Topical skin preparations

Abstract

This invention provides a novel active ingredient that can be incorporated into topical skin preparations and is useful for promoting extracellular matrix production and preventing or improving skin thinning. [Solution] A topical skin preparation containing pyridine-3-carboxylic acid amide and tranexamic acid or a derivative thereof as active ingredients.

Description

[Technical Field]

[0001] The present invention relates to pyridine derivatives and topical skin preparations containing pyridine derivatives and other active ingredients. [Background technology]

[0002] Traditionally, skin aging, dryness, rough skin, age spots, and freckles have been known to be phenomena resulting from a complex interplay of internal factors such as inactivation of cell proliferation and differentiation, decreased hormone secretion, and quantitative decrease in extracellular matrix components associated with aging, and external factors such as cell and tissue damage or inflammation caused by reactive oxygen species induced by sunlight (ultraviolet rays).

[0003] In recent years, there has been a growing demand for active ingredients that, in addition to damaging the skin's surface, inhibit the degeneration or cross-linking of extracellular matrix components present in the dermis layer of the skin, thereby preventing and improving wrinkle formation and loss of skin elasticity.

[0004] While various ingredients have been proposed to protect the skin from ultraviolet rays and dryness (Patent Documents 1-3), no active ingredients were known that could improve the condition of the epidermis and suppress the degeneration of extracellular matrix components present in the dermis.

[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 the Invention] [Problems that the invention aims to solve]

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

[0007] The present invention relates to a topical skin preparation comprising a pyridine derivative and one or more 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 hydrolysate thereof (F) Hyaluronic acid hydrolysate or fermented product (G) Extracts or hydrolysates or fermented products thereof of one or more plants selected from among grasses, brassicas, camellias, roses, peonyes, rutaceae, amaranthaceae, zebragrasses, legumes, daisies, legumes, mallows, gentians, mints, lotuses, cucurbits, Araliaceae, nightshades, bignoniaceae, Actinidiaceae, mulberries, irises, bellflowers, olives, Actinidiaceae, rhamnoides, mulberries, orchids, sumac, Garcinia, Valenciaceae, rutaceae, myrtaceae, lilies, cressulaceae, cypress, morning glory, and asparagaceae. (H) An extract or hydrolyzed or fermented product thereof of one or more seaweeds selected from the Laminariaceae, Mylinaceae, Ulvaceae, and Funoriaceae families. (I) Extracts of jellyfish or royal jelly, or hydrolyzed or fermented products thereof. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a topical skin preparation that prevents or improves skin thinning and exhibits effects such as preventing or improving wrinkles or sagging. [Modes for carrying out the invention]

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

[0010] Furthermore, in the present invention, preferred components to combine with pyridine derivatives include ascorbic acid or its derivatives, tranexamic acid or its derivatives, hydroquinone or its derivatives, kojic acid or its derivatives, collagen or its derivatives, hyaluronic acid or its derivatives, yeast extract or its hydrolysate, and plant or animal-derived components.

[0011] Ascorbic acid or its derivatives 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, magnesium L-ascorbic acid-2-sulfate, L-ascorbic acid-2-glucoside, L-ascorbic acid-5-glucoside, ascorbyl tocopheryl maleic acid, potassium ascorbyl tocopheryl phosphate, myristyl 3-glyceryl ascorbate, caprylyl 2-glyceryl ascorbate, and other ascorbic acid sugar derivatives. Examples include acyl derivatives at position 6 (acyl groups such as hexanoyl, octanoyl, and decanoyl groups), L-ascorbic acid tetraisopalmitate, L-ascorbic acid tetralaurate and other L-ascorbic acid tetra fatty acid esters, 3-O-ethyl ascorbic acid, L-ascorbic acid-2-phosphate-6-O-palmitate sodium, glyceryl ascorbic acid or its acylated derivatives, 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, isostearyl ascorbyl phosphate, and the like.

[0012] Examples of derivatives of tranexamic acid include tranexamic acid esters (e.g., lauryl tranexamic acid, hexadecyl tranexamic acid, cetyl tranexamic acid, or their salts), and amide forms of tranexamic acid (e.g., methyl tranexamic acid).

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

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

[0015] In this invention, the yeasts include, for example, 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; and Zygosaccharomyces rouxii. 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; Aureobasidium pullulans, Aureobasidium mansonii, and Aureobasidium Examples include yeasts of the genus Aureobasideium, such as Aureobasideium microstictum. Furthermore, the yeast according to the present invention may be any of the following: sake yeast, wine yeast, beer yeast, yeast derived from plant flowers (rose, plum, cherry, camellia, lily, etc.), or yeast derived from the sea.

[0016] In the present invention, as the collagen, fish-derived collagen is particularly preferable. For example, fish such as red sea bream, southern red sea bream, banded sea bream, and yellowstriped sea bream of the Sparidae family; fish such as red sea bream and kuruma sea bream of the Lutjanidae family; fish such as kobudai, Chinese lantern fish, black porgy, and Japanese parrotfish of the Ephippidae family; fish such as Japanese threadfin bream of the Nemipteridae family; fish such as sea bream, silver sea bream, and goldlined sea bream of the Sparidae family, fish such as pike conger and spotted pike conger of the Congridae family, fish such as eel of the Anguillidae family, fish such as conger eel of the Congridae family, fish of the Salmonidae family, fish of the Squalidae family, etc. can be mentioned. The collagen may be hydrolyzed hydrolyzed collagen, collagen subjected to atelocollagenization or succinylation treatment, or crosslinked collagen. Further, jellyfish-derived collagen, or its hydrolyzed, atelocollagenized or succinylated collagen, or even crosslinked collagen may be used.

[0017] In addition, as plant-derived components, extracts, hydrolysates or fermented products of one or more plants selected from any of Poaceae plants, Brassicaceae plants, Camellia plants, Rosaceae plants, Caryophyllaceae plants, Rutaceae plants, Euphorbiaceae plants, Zosteraceae plants, Fabaceae plants, Asteraceae plants, Fabaceae plants, Malvaceae plants, Gentianaceae plants, Lamiaceae plants, Nymphaeaceae plants, Cucurbitaceae plants, Caprifoliaceae plants, Vitaceae plants, Liliaceae plants, Taxodiaceae plants, Convolvulaceae plants and Araliaceae plants can be mentioned. As seaweed-derived components, extracts, hydrolysates or fermented products of one or more seaweeds selected from any of Laminariaceae, Alariaceae, Ulvaceae and Gelidiaceae can be mentioned. Further, as other natural product-derived components, extracts, hydrolysates or fermented products of jellyfish or royal jelly can be used. Extracts, hydrolysates or fermented products of one or more plants selected from any of these can also be used.

[0018] As the extraction method of the extract derived from the above natural product, a conventional ordinary method can be used. For example, it can be carried out by contacting with an extraction solvent by appropriate means such as an immersion method using a solvent, a countercurrent extraction method, etc. Also, it is possible to prepare 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; hydrocarbon solvents such as n - hexane, toluene, and chloroform, etc. They can be used alone or in combination of two or more. Among them, from the viewpoint of wide applicability to cosmetics, it is preferable to use a single solvent selected from water, lower alcohols, and polyhydric alcohols or a mixed solvent of two or more.

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

[0021] When preparing the extract of the present invention, the pH of the extract is preferably maintained in the range of 4 to 8. In this sense, if necessary, an alkaline regulator such as sodium hydroxide, sodium carbonate, potassium hydroxide, arginine, etc. or an acidic regulator such as hydrochloric acid, acetic acid, sulfuric acid, etc. can be added to the above extraction solvent and adjusted to the desired pH.

[0022] Extraction conditions such as extraction temperature and time vary depending on the type of solvent used and the extraction method, 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] Furthermore, the above-mentioned extracts derived from natural products may be subjected to hydrolysis. For example, when hydrolysis 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; fibrinolytic enzymes such as cellulase, hemicellulase, and pectinase; and lipase, or a combination of one or more enzymes selected from each of these enzyme groups.

[0024] The following are examples of microorganisms (yeast, lactic acid bacteria, koji mold, or Bacillus subtilis) or microorganism-derived components used in the fermentation process to obtain the fermented products described above.

[0025] Furthermore, in this invention, lactic acid bacteria refer to, 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; and Leuconostoc mesenteroides, Leuconostoc lactis, and Leuconostoc citreum. Lactic acid bacteria of the genus Leuconostoc, such as *Leuconostoc citreum*; lactic acid bacteria of the genus Streptococcus, 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*; *Weissella confusa* and *Weissella candureli* Lactobacillus of the genus Veissera, such as Atopobium kandleri; Lactobacillus of the genus Atopobium, such as Atopobium minutum and Atopobium parvulus;Examples include lactic acid bacteria of the genus Vagococcus, such as Vagococcus fluvialis and Vagococcus salmoninarum; and lactic acid bacteria of the genus Pediococcus, 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 fermenting the above-mentioned suspension or extract with microorganisms, it is necessary to sterilize the suspension before the fermentation process to remove any unwanted bacteria that could hinder fermentation. Methods for removing these unwanted bacteria include washing the fermentation material with sterilizing ethanol beforehand and then suspending it in a sterile solvent such as sterile water, or suspending the fermentation material in a solvent and then sterilizing the suspension by heat sterilization. Commonly used heat sterilization methods include autoclave sterilization, where the suspension is heated to 120-130°C for 10-20 minutes, and intermittent sterilization, where the suspension is kept at 80-90°C for 60-120 minutes, once a day for 2-3 days.

[0029] Furthermore, during the fermentation process, sugars such as glucose, galactose, fructose, sucrose, maltose, and lactose may be added as carbon sources.

[0030] The sterilized suspension and culture medium are placed in a fermentation tank, and microorganisms are inoculated into them to induce fermentation. The amount of microorganisms inoculated is 10 7 ~10 8 The appropriate amount is cells / mL. If the inoculation amount exceeds the above range, the fermentation time remains largely unchanged. Conversely, if it falls below the above range, it takes a long time for fermentation to complete, which is undesirable.

[0031] The fermentation temperature is generally in the range of 5 to 50°C, preferably within the optimal growth temperature range for each microorganism. The fermentation period is generally in the range of 1 to 10 days, preferably 2 to 5 days, at the optimal temperature. If the fermentation period is shorter than the above general range, fermentation will not occur sufficiently and the effectiveness of the fermented product tends to decrease. On the other hand, if it is extended beyond 10 days, not only will no further increase in effectiveness be observed, but discoloration and an increase in fermentation odor will occur, both of which are undesirable.

[0032] When the composition of the present invention is incorporated into a topical skin preparation, in addition to the essential components of the above composition, ingredients commonly used in cosmetics, such as oily components, surfactants (synthetic and natural), moisturizers, anti-inflammatory agents, thickeners, preservatives and bactericides, anti-acne agents, cell activators, powder components, UV absorbers, antioxidants, whitening agents, anti-wrinkle agents, pigments, fragrances, etc., may be added as needed.

[0033] Here, oily components include, for example, plant-derived oils and fats such as olive oil, jojoba oil, castor oil, soybean oil, rice oil, rice germ oil, coconut oil, palm oil, cocoa oil, meadowfoam oil, shea butter, tea tree oil, avocado oil, macadamia nut oil, bergamot oil, lavender oil, rose oil, chamomile oil, etc.; vitamin A oil; animal-derived oils and fats such as mink oil, turtle oil, etc.; waxes such as beeswax, carnauba wax, rice wax, lanolin, etc.; liquid paraffin, petrolatum, paraffin wax. Examples include hydrocarbons such as custard 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-ethylhexylglyceride, and higher fatty acid octyldodecyl (octyldodecyl stearate, etc.).

[0034] Examples of surfactants 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 alkylphenyl ether sulfates, polyoxyethylene alkyl ether phosphates, α-sulfonated fatty acid alkyl ester salts, and polyoxyethylene Anionic surfactants such as lenalkylphenyl ether phosphates; cationic 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-dialkylmorphonium salts, polyethylene polyamine fatty acid amide salts; and amphoteric surfactants such as N,N-dimethyl-N-alkyl-N-carboxymethylammonium betaine, N,N,N-trialkyl-N-alkyleneammonium carboxybetaine, and N-acylamidopropyl-N′,N′-dimethyl-N′-β-hydroxypropylammonium sulfobetaine can be used.

[0035] As emulsifiers and / or emulsifying aids, stevia derivatives such as enzyme-treated stevia, saponins or their derivatives, casein or its salts (sodium, etc.), sugar-protein complexes, sucrose or its esters, lactose, water-soluble polysaccharides derived from soybeans, complexes of soybean-derived proteins and polysaccharides, lanolin or its derivatives, cholesterol, stevia derivatives (such as enzyme-treated stevia), silicates (aluminum, magnesium, etc.), carbonates (calcium, sodium, etc.), saponins and their derivatives, lecithin and its derivatives (such as hydrogenated lecithin), lactic acid bacteria-fermented rice, lactic acid bacteria-fermented germinated rice, lactic acid bacteria-fermented grains (wheat, beans, grains, etc.), etc. may also be included.

[0036] Examples of humectants include glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, xylitol, sodium pyrrolidone carboxylate, and sugars such as trehalose and raffinose, mucopolysaccharides (e.g., hyaluronic acid and its derivatives, hyaluronic acid ferment filtrate, 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 acid octyldodecyl, seaweed extracts, estradiol, various amino acids and their derivatives.

[0037] Examples of thickening agents include components derived from brown algae, green algae, or red algae such as alginic acid, agar, carrageenan, and fucoidan; polysaccharides such as pectin and aloe polysaccharide; gums such as tragacanth gum, locust bean gum, xanthan gum, and guar gum; cellulose derivatives such as carboxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; synthetic polymers such as carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, and acrylic acid / methacrylic acid copolymer; hyaluronic acid and its derivatives; polyglutamic acid and its derivatives, polyacrylic acid, etc.

[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 its derivatives.

[0039] Examples of preservatives and disinfectants include urea; benzoic acid or its salts, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate; phenoxyethanol, dichlorophene, hexachlorophene, chlorhexidine hydrochloride, benzalkonium chloride, salicylic acid, sodium salicylate, zinc pyrithione, benzalkonium chloride, ethanol, undecylenic acid, phenols, and aluminum bromide. These include chloroisoquinolinium, resorcinol, jamal (imidazodinylurea), isopropylmethylphenol, triclosan, trichlorocarbanide, trichlorohydroxydiphenol ether, hinokitiol, 1,2-pentanediol, propanediol, concentrated benzalkonium chloride solution 50, essential oils such as peppermint oil and eucalyptus oil, tree bark distillates, radish ferment filtrate, plant-derived ethanol such as sugarcane and corn, or 1,3-butylene glycol.

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

[0041] Examples of anti-acne agents include sulfur, salicylic acid or its salts, photosensitizer 201, and pyridoxine dicaprylate.

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

[0043] Examples of UV absorbers include ethyl para-aminobenzoate, ethylhexyl para-dimethylaminobenzoate, amyl salicylate and its derivatives, 2-ethylhexyl para-methoxycinnamate, 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 carotenoids such as butylhydroxyanisole, butylhydroxytoluene, propyl gallate, and astaxanthin, vitamin E and its derivatives (e.g., tocopherol acetate, tocopherol nicotinate), and vitamin A or its derivatives (e.g., retinol palmitate).

[0045] Furthermore, examples of whitening agents include one or more selected from ellagic acid and its derivatives, resorcinol derivatives, potassium 4-methoxysalicylate, magnolignan (5,5'-dipropyl-biphenyl-2,2'-diol), hydroxybenzoic acid and its derivatives, vitamin E and its derivatives, α-hydroxy acids, 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; and examples of α-hydroxy acids include lactic acid, malic acid, succinic acid, citric acid, and α-hydroxyoctanoic acid.

[0047] Next, the present invention will be described in more detail with reference to manufacturing examples, formulation examples, and test examples, but the present invention is not limited thereto. In the following, all parts refer to parts by weight, and all percentages refer to weight percent.

[0048] Example 1. Evaluation of fibroblast activation effect Human dermal fibroblast cells NB1RGB were placed in 1 × 10⁶ wells of a 96-well microplate containing 0.5% NCS-containing Eagle Minimum Essential Medium. 4 Cells were seeded per well and pre-cultured for 1 day under conditions of 37°C and 5.0% CO2. 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 adding the sample solution, the cells were cultured for a further 3 days under the same conditions as the pre-culture. Next, the medium was removed, 0.03% MTT was added, and the cells were held at 37°C for 1 hour. The resulting 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 procedure was performed for a control in which medium was added instead of the sample solution. The relative value of the MTT value with each sample added to the MTT value obtained here was calculated and expressed as the fibroblast MTT activity rate (%). In addition, to confirm that the test system was functioning correctly, the same test was performed when 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] JPEG2026108798000001.jpg52124

[0050] As shown in Table 1, compound 1 was confirmed to exert a fibroblast-activating effect. Furthermore, since the positive control, glycol, also showed a similar effect, it was confirmed that the experimental system was performed correctly.

[0051] Test Example 2. Evaluation of the effect of promoting collagen synthesis. Human dermal fibroblast cells NB1RGB were placed in 1 × 10⁶ wells of a 96-well microplate containing 0.5% NCS-containing Eagle Minimum Essential Medium. 4Cells were seeded per well and pre-cultured for 1 day under conditions of 37°C and 5.0% CO2. Then, the pre-prepared sample solution (compound 1) was added to the culture medium in which the cells were pre-cultured to a final concentration of 1 mM to set up test groups. After adding the sample solution, the cells were cultured for a further 5 days under the same conditions as the pre-culture in each medium. Next, the medium was removed, the cells were fixed with cold methanol and cold ethanol, and then stained with a saturated picric acid aqueous 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 procedure was performed for the control group (without sample addition, where medium was added instead of the sample solution), and the relative amount of collagen with each sample added to the amount of collagen obtained here was calculated and expressed as the collagen synthesis rate (%). Furthermore, to confirm that the test system was functioning correctly, the same test was performed when 1 mM magnesium ascorbic acid phosphate (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] JPEG2026108798000002.jpg52125

[0053] As shown in Table 2, we confirmed that compound 1 has the effect of promoting collagen synthesis in fibroblasts. Furthermore, since the positive target APM also showed a similar effect, we confirmed that the experimental system was performed correctly.

[0054] Test Example 3. Evaluation of filaggrin gene expression and involucrin gene expression Normal human epidermal cells were grown in HuMedia KG2 medium (Kurabo Industries Ltd.) containing growth additives in a 6x10⁶ ratio. 5The solution was prepared at a concentration of 1 / mL, and 1 mL was seeded into a φ6 cm petri dish. The cells were cultured at 37°C under 5% CO2 and saturated steam. After 24 hours of culture, compound 1 was added to the culture medium to a final concentration of 1 mM, and the cells were cultured again. The same procedure was followed for the control group (no sample added). After 24 hours of culture, cells from each test group were collected using 1 mL of Trizol reagent (Invitrogen). 200 μL of chloroform (Wako Pure Chemical Industries, Ltd.) was added to the collected cells and mixed by stirring. The cells were then centrifuged at 15,000 rpm at 4°C for 15 minutes using a centrifuge (TOMY MX-160), and 400 μL of the aqueous layer was collected. 500 μL of isopropanol (Wako Pure Chemical Industries, Ltd.) was added to the collected aqueous layer and mixed by stirring. The cells were then centrifuged at 15,000 rpm at 4°C for 15 minutes to obtain a total RNA precipitate. The total RNA was washed with 1 mL of 75% ethanol and stirred, then centrifuged at 15,000 rpm at 4°C for 15 minutes to collect the precipitate. The collected total RNA was reverse transcribed using a designated kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) [Takara Bio Inc.]) to synthesize cDNA. The synthesized cDNA was used as a sample to detect filaggrin gene expression, involucrin gene expression, and internal standard β-actin gene expression using Thermal Cycler Dice® Real Time System Single (Takara Bio Inc.) and SYBR® Premix Ex Taq™ II (Perfect Real Time) [Takara Bio Inc.]. Here, β-actin is one of the housekeeping genes (genes that are commonly expressed in a constant amount in many tissues and cells, are always expressed, and are essential for cell maintenance and proliferation), and because its expression level is always constant, it is used as an internal standard in PCR experiments. The test results compared the expression levels of the filaggrin gene and the involucrin gene in each test group, while keeping the expression level of the β-actin gene constant.In this study, the relative expression level of each gene in the test group was calculated, with the expression level of the control group set to 100.

[0055] The results of Test Example 3 are shown in Table 3. [Table 3] JPEG2026108798000003.jpg50159

[0056] As shown in Table 3, compound 1 was confirmed to have the effect of enhancing the expression of filaggrin and involucrin genes. This enhancement of gene expression suggests an effect of improving the barrier function in the epidermis.

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

[0058] Test Example 4. Evaluation of HIF-1α transcriptional activity Normal human epidermal cells were grown in Humedia-KG2 [Kurabo Corporation] containing a growth additive, resulting in 1 × 10⁶ cells. 5The solution was prepared at a concentration of 100 μL / mL, seeded into a 96-well microplate, and cultured at 37°C under 5% CO2 and saturated steam. After 24 hours of culture, a firefly luciferase reporter vector incorporating the HIF-1α binding nucleotide sequence (HRE) and a vector incorporating sea urchin luciferase as an internal standard (Cignal HIF Pathway Reporter Assay Kit) [QIAGEN] were introduced into the cells using ViaFect transfection reagent (Promega). 24 hours later, the sample solution was added to the culture medium. Here, compound 1 was used as the sample solution and added to the medium to a final concentration of 1 mM or 2 mM. 24 hours later, 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 measured value of firefly luciferase (HRE transcription amount) by the measured value of sea urchin luciferase (cell volume). The relative value was calculated by setting the HIF-1α transcriptional activity of the control group, which had culture medium added instead of the sample solution, to 100.

[0059] The results of Test Example 4 are shown in Table 4. [Table 4] JPEG2026108798000004.jpg52125

[0060] As shown in Table 4, compound 1 was confirmed to enhance HIF-1α transcriptional activity. This enhancement of gene expression suggests that it improves the decline in HIF-1α transcriptional activity due to aging, maintains the functionality of stem cells, and thereby improves the condition of the epidermis and reduces thinning.

[0061] Test Example 3: Monitor Test (1) Sample preparation The control lotion and the lotion for sample 1 shown in Table 5 were prepared. [Table 5] JPEG2026108798000005.jpg71128 (2) Test method Replicas were taken of wrinkles around the eyes before the start of the experiment. Subjects applied an appropriate amount of Control lotion to the outer corner of their right eye and lotion B (Sample 1) to the outer corner of their left eye twice daily, morning and evening. The subjects were not informed of the contents of the lotions, and the experiment was conducted in a blind state. The state of wrinkles after 4 months was determined by taking replicas. After the experiment, the wrinkle area ratio and wrinkle volume ratio were analyzed from the collected replicas using oblique light analysis. (3) Test results The test results are shown in Table 6. [Table 6] JPEG2026108798000006.jpg50117

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

[0063] Pyridine derivatives include ascorbic acid derivatives, tranexamic acid or its derivatives, hydroquinone or its derivatives, kojic acid or its derivatives, collagen or its hydrolysates, yeast extracts or hydrolysates, lactic acid bacteria cultures, grasses, cruciferous plants, camellias, roses, peonyes, citrus plants, amaranthaceae plants, zebra plants, legumes, daisies, legumes, mallows, gentians, mints, lotus, cucurbits, Araliaceae plants, nightshades, bignoniaceae plants, Actinidiaceae plants, mulberries, irises, bellflowers, olives, Actinidiaceae plants, and mulberries. It is preferable to combine it with one or more of the following: an extract or hydrolyzed or fermented product thereof from one or more plants selected from the Rhamnaceae, Orchidaceae, Anacardiaceae, Garciniaaceae, Valenciaceae, Rutaceae, Myrtaceae, Liliaceae, Crassulaceae, Cupressaceae, Convolvulaceae, and Asparagaceae; an extract or hydrolyzed or fermented product thereof from one or more seaweeds selected from the Laminariaceae, Mylinaceae, and Ulvaceae; jellyfish (autolyzed products of moon jellyfish, Echizen jellyfish, etc.); hydrolyzed or fermented product of hyaluronic acid; and an extract or hydrolyzed or fermented product thereof from royal jelly.

[0064] As plant-derived components from the grass family, rice leaf hydrolysate, rice extract hydrolysate, rice bran extract hydrolysate, germinated brown rice hydrolysate, rice ferment filtrate, sake lees extract derived from sake, bamboo shoot peel extract of Madake or Moso bamboo, and adlay seed ferment. As plant-derived components from the Brassicaceae family, extracts or hydrolysates or fermentations thereof of the seeds of Hakugai, Ougai, or Kokugai are particularly preferred. As plant-derived components from the Camellia family, green tea (Yabukita, Samidori, Asahi, Gokou, Ujimidori, Kyomidori, Ujihikari, Samidori, Benifuki, etc.) and black tea (Darjeeling, Assam, Ceylon, Earl Grey, Honey Black Tea, etc.) are particularly preferred. As plant-derived components from the Rosaceae family, extracts of Damask rose flowers, peach flowers, leaves, or immature fruits, apricot fruit or seed extracts, strawberry flower extracts, and cherry blossom or leaf extracts are preferred. Furthermore, as ingredients derived from Paeoniaceae plants, extracts of peony root or flower, and peony flower or root are preferred. As ingredients derived from Amaranthaceae plants, glasswort extract is particularly preferred. As ingredients derived from Zosteraceae plants, eelgrass or dwarf eelgrass extract is particularly preferred. As ingredients derived from Fabaceae plants, extracts of white soybeans or black soybeans or their hydrolysates or fermented soy milk liquid, adzuki bean extract, red clover extract, and kudzu root extract are particularly preferred. As ingredients derived from Asteraceae plants, burdock root extract, sunflower sprout extract, starflower extract, arnica extract, or chamomile flower extract are particularly preferred. As ingredients derived from Malvaceae plants, fermented products of hibiscus, rose of Sharon, or hibiscus are preferred. As ingredients derived from Gentianaceae plants, gentian extract is preferred. As ingredients derived from Lamiaceae plants, green perilla extract and purple beautyberry fruit extract are preferred. As for ingredients derived from Nelumbonaceae plants, lotus flower or lotus seed extract or lotus seed ferment is particularly preferred. As for ingredients derived from Cucurbitaceae plants, loofah extract is particularly preferred. As for ingredients derived from Araliaceae plants, ginseng extract or ferment is preferred. As for ingredients derived from Solanaceae plants, eggplant (long eggplant, water eggplant, American eggplant, Kamo eggplant, etc.) extract is an example. As for ingredients derived from Bignoniaceae plants, Pau d'arco bark extract is preferred. As for ingredients derived from Actinidiaceae plants, immature kiwi extract is preferred.Preferred ingredients from the Moraceae family include mulberry bark extract, mulberry fruit extract, and fig fruit or bark extract. Preferred ingredients from the Rhamnaceae family include jujube fruit extract. Preferred ingredients from the Iridaceae family include saffron. Preferred ingredients from the Campanulaceae family include root extract or hydrolysate of Codonopsis lanceolata. Preferred ingredients from the Anacardiaceae family include mango fruit extract. Preferred ingredients from the Garciniaaceae family include mangosteen fruit extract. Preferred ingredients from the Valenciaceae family include cherimoya fruit extract. Preferred ingredients from the Rutaceae family include Satsuma mandarin, bergamot fruit extract, grapefruit or pomelo fruit (including immature fruit) extract, or sansho pepper seed extract. Preferred ingredients from the Liliaceae family include hemp lily, daylily, Casablanca lily, Madonna lily, or Lilium japonicum extract. As for ingredients derived from Crassulaceae plants, extracts or fermented products of Rhodiola rosea are particularly preferred. As for ingredients derived from Oleaceae plants, extracts of jasmine flowers are particularly preferred. As for ingredients derived from Cupressaceae plants, extracts of Juniperus chinensis fruit are particularly preferred. As for ingredients derived from Myrtaceae plants, extracts of guava leaves are particularly preferred. As for Orchidaceae plants, extracts of Bletilla striata root are particularly preferred. As for ingredients derived from Convolvulaceae plants, extracts or fermented products thereof of sweet potato or extracts or fermented products thereof of sweet potato shochu lees are preferred. Also, as for plants of Asparagaceae, asparagus (green asparagus and white asparagus) is preferred. As for ingredients derived from Laminariaceae seaweed, extracts of kelp are particularly preferred, as for ingredients derived from Mirinaceae seaweed, extracts of Sargassum fuciformis are preferred, and as for ingredients derived from Ulvaceae seaweed, extracts of Ulva lactuca are particularly preferred. As for ingredients derived from Seaweed of the Seaweedaceae family, extracts of Seaweed are particularly preferred.

[0065] Test Example 7. Evaluation Test of Fibroblast Activation Effect The synergistic effect of compound 1 in combination with one of the following components was confirmed in Test Example 1: compound 1 with yeast hydrolysate (component 1), rice bran extract hydrolysate (component 2), adlay seed ferment (component 3), glasswort extract (component 4), seagrass extract (component 5), chamomile extract (component 6), sunflower sprout extract (component 7), hibiscus flower ferment (component 8), perilla leaf extract (component 9), Japanese beautyberry fruit extract (component 10), gentian extract (component 11), lotus seed ferment (component 12), loofah extract (component 13), jujube fruit extract (component 14), codonopsis pilosula root hydrolysate (component 15), daylily bud ferment (component 16), orchid root extract (component 17), and kelp root extract (component 18).

[0066] Here, for example, component 1 can be produced by the following method. Specifically, yeast (Saccharomyces cerevisiae) was added to 100 mL of GP medium containing 1.0% glucose and 0.5% peptone, which had been pre-sterilized by autoclaving. The medium was then cultured at 30°C with aeration and stirring to obtain a pre-culture solution. This pre-culture solution was then added to 900 mL of the same GP medium, which had been prepared separately and autoclaved, and cultured at 30°C with aeration and stirring to obtain a yeast slurry. Purified water and 1N hydrochloric acid solution were added to this yeast slurry, and acid hydrolysis treatment was carried out at 90°C with stirring for 2 hours. After that, 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] Furthermore, for example, component 2 is described in JP 2000-264834, component 3 is described in JP 2010-138139, component 4 is described in JP 2005-145878, component 5 is described in JP 2012-077035, component 7 is described in JP 2016-000706, component 8 is described in JP 2006-347925, component 9 is described in JP 2014-169253, component 10 is described in JP 2011-225503, and component 11 is described in JP 2 The following can be prepared based on the description in Japanese Patent Publication No. 016-222622, Component 12 is described in Japanese Patent Publication No. 2005-298489, Component 13 is described in Japanese Patent Publication No. 2016-222622, Component 14 is described in Japanese Patent Publication No. 2019-119713, Component 15 is described in Japanese Patent Publication No. 2018-193335, Component 16 is described in Japanese Patent Publication No. 2018-193336, Component 17 is described in Japanese Patent Publication No. 2004-262894, and Component 18 is described in Japanese Patent Publication No. 2005-314230.

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

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

[0070] The results of Test Example 7 are shown in Tables 7a to 7d. [Table 7a] JPEG2026108798000007.jpg131134[Table 7b] JPEG2026108798000008.jpg132135 [Table 7c] JPEG2026108798000009.jpg132139[Table 7d] JPEG2026108798000010.jpg88135

[0071] As shown in Tables 7a to 7d, it was confirmed that Compound 1 exhibits a synergistic effect in fibroblast activation when used in combination with any one of Components 1 to 18. Therefore, Compound 1, when used in combination with any one of Components 1 to 18, is expected to activate dermal cells, promote the synthesis of ECM components, and improve wrinkles, sagging, etc.

[0072] Test Example 8. Evaluation of the synergistic effect of promoting collagen synthesis. The synergistic effect of compound 1 in promoting collagen synthesis was confirmed using the same method as in Test Example 2 for combination compositions of compound 1 with any one of the following components: eelgrass extract (component 19), rice extract hydrolysate (component 20), royal jelly ferment (component 21), rice leaf hydrolysate (component 22), bamboo shoot peel extract (component 23), black bean hydrolysate (component 24), black soybean ferment filtrate (component 25), white soybean ferment (component 26), ginseng extract (component 27), and eggplant extract (component 28). Furthermore, the collagen synthesis promoting effect was also confirmed for ascorbic acid 2-glucoside, which is preferably used in combination with compound 1. Here, for example, component 19 can be prepared based on the description in Japanese Patent Publication No. 2012-077035, component 20 based on the description in Japanese Patent Publication No. 04-029776, component 21 based on the description in Japanese Patent Publication No. 2006-143676, component 22 based on the description in Japanese Patent Publication No. 2013-103906, component 23 based on Japanese Patent Publication No. 2015-113291, component 24 based on the description in Japanese Patent Publication No. 2019-014669, component 26 based on the description in Japanese Patent Publication No. 2016-222622, and component 28 based on the description in Japanese Patent Publication No. 2008-69074.

[0073] Component 25 can be prepared by the following manufacturing example: 50 g of crushed black soybean seeds are added to 400 g of purified water and heat-sterilized. To this suspension, 10 g of lactic acid bacteria (Lactobacillus delbrueckii) are added. 8 The culture was inoculated at a dose of 1 / mL and incubated under a nitrogen stream at 30°C for 3 days. After incubation, the culture solution was heat-sterilized, filtered, and 707 g of lactic acid bacteria fermented soybean seed solution (solid content 6.08%) was obtained.

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

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

[0076] The results of the above test are shown in Table 8. [Table 8a] JPEG2026108798000011.jpg157134 [Table 8b] JPEG2026108798000012.jpg108132

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

[0078] Test Example 9. Evaluation of MCSP expression-promoting effect The MCSP expression-promoting effect of compound 1 was evaluated using MCSP (Melanoma-associated chondroitin sulfate proteoglycan), a marker protein for epidermal stem cells. Furthermore, the MCSP expression-promoting effect of one of the following components was evaluated: Callicarpa japonica fruit extract (component 10), Ziziphus jujuba fruit extract (component 14), and Eggplant extract (component 28).

[0079] Normal epidermal keratinocytes (NHEK(F)) are divided into 8 × 10 3After seeding cells in a 96-well plate at a cell / well ratio, the cells were cultured for 24 hours at 37°C using HuMedia-KG2 medium (Kurabo Industries Ltd.). After culturing, 1 mM or 2 mM of the compound 1 was added to the medium as a sample solution, and the cells were cultured for a further 48 hours. After culturing, immunoassay was performed using MCSP antibody. Specifically, after washing with PBS(-), the cells were fixed by treating them with 15% neutral buffered formalin for 30 minutes, then immersed in 0.5% Triton X-100 solution for 1 hour, followed by blocking with a 5-fold diluted Blocking One P (Nacalai Tesque) solution for 2 hours. MCSP antibody was then added, and the cells were allowed to stand at room temperature for 1 hour. Next, the cells were washed with PBS(-), a fluorescently labeled secondary antibody was added, and the cells were allowed to stand in the dark for a certain period of time. Finally, the cells were washed with PBS(-) and the fluorescence intensity was measured. First, using a fluorescence microplate reader (Fluoroscan Ascent, Thermo Fisher Scientific), the fluorescence label of the secondary antibody (Alexa Fluor488) was measured at Ex=485nm and Em=520nm. Subsequently, DNA staining with Hoechst33342 was performed, and measurements were taken at Ex=355nm and Em=460nm. The MCSP expression level was determined by dividing the fluorescence intensity of Alexa Fluor488 in each test group by the fluorescence intensity of Hoechst33342. The same procedure was performed for the control group (no sample added), where PBS(-) was added instead of the sample solution. The relative value of the MCSP expression level with each sample added to the MCSP expression level obtained here was calculated and expressed as the MCSP expression enhancement (%).

[0080] The results of Test Example 9 are shown in Table 9. [Table 9] JPEG2026108798000013.jpg82127

[0081] As shown in Table 9, Compound 1 was confirmed to exhibit an MCSP expression-promoting effect. This suggests that it may have the effect of maintaining the stem cell properties of epidermal cells. Furthermore, since components 10, 14, and 28 also exhibit MCSP expression-promoting effects, it is predicted that a synergistic effect of promoting MCSP expression will be achieved by using Compound 1 in combination with any one of components 10, 14, or 28.

[0082] Test Example 10. Evaluation of various gene expression using a three-dimensional model. A three-dimensional skin model, TEST SKIN LSE-high (Roman Skin Lab Co., Ltd.), was cultured according to standard procedures. After 24 hours, an aqueous solution (5% concentration) of compound 1 was added to the tissue, and it was cultured for another day. Simultaneously, a control model with no additives was cultured in the same manner. After the culture period, the tissue from each test group was collected with 1 mL of Trizol reagent (Invitrogen). 200 μL of chloroform (Wako Pure Chemical Industries, Ltd.) was added to the collected tissue and stirred. The mixture was then centrifuged at 15,000 rpm at 4°C for 15 minutes using a centrifuge (TOMY MX-160), and 400 μL of the aqueous layer was collected. 500 μL of isopropanol (Wako Pure Chemical Industries, Ltd.) was added to the collected aqueous layer and stirred. The mixture was then centrifuged at 15,000 rpm at 4°C for 15 minutes to obtain a total RNA precipitate. The total RNA was washed by adding 1 mL of 75% ethanol and stirring, and the precipitate was collected after centrifugation at 15,000 rpm at 4°C for 15 minutes. The recovered total RNA was reverse transcribed using a designated kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) (Takara Bio Inc.)) to synthesize cDNA. Using this synthesized cDNA as a sample, the expression of various target genes and the expression of the internal standard GAPDH gene were detected using Thermal Cycler Dice® Real Time System Single (Takara Bio Inc.) and SYBR® Premix Ex Taq™ II (Perfect Real Time) (Takara Bio Inc.). Here, GAPDH is one of the housekeeping genes (genes that are commonly expressed in a constant amount in many tissues and cells, and are always expressed and essential for cell maintenance and proliferation), and since its expression level is always constant, it is used as an internal standard in PCR experiments. The test results compared the expression levels of various target genes in each test group, with the expression level of the GAPDH gene kept constant. In this test system, the relative expression level of each gene in the group treated with compound 1 was determined, with the expression level of each gene in the control group set to 100.

[0083] The results of Test Example 10 are shown in Table 10. [Table 10] JPEG2026108798000014.jpg78143

[0084] As shown in Table 10, it was confirmed that Compound 1 enhanced the expression of laminin α chain (LAMA1) involved in the binding of the basement membrane and the epidermis and also involved in epidermal turnover, sphingomyelinase 1 (SMPD1) involved in ceramide synthesis, occludin (OCLN) and claudin (CLDN) involved in the synthesis of tight junctions, type I collagen α1 chain (COL1A1) involved in the elasticity of the dermis, and type IV collagen α1 chain (COL4A1) which is a protein constituting the basement membrane and involved in epidermal turnover. Thus, it is suggested that Compound 1 contributes to moisturizing based on the ceramide synthesis promoting effect, improvement of the barrier function, improvement of elasticity and wrinkles based on the collagen synthesis promoting effect, improvement of the barrier function based on the tight junction synthesis promoting effect, and basement membrane care based on the type IV collagen synthesis promoting effect.

[0085] Test Example 11. Evaluation of Tyrosinase Gene Expression Normal melanocytes NHEM were cultured in DermaLife medium (manufactured by Kurabo Industries Ltd.) at 6×10 4The cells / mL of the compound were prepared, and 1 mL was seeded into a 24-well plate. The cells were cultured at 37°C under 5% CO2 and saturated steam. After 24 hours of culture, a culture medium containing compound 1 at a final concentration of 2 mM was added and the cells were cultured. As a comparison, a control group was set up in which only the culture medium was added. After 24 hours of culture, the cells from each control group were harvested with 0.5 mL of Trizol reagent (Invitrogen). 100 μL of chloroform (Wako Pure Chemical Industries, Ltd.) was added to the harvested cells and mixed by stirring. The cells were then centrifuged at 15,000 rpm at 4°C for 15 minutes using a centrifuge (TOMY MX-160), and 200 μL of the aqueous layer was collected. 250 μL of isopropanol (Wako Pure Chemical Industries, Ltd.) was added to the collected aqueous layer and mixed by stirring. The cells were then centrifuged at 15,000 rpm at 4°C for 15 minutes to obtain a total RNA precipitate. The total RNA was washed with 1 mL of 75% ethanol and stirred, and the precipitate was collected after centrifugation at 15,000 rpm at 4°C for 15 minutes. The recovered total RNA was reverse transcribed using a designated kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) (Takara Bio Inc.)) to synthesize cDNA. The synthesized cDNA was used as a sample to detect the expression of the tyrosinase gene and the expression of the internal standard substance β-actin gene using Thermal Cycler Dice® Real Time System Single (Takara Bio Inc.) and SYBR® Premi×E×Taq™ II (Perfect Real Time) (Takara Bio Inc.). Here, β-actin is one of the housekeeping genes (genes that are commonly expressed in a constant amount in many tissues and cells, and are always expressed and essential for cell maintenance and proliferation), and since its expression level is always constant, it is used as an internal standard in PCR experiments. The test results compared the expression levels of each gene in each test group, with the expression level of the β-actin gene set to 1.

[0086] The results of Test Example 11 are shown in Table 11. [Table 11] JPEG2026108798000015.jpg36141

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

[0088] Test Example 12. Evaluation of PAR2 gene expression Normal human epidermal cells were grown in 6 x 10⁶ units using HuMediaKG2 [Kurabo Corporation] containing a growth additive. 4The cells / mL were prepared, and 1 mL was seeded into a 24-well plate and cultured at 37°C under 5% CO2 and saturated steam. After 24 hours of culture, a culture medium containing compound 1 at a final concentration of 5 mM was added and culture was continued. As a comparison, a control group was set up in which only the culture medium was added. After 24 hours of culture, cells from each control group were harvested with 0.5 mL of Trizol reagent (Invitrogen). 100 μL of chloroform (Wako Pure Chemical Industries, Ltd.) was added to the harvested cells and mixed by stirring. The mixture was then centrifuged at 15,000 rpm at 4°C for 15 minutes using a centrifuge (TOMY MX-160), and 200 μL of the aqueous layer was collected. 250 μL of isopropanol (Wako Pure Chemical Industries, Ltd.) was added to the collected aqueous layer and mixed by stirring. The mixture was then centrifuged at 15,000 rpm at 4°C for 15 minutes to obtain a total RNA precipitate. The total RNA was washed by adding 1 mL of 75% ethanol and stirring, and the precipitate was collected after centrifugation at 15,000 rpm at 4°C for 15 minutes. The collected total RNA was reverse transcribed using a designated kit (PrimeScript RT reagent Kit with gDNA Eraser (Perfect Real Time) (Takara Bio Inc.)) 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® Real Time System Single (Takara Bio Inc.) and SYBR® Premi×E×Taq™ II (Perfect Real Time) (Takara Bio Inc.). Here, β-actin is one of the housekeeping genes (genes that are commonly expressed in a constant amount in many tissues and cells, and are always expressed and essential for cell maintenance and proliferation), and since its expression level is always constant, it is used as an internal standard in PCR experiments. The test results compared the expression levels of each gene in each test group, with the expression level of the β-actin gene set to 1.

[0089] The results of Test Example 12 are shown in Table 12. [Table 12] JPEG2026108798000016.jpg35141

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

[0091] Prescription 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 glycyrrhetinate 0.05 Isopropylmethylphenol 0.1 Align In 0.1 D-Panthenyl 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, in an amount that makes the total volume 100 parts.

[0092] Prescription 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, in an amount that makes the total volume 100 parts.

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

[0094] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

[0096] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0097] Prescription example 7. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of bamboo shoot peel extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0098] Prescription 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 seed product were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

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

[0101] Prescription Example 11: Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Benifuki tea extract were used instead of the yeast hydrolysate in Manufacturing Example 1 included in Formulation Example 2.

[0102] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

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

[0105] Prescription example 15. Lotion A lotion was prepared in the same manner as in Formulation Example 2, except that 2.0 parts of an immature peach fruit extract was used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0106] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0107] Prescription 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 were used instead of the yeast hydrolysate in Manufacturing Example 1 included in Formulation Example 2.

[0108] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0109] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

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

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

[0113] Prescription 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 product were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0114] Prescription example 24. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of hydrolyzed black soybeans were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0115] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0116] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0117] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0118] Prescription example 28. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of kudzu root extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0119] Prescription 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 were used instead of the yeast hydrolysate in Manufacturing Example 1 included in Formulation Example 2.

[0120] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0121] Prescription example 31. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of *Lysimachia japonica* leaf extract was used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

[0123] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

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

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

[0127] Prescription example 37. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Callicarpa japonica fruit extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0128] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included 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 ferment was used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

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

[0132] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0133] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

[0135] Prescription example 45. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of mulberry bark extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0136] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0137] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0138] Prescription example 48. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of hydrolyzed root extract of Codonopsis lanceolata was used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0139] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0140] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0141] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0142] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0143] Prescription example 53. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of immature grapefruit fruit extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

[0145] Prescription example 55. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of sansho seed extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

[0147] Prescription example 57. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of licorice flower or bud extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0148] Prescription example 58. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of fermented daylily flower or bud product were used instead of the yeast hydrolysate in Production Example 1 included 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0150] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0151] Prescription example 61. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Lilium japonicum flower or bud extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0152] Prescription example 62. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of Rhodiola rosea fermentate were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0153] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0154] Prescription example 64. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of juniper fruit extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0155] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

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

[0157] Prescription 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 were used instead of the yeast hydrolysate in Production Example 1 included 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 were used instead of the yeast hydrolysate in Production Example 1 included 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 were used instead of the yeast hydrolysate in Manufacturing Example 1 included in Formulation Example 2.

[0160] Prescription example 70. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of sea lettuce extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0161] Prescription example 71. Lotion A lotion was obtained in the same manner as in Formulation Example 2, except that 2.0 parts of a cypress extract was used instead of the yeast hydrolysate in Production Example 1 included 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 seaweed extract were used instead of the yeast hydrolysate in Production Example 1 included in Formulation Example 2.

[0163] Prescription example 73. Lotion A lotion was prepared in the same manner as in Formulation Example 2, except that 2.0 parts of red ginseng extract were used instead of the yeast hydrolysate in Production Example 1 included 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 fermented ginseng were used instead of the yeast hydrolysate in Production Example 1 included 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, in an amount that makes the total volume 100 parts.

[0166] Prescription example 76. Emulsion [Ingredients] Part Squalane 5.0 Cyclopentasiloxane 1.0 Hexaran 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 Magnesium ascorbic acid phosphate 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 fuciformis polysaccharide 0.2 Sodium hyaluronate 0.01 Tocopherol acetate 0.3 Tocopherol nicotinate 0.1 Glycyrrhizic acid 0.1 Dipotassium glycyrrhizinate 0.1 Isopropylmethylphenol 0.1 Water-soluble collagen 1.0 Hydrolyzed collagen 1.0 Sodium hyaluronate 1.0 Ginseng root ferment 1.0 Panax ginseng root extract 1.0 Hibiscus flower fermented liquid 1.0 Job's tears seed fermented product 1.0 Hydrolyzed sansho pepper seeds 0.5 Rice bran extract hydrolyzate 0.5 Purified water, in an amount that makes the total volume 100 parts.

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

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

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

[0170] Prescription example 80. Cream [Ingredients] Part Olive oil 5.0 Jojoba oil 5.0 Squalane 5.0 Hexyldecyl isostearate 5.0 Lauroyl glutamate di(octyldodecyl / phytosteryl) (Behenir) 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-Panthenyl 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 Rice fermentation 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, in an amount that makes the total volume 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, in an amount that makes the total volume 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 Seagrass extract 1.0 Stephania tetrandra root extract 0.01 Panax ginseng extract 0.1 Seagrass extract 1.0 Bamboo shoot peel extract 1.0 Pau d'arco bark extract 1.0 Black rice hydrolyzate 1.0 Purified water in an amount such that the total amount is 100 parts

[0173] Example 83. Hair conditioner [Ingredients] parts 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 Akesiso extract 1.0 Black soybean hydrolyzate 1.0 Soy milk fermented product 1.0 Black soybean fermented product 1.0 Allantoin 0.1 Isopropylmethylphenol 0.1 Dipotassium glycyrrhizinate 0.1 Salicylic acid 0.1 Sulfur 0.5 Alkylisoguinolinium bromide solution (75%) 0.06 Zinc pyrithione 0.3 Methylparaben 0.1 Triclosan 0.2 Resorcinol 0.1 Purified water in an amount such that the total amount is 100 parts

[0174] Formulation example 84. Cleansing cosmetic [Ingredients] parts Potassium cocoyl glycinate 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 Pigeon pea seed ferment 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 Triclocarban 0.5 Triclosan monohydrate 0.2 Concentrated benzalkonium chloride solution 50 0.2 Benzalkonium chloride 0.1 Red ginseng root 0.5 Purified water Amount to make the total amount 100 parts

[0175] Formulation example 85. Sheet mask Impregnate the non-woven fabric with the following components to obtain a sheet mask. [Components] parts 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 Zostera marina extract 1.0<0​​​​​​​​​ [Ingredients] Part Ethanol 2.0 Glycerin 5.0 1,3-Butylene glycol 5.0 Methylparaben 0.1 Hyaluronic acid hydrolysate 1.0 Hyaluronic acid lactic acid bacteria fermented product 1.0 Lotus seed extract 1.0 Lactic acid bacteria culture 1.0 Cherry blossom 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 Sea lettuce extract 1.0 Katamenkirinsai extract 1.0 Citric acid 0.3 Sodium citrate 0.6 Purified water, in an amount that makes the total volume 100 parts.

Claims

[Claim 1] A topical skin preparation containing pyridine-3-carboxylic acid amide and tranexamic acid or a derivative thereof as active ingredients.

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