WO2015015816A1 - Activateur de fibroblaste - Google Patents

Activateur de fibroblaste Download PDF

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Publication number
WO2015015816A1
WO2015015816A1 PCT/JP2014/052076 JP2014052076W WO2015015816A1 WO 2015015816 A1 WO2015015816 A1 WO 2015015816A1 JP 2014052076 W JP2014052076 W JP 2014052076W WO 2015015816 A1 WO2015015816 A1 WO 2015015816A1
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WIPO (PCT)
Prior art keywords
food
present
skin
collagen
mass
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PCT/JP2014/052076
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English (en)
Japanese (ja)
Inventor
美順 田中
かずみ 鍋島
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森永乳業株式会社
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Priority to JP2014505296A priority Critical patent/JPWO2015015816A1/ja
Publication of WO2015015816A1 publication Critical patent/WO2015015816A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use

Definitions

  • the present invention relates to a fibroblast activator.
  • the fibroblast activator can be used as a medicine, a quasi-drug, an external preparation for skin, a cosmetic, a food or drink, a food additive, a feed, and the like.
  • Fibroblasts are connective tissue cells in the animal body, characterized by good growth of the rough endoplasmic reticulum and the Golgi apparatus, with an elliptical nucleus and a spindle-shaped protoplasm. Fibroblasts are cells belonging to the mesenchymal system that exist in many organs, including cells that fill the parenchymal cells. In addition, they exist in primary cultures such as cancer tissues and muscles. Collectively refer to cells that do. Fibroblasts are developmentally derived from mesoderm cells. When fibroblasts differentiated from mesenchyme are stimulated, rough endoplasmic reticulum and Golgi bodies increase and special granules are formed.
  • Fibroblasts play an important role in organ morphogenesis and create fibrous connective tissue between cells and tissues and tissues.
  • extracellular matrix components such as collagen and hyaluronic acid produced by fibroblasts have a great influence on skin elasticity, water content, flexibility, and the like.
  • the skin consists of three layers: the subcutaneous tissue, the dermis, and the epidermis, and the dermis is the widest part of the dermis, which is rich in collagen and hyaluronic acid, which are present in the dermis
  • fibroblasts not only produce extracellular matrix components, but also interact with collagen fibers, that is, have an action of pulling the collagen fibers (collagen contraction action), thereby creating a resilient dermis. , Skin firmness is formed.
  • fibroblasts are scattered in connective tissues throughout the body such as bone, cartilage, vascular wall, ligament, tendon, ophthalmic vitreous, and umbilical cord to produce extracellular matrix components. Since it is known to play an important role in the connection of each tissue and organ, a decrease in the function of producing the component can cause the formation of the tissue, and when the tissue is damaged, the component It is possible to cure the injury by promoting the production of.
  • collagen produced by fibroblasts plays a role in maintaining the structure in gingival tissue.
  • periodontal disease such as gingivitis, periodontitis, or alveolar pus leakage that develops in the periodontal tissue progresses
  • collagen in the gingival tissue is degraded by periodontal disease bacteria.
  • collagen in the gingival tissue is also degraded by collagen degrading enzymes produced from tissues invaded by periodontal disease bacteria. Therefore, promoting collagen synthesis in periodontal tissue cells and supplementing collagen degraded by periodontal disease is effective in treating or preventing periodontal disease.
  • Corneal fibroblasts are present in the parenchymal layer that maintains the transparency and shape of the cornea.
  • the main constituent of the corneal stroma is collagen, and the others are proteoglycan, fibronectin and the like. Since the cornea is close to the outside world, it easily causes damage. Examples thereof include contact lens wear, dry eye, bacterial infection, ultraviolet rays, and trauma. Collagen is known to be effective for such corneal injury.
  • Hyaluronic acid is also known to be useful for tear reduction, cornea protection, prevention of corneal surface drying, and prevention of corneal epithelial shedding. Therefore, it is expected that corneal injury is cured by activating fibroblasts in the cornea and promoting production of extracellular matrix components such as collagen and hyaluronic acid.
  • Hyaluronic acid exists as a main component of joint fluid in joints, and plays a role of a cushion to relieve articular cartilage nutrition and external impact.
  • cartilage it is known to be an important component involved in the polymerization of proteoglycan molecules.
  • Hyaluronic acid is considered to be useful for osteoarthritis, a disease in which joint function is destroyed due to wear and degeneration of articular cartilage. It is also widely used in clinical practice (Non-patent Document 1). However, although such joint treatment temporarily improves joint function, it is necessary to inject regularly into the joint, so it is highly invasive and suffers from the patient. There was a need for therapy.
  • extracellular matrix components such as collagen have various effects such as scleroderma symptoms, in particular Raynaud's phenomenon and skin ulcer improving action (Patent Document 1), breast augmentation action (Patent Document 2) and the like. It is known to have an effect.
  • conogenin a fibroblast activator containing a conagenin derivative, a collagen production promoter, a collagen contraction promoter, or a hyaluronic acid production promoter
  • phytosterols such as ⁇ -sitosterol, stigmasterol and campesterol Collagen production promoter
  • collagen production promoter (patent document 5) containing piceatannol derived from passion fruit seed extract as an active ingredient
  • collagen production promoter containing beech family beech plant extract Patent Literature 6
  • Collagen Anaphoris Busua Extract or Toxaceae Exicatum Diffusam Extract
  • Collagen Production Promoter Patent Literature 7
  • Hyaluronic Acid Production Promoter Containing ⁇ -Sitosterol Patent Literature 8
  • An aloe vera water extract as an active ingredient Examples include a glutamate decarboxylase activator and a skin antiaging agent (Patent Document 9).
  • Patent Document 10 rophenol compounds have so far been antioxidant
  • Patent Documents 11, 12 and 13 improved hyperglycemia
  • Patent Documents 14 and 15 improved pancreatic function
  • Patent Document 16 improved insulin resistance
  • the object of the present invention is to provide a fibroblast activator that is highly safe and can be used as a medicine, quasi-drug, external preparation for skin, cosmetics, food and drink, food additive, feed, and the like.
  • a rophenol compound has a fibroblast activation action and can promote production of various extracellular matrix components.
  • the present invention has been completed.
  • a fibroblast activator containing a rophenol compound [1] A fibroblast activator containing a rophenol compound. [2] The fibroblast activator according to [1] for promoting collagen production. [3] The fibroblast activator according to [1] for promoting hyaluronic acid production. [4] The rophenol compound is 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol, and 4-methylstigmast-7-en-3-ol. The fibroblast activator according to any one of [1] to [3], selected from: [5] A food or drink containing the fibroblast activator according to any one of [1] to [4].
  • the fibroblast activator of the present invention contains a rophenol compound as an active ingredient.
  • R1 is preferably any one of the groups represented by the following formulae.
  • Preferred rophenol compounds include 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstigmast-7-en-3-ol. .
  • Each compound has a structure represented by the following formulas (2), (3) and (4), respectively.
  • 4-methylcholest-7-en-3-ol is represented by the formula (1), wherein one of R2 and R3 is a hydrogen atom, the other is a methyl group, R4 is a hydroxyl group, and R1 is A group represented by formula (vi) (wherein Rc is —H, Rd is —CH 3 );
  • 4-methylergost-7-en-3-ol is represented by the formula (1), wherein one of R2 and R3 is a hydrogen atom, the other is a methyl group, R4 is a hydroxyl group, and R1 is A group represented by the above formula (vi) (wherein Rc and Rd are both —CH 3 );
  • 4-methylstigmast-7-en-3-ol has the following formula (1): one of R2 and R3 is a hydrogen atom, the other is a methyl group, and R4 is a hydroxyl group.
  • R1 is a group represented by the formula (i).
  • the rophenol compound can be chemically produced according to a known production method. For example, it can be synthesized according to the supplement data described in Vitali Matyash et al., PLOS BIOLOGY, Volume 2, Issue 10, e280, 2004.
  • rophenol compounds are contained in plants, and the compounds of the present invention can be produced according to known methods for producing rophenol (Biochemical Experimental Method 24, Fat Lipid Metabolism Experiment). Law, Yasuhiro Yamada, Academic Publishing Center, page 174, 1989).
  • a method such as a hot water extraction method, an organic solvent extraction method, a supercritical extraction method or a subcritical extraction method.
  • organic solvent examples include ethanol, methanol, butanol, propylene glycol, chloroform, acetone, ethyl acetate, and the like. Particularly, ethyl acetate and butanol mixed solution (3: 1) or chloroform / methanol mixed solution (2 : 1) etc. are preferable.
  • Examples of the supercritical extraction method or subcritical extraction method include known methods described in Patent Document 11 and the like.
  • Examples of extraction solvents used for supercritical extraction include carbon dioxide, dimethyl ether, methane, ethane, propane, ethylene, propylene, benzene, toluene, ammonia, nitrogen, and nitric oxide. Carbon dioxide gas that is fluid, tasteless, odorless, explosive, safe and economical in process is preferred.
  • the extraction temperature and pressure in the extraction method are not limited as long as the extraction solvent can be brought into a supercritical state or a subcritical state.
  • the extraction temperature may be 40 to 100 ° C., preferably 50 to 70 ° C.
  • Examples of the pressure include 10 to 50 Mpa, and preferably 15 to 25 Mpa.
  • Examples of the extraction time include 30 to 240 minutes, and preferably 60 to 120 minutes.
  • an entrainer for example, by adding one or more of water, ethanol, acetone, ethyl acetate, methylene chloride, hexane, propane, urea, etc. to the extraction solvent or extraction raw material, the extraction efficiency can be improved or selected. Sex can be changed.
  • the rophenol compound may be produced biologically using microorganisms or the like, or may be produced using microorganism-derived enzymes.
  • the molecular weight, structure, etc. of the compound produced as described above can be determined or confirmed by, for example, a mass spectrum (MS) method and a nuclear magnetic resonance spectrum (NMR) method.
  • the rophenol compound may be a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include both metal salts (inorganic salts) and organic salts, the list of which is “Remington's Pharmaceutical Sciences, 17th Edition, 1985, What is published in "page 1418" is illustrated.
  • inorganic acid salts such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and sulfate, malate, maleate, fumarate, tartrate
  • Organic salts such as succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, and stearate are included without limitation.
  • solvates such as a hydrate of the said compound or its pharmaceutically acceptable salt, can also be used.
  • the fibroblast activator of the present invention contains a rophenol compound as an active ingredient.
  • the compound may be one kind or plural kinds.
  • the content of the rophenol compound in the fibroblast activator of the present invention can be appropriately selected according to the target disease, administration subject, etc., but is preferably at least 0.0001% by mass, more preferably at least at the total amount. 0.001% by weight, more preferably at least 0.005% by weight, particularly preferably at least 0.01% by weight.
  • the upper limit of the amount in the medicament of the present invention is not particularly limited, but the total amount is 90% by mass or less, preferably 70% by mass or less, more preferably 50% by mass or less.
  • the “fibroblast activation effect” means an action for promoting the proliferation of fibroblasts and an action for activating various functions of fibroblasts.
  • the functions of the fibroblasts include mucopolysaccharides such as hyaluronic acid, collagen matrix, and extracellular matrix component production promoting action such as fibronectin, collagen contraction action, and the like.
  • the fibroblast activator of the present invention can be used in the forms of pharmaceuticals, quasi drugs, external preparations for skin, cosmetics, foods and drinks, food additives, feeds, and the like.
  • the fibroblast activator of the present invention in a form using the fibroblast activator of the present invention as a medicine or quasi-drug (referred to as “medicament of the present invention”), it can be administered orally or parenterally to mammals including humans.
  • the medicament of the present invention can be used for preventing and / or treating a disease or condition involving an extracellular matrix component.
  • diseases or symptoms include skin aging, skin or bust firmness, gloss and / or loss of elasticity, wrinkles, tarmi, cuts, lacerations, split wounds, abrasions, bruises, wounds, burns , Pressure ulcer, gingivitis, periodontitis, alveolar pyorrhea, keratitis, dry eye, hyperemia, cornea erosion, flying mosquito disease, arthritis, osteoarthritis, spondyloarthritis, scleroderma, Raynaud, skin ulcer, etc. It is possible to illustrate. Among them, the medicament of the present invention has a remarkable effect particularly on the prevention and / or treatment of skin aging, skin firmness, gloss and / or elasticity reduction, wrinkles and tarmi.
  • the form of the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected depending on the therapeutic purpose and usage. Specifically, tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, syrups, suppositories, injections, ointments, gels, patches, eye drops, nasal drops Etc. can be illustrated.
  • the administration time of the medicament of the present invention is not particularly limited, and can be appropriately selected according to the target disease, administration form, and the like.
  • the dosage is preferably determined according to the preparation form, usage, patient age, sex, other conditions, the degree of symptoms, and the like.
  • the dosage of the medicament of the present invention is appropriately selected depending on the usage, patient age, sex, disease severity, other conditions, and the like.
  • the range is preferably 0.001 to 50 mg / kg / day, more preferably 0.01 to 1 mg / kg / day.
  • one of the preferred forms of the medicament of the present invention is that the rophenol compound is administered in a total amount, preferably 0.001 to 50 mg / kg / day, more preferably 0.01 to 1 mg / kg / day. It is a medicine used for
  • the medicament of the present invention is an active ingredient according to the disease or symptom to be prevented or treated, for example, skin aging, skin firmness, gloss and / or so long as it does not impair the fibroblast activation action of the rophenol compound. It may contain other components having an improved and / or preventive action such as reduced elasticity, wrinkles and tarmi.
  • the medicament of the present invention may contain an additive commonly used for medicaments.
  • additives include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents, solvents for injections, and the like.
  • excipient include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, and gentian powder.
  • binder examples include starch, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, and the like.
  • disintegrant examples include starch, agar, gelatin powder, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, and sodium alginate.
  • lubricant examples include magnesium stearate, hydrogenated vegetable oil, and macrogol.
  • the stabilizer examples include paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.
  • flavor, etc. are mentioned, for example.
  • the diluent or solvent for injection include water, ethanol, glycerin and the like.
  • the medicament of the present invention exhibits an excellent effect of promoting the production of extracellular matrix components by the fibroblast activation action of the rophenol compound.
  • the external preparation for skin of the present invention includes those classified into any of pharmaceuticals, quasi drugs and cosmetics as long as they are applied to the skin.
  • the skin external preparation of this invention can be manufactured by mix
  • Other matters such as a preferable preparation form of the compound are as described in the “medicament of the present invention” or “the cosmetic of the present invention”.
  • the disease or symptom involving production of extracellular matrix components by fibroblasts is prevented and / or improved.
  • diseases or symptoms include skin aging, skin or bust firmness, gloss and / or loss of elasticity, wrinkles, tarmi, cuts, lacerations, split wounds, abrasions, bruises, wounds, burns Examples include pressure ulcers, gingivitis, periodontitis, alveolar pyorrhea, and skin ulcers.
  • the cosmetics of the present invention have a remarkable effect on the prevention and / or improvement of skin aging, skin firmness, gloss and / or elasticity, wrinkles and tarmi.
  • the cosmetic of the present invention is a person who needs prevention of disease events or reduction of the risk of expression, i.e., aging, UV exposure or stress, etc., production of extracellular matrix components by fibroblasts is reduced, Useful for those at risk of accelerating the degradation of the component.
  • the cosmetic of the present invention contains a rophenol compound as an active ingredient.
  • the compound may be one kind or plural kinds.
  • basic cosmetics such as lotion, emulsion, cream, ointment, gel, lotion, oil, pack, mist, facial cosmetic sheet mask, shaving agent, facial cleanser, skin cleanser, shampoo, rinse, hair treatment
  • Hair cosmetics such as hairdressing, perm, hair art, hair dye, hair growth and hair nourishing
  • makeup cosmetics such as foundation, lipstick, blusher, eye shadow, eyeliner, mascara, perfume, antiperspirant, Examples include bathing agents, mouthwashes, toothpastes, mouth fresheners, and the like.
  • the cosmetic of the present invention may contain other active ingredients as long as the fibroblast activation action of the rophenol compound is not impaired.
  • active ingredients for example, moisturizing agents, whitening agents, anti-inflammatory agents, ultraviolet absorbers, ultraviolet scattering agents, vitamins, antioxidants, plant or microorganism-derived cosmetic ingredients, and the like can be mentioned.
  • humectant examples include sodium dl-pyrrolidonecarboxylate, lactic acid, sodium lactate, polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, hexylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, Examples include mucoitin sulfate, caronic acid, and atelocollagen.
  • whitening agent examples include arbutin, vitamin C, ascorbic acid, placenta extract, glutathione and the like.
  • anti-inflammatory agent examples include glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, and the like.
  • ultraviolet scattering agent examples include titanium oxide, zinc oxide, talc, bentonite and kaolin.
  • vitamin A or a derivative thereof examples include vitamin A or a derivative thereof, vitamin B2 or a derivative thereof, vitamin B6 or a derivative thereof, vitamin B12 or a derivative thereof, vitamin B15 or a derivative thereof, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, vitamin E acetate , Vitamin Ds, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone and the like.
  • antioxidants examples include tocopherol and derivatives thereof, butylhydroxyanisole, dibutylhydroxytoluene, sodium bisulfite, erythorbic acid and salts thereof, flavonoids, glutathione, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase, thioredoxin , Taurine, thiotaurine, hypotaurine and the like.
  • cosmetic components examples include lactoferrins or hydrolysates thereof, ⁇ -lactoglobulin, ⁇ -casein, casein phosphooligopeptide, lactobacillus-derived components, yeast-derived components, and the like.
  • additive component examples include the following.
  • surfactants include higher alkyl sulfates, alkyl ether sulfates, higher fatty acid amide sulfonates, phosphate ester salts, sulfosuccinates, alkylbenzene sulfonates, N-acyl glutamates, higher fatty acid ester sulfates.
  • higher fatty acids examples include lauric acid, myristic acid, palmitic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, behenic acid, 12-hydroxystearic acid, isostearic acid, undesic acid, tallic acid, eicosapentaenoic acid, docosahexaene There are acids.
  • silicone examples include chain polysiloxanes such as dimethylpolysiloxane and methylphenylpolysiloxane, cyclic polysiloxanes such as decamethylcyclopolysiloxane, and network structures such as silicone resins.
  • Examples of natural water-soluble polymers include pectin, gum arabic, carrageenan, tragacanth gum, guar gum, carob gum, starch, xanthan gum, dextran, pullulan, collagen, casein, hyaluronic acid and gelatin.
  • Examples of the semi-synthetic water-soluble polymer include cellulose polymers such as sodium carboxymethylcellulose, methylcellulose, and nitrocellulose, alginic acid polymers such as sodium alginate, and starch polymers such as carboxymethyl starch.
  • Examples of the synthetic water-soluble polymer include vinyl polymers such as polyvinyl alcohol and carboxyvinyl polymer, polyoxyethylene polymers such as polyethylene glycol 2000, and copolymer polymers such as polyoxyethylene polyoxypropylene copolymer. And acrylic polymers such as polyacrylamide, polyethylenimine, and cationic polymers.
  • the powder component examples include talc, silica, kaolin, mica, sericite, magnesium carbonate, calcium carbonate, silicate, barium sulfate, calcined gypsum, fluorapatite, ceramic powder and other inorganic powders, nylon powder, polyethylene powder, There are organic powders such as polystyrene powder and cellulose powder.
  • coloring agents include inorganic pigments such as iron oxide, titanium dioxide, carbon black, and cobalt violet, organic pigments such as red 201, red 3, yellow 205, and yellow 4, chlorophyll, ⁇ -carotene, astaxanthin, and lycopene And natural pigments such as safflower and turmeric.
  • preservatives examples include ethanol, benzalkonium chloride, benzoate, salicylate, sorbate, and paraoxybenzoate.
  • chelating agents include sodium ethylenediaminetetraacetate, sodium polyphosphate, citric acid and the like.
  • the content of the rophenol compound in the cosmetic of the present invention can be appropriately selected according to the purpose, usage and the like, but is preferably at least 0.0001% by mass, more preferably at least 0.001% by mass in total. More preferably, it is at least 0.005% by mass, particularly preferably at least 0.01% by mass.
  • the upper limit of the amount in the cosmetic of the present invention is not particularly limited, but the total amount is 90% by mass or less, preferably 70% by mass or less, more preferably 50% by mass or less.
  • diseases or symptoms include skin aging, skin or bust firmness, gloss and / or loss of elasticity, wrinkles, tarmi, cuts, lacerations, split wounds, abrasions, bruises, wounds, burns , Pressure ulcer, gingivitis, periodontitis, alveolar pyorrhea, keratitis, dry eye, hyperemia, cornea erosion, flying mosquito disease, arthritis, osteoarthritis, spondyloarthritis, scleroderma, Raynaud, skin ulcer, etc. It is possible to illustrate.
  • the food and drink of the present invention have a remarkable effect on the prevention and / or improvement of skin aging, skin firmness, gloss and / or reduced elasticity, wrinkles and tarmi, It can be used as a food or drink.
  • the food or drink of the present invention is a person who needs to prevent or reduce the risk of expression of a disease event, i.e., aging, UV exposure or stress, etc., so that production of extracellular matrix components by fibroblasts is reduced, Useful for those at risk of accelerating the degradation of the component.
  • “food and beverage” includes food and beverages consumed by humans and feeds consumed by animals other than humans.
  • the food / beverage products of this invention contain a rophenol compound as an active ingredient.
  • the compound may be one kind or plural kinds.
  • the amount of the rophenol compound in the food / beverage product of the present invention is appropriately set depending on the form of the food / beverage product, but is preferably a total amount of at least 0.0001% by mass, more preferably at least 0.001% by mass, and still more preferably at least 0.005% by weight, particularly preferably at least 0.01% by weight.
  • the upper limit of the said quantity in the food / beverage products of this invention is not restrict
  • the amount of the compound in the food and drink of the present invention is preferably a total amount of rophenol compound, preferably 0.001 to 50 mg / kg / day, more preferably 0.01 to 1 mg, depending on the form of the food or drink. / Kg / day can be an appropriate amount for ingestion. Therefore, one of the preferred forms of the food and drink of the present invention is to take the rophenol compound in a total amount of preferably 0.001 to 50 mg / kg / day, more preferably 0.01 to 1 mg / kg / day. It is a food and drink used for food.
  • the food or drink of the present invention preferably further contains an emulsifier.
  • an emulsifier is not particularly limited as long as it can be used for food.
  • the food / beverage products containing an emulsifier have high dispersibility of the rophenol compound, they are excellent in stability of the effect.
  • the food or drink of the present invention is preferably a functional food or drink or a beauty food or drink.
  • a functional food or drink means a food on which a disease prevention effect or a disease risk reduction effect is directly or indirectly displayed.
  • the food and drink for beauty means foods that are directly or indirectly displayed for the purpose of beautifully preparing the face, body, and skin.
  • Examples of the form of the food and drink of the present invention include beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit juice drinks, and lactic acid bacteria drinks (including concentrated concentrates and powders for preparation of these drinks); ice cream, ice sherbet, shaved ice, etc.
  • beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit juice drinks, and lactic acid bacteria drinks (including concentrated concentrates and powders for preparation of these drinks); ice cream, ice sherbet, shaved ice, etc.
  • Noodles such as buckwheat, udon, harusame, gyoza skin, sushi mai, noodles such as Chinese noodles and instant noodles; rice cakes, chewing gum, candy, gum, chocolate, tablet confectionery, snack confectionery, biscuits, jelly, jam, cream, baked Confectionery such as confectionery; processed fishery and livestock products such as kamaboko, ham, sausage; dairy products such as processed milk, milk drinks, fermented milk, butter; prepared foods; breads; other enteral nutrition foods, liquid foods, childcare Milk and sports drinks.
  • the food or drink of the present invention is labeled with indications such as “to activate fibroblasts”, “to promote production of extracellular matrix components”, “to promote production of collagen or hyaluronic acid”, etc. It is preferable to use the form. That is, it is preferable to sell the food / beverage products of this invention as the food / beverage products for promotion of the production of an extracellular matrix component containing the rophenol compound as an active ingredient, to which the above-mentioned uses are applied.
  • the “display” includes all displays having a function of informing the consumer of the use. In other words, any display capable of recalling / analyzing the application corresponds to the “display” regardless of the purpose of display, the content of display, the object / medium to be displayed, and the like. In addition, the “display is attached” means that there is a display act that tries to recognize the display in association with the food or drink (product).
  • the display act is one in which the consumer can directly recognize the use.
  • the use of the use of the above-mentioned use on the product or the product packaging related to the food or drink of the present invention, the advertisement related to the product, the price list or transaction documents (including those provided by electromagnetic methods) Can be exemplified.
  • the displayed content is a display approved by the government or the like (for example, a display that is approved based on various systems determined by the government and is performed in a mode based on such approval). Is preferred.
  • the display of health foods, functional foods and drinks, beauty foods and drinks, enteral nutritional foods, special-purpose foods, health functional foods, foods for specified health, nutritional functional foods, quasi drugs, and the like can be exemplified.
  • a display approved by the Ministry of Health, Labor and Welfare for example, a display approved by a food system for specific health use or a system similar thereto can be exemplified. Examples of the latter can include a display as a food for specified health use, a display as a condition specific food for specified health use, a display that affects the structure and function of the body, a display for reducing disease risk, etc.
  • Speaking of the health promotion law enforcement regulations (April 30, 2003 Ministry of Health, Labor and Welfare Ordinance No. 86) labeling as food for specified health use (especially labeling the use of health), and similar
  • the display can be listed as a typical example.
  • the wording indicating the use is limited to words such as “to activate fibroblasts”, “to promote production of extracellular matrix components”, and “to promote production of collagen or hyaluronic acid”. Even if it is other words, the language expressing the fibroblast activation action or effect, the action or effect of preventing a disease or symptom involving an extracellular matrix component, and the risk of occurrence of the disease or symptom are reduced. Needless to say, any word including expressions relating to the action or effect is included in the scope of the present invention. For example, “For those who are concerned about skin firmness, gloss, wrinkles, and talmi”, “Repair wounds quickly without leaving traces”, “For joint pain”, “For those who are hard on the eyes of PC work” And the like.
  • the food and drink of the present invention preferably includes a display of the active ingredient, and further a display showing the relationship between the use and the active ingredient.
  • the food and drink of the present invention can also be in the form of animal feed, and the form is not particularly limited.
  • grains such as corn, wheat, barley, rye, and milo; soybean oil meal, rapeseed oil meal, palm Vegetable oils such as oil lees and flaxseed oil lees; bran such as bran, wheat straw, rice bran and defatted rice lees; production varieties such as corn gluten meal and corn jam meal; fish meal, skim milk powder, whey, yellow grease, tallow, etc.
  • Examples of the form of the feed include pet food, livestock feed, and fish feed.
  • diseases or symptoms include skin aging, skin or bust firmness, gloss and / or loss of elasticity, wrinkles, tarmi, cuts, lacerations, split wounds, abrasions, bruises, wounds, burns , Pressure ulcer, gingivitis, periodontitis, alveolar pyorrhea, keratitis, dry eye, hyperemia, cornea erosion, flying mosquito disease, arthritis, osteoarthritis, spondyloarthritis, scleroderma, Raynaud, skin ulcer, etc. It can be illustrated. Among them, particularly, it has a remarkable effect on the prevention and / or improvement of skin aging, skin firmness, gloss and / or elasticity reduction, wrinkles and tarmi.
  • the food or drink to which the food additive of the present invention is added is a person who needs to prevent or reduce the risk of developing the above-mentioned disease event, i.e., aging, UV exposure or stress, etc. Useful for people who are at a risk of reduced production or accelerated degradation of the component.
  • the food additive of the present invention contains a rophenol compound as an active ingredient.
  • the compound may be one kind or plural kinds.
  • the amount of the rophenol compound in the food additive of the present invention is appropriately set, but is preferably at least 0.001% by mass, more preferably at least 0.01% by mass, and even more preferably at least 0.05% by mass. %, Particularly preferably at least 0.1% by weight.
  • the upper limit of the amount in the food additive of the present invention is not particularly limited, but is 90% by mass or less, preferably 70% by mass or less, and more preferably 50% by mass or less in terms of the total amount.
  • the food additive of the present invention preferably further contains an emulsifier.
  • an emulsifier is not particularly limited as long as it can be used for food.
  • an emulsifier in the food additive of the present invention, the dispersibility of the rophenol compound, which is the active ingredient of the food additive of the present invention, in water-soluble food and drink is improved.
  • the normal form of food additives such as a powder, a granule, a tablet, a liquid, can be taken.
  • the food additive of the present invention contains the above-mentioned emulsifier, it is particularly preferable that the food additive is in an emulsifier form.
  • the food additive of the present invention may contain additives such as commonly used excipients in addition to the rophenol compound and emulsifier as active ingredients. Moreover, the well-known other component normally used for a food additive may be included.
  • the food additive of the present invention can be produced by blending a rophenol compound as an active ingredient.
  • the food additive of the present invention can be produced by a known method, for example, by formulating the active ingredient, preferably with the emulsifier, and optionally with the additive or other ingredients.
  • the food additive of the present invention can be used for producing the food and drink of the present invention described above.
  • the amount added to the food or drink can be appropriately adjusted based on the amount of the rophenol compound as the active ingredient in the food or drink of the present invention described above.
  • the food additive of the present invention is labeled with indications such as “to activate fibroblasts”, “to promote production of extracellular matrix components” and “to promote production of collagen or hyaluronic acid”. It is preferable to adopt the form. “Display” and “display act” are as described in the section of “Food and Drink of the Present Invention”.
  • test substance 1 4-methylcholest-7-en-3-ol (hereinafter referred to as test substance 1), 4-methylergost-7-en-3-ol (hereinafter referred to as test substance 2), And 4-methylstigmast-7-en-3-ol (hereinafter referred to as “test substance 3”) are dissolved in DMSO, and FM medium (Fibroblast Medium: Science Cell Research Laboratories, Inc.) is used to obtain a predetermined concentration. Manufactured by Cosmo Bio). Further, stigmasterol, campesterol, and ⁇ -sitosterol (all manufactured by Tama Seikagaku Co., Ltd.) were similarly prepared as positive controls as substances known to have a fibroblast activation effect.
  • test substance 3 4-methylcholest-7-en-3-ol
  • test substance 2 4-methylergost-7-en-3-ol
  • test substance 3 4-methylstigmast-7-en-3-ol
  • hyaluronic acid quantitative ELISA kit manufactured by Biotech Trading Partners: obtained from Funakoshi. 100 ⁇ L of the collected culture supernatant or 100 ⁇ L of hyaluronic acid standard solution (50 to 800 ng / mL) was added to a microplate on which hyaluronic acid binding protein (HABP) was immobilized, and reacted at room temperature for 1 hour. After the reaction, each well of the microplate was washed with a washing buffer, and 100 ⁇ L of horseradish peroxidase (HRP) -labeled HABP was added and reacted at room temperature for 30 minutes.
  • HRP horseradish peroxidase
  • each well of the microplate was washed again with a washing buffer, 100 ⁇ L of enzyme substrate was added, and then allowed to stand at room temperature for 30 minutes in the dark. Thereafter, 100 ⁇ L of a reaction stop solution was added to each well, and after mixing, absorbance was measured at a main wavelength of 450 nm and a sub wavelength of 650 nm. The amount of hyaluronic acid in the culture supernatant was calculated by creating a calibration curve with the reference standard reagent and calculating from this relational expression. Absorbance of culture supernatant / absorbance of reference standard reagent x 50 to 800 ng / mL (concentration of reference standard reagent)
  • Tables 1 and 2 show that by adding a test substance to fibroblasts and culturing for 48 hours, the production of both collagen and hyaluronic acid is promoted, that is, fibroblasts are activated. It is shown that.
  • the test substance with the same concentration had collagen and hyaluron. Both acids showed a clearly high production promoting effect. This indicates that the test substances 1, 2 and 3 have a fibroblast activation action superior to that of the conventional substance.
  • Patent Documents 10 to 17 Since it is known that rophenol compounds are taken into the blood circulating in the body by oral administration (Patent Documents 10 to 17), pharmaceuticals, foods and drinks, food additives or feeds containing the compounds are known. It is clear that the same fibroblast activation effect as described above can be obtained by oral ingestion.
  • polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water, dissolved by heating, and kept at 70 ° C. to obtain two solutions. Separately from the first and second liquids, all the remaining components were mixed and dissolved at 70 ° C. to obtain three liquids. Subsequently, after adding 3 liquids to 2 liquids, 1 liquid was further added to this, and it emulsified uniformly with the homomixer, and it cooled to 30 degreeC, stirring well after emulsification, and prepared emulsion.
  • the fibroblast activator of the present invention activates fibroblasts, it can be applied to any disease or condition related to a decrease in the number of fibroblasts or a decrease in the function of fibroblasts.
  • the fibroblast activator of the present invention has an action of promoting the production of extracellular matrix components from fibroblasts, it causes diseases related to extracellular matrix such as skin aging, skin or bust tension.

Abstract

La présente invention vise à proposer un activateur de fibroblaste qui est très sûr et peut être utilisé comme produit pharmaceutique, quasi-médicament, préparation pour peau externe, produit cosmétique, aliment ou boisson, additif alimentaire ou aliment pour animaux, etc. L'activateur de fibroblaste combine un composé de rophénol sous la forme d'un constituant efficace de celui-ci. Le composé de rophénol active des fibroblastes et peut favoriser la production de collagène, d'hyaluronane et d'autres constituants de matrice extracellulaire.
PCT/JP2014/052076 2013-07-30 2014-01-30 Activateur de fibroblaste WO2015015816A1 (fr)

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JP2017128560A (ja) * 2016-01-14 2017-07-27 日本メナード化粧品株式会社 角栓分解促進剤
JP2017178935A (ja) * 2016-03-29 2017-10-05 株式会社ファンケル キマーゼ阻害用組成物
WO2019188490A1 (fr) * 2018-03-29 2019-10-03 森永乳業株式会社 Composition pour améliorer la résistance aux rayons ultraviolets
WO2019188491A1 (fr) * 2018-03-29 2019-10-03 森永乳業株式会社 Composition anti-âge
WO2020246468A1 (fr) 2019-06-06 2020-12-10 ビタミンＣ６０バイオリサーチ株式会社 Activateur cellulaire de cellule animale

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017128560A (ja) * 2016-01-14 2017-07-27 日本メナード化粧品株式会社 角栓分解促進剤
JP2017178935A (ja) * 2016-03-29 2017-10-05 株式会社ファンケル キマーゼ阻害用組成物
WO2019188490A1 (fr) * 2018-03-29 2019-10-03 森永乳業株式会社 Composition pour améliorer la résistance aux rayons ultraviolets
WO2019188491A1 (fr) * 2018-03-29 2019-10-03 森永乳業株式会社 Composition anti-âge
JPWO2019188491A1 (ja) * 2018-03-29 2021-04-01 森永乳業株式会社 抗老化用組成物
WO2020246468A1 (fr) 2019-06-06 2020-12-10 ビタミンＣ６０バイオリサーチ株式会社 Activateur cellulaire de cellule animale
KR20220003051A (ko) 2019-06-06 2022-01-07 비타민 씨60 바이오리서치 가부시키가이샤 동물 세포의 세포 부활제

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