Skin external agent

Abstract

To provide novel active components which can be added to skin external agents and are useful for promoting extracellular matrix production and preventing or improving skin thinning.SOLUTION: Provided is a skin external agent containing a pyridine derivative, or a pyridine derivative and at least any one of an ascorbic acid derivative, tranexamic acid or a derivative thereof, hydroquinone or a derivative thereof and kojic acid or a derivative thereof, collagen or a derivative thereof, hyaluronic acid or a derivative thereof, as well as a component derived from plants, animals, or microorganisms.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pyridine derivative and an external skin preparation containing the pyridine derivative and other active ingredients. [Background technology]

[0002] It has been known that skin aging, dryness, rough skin, spots, and freckles are phenomena that arise from a complex interaction of internal factors, such as the inactivation of cell proliferation and differentiation, decreased hormone secretion, and a quantitative decrease in extracellular matrix components that accompanies aging, and external factors, such as cell and tissue damage caused by active oxygen induced by sunlight (ultraviolet rays) or inflammation.

[0003] In recent years, there has been a demand for active ingredients that can suppress the denaturation or crosslinking of extracellular matrix components present in the dermis layer of the skin, in addition to damaging the surface of the skin, and prevent or improve the formation of wrinkles and loss of skin elasticity.

[0004] Although ingredients that protect the skin from ultraviolet rays, dryness, and the like have been proposed in the past (Patent Documents 1 to 3), no active ingredients were known whose functions of improving the condition of the epidermis of the skin and suppressing the degeneration of extracellular matrix components present in the dermis were fully elucidated.

[0005] [Patent Document 1] Japanese Patent Publication No. 51-123836 [Patent Document 2] Japanese Patent Publication No. 05-500230 [Patent Document 3] Japanese Patent Application Publication No. 09-194383 DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0006] The present invention aims to discover an active ingredient that promotes the production of extracellular matrix, prevents or improves the phenomenon of thinning of the skin caused by ultraviolet rays, aging, decreased hormone secretion, etc., and prevents or improves wrinkles and sagging of the epidermis and dermis. [Means for solving the problem]

[0007] The present invention relates to an external skin preparation comprising a pyridine derivative and at least one of the following (B) to (I): (B) Tranexamic acid or its derivatives (C) Hydroquinone or its derivatives (D) Kojic acid or its derivatives (E) Yeast extract or its hydrolysate (F) Hyaluronic acid hydrolysate or fermentation product (G) An extract, hydrolysate or fermentation product thereof of one or more plants selected from among plants of the family Poaceae, Brassicaceae, Theaceae, Rosaceae, Paeoniaceae, Rutaceae, Amaranthaceae, Zosteraeae, Fabaceae, Asteraceae, Legumes, Malvaceae, Gentianaceae, Lamiaceae, Nelumbaceae, Cucurbitaceae, Araliaceae, Solanaceae, Bignoniaceae, Actinidiaceae, Mulberry, Iridaceae, Campanulaceae, Oleaceae, Actinidiaceae, Rhamnoniaceae, Mulberry, Orchidaceae, Anacardiaceae, Garciniaceae, Valenciaceae, Rutaceae, Myrtaceae, Liliaceae, Crassulaceae, Cupressaceae, Convolvulaceae and Asparagaceae. (H) An extract of one or more seaweeds selected from the family Laminaria, Laminaceae, Ulvaceae, and Funoriaceae, or a hydrolysate or fermentation product thereof. (I) Extracts of jellyfish or royal jelly, or their hydrolysates or fermentation products. Effect of the Invention

[0008] According to the present invention, it is possible to provide an external skin preparation which prevents or improves thinning of the skin and exhibits the effects of preventing or improving wrinkles or sagging. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Preferred embodiments of the present invention will now be described in detail. In the present invention, examples of pyridine derivatives include pyridine-3-carboxylic acid, pyridine-3-carboxylic acid amide (also known as niacinamide), isoniazid, and the like.

[0010] In the present invention, examples of components with which a pyridine derivative is preferably combined include ascorbic acid or a derivative thereof, tranexamic acid or a derivative thereof, hydroquinone or a derivative thereof, kojic acid or a derivative thereof, collagen or a derivative thereof, hyaluronic acid or a derivative thereof, yeast extract or a hydrolysate thereof, and plant- or animal-derived components.

[0011] Examples of ascorbic acid or a derivative thereof include ascorbic acid ester salts such as sodium ascorbate, calcium ascorbate, sodium L-ascorbic acid 2-phosphate, magnesium L-ascorbic acid 2-phosphate, sodium L-ascorbic acid 2-sulfate, and magnesium L-ascorbic acid 2-sulfate; ascorbic acid sugar derivatives such as L-ascorbic acid 2-glucoside, L-ascorbic acid 5-glucoside, ascorbyl tocopheryl maleate, ascorbyl tocopheryl phosphate K, myristyl 3-glyceryl ascorbate, and caprylyl 2-glyceryl ascorbate; and ascorbic acid sugar derivatives thereof. ascorbic acid tetraisopalmitate, L-ascorbic acid tetralaurate and other L-ascorbic acid tetrafatty acid esters, 3-O-ethyl ascorbic acid, L-ascorbic acid-2-phosphate-6-O-sodium palmitate, glyceryl ascorbic acid or an acylated derivative thereof, ascorbic acid glycerin derivatives such as bisglyceryl ascorbic acid, L-ascorbic acid aminopropyl phosphate, hyaluronic acid derivatives of L-ascorbic acid, 3-OD lactose-L-ascorbic acid, and isostearyl ascorbyl phosphate.

[0012] Examples of the derivatives of tranexamic acid include tranexamic acid esters (for example, tranexamic acid lauryl ester, tranexamic acid hexadecyl ester, tranexamic acid cetyl ester, or salts thereof), and amides of tranexamic acid (for example, tranexamic acid methylamide).

[0013] Examples of hydroquinone derivatives include arbutin (hydroquinone-β-D-glucopyranoside) and α-arbutin (hydroquinone-α-D-glucopyranoside).

[0014] Examples of the derivatives of kojic acid include kojic acid esters such as kojic acid monobutyrate, kojic acid monocaprate, kojic acid monopalmitate, and kojic acid dibutyrate, kojic acid ethers, and kojic acid sugar derivatives such as kojic acid glucoside.

[0015] In the present invention, examples of yeast include yeasts of the genus Saccharomyces, such as Saccharomyces cerevisiae, Saccharomyces awamori, Saccharomyces chevalieri, Saccharomyces carlsbergensis, and Saccharomyces bayonus; yeasts of the genus Galactomyces; yeasts of the genus Torulaspora, such as Torulaspora delbruekii, Torulaspora fermentati, and Torulaspora rosei; yeasts of the genus Torulaspora, such as Zygosaccharomyces rouxii, Zygosaccharomyces Yeasts of the genus Zygosaccharomyces, such as Zygosaccharomyces soya, Zygosaccharomyces sake, Zygosaccharomyces miso, and Zygosaccharomyces lactis; yeasts of the genus Candida, such as Candida versatilis, Candida etchellsii, Candida kefyr, Candida sake, and Candida scottii; yeasts of the genus Candida, such as Aureobasidium Pullulans, Aureobasidium mansonii, and Aureobasidium Examples of yeasts of the genus Aureobasidium include Aureobasideium microstictum. The yeast according to the present invention may be any of sake yeast, wine yeast, brewer's yeast, yeast derived from plant flowers (rose, plum, cherry, camellia, lily, etc.), and yeast derived from the sea.

[0016] In the present invention, collagen derived from fish is particularly preferred, for example, fish such as alfonsino, pacific blue-eyed bream, balloon alfonsino, and alfonsino from the family Alfonsidae; fish such as scorpionfish and scorpionfish from the family Scorpaenidae; fish such as scorpionfish, scorpionfish, kichiji, and scorpionfish from the family Scorpaenidae; fish such as threadfin bream from the family Scorpaenidae; fish such as red sea bream, red sea bream, and yellow sea bream from the family Sparidae; fish such as conger eel and conger eel from the family Anguillidae; fish such as Japanese conger eel from the family Conger eel; fish from the family Salmonidae; and fish from the family Sharkidae. Collagen may be hydrolyzed collagen, collagen treated with atelosylation or succinylation, or collagen treated with crosslinking. Collagen derived from jellyfish, collagen treated with hydrolysis, atelosylation, or succinylation, or collagen treated with crosslinking may also be used.

[0017] In addition, examples of plant-derived ingredients include Gramineae plants, Cruciferae plants, Theaceae plants, Rosaceae plants, Paeoniaceae plants, Rutaceae plants, Amaranthaceae plants, Zosteraeae plants, Leguminosae plants, Asteraceae plants, Fabaceae plants, Malvaceae plants, Gentianaceae plants, Lamiaceae plants, Nelumbaceae plants, Cucurbitaceae plants, Araliaceae plants, Solanaceae plants, Bignoniaceae plants, Actinidiaceae plants, Mulberry plants, Iridaceae plants, Campanulaceae plants, Oleaceae plants, Actinidiaceae plants, Rhamnaceae plants, and Mulberry plants. Examples of the extracts include those of one or more plants selected from the family Orchidaceae, Anacardiaceae, Garciniae, Valenciaceae, Rutaceae, Myrtaceae, Liliaceae, Crassulaceae, Cupressaceae, Convolvulaceae, and Asparagaceae, and examples of the seaweed-derived components include those of one or more seaweeds selected from the family Laminariae, Laminaceae, Ulvae, and Funoriaceae, and examples of the extracts include those of one or more seaweeds selected from the family Laminariae, Laminaceae, Ulvae, and Funoriaceae. In addition, examples of the natural product-derived components include those of jellyfish or royal jelly, and examples of the extracts include those of one or more hydrolysates or fermentates. Examples of the extracts include those of one or more plants selected from the family Laminaceae, Laminaceae, Ulvae, and Funoriaceae. Examples of the extracts include those of one or more plants selected from the family Laminaceae, Laminaceae, Ulvae, and Funoriaceae, and examples ...

[0018] The above-mentioned extracts derived from natural products may be extracted by conventional methods, for example, by contacting the extract with an extraction solvent by appropriate means such as a soaking method using a solvent, a countercurrent extraction method, etc. Also, the preparation can be performed by using a supercritical extraction method.

[0019] Examples of the extraction solvent include water, lower alcohols such as methanol, ethanol, and propanol, higher alcohols such as oleyl alcohol, stearyl alcohol, and octyldodecanol, polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, and glycerin, esters such as ethyl acetate, butyl acetate, methyl propionate, and 2-ethylhexyl glyceride, ketones such as acetone and methyl ethyl ketone, ethers such as ethyl ether and isopropyl ether, and hydrocarbon solvents such as n-hexane, toluene, and chloroform, which are used alone or in combination. Among these, it is preferable to use a single solvent or a mixed solvent of two or more solvents selected from water, lower alcohols, and polyhydric alcohols, because they can be widely applied to cosmetics.

[0020] When a mixed solvent is used, the mixing ratio is preferably in the range of, for example, a volume ratio (hereinafter the same) of 1:1 to 25:1 for a mixed solvent of water and ethyl alcohol, 1:1 to 20:1 for a mixed solvent of water and glycerin, and 1:1 to 20:1 for a mixed solvent of water and 1,3-butylene glycol.

[0021] In preparing the extract of the present invention, it is preferable to maintain the pH of the extract in the range of 4 to 8. In this sense, if necessary, an alkalinity regulator such as sodium hydroxide, sodium carbonate, potassium hydroxide, or arginine, or an acidity regulator such as hydrochloric acid, acetic acid, or sulfuric acid may be added to the above-mentioned extraction solvent to adjust the pH to the desired level.

[0022] The extraction conditions such as extraction temperature and time vary depending on the type of solvent used, the extraction method, etc., but for example, in the case of the immersion method, the extraction temperature is preferably in the range of 4 to 90°C, and the extraction time is preferably about 0.1 to 1 week.

[0023] In addition, the above-mentioned extracts derived from natural products may be subjected to hydrolysis treatment. For example, when hydrolysis treatment is performed using an enzyme, it is preferable to use one enzyme selected from proteolytic enzymes such as actinase, papain, chymopapain, trypsin, and pepsin; starch-degrading enzymes such as glucoamylase, α-amylase, and β-amylase; cellulose-degrading enzymes such as cellulase, hemicellulase, and pectinase; and lipolytic enzymes such as lipase; or a combination of one or more enzymes selected from each of the above enzyme groups.

[0024] Examples of the microorganisms (yeast, lactic acid bacteria, koji mold, or Bacillus subtilis) or components derived from microorganisms used in the fermentation treatment to obtain the above-mentioned fermented products include the following.

[0025] In the present invention, lactic acid bacteria include, for example, lactic acid bacteria of the genus Lactobacillus, such as Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus casei, and Lactobacillus delbrueckii; lactic acid bacteria of the genus Carnobacterium, such as Carnobacterium divergens and Carnobacterium piscicola; lactic acid bacteria of the genus Carnobacterium, such as Leuconostoc mesenteroides, Leuconostoc lactis, and Leuconostoc citreum. lactic acid bacteria of the genus Leuconostoc such as Streptococcus faecalis and Streptococcus pyogenes; lactic acid bacteria of the genus Enterococcus such as Enterococcus caseliflavus and Enterococcus sulfreus; lactic acid bacteria of the genus Lactococcus such as Lactococcus plantarum, Lactococcus lactis, and Lactococcus rafinolactis; lactic acid bacteria of the genus Lactococcus such as Weissella confusa and Weissella candoureri. Lactic acid bacteria of the genus Veicella, such as Atopobium kandleri; lactic acid bacteria of the genus Atopobium, such as Atopobium minutum and Atopobium parvulus;Examples of lactic acid bacteria include Vagococcus genus lactic acid bacteria such as Vagococcus fluvialis and Vagococcus salmoninarum; Pediococcus genus lactic acid bacteria such as Pediococcus damnosus and Pediococcus pentosaceus.

[0026] In the present invention, examples of koji mold include yellow koji molds such as Aspergillus oryzae, Aspergillus flavus, Aspergillus polyoxogenes, and Aspergillus sojae; black koji molds such as Aspergillus awamori, Aspergillus kawauchii, Aspergillus usami, and Aspergillus niger; and red koji molds such as Monascus anka and Monascus pilosus.

[0027] In the present invention, examples of Bacillus subtilis include Bacillus natto, Bacillus subtilis, and Bacillus circulans.

[0028] When the above-mentioned suspension or extract is fermented by a microorganism, it is necessary to remove unwanted bacteria that hinder fermentation by sterilization before the fermentation step. As a method for sterilizing and removing the unwanted bacteria, a method of washing the fermentation material with sterilizing ethanol or the like in advance and then suspending it in a sterile solvent such as sterile water may be used, or the fermentation material may be suspended in a solvent and then sterilized by heat sterilization or the like. As the heat sterilization treatment, a heat sterilization method such as an autoclave sterilization method in which the suspension is heated at 120 to 130°C for 10 to 20 minutes or an intermittent sterilization method in which the suspension is kept at 80 to 90°C for 60 to 120 minutes and is repeated once a day for 2 to 3 days is generally used.

[0029] During the fermentation treatment, sugars such as glucose, galactose, fructose, sucrose, maltose, lactose, etc. may be added as a carbon source.

[0030] The sterilized suspension and culture liquid are placed in a fermentation tank, and microorganisms are inoculated into it to ferment. The inoculation amount of the microorganism is 10 7 ~10 8 If the inoculum amount is more than the above range, the fermentation time will not change much, while if it is less than the above range, it will take a long time to complete the fermentation, which is not preferable.

[0031] The fermentation temperature is generally in the range of 5 to 50°C, preferably in the range of the optimum temperature for growth of each microorganism. The fermentation period is generally 1 to 10 days, preferably 2 to 5 days, at the optimum temperature. If the fermentation period is shorter than the above-mentioned general range, the fermentation does not proceed sufficiently and the effectiveness of the fermented product tends to decrease, while if the fermentation period is longer than 10 days, not only will no further increase in effectiveness be observed, but coloring and an increase in fermentation odor will occur, both of which are undesirable.

[0032] When the composition of the present invention is incorporated into an external skin preparation, in addition to the above-mentioned composition as the essential components, components usually used in cosmetics, such as oily components, surfactants (synthetic and natural), moisturizers, anti-inflammatory agents, thickeners, preservatives and germicides, anti-acne agents, cell activators, powder components, ultraviolet absorbers, antioxidants, whitening agents, anti-wrinkle agents, pigments, fragrances, etc., can be appropriately incorporated as necessary.

[0033] Here, examples of oily components include olive oil, jojoba oil, castor oil, soybean oil, rice oil, rice germ oil, coconut oil, palm oil, cacao oil, meadowfoam oil, shea butter, tea tree oil, avocado oil, macadamia nut oil, bergamot oil, lavender oil, rose oil, bergamot oil, chamomile oil, and other plant-derived oils and fats such as squalane; vitamin A oil; animal-derived oils and fats such as mink oil and turtle oil; waxes such as beeswax, carnauba wax, rice wax, and lanolin; liquid paraffin, petrolatum, and paraffin wax. Examples of such fatty acids include hydrocarbons such as cocos and squalane; fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, isostearic acid, and cis-11-eicosenoic acid; higher alcohols such as lauryl alcohol, cetanol, pantothenyl alcohol, and stearyl alcohol; synthetic esters and synthetic triglycerides such as isopropyl myristate, isopropyl palmitate, butyl oleate, 2-ethylhexyl glyceride, and higher fatty acid octyldodecyl (e.g., octyldodecyl stearate).

[0034] Examples of the surfactant include nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitol fatty acid esters; fatty acid salts, alkyl sulfates, alkylbenzene sulfonates, polyoxyethylene alkyl ether sulfates, polyoxyethylene fatty amine sulfates, polyoxyethylene alkyl phenyl ether sulfates, polyoxyethylene alkyl ether phosphates, α-sulfonated fatty acid alkyl ester salts, polyoxyethylene Examples of the surfactants that can be used include anionic surfactants such as quaternary ammonium salts, primary to tertiary fatty amine salts, trialkylbenzylammonium salts, alkylpyridinium salts, 2-alkyl-1-alkyl-1-hydroxyethylimidazolinium salts, N,N-dialkylmorpholinium salts, and polyethylene polyamine fatty acid amide salts; and amphoteric surfactants such as N,N-dimethyl-N-alkyl-N-carboxymethylammoniobetaine, N,N,N-trialkyl-N-alkyleneammoniocarboxybetaine, N-acylamidopropyl-N', N'-dimethyl-N'-β-hydroxypropylammoniosulfobetaine.

[0035] Examples of the emulsifier and / or emulsifier aid that can be blended include stevia derivatives such as enzyme-treated stevia, saponin or its derivatives, casein or its salts (sodium, etc.), sugar and protein complexes, sucrose or its esters, lactose, soy-derived water-soluble polysaccharides, soy-derived protein and polysaccharide complexes, lanolin or its derivatives, cholesterol, stevia derivatives (enzyme-treated stevia, etc.), silicates (aluminum, magnesium, etc.), carbonates (calcium, sodium, etc.), saponin and its derivatives, lecithin and its derivatives (hydrogenated lecithin, etc.), lactic acid bacteria-fermented rice, lactic acid bacteria-fermented germinated rice, lactic acid bacteria-fermented grains (wheat, beans, millet, etc.), etc.

[0036] Examples of moisturizing agents include glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, xylitol, sodium pyrrolidone carboxylate, and the like, as well as sugars such as trehalose and raffinose, mucopolysaccharides (e.g., hyaluronic acid and its derivatives, hyaluronic acid fermentation liquid, chondroitin and its derivatives, heparin and its derivatives, etc.), elastin and its derivatives, collagen and its derivatives, collagen peptides, NMF-related substances, lactic acid, urea, higher fatty acids octyldodecyl, seaweed extracts, estradiol, various amino acids and their derivatives.

[0037] Examples of thickening agents include ingredients derived from brown algae, green algae, or red algae, such as alginic acid, agar, carrageenan, and fucoidan; polysaccharides such as pectin and aloe polysaccharides; gums such as tragacanth gum, locust bean gum, xanthan gum, and guar gum; cellulose derivatives such as carboxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose; synthetic polymers such as carboxyvinyl polymers, alkyl-modified carboxyvinyl polymers, polyvinyl alcohol, polyvinylpyrrolidone, and acrylic acid-methacrylic acid copolymers; hyaluronic acid and its derivatives; polyglutamic acid and its derivatives, and polyacrylic acid.

[0038] Anti-inflammatory agents include allantoin, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, β-glycyrrhetinic acid, stearyl glycyrrhetinate, ε-aminocaproic acid, d-camphor, dl-camphor, zinc oxide, panthenol, pyridoxine hydrochloride, and riboflavin or a derivative thereof.

[0039] Examples of preservatives and disinfectants include urea; benzoic acid or its salts, paraoxybenzoic acid esters such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate; phenoxyethanol, dichlorophene, hexachlorophene, chlorhexidine hydrochloride, benzalkonium chloride, salicylic acid, sodium salicylate, zinc pyrithione, benzalkonium chloride, ethanol, undecylenic acid, phenols, and alkane bromide. These include kilisoquinolinium, resorcinol, jamal (imidazolidinyl urea), isopropyl methylphenol, triclosan, trichlorocarbanide, trichlorohydroxydiphenol ether, hinokitiol, 1,2-pentanediol, propanediol, concentrated benzalkonium chloride solution 50, essential oils such as peppermint oil and eucalyptus oil, bark distillate, fermented radish liquid, ethanol derived from plants such as sugar cane and corn, or 1,3-butylene glycol.

[0040] Examples of cell activators include pantothenyl alcohol, menthol, dl-menthol, and γ-oryzanol.

[0041] Anti-acne agents include sulfur, salicylic acid or its salts, photosensitizer No. 201, pyridoxine dicaprylate, and the like.

[0042] Examples of powder components include sericite, titanium oxide, talc, kaolin, bentonite, zinc oxide, magnesium carbonate, magnesium oxide, zirconium oxide, barium sulfate, silicic anhydride, mica, nylon powder, polyethylene powder, silk powder, cellulose-based powder, powder of grains (rice, wheat, corn, millet, etc.), powder of beans (soybeans, adzuki beans, etc.), etc.

[0043] Examples of ultraviolet absorbers include ethyl paraaminobenzoate, ethylhexyl paradimethylaminobenzoate, amyl salicylate and its derivatives, 2-ethylhexyl paramethoxycinnamate, octyl cinnamate, oxybenzone, 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-tert-butyl-4-methoxybenzoylmethane, 2-(2-hydroxy-5-methylphenyl)benzotriazole, urocanic acid, ethyl urocanate, and aloe extract.

[0044] Examples of antioxidants include butylhydroxyanisole, butylhydroxytoluene, propyl gallate, carotenoids such as astaxanthin, vitamin E and its derivatives (for example, tocopherol acetate, tocopherol nicotinate), vitamin A and its derivatives (retinol palmitate, etc.).

[0045] Further, examples of whitening agents include one or more selected from ellagic acid and its derivatives, resorcinol derivatives, potassium 4-methoxysalicylic acid, magnolignan (5,5'-dipropyl-biphenyl-2,2'-diol), hydroxybenzoic acid and its derivatives, vitamin E and its derivatives, α-hydroxy acid, and AMP (adenosine monophosphate, adenosine monophosphate).

[0046] Examples of resorcinol derivatives include 4-n-butylresorcinol and 4-isoamylresorcinol. Examples of 2,5-dihydroxybenzoic acid derivatives include 2,5-diacetoxybenzoic acid, 2-acetoxy-5-hydroxybenzoic acid, and 2-hydroxy-5-propionyloxybenzoic acid. Examples of α-hydroxy acids include lactic acid, malic acid, succinic acid, citric acid, and α-hydroxyoctanoic acid.

[0047] The present invention will now be described in more detail with reference to Production Examples, Formulation Examples and Test Examples, but the present invention is not limited thereto. In the following, all parts are by weight and all % are by weight.

[0048] Example 1. Evaluation of fibroblast activation effect Human dermis-derived fibroblasts, NB1RGB, were cultured in a 96-well microplate containing 0.5% NCS-containing Eagle's minimum essential medium at 1 × 10 4 The cells were seeded per well and pre-cultured for 1 day under conditions of 37°C and 5.0% CO2, and then a pyridine derivative (pyridine-3-carboxylic acid amide, hereinafter referred to as Compound 1) was added as a sample solution to a final concentration of 1 mM. After the addition of the sample solution, the cells were further cultured for 3 days under the same conditions as the pre-culture. Next, the medium was removed, 0.03% MTT was added, and the cells were kept at 37°C for 1 hour. The generated formazan was extracted with isopropanol, and the MTT value was measured at a wavelength of 570-630 nm using a microplate reader (Model 680, Bio-Rad). The same operation as above was also performed on the control (Control) in which the medium was added instead of the sample solution, and the relative value of the MTT value obtained when each sample was added to the MTT value obtained here was calculated, and this was used as the fibroblast MTT activity rate (%). In addition, in order to confirm whether the test system was functioning normally, a similar test was also performed on the case in which 100 mM glucose was added as a positive control instead of the sample solution.

[0049] The results of Test Example 1 are shown in Table 1 below. [Table 1] JPEG2025028969000001.jpg52124

[0050] As shown in Table 1, it was confirmed that Compound 1 exerts a fibroblast activation effect. In addition, since glucose, the positive control, also showed a similar effect, it was confirmed that this experimental system was performed normally.

[0051] Test Example 2. Evaluation of collagen synthesis promotion effect Human dermis-derived fibroblasts, NB1RGB, were cultured in a 96-well microplate containing 0.5% NCS-containing Eagle's minimum essential medium at 1 × 10 4After seeding at 1000 cells / well and pre-cultivating for 1 day under conditions of 37°C and 5.0% CO2, a test group was set by adding a sample solution (compound 1) prepared in advance to the medium in which the cells were pre-cultivated to a final concentration of 1 mM. After adding the sample solution, the cells were further cultured for 5 days under the same conditions as the pre-cultivation conditions using each medium. Next, the medium was removed, the cells were fixed with cold methanol and cold ethanol, and then stained with a saturated aqueous picric acid solution containing 0.1% Sirius Red. After washing with purified water, extraction was performed with a 0.1% NaOH:methanol = 1:1 solution, and the amount of collagen was measured at a wavelength of 540 nm using a microplate reader (Model 680, Bio-Rad). The same operation as above was performed for the case of no sample addition (Control) in which the medium was added instead of the sample solution, and the relative value of the collagen amount when each sample was added to the collagen amount obtained here was obtained, and the collagen synthesis rate (%) was obtained. In addition, in order to confirm whether the test system was functioning normally, a similar test was performed in which 1 mM ascorbyl phosphate magnesium salt (APM) was added as a positive control instead of the sample solution.

[0052] The results of Test Example 2 are shown in Table 2 below. [Table 2] JPEG2025028969000002.jpg52125

[0053] As shown in Table 2, it was confirmed that Compound 1 exhibits the effect of promoting collagen synthesis in fibroblasts. In addition, since the positive control APM also showed the same effect, it was also confirmed that this experimental system was performed normally.

[0054] Test Example 3. Evaluation of filaggrin gene expression and involucrin gene expression Normal human epidermal cells were cultured at 6 × 10 in HuMedia KG2 medium (Kurabo) containing a growth additive. 5The cells were prepared at a concentration of 1 / mL, 1 mL of which was inoculated into a φ6 cm petri dish and cultured at 37°C under 5% CO2 and saturated water vapor. After 24 hours of culture, compound 1 was further added to the medium to a final concentration of 1 mM and cultured. The same operation as above was also performed for the case of no sample addition (Control). After 24 hours of culture, the cells in each test group were recovered with 1 mL of Trizol reagent (Invitrogen). 200 μL of chloroform (Wako Pure Chemical Industries) was added to the recovered cells and mixed by stirring, and centrifuged for 15 minutes at 15,000 rpm and 4°C in a centrifuge (TOMY / MX-160), and 400 μL of only the aqueous layer was separated. 500 μL of isopropanol (Wako Pure Chemical Industries) was added to the recovered aqueous layer and mixed by stirring, and centrifuged for 15 minutes at 15,000 rpm and 4°C to obtain a precipitate of total RNA. 1 mL of 75% ethanol was added to the total RNA, stirred and washed, and centrifuged at 15,000 rpm and 4°C for 15 minutes to recover the precipitate. The recovered total RNA was reverse transcribed using a specified kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) [Takara Bio]) to synthesize cDNA. Using the synthesized cDNA as a sample, the expression of the filaggrin gene, the expression of the involucrin gene, and the expression of the internal standard β-actin gene were detected using Thermal Cycler Dice (registered trademark) Real Time System Single (Takara Bio) and SYBR (registered trademark) Premix Ex TaqTM II (Perfect Real Time) [Takara Bio]. Here, β-actin is one of the housekeeping genes (genes that are expressed in a constant amount in many tissues and cells, are constantly expressed, and are essential for the maintenance and proliferation of cells), and since its expression level is always constant, it is used as an internal standard in PCR experiments. The test results were compared by comparing the expression levels of the filaggrin gene and the involucrin gene in each test group, with the expression level of the β-actin gene held constant.In this test system, the expression level of each gene in the test group was determined as a relative value when the expression level of the gene in the control group was set to 100.

[0055] The results of Test Example 3 are shown in Table 3. [Table 3] JPEG2025028969000003.jpg50159

[0056] As shown in Table 3, it was confirmed that Compound 1 has the effect of enhancing the expression of the filaggrin gene and the involucrin gene. This enhancement of gene expression suggests an effect of enhancing the barrier function in the epidermis.

[0057] To evaluate skin thinning, we focused on the hypoxia-inducible factor HIF-1α (Biochemistry, Vol. 85, No. 3, pp. 187-195, 2013), which is involved in homeostatic mechanisms such as maintaining stem cells and controlling inflammation, and measured the effect of the active ingredient of the present invention in promoting the transcriptional activity of HIF-1α.

[0058] Test Example 4. Evaluation of transcriptional activity of HIF-1α Normal human epidermal cells were grown at 1 × 10 in Humedia-KG2 (Kurabo) containing a growth additive. 5The cells were prepared at a concentration of 100 μL / mL, seeded in a 96-well microplate, and cultured at 37°C under 5% CO2 and saturated water vapor. After 24 hours of culture, a firefly luciferase reporter vector incorporating a base sequence (HRE) to which HIF-1α binds and a vector incorporating Renilla luciferase as an internal standard (Cignal HIF Pathway Reporter Assay Kit) [QIAGEN] were introduced into the cells using ViaFect transfection reagent (Promega). After 24 hours, a sample solution was added to the medium. Here, the compound 1 was used as the sample solution, and was added to the medium to a final concentration of 1 mM or 2 mM. After 24 hours, the cell contents were extracted, and the luciferase activity of the cell extract was measured using a luciferase assay system (Promega) and a luminometer (Promega GloMax-Multi+Detection System). The HIF-1α transcriptional activity per cell was calculated by dividing the firefly luciferase measurement (HRE transcription amount) by the Renilla luciferase measurement (cell amount). The HIF-1α transcriptional activity in the control group, in which culture medium was added instead of the sample solution as a control, was set at 100, and the relative value was calculated.

[0059] The results of Test Example 4 are shown in Table 4. [Table 4] JPEG2025028969000004.jpg52125

[0060] As shown in Table 4, it was confirmed that Compound 1 exhibits the effect of enhancing HIF-1α transcription activity. This enhancement of gene expression improves the decline in HIF-1α transcription activity due to aging, and it is suggested that the functionality of stem cells is maintained, thereby improving the epidermal condition and thinning.

[0061] Test example 3. Monitor test (1) Sample preparation A control lotion and sample 1 lotion shown in Table 5 were prepared. [Table 5] JPEG2025028969000005.jpg71128 (2) Test method Before the start of the test, replicas were taken of wrinkles on the corners of the eyes. The subjects were asked to apply an appropriate amount of the control lotion to the corners of the right eye and sample 1 lotion B to the corners of the left eye twice a day, morning and evening. The test was conducted in a blinded state, without the subjects being informed of the contents of the lotions. The condition of the wrinkles after four months was judged by taking replicas. After the test was completed, the wrinkle area ratio and wrinkle volume ratio were analyzed for the replicas taken using oblique light analysis. (3) Test results The test results are shown in Table 6. [Table 6] JPEG2025028969000006.jpg50117

[0062] As shown in Table 6, it was confirmed that Compound 1 exhibits an effect of improving wrinkles.

[0063] The pyridine derivative may further be selected from the group consisting of ascorbic acid derivatives, tranexamic acid or derivatives thereof, hydroquinone or derivatives thereof, kojic acid or derivatives thereof, collagen or hydrolysates thereof, yeast extracts or hydrolysates thereof, lactic acid bacteria cultures, Gramineae plants, Cruciferae plants, Theaceae plants, Rosaceae plants, Paeoniae plants, Rutaceae plants, Amaranthaceae plants, Zosteraeae plants, Leguminosae plants, Asteraceae plants, Fabaceae plants, Malvaceae plants, Gentianaceae plants, Lamiaceae plants, Nelumbaceae plants, Cucurbitaceae plants, Araliaceae plants, Solanaceae plants, Bignoniaceae plants, Actinidiaceae plants, Mulberry plants, Iridaceae plants, Campanulaceae plants, Oleaceae plants, Actinidiaceae plants, Mulberry plants, and extracts or hydrolysates or fermented products thereof of one or more plants selected from among Rhamnaceae plants, Orchidaceae plants, Anacardiaceae plants, Garcinia plants, Valenciaceae plants, Rutaceae plants, Myrtaceae plants, Liliaceae plants, Crassulaceae plants, Cupressaceae plants, Convolvulaceae plants, and Asparagaceae families; extracts or hydrolysates or fermented products thereof of one or more seaweeds selected from among Laminaria, Laminaceae, and Ulvulaceae families; jellyfish (autolyzed products of moon jellyfish, Nomura's jellyfish, etc.); hydrolysates or fermented products of hyaluronic acid; and extracts or hydrolysates or fermented products of royal jelly.

[0064] As the components derived from plants of the Gramineae family, in particular, hydrolyzed rice leaves, hydrolyzed rice extracts, hydrolyzed rice bran extracts, hydrolyzed germinated brown rice, fermented rice liquid, sake lees extracts derived from sake, bamboo shoot skin extracts of Madake or Moso bamboo, and fermented pearl barley seeds are preferred. As the components derived from plants of the Brassicaceae family, in particular, extracts of seeds of Hakugai, Ogai or Kokugai or their hydrolysates or fermented products are preferred. As the components derived from plants of the Theaceae family, in particular, green tea (Yabukita, Samidori, Asahi, Goko, Ujimidori, Kyomidori, Ujihikari, Samidori, Benifuki, etc.) and black tea (Darjeeling, Assam, Ceylon, Earl Grey, honey-scented black tea, etc.) are preferred. As the components derived from plants of the Rosaceae family, extracts of Damask rose flowers, extracts of peach flowers, leaves or immature fruits, extracts of apricot fruits or seeds, extracts of strawberry flowers, and extracts of cherry blossoms or leaves are preferred. As the component derived from a plant of the family Paeoniaceae, an extract of the root or flower of the peony and an extract of the flower or root of the peony are preferred. As the component derived from a plant of the family Amaranthaceae, an extract of Salicornia herbacea is particularly preferred. As the component derived from a plant of the family Zosteraea, an extract of Zostera marina or Zostera koa is particularly preferred. As the component derived from a plant of the family Fabaceae, an extract of white soybean or black soybean or a hydrolyzate thereof, or a fermented soy milk liquid, an extract of adzuki bean, an extract of red clover, and an extract of pueraria lobata root are particularly preferred. As the component derived from a plant of the family Asteraceae, an extract of burdock root, an extract of sunflower sprouts, an extract of Acanthus gracilis, an extract of Arnica officinalis, or an extract of chamomile flower are particularly preferred. As the component derived from a plant of the family Malvaceae, a fermented product of hibiscus, Rose of Sharon, or Hibiscus is preferred. As the component derived from a plant of the family Gentianaceae, an extract of gentiana is preferred. As the plant of the family Lamiaceae, an extract of perilla frutescens and an extract of the fruit of Acanthus purpurea are preferred. As the component derived from a plant of the Nelumbinaceae family, particularly preferred is a lotus flower or lotus seed extract or a fermented lotus seed product. As the component derived from a plant of the Cucurbitaceae family, particularly preferred is a loofah extract. As the component derived from a plant of the Araliaceae family, a ginseng extract or fermented product is preferred. As the component derived from a plant of the Solanaceae family, an extract of eggplant (long eggplant, water eggplant, rice eggplant, Kamo eggplant, etc.) is included. As the component derived from a plant of the Bignoniaceae family, a Pau d'Arco bark extract is preferred. As the component derived from a plant of the Actinidiaceae family, an unripe kiwi extract is preferred.As the component derived from a plant of the family Mulberry, a mulberry fruit extract, or an extract of the fruit or bark of fig is preferred. As the component derived from a plant of the family Rhamnaceae, a jujube fruit extract is preferred. As the component derived from a plant of the family Iridaceae, a saffron is preferred. As the component derived from a plant of the family Campanulaceae, an extract or hydrolysate of the root of Codonopsis arvensis is preferred. As the component derived from a plant of the family Anacardiaceae, a mango fruit extract is particularly preferred. As the component derived from a plant of the family Garcinia, a mangosteen fruit extract is particularly preferred. As the component derived from a plant of the family Valenciaceae, a cherimoya fruit extract is preferred. As the component derived from a plant of the family Rutaceae, an extract of Satsuma mandarin, a bergamot fruit, an extract of grapefruit or a banpeiyu fruit (including immature fruits), or an extract of a seed of pepper is preferred. As the component derived from a plant of the family Liliaceae, an extract of daylily, daylily, Casablanca, Madonna lily, or lily of the valley is preferred. As the component derived from a Crassulaceae plant, in particular, an extract or fermented product of Rhodiola rosea (Rhododendron amplexicaule). As the component derived from a plant of the Oleaceae family, in particular, an extract of jasmine flower is preferred. As the plant of the Cupressaceae family, in particular, an extract of Juniperus communis fruit is preferred. As the component derived from a plant of the Myrtaceae family, in particular, an extract of guava leaf is preferred. As the plant of the Orchidaceae family, in particular, an extract of Bletilla serrata root (white and red) is preferred. As the component derived from a plant of the Convolvulaceae family, an extract of sweet potato or its fermentation product, or an extract of sweet potato shochu lees or its fermentation product is preferred. As the plant of the Asparagaceae family, asparagus (green asparagus and white asparagus) is preferred. As the component derived from seaweed of the Laminaceae family, in particular, a kelp extract is preferred, as the component derived from seaweed of the Mirinaceae family, an extract of Acanthus pertusa is preferred, and as the component derived from seaweed of the Ulva family, an extract of Ulva pertusa is preferred. As the component derived from seaweed of the Funoriaceae family, an extract of Funori is preferred.

[0065] Test Example 7. Evaluation test of fibroblast activation effect The synergistic effect of fibroblast activation was confirmed by the same method as in Test Example 1 for a combination composition of the present compound 1 and any one of yeast hydrolysate (component 1), rice bran extract hydrolysate (component 2), Job's tears seed fermentation product (component 3), Salicornia extract (component 4), eelgrass extract (component 5), chamomile extract (component 6), sunflower sprout extract (component 7), hibiscus flower fermentation product (component 8), perilla leaf extract (component 9), purple bark extract (component 10), gentian extract (component 11), lotus seed fermentation product (component 12), loofah extract (component 13), jujube fruit extract (component 14), Codonopsis gracilis root (codonopsis) hydrolysate (component 15), day lily bud fermentation product (component 16), striated lanthanum root extract (component 17), and kelp root extract (component 18).

[0066] Here, for example, component 1 can be produced by the following method. That is, yeast (Saccharomyces cerevisiae) was added to 100 mL of GP medium containing 1.0% glucose and 0.5% peptone, which had been sterilized by high pressure in advance, and then cultured with aeration and agitation at 30°C to obtain a pre-culture solution. This pre-culture solution was added to 900 mL of the same GP medium as above, which had been separately prepared and sterilized by high pressure, and cultured with aeration and agitation at 30°C to obtain a yeast slurry. Purified water and 1N hydrochloric acid solution were added to this yeast slurry, and acid hydrolysis treatment was performed for 2 hours with stirring at 90°C. Thereafter, the treated solution was filtered, and the pH was adjusted to pH 5.5 with 1N sodium hydroxide solution to obtain a yeast hydrolysate.

[0067] For example, component 2 is described in JP-A-2000-264834, component 3 is described in JP-A-2010-138139, component 4 is described in JP-A-2005-145878, component 5 is described in JP-A-2012-077035, component 7 is described in JP-A-2016-000706, component 8 is described in JP-A-2006-347925, component 9 is described in JP-A-2014-169253, component 10 is described in JP-A-2011-225503, and component 11 is described in JP-A-2012-077035. Component 12 can be prepared based on the description in JP 2005-298489 A, component 13 can be prepared based on the description in JP 2016-222622 A, component 14 can be prepared based on the description in JP 2019-119713 A, component 15 can be prepared based on the description in JP 2018-193335 A, component 16 can be prepared based on the description in JP 2018-193336 A, component 17 can be prepared based on the description in JP 2004-262894 A, and component 18 can be prepared based on the description in JP 2005-314230 A.

[0068] Incidentally, component 6 can be prepared according to the following manufacturing example: First, 1000 g of purified water was added to 100 g of dried chamomile flowers, and the mixture was extracted at 4°C for 48 hours, and then filtered to obtain 870 g of a brown, transparent chamomile extract (solid concentration 1.02%).

[0069] In Test Example 2, a sample solution (any one of components 1 to 18) was prepared by adding each component to the medium so that the final concentration of each component as a solution relative to the total volume of the medium was 1.0% or 2.0%.

[0070] The results of Test Example 7 are shown in Tables 7a to 7d. [Table 7a] JPEG2025028969000007.jpg131134[Table 7b] JPEG2025028969000008.jpg132135 [Table 7c] JPEG2025028969000009.jpg132139[Table 7d] JPEG2025028969000010.jpg88135

[0071] As shown in Tables 7a to 7d, it was confirmed that the present compound 1 exerts a synergistic effect of fibroblast activation when used in combination with any one of ingredients 1 to 18. As a result, the present compound 1 is expected to have a synergistic effect of activating dermal cells, promoting the synthesis of ECM components, and improving wrinkles, sagging, and the like, when used in combination with any one of ingredients 1 to 18.

[0072] Test Example 8. Evaluation of synergistic effect in promoting collagen synthesis A synergistic effect of promoting collagen synthesis was confirmed for a combination composition of the present compound 1 with any one of eelgrass extract (component 19), rice extract hydrolysate (component 20), and royal jelly fermentation product (component 21), rice leaf hydrolysate (component 22), bamboo shoot skin extract (component 23), black soybean hydrolysate (component 24), black soybean fermentation liquid (component 25), white soybean fermentation product (component 26), ginseng extract (component 27), and eggplant extract (component 28) by the same method as in Test Example 2. In addition, the collagen synthesis promoting effect was confirmed for ascorbic acid 2-glucoside, which is preferably used in combination with the present compound 1. Here, for example, component 19 can be prepared based on the description in JP-A-2012-077035, component 20 can be prepared based on the description in JP-A-04-029776, component 21 can be prepared based on the description in JP-A-2006-143676, component 22 can be prepared based on the description in JP-A-2013-103906, component 23 can be prepared based on the description in JP-A-2015-113291, component 24 can be prepared based on the description in JP-A-2019-014669, component 26 can be prepared based on the description in JP-A-2016-222622, and component 28 can be prepared based on the description in JP-A-2008-69074.

[0073] Ingredient 25 can be prepared by the following manufacturing example. That is, 400 g of purified water was added to 50 g of crushed black soybean seeds and sterilized by heating. 100 ml of lactic acid bacteria (Lactobacillus delbrueckii) was added to this suspension. 8 The cells were inoculated at 1000 / mL and cultured stationarily for 3 days at 30° C. under a nitrogen stream. After the culture was completed, the culture was sterilized by heating and filtered to obtain 707 g of a solution of lactic acid bacteria fermented soybean seeds (solid concentration 6.08%).

[0074] Also, component 27 can be prepared by the following manufacturing example. That is, 400 g of purified water and 170 g of 1,3-butylene glycol were added to 100 g of dried ginseng, and the mixture was stirred at 40° C. for 24 hours. This was filtered to obtain 500 g of a brown, transparent carrot extract solution (solid concentration: 3.54%).

[0075] In Test Example 2, a sample solution (any one of components 19 to 28) was prepared by adding each component to the medium so that the final concentration of each component as a solution relative to the total volume of the medium was 1.0% or 2.0%.

[0076] The results of the above tests are shown in Table 8. [Table 8a] JPEG2025028969000011.jpg117101 [Table 8b] JPEG2025028969000012.jpg93101

[0077] As shown in Tables 8a and 8b, it was confirmed that compound 1 exerts a synergistic effect in promoting collagen synthesis when used in combination with any of ingredients 19 to 28.

[0078] Test Example 9. Evaluation of the effect of promoting MCSP expression Using MCSP (Melanoma-associated chondroitin sulfate proteoglycan), a marker protein of epidermal stem cells, the MCSP expression promoting effect of the present compound 1 was evaluated. Furthermore, the MCSP expression promoting effect of any one of the following components was evaluated: Verniciflua fruit extract (component 10), jujube fruit extract (component 14), and eggplant extract (component 28).

[0079] Normal epidermal keratinocytes (NHEK(F)) were added at 8 × 10 3After seeding the cells in a 96-well plate at cell / well, the cells were cultured at 37°C for 24 hours using HuMedia-KG2 medium (Kurashiki Boseki Co., Ltd.). After the culture, 1 mM or 2 mM of the present compound 1 was added to the medium as a sample solution, and the cells were further cultured for 48 hours. After the culture was completed, immunological detection was performed using MCSP antibody. That is, after washing with PBS(-), the cells were fixed by treatment with 15% neutral buffered formalin solution for 30 minutes, permeation treatment with 0.5% Triton X-100 solution for 1 hour, blocking by treatment with 5-fold diluted Blocking One P (Nacalai Tesque) solution for 2 hours, MCSP antibody was added, and the cells were left to stand at room temperature for 1 hour. Next, the cells were washed with PBS(-), and a fluorescently labeled secondary antibody was added and the cells were further left to stand in the dark for a certain period of time. After that, the cells were washed with PBS(-), and the fluorescence intensity was measured. First, the fluorescent label of the secondary antibody (Alexa Fluor 488) was measured at Ex = 485 nm and Em = 520 nm using a fluorescent microplate reader (Fluoroscan Ascent, Thermo Fisher Scientific), and then DNA staining with Hoechst 33342 was performed and measured at Ex = 355 nm and Em = 460 nm. The MCSP expression level was calculated by dividing the fluorescence intensity of Alexa Fluor 488 in each test group by the fluorescence intensity of Hoechst 33342. The same operation as above was also performed for the case where no sample was added (Control) in which PBS (-) was added instead of the sample solution. The relative value of the MCSP expression level when each sample was added to the MCSP expression level obtained here was calculated and used as the MCSP expression promotion level (%).

[0080] The results of Test Example 9 are shown in Table 9. [Table 9] JPEG2025028969000013.jpg82127

[0081] As shown in Table 9, it was confirmed that the present compound 1 exhibits an effect of promoting MCSP expression. This suggests that it has an effect of maintaining the stemness of epidermal cells. In addition, since component 10, component 14, and component 28 also exhibit an effect of promoting MCSP expression, it is predicted that a synergistic effect of promoting MCSP expression will be exhibited by using the present compound 1 in combination with any one of component 10, component 14, and component 28.

[0082] Test Example 10. Evaluation of various gene expression using three-dimensional models A three-dimensional skin model TEST SKIN LSE-high (Roman Skin Lab Co., Ltd.) was cultured according to a conventional method. After 24 hours, an aqueous solution of the present compound 1 (5% concentration) was added to the tissue, and the tissue was cultured for another day. At the same time, a model without any addition was cultured in the same manner as a control. After the culture was completed, the tissues of each test group were collected with 1 mL of Trizol reagent (Invitrogen). 200 μL of chloroform (Wako Pure Chemical Industries, Ltd.) was added to the collected tissue, stirred and mixed, and centrifuged at 15,000 rpm and 4 ° C for 15 minutes in a centrifuge (TOMY / MX-160), and 400 μL of only the aqueous layer was collected. 500 μL of isopropanol (Wako Pure Chemical Industries, Ltd.) was added to the collected aqueous layer, stirred and mixed, and centrifuged at 15,000 rpm and 4 ° C for 15 minutes to obtain a precipitate of total RNA. 1 mL of 75% ethanol was added to the total RNA, stirred and washed, and centrifuged at 15,000 rpm and 4°C for 15 minutes to recover the precipitate. The recovered total RNA was reverse transcribed using a specified kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) (Takara Bio)) to synthesize cDNA. Using this synthesized cDNA as a sample, expression of various target genes and expression of the internal standard GAPDH gene were detected using Thermal Cycler Dice (registered trademark) Real Time System Single (Takara Bio) and SYBR (registered trademark) Premix Ex TaqTM II (Perfect Real Time) [Takara Bio]. Here, GAPDH is one of the housekeeping genes (genes that are expressed in a constant amount in common in many tissues and cells, are constantly expressed, and are essential for the maintenance and proliferation of cells), and since its expression amount is always constant, it is used as an internal standard in PCR experiments. The test results were obtained by comparing the expression levels of various target genes in each test group when the expression level of the GAPDH gene was kept constant. In this test system, the expression level of each gene in the control group was set to 100, and the relative value of the expression level of the gene in the group to which Compound 1 was added was calculated.

[0083] The results of Test Example 10 are shown in Table 10. [Table 10] JPEG2025028969000014.jpg78143

[0084] As shown in Table 10, it was confirmed that compound 1 enhances the expression of laminin α chain (LAMA1), which is involved in the binding of basement membrane and epidermis and is also involved in epidermal turnover, sphingomyelinase 1 (SMPD1), which is involved in ceramide synthesis, occludin (OCLN) and claudin (CLDN), which are involved in the synthesis of tight junctions, type I collagen α1 chain (COL1A1), which is involved in dermal firmness, and type IV collagen α1 chain (COL4A1), which is a protein that constitutes the basement membrane and is involved in epidermal turnover. This suggests that compound 1 contributes to moisturizing based on the ceramide synthesis promotion effect, improvement of barrier function, firmness based on the collagen synthesis promotion effect, improvement of wrinkles, improvement of barrier function based on the tight junction synthesis promotion effect, and basement membrane care based on the type IV collagen synthesis promotion effect.

[0085] Test Example 11. Evaluation of tyrosinase gene expression Normal melanocytes (NHEM) were cultured in DermaLife medium (Kurabo) at 6 × 10 4The cells were prepared at a concentration of 1 / mL, 1 mL of the solution was seeded on a 24-well plate, and cultured at 37°C under 5% CO2 and saturated water vapor. After 24 hours of culture, a culture medium containing the present compound 1 at a final concentration of 2 mM was added and cultured. In addition, a test group (control group) was set in which a culture medium containing only the medium was added as a control for comparison. After 24 hours of culture, the cells in each test group were recovered with 0.5 mL of Trizol reagent (Invitrogen). 100 μL of chloroform (Wako Pure Chemical Industries) was added to the recovered cells, stirred and mixed, and centrifuged at 15,000 rpm and 4°C for 15 minutes using a centrifuge (TOMY / MX-160), and then 200 μL of only the aqueous layer was separated. 250 μL of isopropanol (Wako Pure Chemical Industries) was added to the recovered aqueous layer, stirred and mixed, and centrifuged at 15,000 rpm and 4°C for 15 minutes to obtain a precipitate of total RNA. 1 mL of 75% ethanol was added to the total RNA, stirred and washed, and centrifuged at 15,000 rpm and 4°C for 15 minutes to recover the precipitate. The recovered total RNA was reverse transcribed using a specified kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) (Takara Bio)) to synthesize cDNA. Using the synthesized cDNA as a sample, the expression of the tyrosinase gene and the expression of the internal standard β-actin gene were detected using Thermal Cycler Dice (registered trademark) Real Time System Single (Takara Bio) and SYBR (registered trademark) Premi×E×TaqTM II (Perfect Real Time) [Takara Bio]. Here, β-actin is one of the housekeeping genes (genes that are expressed in a constant amount in common in many tissues and cells, are constantly expressed, and are essential for the maintenance and proliferation of cells), and since the expression amount is always constant, it is used as an internal standard in PCR experiments. The test results were calculated by comparing the expression level of each gene in each test group, with the expression level of the β-actin gene set at 1.

[0086] The results of Test Example 11 are shown in Table 11. [Table 11] JPEG2025028969000015.jpg36141

[0087] As shown in Table 11, it was confirmed that the present compound 1 suppresses the expression of the tyrosinase gene. This suggests that the present compound 1 has an effect of improving pigmentation such as age spots and freckles based on the suppression of tyrosinase activity.

[0088] Test Example 12. Evaluation of PAR2 gene expression Normal human epidermal cells were grown at 6 × 10 in HuMediaKG2 (Kurabo) containing a growth additive. 4The cells were prepared at a concentration of 1 / mL, 1 mL of the solution was seeded on a 24-well plate, and cultured at 37°C under 5% CO2 and saturated water vapor. After 24 hours of culture, a culture medium containing the present compound 1 at a final concentration of 5 mM was added and cultured. In addition, a test group (control group) was set in which a culture medium containing only the medium was added as a control for comparison. After 24 hours of culture, the cells in each test group were recovered with 0.5 mL of Trizol reagent (Invitrogen). 100 μL of chloroform (Wako Pure Chemical Industries) was added to the recovered cells, stirred and mixed, and centrifuged at 15,000 rpm and 4°C for 15 minutes using a centrifuge (TOMY / MX-160), and then 200 μL of only the aqueous layer was separated. 250 μL of isopropanol (Wako Pure Chemical Industries) was added to the recovered aqueous layer, stirred and mixed, and centrifuged at 15,000 rpm and 4°C for 15 minutes to obtain a precipitate of total RNA. 1 mL of 75% ethanol was added to the total RNA, stirred and washed, and centrifuged at 15,000 rpm and 4°C for 15 minutes to recover the precipitate. The recovered total RNA was reverse transcribed using a specified kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) (Takara Bio)) to synthesize cDNA. The synthesized cDNA was used as a sample to detect the expression of the PAR2 gene and the expression of the internal standard β-actin gene using Thermal Cycler Dice (registered trademark) Real Time System Single (Takara Bio) and SYBR (registered trademark) Premi×E×TaqTM II (Perfect Real Time) [Takara Bio]. Here, β-actin is one of the housekeeping genes (genes that are expressed in a constant amount in many tissues and cells, are constantly expressed, and are essential for the maintenance and proliferation of cells), and since its expression level is always constant, it is used as an internal standard in PCR experiments. The test results were calculated by comparing the expression level of each gene in each test group, with the expression level of the β-actin gene set at 1.

[0089] The results of Test Example 12 are shown in Table 12. [Table 12] JPEG2025028969000016.jpg35141

[0090] As shown in Table 12, it was confirmed that the present compound 1 suppresses the expression of the PAR2 gene, which is involved in the transfer of melanosomes from melanocytes to keratinocytes. This suggests that the present compound 1 suppresses the transfer of melanosomes from melanocytes to keratinocytes and has an inhibitory effect on pigmentation.

[0091] Formulation example 1. Lotion [Ingredients] Part Eucalyptus oil 0.2 Polyoxyethylene (5.5) Cetyl Alcohol 5.0 This compound 1 5.0 Tocopherol acetate 0.02 Dipotassium glycyrrhizinate 0.5 Monoammonium glycyrrhizinate 0.5 Stearyl glycyrrhizinate 0.05 Isopropyl methylphenol 0.1 Aligned in 0.1 D-Pantothenyl alcohol 0.1 Salicylic acid 0.5 Urea 5.0 l-Menthol 0.9 dl-Menthol 0.2 1,3-Butylene glycol 5.0 Sodium citrate 0.2 Methylparaben 0.1 Hinokitiol 0·003 Photosensor No. 201 0.002 Purified water (enough to make the total amount 100 parts)

[0092] Formulation example 2: Lotion [Ingredients] Part Glyceryl Caprylate 3.0 Polyglyceryl-10 Laurate 3.0 Cetanol 2.0 Behenyl Alcohol 2.0 Methylparaben 0.1 This compound 1 5.0 Yeast hydrolyzate 2.0 Ascorbic Acid 3.0 Glycyrrhizic acid 0.5 β-Glycyrrhetinic acid 0.05 Tocopherol nicotinate 0.1 Resorcinol 0.1 Zinc Oxide 2.0 dl-Camphor 0.5 Glycerin 2.0 1,3-Butylene glycol 5.0 Potassium hydroxide 0.5 Purified water (enough to make the total amount 100 parts)

[0093] Formulation example 3. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that the yeast hydrolysate contained in Formulation Example 2 was replaced with 2.0 parts of rice leaf hydrolysate.

[0094] Formulation example 4: Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of rice extract hydrolysate was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0095] Formulation example 5. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of rice bran extract hydrolysate was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0096] Formulation example 6. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of rice fermentation liquid was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0097] Formulation example 7. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that the yeast hydrolysate of Production Example 1 contained in Formulation Example 2 was replaced with 2.0 parts of bamboo shoot skin extract.

[0098] Formulation example 8. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of fermented Job's tears seeds were used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0099] Formulation example 9. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of a sake lees extract derived from sake was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0100] Formulation example 10. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of white mustard hydrolysate was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0101] Formulation example 11. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Benifuuki tea extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0102] Formulation example 12. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of honey-scented black tea extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0103] Formulation example 13. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Rosa damask flower extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0104] Formulation example 14. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of peach flower extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0105] Formulation example 15. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of unripe peach extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0106] Formulation example 16. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of apricot fruit extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0107] Formulation example 17. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of cherry blossom extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0108] Formulation example 18. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of peony flower extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0109] Formulation example 19. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of peony root extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0110] Formulation example 20. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Salicornia herb extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0111] Formulation example 21. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of eelgrass extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0112] Formulation example 22. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that the yeast hydrolysate of Production Example 1 contained in Formulation Example 2 was replaced with 2.5 parts of water-soluble collagen and 2.5 parts of hydrolyzed collagen.

[0113] Formulation example 23. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of fermented black soybean was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0114] Formulation example 24. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of black soybean hydrolysate was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0115] Formulation example 25. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of fermented soy milk was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0116] Formulation example 26. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of adzuki bean extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0117] Formulation example 27. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of red clover root extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0118] Formulation example 28. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of pueraria lobata root extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0119] Formulation example 29. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of burdock root extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0120] Formulation example 30. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of sunflower sprout extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0121] Formulation example 31. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Mugwort leaf extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0122] Formulation example 32. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of chamomile extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0123] Formulation example 33. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of arnica flower extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0124] Formulation example 34. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of gentian extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0125] Formulation example 35. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of hibiscus flower fermentation product was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0126] Formulation example 36. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of perilla leaf extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0127] Formulation example 37. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Veronica purpurea fruit extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0128] Formulation example 38. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of lotus seed extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0129] Prescription example 39. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of lotus seed fermentation product was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0130] Formulation example 40. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of loofah extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0131] Formulation example 41. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of ginseng extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0132] Formulation example 42. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of eggplant fruit extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0133] Formulation example 43. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of pau d'arco bark extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0134] Formulation example 44. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of unripe kiwi extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0135] Formulation example 45. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Sophora umbellata extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0136] Formulation example 46. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of mulberry fruit extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0137] Formulation example 47. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of fig bark extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0138] Formulation example 48. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of a hydrolysate of Codonopsis arvensis root extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0139] Formulation example 49. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of jujube fruit extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0140] Formulation example 50. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of saffron flower extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0141] Formulation example 51. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of a mixture of mango fruit extract, mangosteen fruit extract and cherimoya fruit extract was used instead of the yeast hydrolysate of Manufacturing Example 1 contained in Formulation Example 2.

[0142] Formulation example 52. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of bergamot fruit extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0143] Formulation example 53. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of unripe grapefruit extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0144] Formulation example 54. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Banpeiyu fruit extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0145] Formulation example 55. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Zanthoxylum nigra seed extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0146] Formulation example 56. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of a daylily flower or bud extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0147] Formulation example 57. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of an extract of Helianthus japonica flower or bud was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0148] Formulation example 58. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of a fermented product of day lily flowers or buds was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0149] Prescription example 59. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Casablanca flower or bud extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0150] Formulation example 60. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Madonna lily flower or bud extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0151] Formulation example 61. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of a lily of the valley flower or bud extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0152] Formulation example 62. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Rhodiola rosea (Rhodiola tenuifolia) fermentation product was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0153] Formulation example 63. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of jasmine flower extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0154] Formulation example 64. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Juniperus communis fruit extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0155] Formulation example 65. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of guava leaf extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0156] Formulation example 66. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Bletilla serrata root extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0157] Formulation example 67. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of sweet potato shochu lees extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0158] Prescription Example 68. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of white asparagus extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0159] Prescription Example 69. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of kelp extract was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0160] Prescription example 70. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that the yeast hydrolysate of Production Example 1 contained in Formulation Example 2 was replaced with 2.0 parts of Ulva extract.

[0161] Prescription Example 71. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Eucheuma mume extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0162] Prescription Example 72. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Funori extract was used instead of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0163] Prescription Example 73. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of red ginseng extract was used instead of the yeast hydrolysate of Preparation Example 1 contained in Formulation Example 2.

[0164] Prescription Example 74. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of ginseng fermentation product was used in place of the yeast hydrolysate of Production Example 1 contained in Formulation Example 2.

[0165] Prescription Example 75. Lotion [Ingredients] Part Jojoba oil 1.0 Polyoxyethylene (5.5) Cetyl Alcohol 5.0 Methylparaben 0.1 This compound 1 5.0 Ascorbic Acid Glucoside 2.0 Tranexamic acid 2.0 ε-Aminocaproic acid 0.1 Sulfur 0.2 Estradiol 0.1 Pyridoxine hydrochloride 0.5 Glycerin 5.0 1,3-Butylene glycol 5.0 Sodium citrate 0.2 Sodium metabisulfite 0.2 d-Camphor 0.1 Purified water (enough to make the total amount 100 parts)

[0166] Prescription Example 76. Emulsion [Ingredients] Part Squalane 5.0 Cyclopentanesiloxane 1.0 Hexalan 3.0 Hexyldecyl Isostearate 1.0 Caprylic / Capric Triglyceride 1.0 Polyglyceryl-10 Laurate 5.0 Polyglyceryl-10 Isostearate 5.0 Ascorbyl Dipalmitate 15.0 Hydrogenated soy lecithin 1.5 This compound 1 2.0 Ascorbic acid phosphate magnesium salt 3.0 Arbutin 3.0 Potassium hydroxide 0.5 Glycerin 3.0 1,3-Butylene glycol 2.0 Carboxymethylcellulose 0.3 Xanthan gum 0.2 Tremella polysaccharide 0.2 Sodium hyaluronate 0.01 Tocopherol acetate 0.3 Tocopherol nicotinate 0.1 Glycyrrhizic acid 0.1 Dipotassium glycyrrhizinate 0.1 Isopropyl methylphenol 0.1 Water-soluble collagen 1.0 Hydrolyzed Collagen 1.0 Sodium hyaluronate 1.0 Fermented ginseng root 1.0 Panax ginseng root extract 1.0 Hibiscus flower fermentation liquid 1.0 Fermented Job's Tears Seeds 1.0 Pepper seed hydrolysate 0.5 Rice bran extract hydrolyzate 0.5 Purified water (enough to make the total amount 100 parts)

[0167] Prescription Example 77. Emulsion An emulsion was obtained in the same manner as in Formulation Example 74, except that, among the ingredients of Formulation Example 76, 2.0 parts of L-ascorbic acid-2-glucoside were used in place of 2.0 parts of ascorbic acid phosphate magnesium salt.

[0168] Prescription Example 78. Emulsion An emulsion was obtained in the same manner as in Formulation Example 74, except that of Formulation Example 76, 2.0 parts of tranexamic acid were used in place of 2.0 parts of magnesium ascorbyl phosphate and 0.5 parts of potassium hydroxide.

[0169] Prescription Example 79. Emulsion An emulsion was obtained in the same manner as in Formulation Example 74, except that 3.0 parts of 3-O-ethyl ascorbic acid was used in place of 2.0 parts of magnesium ascorbyl phosphate in Formulation Example 76.

[0170] Prescription example 80. Cream [Ingredients] Part Olive oil 5.0 Jojoba oil 5.0 Squalane 5.0 Hexyldecyl Isostearate 5.0 Di(octyldodecyl) lauroyl glutamate / phytosteryl / Behenyl) 5.0 Glyceryl Caprylate 1.0 Glyceryl stearate 1.0 Isostearyl glyceryl 3.0 γ-Oryzanol 0.1 Behenyl Alcohol 2.0 Palmitic acid 2.5 D-Pantothenyl Alcohol 3.0 Allantoin 0.1 Riboflavin 0.01 Resorcinol 0.1 Benzalkonium chloride 0.05 Urea 3.0 β-Glycyrrhetinic acid 0.1 Stearyl Glycyrrhetinate 0.1 Ammonium glycyrrhizinate 0.1 This compound 1 3.0 Lactic acid fermented rice 2.0 Hydrogenated lecithin 0.5 Hydrogenated lysolecithin 0.5 Oil-soluble ginseng extract 2.0 Sweet potato shochu lees liquid 1.0 Guava Leaf Extract 1.0 Hydrolyzed Rice Extract 2.0 Fermented rice liquid 1.0 Water-soluble collagen 1.0 Hydrolyzed Collagen 1.0 Xanthan gum 1.0 Zinc oxide 0.5 dl-Camphor 0.3 l-Menthol 0.5 Purified water (enough to make the total amount 100 parts)

[0171] Example 81. Pack Dipropylene glycol 5.0 Polyoxyethylene (60) hydrogenated castor oil 5.0 Cetanol 3.0 Behenyl Alcohol 3.0 Allantoin 0.1 Dipotassium glycyrrhizinate 0.1 Ammonium glycyrrhizinate 0.1 β-Glycyrrhetinic acid 0.1 Stearyl Glycyrrhetinate 0.1 Salicylic acid 0.1 Tocopherol acetate 0.5 Tocopherol nicotinate 0.1 D-Pantothenyl alcohol 0.3 Resorcinol 0.1 Sulfur 2.0 Estradiol 0.002 This compound 1 3.0 Yeast hydrolyzate 3.0 Water-soluble collagen 1.0 Panax ginseng root (red ginseng) extract 1.0 Sunflower Sprout Extract 1.0 Guava Leaf Extract 1.0 Xanthan gum 2.0 Polyglyceryl-6 Myristate 1.0 Potassium cocoyl glutamate 1.0 Hydrogenated Lecithin 3.0 Hydroxylated Lecithin 3.0 Purified water (enough to make the total amount 100 parts)

[0172] Prescription example 82. Hair shampoo [Ingredients] Part Sodium Laureth Sulfate 10.0 Glyceryl Monostearate 1.0 Coconut oil fatty acid diethanolamide 2.0 Polyoxyethylene (40) hydrogenated castor oil 0.5 Benzalkonium chloride 1.0 Stearyl Alcohol 2.0 Behenyl Alcohol 2.0 Dimethicone 3.0 This compound 1 3.0 Allantoin 0.1 Dipotassium glycyrrhizinate 0.1 Salicylic acid 0.1 Sodium Salicylate 0.1 Tocopherol acetate 0.1 Pyrithione Zinc 0.3 Benzoic acid 0.2 Triclosan 0.2 Citric acid 0.1 Propylene glycol 2.0 Kelp extract 1.0 Burdock extract 1.0 Arrowroot extract 1.0 Eelgrass extract 1.0 Tamasakizurafuji Root Extract 0.01 Panax ginseng extract 0.1 Eelgrass extract 1.0 Bamboo shoot skin extract 1.0 Pau d'Arco Bark Extract 1.0 Black rice hydrolysate 1.0 Purified water (enough to make the total amount 100 parts)

[0173] Example 83. Hair conditioner [Ingredients] Part Polyoxyethylene (10) hydrogenated castor oil 1.0 Distearyldimethylammonium chloride 1.5 Stearyltrimethylammonium chloride 2.0 Glyceryl 2-ethylhexanoate 1.0 Benzalkonium chloride 1.0 Cetanol 3.0 Stearyl alcohol 1.0 This compound 1 3.0 Salicornia extract 1.0 Black soybean hydrolysate 1.0 Fermented soy milk 1.0 Fermented black soybeans 1.0 Allantoin 0.1 Isopropyl methylphenol 0.1 Dipotassium glycyrrhizinate 0.1 Salicylic acid 0.1 Sulfur 0.5 Alkylisoquinolinium bromide solution (75%) 0.06 Pyrithione Zinc 0.3 Methylparaben 0.1 Triclosan 0.2 Resorcinol 0.1 Purified water (enough to make the total amount 100 parts)

[0174] Formulation example 84. Cleansing cosmetics [Ingredients] Part Potassium cocoyl glycine 5.0 Glycerin 10.0 Glyceryl Caprylate 1.0 Sodium lauroyl aspartate 10.0 Water-soluble collagen 5.0 Cetanol 3.0 Myristyl Alcohol 3.0 Fermented Job's Tears Seeds 2.0 Isopropyl methyl alcohol 0.1 Allantoin 0.1 Sulfur 0.5 Glycyrrhizic acid 0.1 Dipotassium glycyrrhizinate 0.1 Monoammonium glycyrrhizinate 0.1 β-Glycyrrhetinic acid 0.05 Stearyl Glycyrrhetinate 0.1 Salicylic acid 0.2 Tocopherol acetate 0.2 Triclosan 0.1 Trichlorocarbanide 0.5 Trichlorohydroxydiphenyl ether 0.2 Concentrated benzalkonium chloride solution 50 0.2 Benzalkonium chloride 0.1 Panax ginseng root (red ginseng) 0.5 Purified water (enough to make the total amount 100 parts)

[0175] Formulation example 85. Sheet mask A sheet mask is obtained by impregnating a nonwoven fabric with the following components. [Ingredients] Part This compound 1 3.0 Glycerin 3.0 1,3-Butylene glycol 2.0 L-Ascorbic Acid 2-Glucoside 2.0 Methylparaben 0.2 Citric acid 0.1 Sodium citrate 0.3 Xanthan gum 1.0 Water-soluble collagen 1.0 Sodium hyaluronate 1.0 Eelgrass extract 1.0 Rice extract hydrolyzate 1.0 Potassium hydroxide (appropriate amount) Purified water (enough to make the total amount 100 parts)

[0176] Prescription example 86. Beauty serum [Ingredients] Part Ethanol 2.0 Glycerin 5.0 1,3-Butylene glycol 5.0 Methylparaben 0.1 Hyaluronic Acid Hydrolysate 1.0 Hyaluronic acid fermentation product 1.0 Lotus Seed Extract 1.0 Lactic acid bacteria culture 1.0 Sakura flower extract 1.0 Sake lees extract 1.0 Peony root extract 1.0 Peach kernel extract 1.0 Soo leaf extract 1.0 Chamomile flower extract 1.0 Kelp extract 1.0 Ulva extract 1.0 Eucheuma muscaria extract 1.0 Citric acid 0.3 Sodium citrate 0.6 Purified water (enough to make the total amount 100 parts)

Claims

[Claim 1] A skin topical preparation comprising a pyridine derivative and one or more of the following (B) to (I): (B) Tranexamic acid or a derivative thereof (C) Hydroquinone or its derivatives (D) Kojic acid or its derivatives (E) Yeast extract or its hydrolysate (F) Hyaluronic acid hydrolysate or fermentation product (G) Extracts of one or more plants selected from the group consisting of Gramineae plants, Brassicaceae plants, Theaceae plants, Rosaceae plants, Paeoniaceae plants, Rutaceae plants, Amaranthaceae plants, Zosteraeae plants, Fabaceae plants, Asteraceae plants, Fabaceae plants, Malvaceae plants, Gentianaceae plants, Lamiaceae plants, Nelumbaceae plants, Cucurbitaceae plants, Araliaceae plants, Solanaceae plants, Bignoniaceae plants, Actinidiaceae plants, Mulberry plants, Iridaceae plants, Campanulaceae plants, Oleaceae plants, Actinidiaceae plants, Rhamnoniaceae plants, Mulberry plants, Orchidaceae plants, Anacardiaceae plants, Garciniaceae plants, Valenciaceae plants, Rutaceae plants, Myrtaceae plants, Liliaceae plants, Crassulaceae plants, Cupressaceae plants, Convolvulaceae plants, and Asparagaceae plants, or hydrolysates or fermentation products thereof. (H) An extract, hydrolysate or fermentation product thereof of one or more seaweeds selected from the Laminaria family, Lamiaceae family, Ulvaceae family and Funoriaceae family. (I) An extract of jellyfish or royal jelly, or a hydrolysate or fermentation product thereof.

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