratinocytes can be promoted, skin turnover will be promoted and the metabolic function of the skin will be restored, which is believed to improve skin aging such as fine wrinkles, dullness, pigmentation, etc. Conventionally, extracts from Taiso (see Patent Document 1), extracts from Tsuchigai Mo (see Patent Document 2), etc. are known to have the effect of promoting the proliferation of epidermal keratinocytes.

[0005] However, the epidermal keratinocyte proliferation-promoting effect of conventional materials is not sufficient, and there is a strong demand for new epidermal keratinocyte proliferation promoters that have a superior epidermal keratinocyte proliferation-promoting effect and are also highly safe, and there is currently a demand for their rapid development. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2006-316028 A [Patent Document 2] JP 2006-056854 A Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to solve the above-mentioned conventional problems and to achieve the following object: That is, the present invention aims to provide an epidermal keratinocyte proliferation promoter that has an excellent epidermal keratinocyte proliferation promoting effect and is highly safe. Another object of the present invention is to provide an external preparation for skin which has an excellent effect of promoting the proliferation of epidermal keratinocytes and is highly safe. [Means for solving the problem]

[0008] As a result of intensive research conducted by the present inventors to solve the above-mentioned problems, it was discovered that a combination of (A) nicotinamide with (B) at least one selected from the group consisting of peony extract, golden silk extract, noni juice, shell ginger extract, pearl protein hydrolysate, Chinese laurel extract, lychee extract, and oil-soluble licorice extract exerts an even more excellent effect of promoting the proliferation of epidermal keratinocytes, and the present invention was completed based on this discovery.

[0009] The present invention is based on the findings of the present inventors, and the means for solving the above problems are as follows. <1> Nicotinamide, This is an epidermal keratinocyte proliferation promoter characterized by combining at least one selected from the group consisting of peony extract, golden silk extract, noni juice, shell ginger extract, pearl protein hydrolysate, Enmeiso extract, lychee extract, and oil-soluble licorice extract. <2> The above <1> 1. An external skin preparation comprising the epidermal keratinocyte proliferation promoter described in Effect of the Invention

[0010] The epidermal keratinocyte proliferation promoter of the present invention can solve the above-mentioned problems in the past and achieve the above-mentioned objective, thereby providing an epidermal keratinocyte proliferation promoter that has excellent epidermal keratinocyte proliferation promoting effect and is highly safe. According to the topical skin preparation of the present invention, the above-mentioned problems of the related art can be solved and the above-mentioned object can be achieved, and a topical skin preparation having excellent epidermal keratinocyte proliferation-promoting activity and high safety can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] (Epidermal keratinocyte proliferation promoter) The epidermal keratinocyte proliferation promoter of the present invention comprises a combination of (A) nicotinamide (hereinafter sometimes referred to as "component (A)") and (B) at least one selected from the group consisting of peony extract, golden silk extract, noni juice, shell ginger extract, pearl protein hydrolysate, Enmeiso extract, lychee extract, and oil-soluble licorice extract (hereinafter sometimes referred to as "component (B)"), and further contains other components as necessary.

[0012] Although the details of how the combined use of component (A) and component (B) exerts a dramatically improved epidermal keratinocyte proliferation-promoting effect are unknown, it was not previously known that the combination of component (A) and component (B) has such an excellent effect and is extremely useful as an epidermal keratinocyte proliferation-promoting agent, and this is a new discovery by the present inventors.

[0013] The epidermal keratinocyte proliferation promoter may be in an embodiment in which the active ingredients, component (A) and component (B), are contained in the same composition, or in an embodiment in which the active ingredients, component (A) and component (B), are contained in separate compositions and both are used in combination when used. When a plurality of components (B) are used, the active ingredients may all be contained in the same composition, or in an embodiment in which the active ingredients, component (B), are divided into two or more compositions and used in combination when used.

[0014] <Component (A)> The nicotinamide is a compound represented by the following structural formula, and is also called niacinamide or vitamin B3. Nicotinamide is commercially available as a material for cosmetics, quasi-drugs, pharmaceuticals, etc. [ka]

[0015] The nicotinamide may be a synthesized product or a commercially available product.

[0016] The content of the nicotinamide in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0017] <(B) component> The component (B) is at least one selected from the group consisting of peony extract, golden silk extract, noni juice, shell ginger extract, pearl protein hydrolysate, Enmeiso extract, lychee extract, and oil-soluble licorice extract. These may be used alone or in combination of two or more.

[0018] -Peony extract- Peony (scientific name: Paeonia lactiflora) is a perennial plant of the family Paeoniaceae and is readily available in the northeastern region of the Asian continent.

[0019] The peony extract may be prepared from the part of the plant used as the raw material for extraction, or a commercially available product may be used.

[0020] The part of the peony to be extracted is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include the root. The shape, structure and size of the peony extract raw material are not particularly limited and can be appropriately selected depending on the purpose.

[0021] The content of the peony extract in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0022] -Shell ginger extract- Shell ginger (scientific name: Alpinia zerumbet or Alpinia speciosa (Wendl.) K. Schum.) is a perennial evergreen herb belonging to the genus Alpinia in the family Zingiberaceae. It is distributed from southern Kyushu to India and can be easily obtained from these areas.

[0023] The shell ginger extract may be prepared from the part of the shell ginger plant used as the raw material for extraction, or a commercially available product may be used.

[0024] The part of the shell ginger plant that can be extracted is not particularly limited and can be appropriately selected depending on the purpose, but the leaves are preferred. The shape, structure and size of the shell ginger extract raw material are not particularly limited and can be appropriately selected depending on the purpose.

[0025] The content of the shell ginger extract in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0026] - Enmeisou extract - Enmeisou (also known as hikiokoshi) is the whole plant of Enmeisou (scientific name: Isodon japonica), a perennial plant belonging to the mint family, distributed from Hokkaido to Shikoku and Kyushu, and can be easily obtained in these areas.

[0027] The Enmeiso extract may be prepared from the part of the plant used as the raw material for extraction, or a commercially available product may be used.

[0028] The part of the Enmeiso plant to be extracted is not particularly limited and can be appropriately selected depending on the purpose. For example, the whole plant, above-ground parts, etc. can be mentioned. The shape, structure and size of the raw material for extracting Enmeiso are not particularly limited and can be appropriately selected depending on the purpose.

[0029] The content of the Enmeiso extract in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0030] -Lychee extract- Reishi (scientific name: Ganoderma lucidum (Fr.) Karst.) (also known as Ganoderma lucidum) is a basidiomycete fungus in the Polyporaceae family.

[0031] The lychee extract may be prepared from the part of the lychee plant used as the raw material for extraction, or a commercially available product may be used.

[0032] The part of the litchi that can be extracted is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include the fruit body. The shape, structure and size of the litchi extract raw material are not particularly limited and can be appropriately selected depending on the purpose.

[0033] The content of the Ganoderma lucidum extract in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0034] -extraction- The peony extract, shell ginger extract, enmeiso extract, and litchi extract can be easily obtained by a method generally used for plant extraction. The form of the extract is not particularly limited and can be appropriately selected according to the purpose, and examples thereof include the extract itself, a diluted extract, a concentrated extract, a dried product thereof, a crude product thereof, and a purified product thereof.

[0035] The method for preparing the extracts of the peony root, shell ginger, Enmeisou and litchi is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include a method in which the extracted parts are dried and then subjected to solvent extraction as is or after crushing using a crusher. The drying may be performed in the sun or using a commonly used dryer.

[0036] The extraction method is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include a method of extracting using any extraction device at room temperature or under reflux heating, and more specifically, a method of putting the extraction part, which is the extraction raw material, into a treatment tank filled with an extraction solvent, stirring appropriately as necessary, for example, for 30 minutes to 4 hours to elute the soluble components, and then filtering to remove the extraction residue to obtain an extract. The extract may be further dried by distilling off the extraction solvent. In addition, the extract may be used after pretreatment such as degreasing with a non-polar solvent such as hexane. By carrying out pretreatment such as degreasing, extraction with a polar solvent can be carried out efficiently.

[0037] The extraction conditions (extraction time and extraction temperature), the extraction solvent, and the amount of the extraction solvent used are not particularly limited and can be appropriately selected depending on the purpose.

[0038] The extraction solvent is not particularly limited and can be appropriately selected depending on the purpose. Examples of the extraction solvent include water, a hydrophilic solvent, and a mixture thereof.

[0039] The water is not particularly limited and can be appropriately selected depending on the purpose, and includes, for example, pure water, tap water, well water, mineral water, hot spring water, spring water, fresh water, and water that has been subjected to various treatments. Treatments for water include, for example, purification, heating, sterilization, filtration, ion exchange, adjustment of osmotic pressure, buffering, and the like. Water that can be used as the extraction solvent also includes purified water, hot water, ion exchange water, physiological saline, phosphate buffer, phosphate buffered physiological saline, and the like. The water may be used alone or in combination of two or more types.

[0040] The hydrophilic solvent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include lower alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, propyl alcohol, isopropyl alcohol, etc.; lower aliphatic ketones, such as acetone, methyl ethyl ketone, etc.; polyhydric alcohols having 2 to 5 carbon atoms, such as 1,3-butylene glycol, propylene glycol, glycerin, etc. These may be used alone or in combination of two or more kinds.

[0041] The amount of the hydrophilic solvent used relative to the water in the mixed solvent is not particularly limited and can be appropriately selected depending on the purpose. However, when a lower alcohol is used, it is preferable to add 1 to 90 parts by volume relative to 10 parts by volume of water, when a lower aliphatic ketone is used, it is preferable to add 1 to 40 parts by volume relative to 10 parts by volume of water, and when a polyhydric alcohol is used, it is preferable to add 1 to 90 parts by volume relative to 10 parts by volume of water.

[0042] The temperature of the extraction solvent is not particularly limited and can be appropriately selected depending on the purpose, but it is preferable to use the solvent at a temperature between room temperature and the boiling point of the solvent.

[0043] The obtained peony extract, shell ginger extract, enmeisou extract, and lychee extract may be subjected to treatments such as dilution, concentration, drying, purification, etc. according to conventional methods in order to obtain diluted products, concentrates, dried products, crude products, purified products, etc. of the peony extract, shell ginger extract, enmeisou extract, and lychee extract.

[0044] The purification method for the peony extract, the shell ginger extract, the Enmeiso extract, and the Ganoderma lucidum extract is not particularly limited and can be appropriately selected depending on the purpose, and examples of the purification method include liquid-liquid distribution extraction, various types of chromatography, and membrane separation.

[0045] The obtained peony extract, shell ginger extract, enmeiso extract, and litchi extract can be used as they are as active ingredients of the epidermal keratinocyte proliferation promoter, but the concentrates and dried products are preferred in terms of ease of use. In obtaining the dried products, a carrier such as dextrin or cyclodextrin may be added to improve hygroscopicity.

[0046] -Noni juice- The noni fruit (scientific name: Morinda citrifolia) is called Yaeyamaaoki in Japanese and is a plant of the Rubiaceae family. It is distributed from Okinawa to the Ogasawara Islands, Taiwan to China, and the coastal areas of India, and is easily available in these areas. The noni fruit is squeezed with a squeezer or the like to obtain noni juice. The obtained noni juice is dried and used, and freeze-dried product is preferable. It is also possible to use the extract obtained by extracting noni juice. The extract can be easily obtained by the method generally used for plant extraction, and can be extracted in the same manner as the above-mentioned peony extract, shell ginger extract, Enmeisou extract, and lychee extract.

[0047] The noni juice may be prepared from noni fruit or may be a commercially available product.

[0048] The content of the noni fruit juice in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0049] -Pearl protein hydrolysate- The pearl protein hydrolysate (sometimes called "pearl protein extract") is obtained by subjecting the shells of nacre-bearing shellfish and / or pearls to a demineralization process, and then hydrolyzing the pearl protein (conchiolin) obtained thereby.

[0050] The pearl protein hydrolysate used may be one prepared from the shells of nacreous shellfish and / or pearls, or a commercially available product.

[0051] Shells having nacre are not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include the pearl oyster (Pinctada fucata) belonging to the family Mytilidae, the mussel (Mytilus coruscum) and the purple mussel (Mytilus edulis) belonging to the family Mytilidae, the mussel (Hyriopsis schlegelii) and the black mussel (Cristaria plicata) belonging to the family Unionidae, etc. Among these, it is preferable to use the pearl oyster.

[0052] The shells and / or pearls of the nacreous shells are subjected to demineralization treatment either as is or after crushing. The demineralization treatment of the shells and / or pearls may be carried out by a conventional method, for example, by adding an acid or an aqueous solution thereof to the shells and / or pearls and stirring them. The acid that can be used for the demineralization treatment is not particularly limited as long as it can sufficiently dissolve inorganic components such as calcium carbonate contained in the shells and / or pearls, and can be appropriately selected depending on the purpose, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.; organic acids such as oxalic acid, carbonic acid, citric acid, malic acid, maleic acid, tartaric acid, acetic acid, formic acid, etc. These may be used alone or in combination of two or more. The amount of acid or its aqueous solution to be added is not particularly limited as long as it is an amount that can sufficiently dissolve inorganic components such as calcium carbonate contained in the shells and / or pearls, and can be appropriately selected depending on the type of acid used, etc.

[0053] The solution obtained by the demineralization treatment is subjected to solid-liquid separation means such as centrifugation, filtration, decantation, etc. to recover the insoluble matter, and if necessary, purified water is added to the recovered insoluble matter, and washing procedures such as centrifugation and filtration are repeated to recover the insoluble matter. The obtained insoluble matter is then finely pulverized using a grinder, etc., if desired, and dried in a conventional manner to obtain pearl protein (conchiolin).

[0054] The resulting pearl protein (conchiolin) is then hydrolyzed using an aqueous acid or alkali solution. The acid that can be used for the hydrolysis of pearl protein (conchiolin) is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include hydrochloric acid, sulfuric acid, etc. These may be used alone or in combination of two or more kinds. The alkali that can be used in the hydrolysis of pearl protein (conchiolin protein) is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include sodium hydroxide, potassium hydroxide, etc. These may be used alone or in combination of two or more kinds.

[0055] When hydrolysis is carried out using an aqueous acid or alkali solution, there are no particular limitations on the amount of the aqueous acid or alkali solution added or the concentration of the acid or alkali in the aqueous solution, as long as it is an amount that can hydrolyze the pearl protein (conchiolin) contained in the shells and / or pearls but cannot completely decompose them into amino acids, and the amount can be selected appropriately depending on the type of acid or alkali used, etc.

[0056] The conditions for the hydrolysis treatment are not particularly limited and can be appropriately selected depending on the purpose, but can be performed at a temperature of 0 to 130°C, preferably 50 to 110°C, for about 30 minutes to 10 days, preferably 5 hours to 5 days.

[0057] The solution obtained by the hydrolysis treatment is then subjected to removal of acid or alkali, and if necessary, subjected to ultrafiltration treatment to remove high molecular peptides, and further subjected to treatments such as concentration and drying to obtain pearl protein hydrolysate. The acid or alkali can be removed from the solution obtained by hydrolysis by a conventional method, for example, freeze-drying or a method of desalting the solution by neutralizing the acid or alkali in the solution.

[0058] The pearl protein hydrolysate contains molecules with various molecular weights depending on the decomposition and purification conditions, but the range of the molecular weight is not particularly limited and can be appropriately selected depending on the purpose.

[0059] The content of the pearl protein hydrolysate in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0060] -Golden Silk Extract- The golden silk extract (sometimes referred to as "golden silk hydrolysate") is obtained by hydrolyzing golden silk using an aqueous acid or alkali solution.

[0061] The golden silk extract may be prepared from golden silk or may be a commercially available product.

[0062] Golden Silk is a deep yellow silk thread produced by the silkworm moth Bonbix mori. It is a special golden cocoon produced mainly in the Thunghuachang region of Lamphun Province, Thailand, and is also commercially available.

[0063] The acid that can be used for the hydrolysis treatment of golden silk is not particularly limited and can be appropriately selected according to the purpose, and examples thereof include hydrochloric acid, sulfuric acid, etc. These may be used alone or in combination of two or more kinds. In addition, the alkali that can be used for the hydrolysis treatment of golden silk is not particularly limited and can be appropriately selected according to the purpose, and examples thereof include sodium hydroxide, potassium hydroxide, etc. These may be used alone or in combination of two or more kinds.

[0064] When hydrolysis is performed using an aqueous acid or alkali solution, the amount of the aqueous acid or alkali solution added and the concentration of the acid or alkali in the aqueous solution are not particularly limited as long as they are an amount capable of hydrolyzing golden silk, and can be appropriately selected depending on the type of acid or alkali used, etc.

[0065] The conditions for the hydrolysis treatment are not particularly limited and can be appropriately selected depending on the purpose, but can be performed at a temperature of 0 to 130°C, preferably 50 to 120°C, for about 30 minutes to 10 days, preferably 1 hour to 5 days.

[0066] The solution obtained by the hydrolysis treatment is subjected to removal of acid or alkali, and if necessary, subjected to ultrafiltration treatment to remove high molecular weight peptides, and then subjected to further treatments such as concentration and drying to obtain a golden silk extract. The acid or alkali can be removed from the solution obtained by hydrolysis by a conventional method, for example, freeze-drying or a method of desalting the solution by neutralizing the acid or alkali in the solution.

[0067] The content of the golden silk extract in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0068] -Oil-soluble licorice extract- The oil-soluble licorice extract is an extract obtained by using Glycyrrhiza glabra, a perennial herb belonging to the genus Glycyrrhiza of the family Fabaceae, as an extraction raw material and an organic solvent as an extraction solvent.

[0069] The oil-soluble licorice extract may be prepared from the part of the plant used as the raw material for extraction, or a commercially available product may be used.

[0070] The part of licorice to be extracted is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include leaves, stems, flowers, buds, fruits, roots, stolons, and mixtures thereof. Among these, roots and stolons are preferred. The shape, structure and size of the licorice extract raw material are not particularly limited and can be appropriately selected depending on the purpose.

[0071] --extraction-- The oil-soluble licorice extract can be easily obtained by a method generally used for plant extraction using an organic solvent as an extraction solvent. The form of the extract is not particularly limited and can be appropriately selected according to the purpose, and examples thereof include the extract itself, a dilution of the extract, a concentrated extract, a dried product thereof, a crude product thereof, a purified product thereof, etc.

[0072] The method for preparing the licorice extract is not particularly limited and can be appropriately selected according to the purpose. For example, the extract is dried and then subjected to solvent extraction either directly or after crushing using a crusher. The drying can be performed in the sun or using a commonly used dryer. In addition, the raw material for extraction can be the dried root and dried rhizome, which are the raw materials for extracting glycyrrhizin industrially produced, or the water extraction residue after extraction with water to obtain glycyrrhizin, etc.

[0073] The extraction method is not particularly limited and can be appropriately selected depending on the purpose. For example, a method in which an organic solvent is added in an amount 2 to 10 times that of the extraction raw material, and extraction is performed at room temperature while stirring, a method in which extraction is performed by heating under reflux, etc. can be mentioned.

[0074] The extraction conditions (extraction time and extraction temperature), the extraction solvent, and the amount of the extraction solvent used are not particularly limited and can be appropriately selected depending on the purpose.

[0075] The organic solvent that can be used as the extraction solvent is not particularly limited and can be appropriately selected according to the purpose, and examples thereof include benzene, toluene, xylene, ethyl ether, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, dichloroethane, chloroform, ethyl acetate, propyl acetate, butyl acetate, acetone, methanol, ethanol, propanol, aqueous methanol, aqueous ethanol, and aqueous propanol. Furthermore, carbon dioxide can be used as a supercritical fluid. Among these organic solvents, ethanol or aqueous ethanol is preferably used because it causes fewer problems under the Food Sanitation Act.

[0076] The temperature of the extraction solvent is not particularly limited and can be appropriately selected depending on the purpose.

[0077] The oil-soluble licorice extract thus obtained may be subjected to treatments such as dilution, concentration, drying, purification, etc., according to conventional methods in order to obtain a diluted product, concentrate, dried product, crude product, purified product, etc. of the oil-soluble licorice extract.

[0078] The method for purifying the oil-soluble licorice extract is not particularly limited and can be appropriately selected depending on the purpose. For example, purification methods such as liquid-liquid partition extraction, various types of chromatography, and membrane separation can be mentioned.

[0079] The oil-soluble licorice extract obtained can be used as it is as an active ingredient of the epidermal keratinocyte proliferation promoter, but the concentrated liquid and the dried product are preferred in terms of ease of use. In obtaining the dried product, a carrier such as dextrin or cyclodextrin may be added to improve hygroscopicity.

[0080] The content of the oil-soluble licorice extract in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0081] When two or more types of the (B) component are used, the blending ratio of each component, namely, peony extract, golden silk extract, noni juice, shell ginger extract, pearl protein hydrolysate, Enmeiso extract, lychee extract, and oil-soluble licorice extract, is not particularly limited and can be selected appropriately depending on the purpose.

[0082] The total content of the component (B) in the epidermal keratinocyte proliferation promoter is not particularly limited, and can be appropriately adjusted depending on the physiological activity of each of the components.

[0083] The mass ratio of the component (A) to the component (B) in the epidermal keratinocyte proliferation promoter (component (A):component (B)) is not particularly limited and can be appropriately selected depending on the purpose, and may be, for example, 100:0.01 to 100:100. The mass ratio of the component (A) to the component (B) is a value calculated on a solid content basis.

[0084] The epidermal keratinocyte proliferation promoter may consist of only the component (A) and the component (B).

[0085] <Other ingredients> The other components are not particularly limited and can be appropriately selected depending on the form of use of the epidermal keratinocyte proliferation promoter, and examples thereof include excipients, moisture-proofing agents, preservatives, strengthening agents, thickeners, emulsifiers, antioxidants, sweeteners, acidulants, seasonings, colorants, fragrances, whitening agents, moisturizers, oily components, UV absorbers, surfactants, thickeners, alcohols, powder components, coloring agents, aqueous components, water, skin nutrients, etc. In addition, if necessary, substances having an epidermal keratinocyte proliferation promoting effect other than the component (A) and the component (B) may be used. These may be used alone or in combination of two or more.

[0086] The content of the other components in the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose.

[0087] The epidermal keratinocyte proliferation promoter may be a mixture of the above-mentioned components, or the above-mentioned combination of components may be formulated. When the composition is formulated, it can be formulated into any dosage form such as powder, granules, tablets, liquid, etc., according to a conventional method using a pharma- ceutically acceptable carrier such as dextrin, cyclodextrin, or any other auxiliary agent. In this case, examples of the auxiliary agent that can be used include excipients, binders, disintegrants, lubricants, stabilizers, flavorings, and odorants.

[0088] <Application> The use of the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose. Examples of the use include medicines, quasi-drugs, and cosmetics.

[0089] The method of use of the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include oral, parenteral, and external use. Among these, external use is preferred. The epidermal keratinocyte proliferation promoter can be suitably used as an active ingredient of an external skin preparation described below.

[0090] The administration site, dosage, method of use, and dosage form of the epidermal keratinocyte proliferation promoter can be appropriately selected depending on the purpose of use.

[0091] The dosage form of the epidermal keratinocyte proliferation promoter is not particularly limited and can be appropriately selected depending on the purpose. Examples of the dosage form include oral administration agents such as tablets, powders, capsules, granules, extracts, and syrups; parenteral administration agents such as injections, drops, and suppositories; and external applications such as lotions, milky lotions, creams, ointments, beauty essences, lotions, packs, jellies, lip balm, lipstick, foundations, bath additives, soaps, body soaps, astringents, hair tonics, hair lotions, hair creams, hair liquids, pomades, shampoos, rinses, and conditioners. The method for producing each of the above-mentioned formulations of the epidermal keratinocyte proliferation promoter is not particularly limited, and any known method can be appropriately selected.

[0092] The epidermal keratinocyte proliferation promoter of the present invention is preferably applied to humans, but can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, etc.) so long as the respective functional effects are achieved.

[0093] As described above, the epidermal keratinocyte proliferation promoter of the present invention has an excellent epidermal keratinocyte proliferation promoting effect. Therefore, the present invention also relates to a method for promoting epidermal keratinocyte proliferation, which comprises administering the epidermal keratinocyte proliferation promoter to an individual.

[0094] Furthermore, the epidermal keratinocyte proliferation promoter of the present invention can also be used as a reagent for research into the mechanism of action of promoting epidermal keratinocyte proliferation.

[0095] (External skin preparations) The external skin preparation of the present invention contains the epidermal keratinocyte proliferation promoter of the present invention, and further contains other ingredients as necessary. The above-mentioned external preparation for skin has an extremely excellent effect of promoting the proliferation of epidermal keratinocytes, and therefore can be suitably used as an external preparation for skin for promoting skin turnover.

[0096] <Epidermal keratinocyte proliferation promoter> The epidermal keratinocyte proliferation promoter is the epidermal keratinocyte proliferation promoter of the present invention described above. The epidermal keratinocyte proliferation promoter to be incorporated into the topical skin preparation may be a mixture of the component (A) and the component (B) as is, or may be a formulation of the mixture, or the component (A) and the component (B) may be incorporated into different topical skin preparations, and the respective topical skin preparations may be used in combination at the time of use.

[0097] The content of the epidermal keratinocyte proliferation promoter in the skin topical preparation is not particularly limited and can be appropriately adjusted depending on the form of the skin topical preparation and the physiological activity of the active ingredients (the (A) component and the (B) component) in the epidermal keratinocyte proliferation promoter, etc., but is preferably 0.0001% by mass to 20% by mass, and more preferably 0.0001% by mass to 10% by mass, calculated as the total content (converted into solid content) of the (A) component and the (B) component. The skin topical preparation may consist of only the epidermal keratinocyte proliferation promoter.

[0098] <Other ingredients> The other components in the skin topical preparation are not particularly limited and can be appropriately selected depending on the form of use of the skin topical preparation, and examples thereof include main components, auxiliary agents, and other components that are generally used in the manufacture of cosmetics. Examples of the main components, auxiliary agents, and other components that are generally used in the manufacture of cosmetics include astringents, bactericides and antibacterial agents, whitening agents, ultraviolet absorbers, moisturizers, cell activators, anti-inflammatory and anti-allergic agents, antioxidants and active oxygen removers, oils and fats, waxes, hydrocarbons, fatty acids, alcohols, esters, surfactants, and fragrances. These may be used alone or in combination of two or more.

[0099] The content of other ingredients in the skin topical preparation is not particularly limited and can be appropriately selected depending on the purpose.

[0100] The skin external preparations are not limited in classification and include a wide range of skin cosmetics, quasi-drugs, medicines, etc. that are used percutaneously.

[0101] The type of the topical skin preparation is not particularly limited and can be appropriately selected depending on the purpose. Examples of the topical skin preparation include lotion, milky lotion, cream, ointment, beauty serum, lotion, gel, beauty oil, pack, jelly, lip balm, lipstick, foundation, bath additives, soap, body soap, astringent, hair tonic, hair lotion, hair cream, hair liquid, pomade, shampoo, rinse, and conditioner. The method for producing each of the above-mentioned external skin preparations is not particularly limited, and any known method can be appropriately selected.

[0102] The administration site, dosage, method of use and dosage form of the external skin preparation can be appropriately selected depending on the purpose of use.

[0103] The skin topical preparation is suitable for application to humans, but can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, etc.) as long as its functional effects are achieved.

[0104] The topical skin preparation is highly safe and can be used daily, and can effectively exert effects such as promoting skin turnover through its excellent epidermal keratinocyte proliferation promoting effect. Therefore, the present invention also relates to a method for promoting skin turnover, which is characterized by administering the topical skin preparation to an individual.

[0105] Furthermore, the skin external preparation of the present invention can also be used as a reagent for research into the mechanism of skin turnover. EXAMPLES

[0106] Test examples and formulation examples of the present invention will be described below, but the present invention is not limited to these test examples and formulation examples.

[0107] (Test Example 1: Epidermal keratinocyte proliferation promotion test) The following test samples were used and their epidermal keratinocyte proliferation promoting effect was tested according to the following test method. <Test sample> (1) Nicotinamide (DSM) (2) Peony extract 1,500 mL of 80% ethanol solution was added to 100 g of peony root, and the mixture was extracted under reflux for 2 hours and filtered while hot. The extract was dried to obtain peony extract (8 g). (3) Golden silk extract (Golden silk extract BG30, manufactured by Maruzen Pharmaceutical Co., Ltd., obtained by hydrolysis of golden silk) (4) Noni juice Butylene glycol and purified water were added to 100 g of Noni (Japanese citronella) juice, and the resulting extract was dried to obtain Noni extract (5 g). (5) Shell ginger extract 1,500 mL of 80% ethanol solution was added to 100 g of shell ginger leaves, and extraction was performed under reflux for 2 hours, followed by hot filtration. The resulting extract was dried to obtain shell ginger leaf extract (1 g). (6) Pearl protein hydrolysate (pearl protein extract BG-JC <np>(Manufactured by Maruzen Pharmaceutical Co., Ltd.; obtained by hydrolyzing conchiolin, a hard protein contained in the nacre of pearl oysters (Akoya pearl oysters)) (7) Enmeisou Extract 1,500 mL of 80% ethanol solution was added to 100 g of the above-ground part of the plant, and the mixture was extracted under reflux for 2 hours and then filtered while hot. The extract was dried to obtain the Enmeiso extract (11 g). (8) Ganoderma lucidum extract 1,500 mL of purified water was added to 100 g of dried fruit body of Ganoderma lucidum, and the mixture was extracted by heating at 80 to 90° C. for 2 hours and filtered while hot. The obtained extract was dried to obtain Ganoderma lucidum extract (1 g). (9) Oil-soluble licorice extract (oil-soluble licorice extract HG, manufactured by Maruzen Pharmaceutical Co., Ltd., extracted from licorice root flavonoids with ethanol and purified)

[0108] Normal human neonatal epidermal keratinocytes (NHEK) were cultured in normal human epidermal keratinocyte growth medium (KGM), and the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 3.0 × 10 4 After diluting with KGM to a concentration of 100 cells / mL, 100 μL was seeded per well on a collagen-coated 96-well plate and cultured overnight at 37°C under 5% CO2. After culture was completed, 100 μL of the test sample dissolved in KGM was added to each well (see Tables 1 to 8 below for the concentrations of the test samples), and cultured at 37°C under 5% CO2 for 3 days. The epidermal keratinocyte proliferation promoting activity was measured using the MTT assay method. Specifically, after the end of the culture, the medium was removed, and 100 μL of MTT dissolved in PBS(-) at a final concentration of 0.4 mg / mL was added to each well. After 2 hours of culture at 37°C under 5% CO2, blue formazan produced in the cells was extracted with 100 μL of 2-propanol. After extraction, the absorbance at a wavelength of 570 nm was measured. At the same time, the absorbance at a wavelength of 650 nm was measured as turbidity, and the difference between the two was taken as the amount of blue formazan produced. The test was also conducted in the same manner in the absence of the test sample. The method for calculating the epidermal keratinocyte proliferation promotion rate is as follows. Epidermal keratinocyte proliferation promotion rate (%) = (A / B) x 100 A: Amount of blue formazan produced in cells when test sample was added B: Amount of blue formazan produced in cells without the addition of test sample

[0109] [Table 1]

[0110] [Table 2]

[0111] [Table 3]

[0112] [Table 4]

[0113] [Table 5]

[0114] [Table 6]

[0115] [Table 7]

[0116] [Table 8]

[0117] The results in Tables 1 to 8 confirm that the combined use of at least one selected from the group consisting of peony extract, golden silk extract, noni juice, shell ginger extract, pearl protein hydrolysate, Japanese laurel extract, lychee extract, and oil-soluble licorice extract in combination with nicotinamide exhibits an excellent effect of promoting the proliferation of epidermal keratinocytes.

[0118] (Combination example 1) An emulsion having the following composition was prepared by a conventional method. Nicotinamide (same as used in Test Example 1) 0.10 g Peony extract (same as that used in Test Example 1) 0.05g Jojoba oil - 4.00g 1,3-Butylene glycol 3.00g Arbutin 3.00g Polyoxyethylene cetyl ether (20E.O.) 2.50g 2.00g olive oil 2.00g Squalane Cetanol 2.00g Glyceryl Monostearate 2.00g Polyoxyethylene sorbitan oleate (20E.O.) 2.00g Methyl parahydroxybenzoate 0.15g Stearyl glycyrrhetinate 0.10g Phellodendron Bark Extract 0.10g Dipotassium glycyrrhizinate 0.10g Ginkgo Biloba Extract 0.10g 0.10g conchiolin Phellodendron bark extract 0.10g Chamomile extract 0.10g · Fragrance 0.05g · Purified water Remainder (total amount is 100g)

[0119] (Combination example 2) A cream having the following composition was prepared by a conventional method. Nicotinamide (same as used in Test Example 1) 1.0 g Golden silk extract (same as that used in Test Example 1) 0.2g Sophora root extract 0.1g · Scutellaria root extract 0.1g Liquid paraffin 5.0g 4.0g white beeswax Squalane 10.0g Cetanol 3.0g 2.0g Lanolin Stearic acid 1.0g Polyoxyethylene sorbitan oleate (20E.O.) 1.5g Glyceryl monostearate 3.0g Oil-soluble licorice extract (same as that used in Test Example 1) 0.1g 1,3-Butylene glycol 6.0g Methyl parahydroxybenzoate 1.5g · Fragrance 0.1g · Purified water Remainder (total amount is 100g)

[0120] (Combination example 3) A beauty essence having the following composition was prepared by a conventional method. Nicotinamide (same as used in Test Example 1) 2.0 g Noni juice (same as that used in Test Example 1) 0.2g Chamomile extract 0.1g Carrot extract 0.1g 0.3g xanthan gum Hydroxyethylcellulose 0.1g Carboxyvinyl polymer 0.1g 1,3-Butylene glycol 4.0g Dipotassium glycyrrhizinate 0.1g 2.0g glycerin 0.25g potassium hydroxide · Fragrance 0.01g Preservative (methyl parahydroxybenzoate) 0.15g Ethanol 2.0g · Purified water Remainder (total amount is 100g)< / np>

Claims

1. Nicotinamide, An epidermal keratinocyte proliferation promoter characterized by combining at least one selected from the group consisting of peony extract, golden silk extract, noni juice, pearl protein hydrolysate, enmeiso extract, lychee extract, and oil-soluble licorice extract.

2. 2. An external skin preparation for promoting epidermal keratinocyte proliferation, comprising the epidermal keratinocyte proliferation promoter according to claim 1.

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