WO2015015816A1

WO2015015816A1 - Fibroblast activator

Info

Publication number: WO2015015816A1
Application number: PCT/JP2014/052076
Authority: WO
Inventors: 美順田中; かずみ鍋島
Original assignee: 森永乳業株式会社
Priority date: 2013-07-30
Filing date: 2014-01-30
Publication date: 2015-02-05
Also published as: JPWO2015015816A1

Abstract

The present invention addresses the issue of providing a fibroblast activator being highly safe and capable of being used as a pharmaceutical, a quasi-drug, an external skin preparation, a cosmetic, a food or drink, a food additive, or feed, etc. The fibroblast activator combines a rophenol compound as an effective component thereof. The rophenol compound activates fibroblasts and can promote the production of collagen, hyaluronan and other extracellular matrix components.

Description

Fibroblast activator

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. It produces large amounts of extracellular matrix components such as collagen, mucopolysaccharides such as hyaluronic acid, and fibronectin. Fibroblasts play an important role in organ morphogenesis and create fibrous connective tissue between cells and tissues and tissues.

It is known that 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 It is known to produce fibroblasts. 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.
However, when the function of fibroblasts weakens or the number of fibroblasts decreases due to effects such as aging, ultraviolet exposure, and stress, the production of extracellular matrix components such as collagen and hyaluronic acid decreases, Collagen shrinkage due to fibroblasts also weakens, so the skin cannot be moisturized and dries, loses elasticity and flexibility, does not have skin firmness or gloss, and pores spread and become noticeable, wrinkles and tarmi are formed It becomes a situation.

In addition to dermis, 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.

For example, collagen produced by fibroblasts plays a role in maintaining the structure in gingival tissue. However, when 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. Furthermore, 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 (also referred to as corneal parenchymal cells) 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.

When wounds such as cuts, lacerations, split wounds, abrasions, crush wounds, wounds, burns, pressure sores, etc., the dermis and subcutaneous tissue are lost, which is then repaired by fibroblast proliferation and granulation rich in collagen fibers. Is formed. Since this scar is not formed in the skin of an infant whose abundance of hyaluronic acid is higher than that in adults, the production of hyaluronic acid in the skin is considered to suppress scar formation. Therefore, by promoting fibroblasts and promoting production of extracellular matrix components such as collagen and hyaluronic acid, scarless healing that promotes wound healing and suppresses scar formation is expected.

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. In 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.

In addition, 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.

As described above, extracellular matrix components produced by fibroblasts are related to a wide variety of diseases or conditions. Therefore, in order to improve these diseases or conditions, it is required to activate fibroblasts and promote the production of extracellular matrix components, and many have a promoting effect. For example, conogenin, a fibroblast activator containing a conagenin derivative, a collagen production promoter, a collagen contraction promoter, or a hyaluronic acid production promoter (Patent Document 3), phytosterols such as β-sitosterol, stigmasterol and campesterol Collagen production promoter (patent document 4), 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 β-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).

On the other hand, rophenol compounds have so far been antioxidant (Patent Document 10), improved hyperglycemia (Patent Documents 11, 12 and 13), improved pancreatic function (Patent Documents 14 and 15), improved insulin resistance (Patent Document 16). However, it was not known to have a fibroblast activation effect or an extracellular matrix component production promoting effect.

JP 2008-266222 A JP 2008-044890 A International Publication No. 2007/011066 JP 2001-039849 A JP 2010-030911 A Japanese Patent Laid-Open No. 10-203952 JP 2003-176235 A JP 2009-057290 A JP 2003-206225 A International Publication No. 2010/058795 International Publication No. 2007/060911 International Publication No. 2005/095436 International Publication No. 2005/094838 International Publication No. 2006/123464 International Publication No. 2006/123465 International Publication No. 2007/043306 International Publication No. 2007/043294

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. In particular, it is an object of the present invention to provide an external preparation for skin, cosmetics, food and drink, food additives and the like for promoting the production of extracellular matrix components, which effectively activates fibroblasts of the skin.

As a result of intensive studies to solve the above problems, the present inventors have found that a rophenol compound has a fibroblast activation action and can promote production of various extracellular matrix components. The present invention has been completed.

That is, the present invention relates to the following matters.
[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].
[6] A food additive containing the fibroblast activator according to any one of [1] to [4].
[7] A skin external preparation containing the fibroblast activator according to any one of [1] to [4].
[8] A cosmetic containing the fibroblast activator according to any one of [1] to [4].

According to the present invention, fibroblasts can be activated using a rophenol compound.
Moreover, since this invention has a strong fibroblast activation effect | action, it can be used as a more effective fibroblast activator.
Furthermore, since the rophenol compound used in the present invention is one of phytosterols contained in plants, it has high safety and is a pharmaceutical, quasi-drug, external preparation for skin, cosmetics, food and drink, food additives It can be suitably used for preparations and feeds.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the following preferred embodiments, and can be freely modified within the scope of the present invention. In the present specification, the percentage is expressed by mass unless otherwise specified.

The fibroblast activator of the present invention contains a rophenol compound as an active ingredient.

[Rophenol compound]
The rophenol compound (compound having a rophenol skeleton) is represented by the following general formula (1).

In general formula (1), R1 is a linear or branched alkyl group having 5 to 16 carbon atoms, or an alkenyl group containing one or two double bonds. These alkyl groups or alkenyl groups may be substituted alkyl groups or substituted alkenyl groups in which at least one hydrogen atom is substituted with a hydroxyl group and / or a carbonyl group. R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a substituted alkyl group, and R4 forms C═O together with the carbon atoms constituting the ring, or —OH, —OCOCH _{One of the three} . The alkyl group having 1 to 3 carbon atoms is preferably a methyl group, an ethyl group or the like, and particularly preferably a methyl group.

In the general formula (1), 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.

Formula (2): 4-Methylcholest-7-en-3-ol

Formula (3): 4-Methyl Ergost-7-en-3-ol

Formula (4): 4-methylstigmast-7-en-3-ol

That is, 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 ); Further, 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.

In addition, it is known that 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).
For example, it is possible to extract from a plant known to contain a rophenol compound using a method such as a hot water extraction method, an organic solvent extraction method, a supercritical extraction method or a subcritical extraction method.

Examples of the organic solvent 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. For example, 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.
As 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.
Specifically, 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.
Moreover, it can also be set as salts with amino acids, such as metals, such as sodium, potassium, calcium, magnesium, and aluminum, and a lysine. Moreover, solvates, such as a hydrate of the said compound or its pharmaceutically acceptable salt, can also be used.

[Fibroblast activator of the present invention]
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.

In the present invention, the “fibroblast activation effect” means an action for promoting the proliferation of fibroblasts and an action for activating various functions of fibroblasts. Examples of 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.

(Pharmaceutical and quasi-drug 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.
Examples of such 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.

And the medicament of the present invention is a person who needs prevention of disease event or reduction of risk of expression, i.e., aging, UV exposure or stress, etc., the production of extracellular matrix components by fibroblasts is reduced, Useful for people at risk of accelerating decomposition of ingredients.
The medicament of the present invention contains a rophenol compound as an active ingredient. The compound may be one kind or plural kinds.

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. Tablets and granules are sucrose, hydroxypropylcellulose, purified shellac, gelatin, sorbitol, glycerin, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, methyl methacrylate as necessary And a methacrylic acid polymer.

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. Usually, in terms of the amount of the active ingredient, the range is preferably 0.001 to 50 mg / kg / day, more preferably 0.01 to 1 mg / kg / day.
Accordingly, 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.

Moreover, the medicament of the present invention may contain an additive commonly used for medicaments. Examples of additives include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents, solvents for injections, and the like.
Examples of the excipient include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, and gentian powder.
Examples of the binder include starch, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, and the like.
Examples of the disintegrant include starch, agar, gelatin powder, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, and sodium alginate.
Examples of the lubricant include magnesium stearate, hydrogenated vegetable oil, and macrogol.
Examples of the stabilizer 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.
As said flavoring agent, a sweetener, a sour agent, a fragrance | flavor, etc. are mentioned, for example.
Examples of the diluent or solvent for injection include water, ethanol, glycerin and the like.

The medicament of the present invention can be produced by incorporating a rophenol compound as an active ingredient into a pharmaceutical carrier such as a sponge. For example, when a rophenol compound is further added to a collagen sponge used in the dental field or the like, it is possible not only to administer collagen but also to promote collagen production.
Moreover, the pharmaceutical of this invention can be manufactured by formulating the said compound with the additive mentioned above, for example.

The medicament of the present invention may be used alone, but can also be used in combination with a known prophylactic / therapeutic agent for the disease. By using in combination, the preventive / therapeutic effect of the disease can be enhanced. The prophylactic / therapeutic agent for the disease to be used in combination may be contained as a component of the pharmaceutical agent of the present invention, or formulated separately from the pharmaceutical agent of the present invention, placed in combination with the pharmaceutical agent of the present invention, and used in combination when used. It is good as a kit.

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.

(Skin external preparation of the present invention)
In the form using the fibroblast activator of the present invention as a skin external preparation (referred to as “the skin external preparation of the present invention”), a disease or symptom involving production of extracellular matrix components by fibroblasts is prevented and / or Or it can be used to treat. Examples of such 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 ulcers, scleroderma, Raynaud, skin ulcers and the like.
Among these, the skin external preparation of the present invention has a remarkable effect on the prevention and / or treatment of skin aging, skin firmness, gloss and / or elasticity, wrinkles and tarmi. In addition, in the external preparation for skin of the present invention, whether the production of extracellular matrix components by fibroblasts is reduced due to aging, UV exposure or stress, etc. due to the need for prevention of disease events or reduction of the risk of expression. It is useful for those who have a risk of promoting the decomposition of the component.

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 | blending a rophenol compound with the base known normally. 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”.

(Cosmetics of the present invention)
In the form using the fibroblast activator of the present invention as a cosmetic (referred to as “cosmetic of the present invention”), the disease or symptom involving production of extracellular matrix components by fibroblasts is prevented and / or improved. It can be used to Examples of such 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.
Among these, 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.

The cosmetics of the present invention include, for example, topical or systemic skin cleansers, skin cosmetics or medicinal cosmetics, bath preparations used in bath water, oral preparations such as mouthwashes or gargles, etc. Means. The formulation form is not particularly limited, and can be appropriately selected depending on the purpose and usage. For example, 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. 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.

Examples of the humectant 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.

Examples of the whitening agent include arbutin, vitamin C, ascorbic acid, placenta extract, glutathione and the like.

Examples of the anti-inflammatory agent include glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, and the like.

Examples of the ultraviolet absorber include paraaminobenzoic acid ultraviolet absorbers, anthranilic acid ultraviolet absorbers, salicylic acid ultraviolet absorbers, cinnamic acid ultraviolet absorbers, benzophenone ultraviolet absorbers, and sugar ultraviolet absorbers. .

Examples of the ultraviolet scattering agent include titanium oxide, zinc oxide, talc, bentonite and kaolin.

Examples of the vitamin 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, α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate , Vitamin Ds, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone and the like.

Examples of the antioxidant 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.

Examples of the cosmetic components include lactoferrins or hydrolysates thereof, β-lactoglobulin, κ-casein, casein phosphooligopeptide, lactobacillus-derived components, yeast-derived components, and the like.

Further, in the cosmetics of the present invention, generally known additive components can be widely blended within the range in which the desired effects of the present invention are not impaired by the blending, and the desired dosage form and form described above can be used. According to this, it can manufacture with a well-known manufacturing method.

Examples of the additive component include the following.
For example, 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. Anionic surfactants such as ester salts, sulfated oils, POE (polyoxyethylene) alkyl ether carboxylates, POE alkyl allyl ether carboxylates, α-olefin sulfonates, higher fatty acid ester sulfonates; alkyl trimethyl ammonium Salt, dialkyldimethylammonium salt, alkylpyridium salt, alkyldimethylbenzylammonium salt, alkylisoquinonium salt, dialkylmorphonium salt, POE alkylamine, polyamine fatty acid derivative, amino acid Cationic surfactants such as alcohol fatty acid derivatives and benzalkonium chloride; amphoteric surfactants such as imidazoline surfactants and betaine surfactants; sorbitan fatty acid esters, glycerin fatty acid esters, propylene glycol fatty acid esters, hydrogenated castor oil derivatives Lipophilic nonionic surfactants such as POE sorbitan fatty acid ester, POE glycerin fatty acid ester, POE sorbit fatty acid ester, POE fatty acid ester, POE alkyl ether, POE alkyl phenyl ether and the like, and the like .

Oils include olive oil, jojoba oil, camellia oil, avocado oil, sesame oil, palm oil, evening primrose oil, macadamian nut oil, rapeseed oil, castor oil, linseed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, Examples include plant oils such as rice bran oil, cacao butter, coconut oil, horse oil, lanolin, beeswax, carnauba wax, molasses, candelilla wax and squalane; mineral oils such as petrolatum and liquid paraffin.

Examples of higher fatty acids 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.

Examples of higher alcohols include lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, and oleyl alcohol.

Synthetic esters include, for example, cetyl octanoate, octyldodecyl myristate, isopropyl myristate, myristyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, decyl orenate, dimethyl octanoate, cetyl lactate, lactic acid There is myristyl.

Examples of silicone 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.

Examples of the powder component 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.

Examples of 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, β-carotene, astaxanthin, and lycopene And natural pigments such as safflower and turmeric.

Examples of preservatives include ethanol, benzalkonium chloride, benzoate, salicylate, sorbate, and paraoxybenzoate.

Examples of 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.

(Food and drink and feed of the present invention)
In the form using the fibroblast activator of the present invention as a food or drink (referred to as “food or drink of the present invention”), the disease or symptom involving production of extracellular matrix components by fibroblasts is prevented and / or improved. It can be used to Examples of such 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, in particular, 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. In addition, 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.

In the present invention, “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. Moreover, although the upper limit of the said quantity in the food / beverage products of this invention is not restrict | limited in particular, 90 mass% or less, Preferably it is 70 mass% or less by a total amount, More preferably, 50 mass% or less is illustrated.

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. Such an emulsifier is not particularly limited as long as it can be used for food. For example, it is preferable to use glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, lecithin and the like which are approved as food additives in Japan.
Furthermore, since 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. For example, foods sold in the form of specified health foods and health supplements in Japan at present.
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. 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.

In particular, as a form of functional food or drink or beauty food or drink, it is said that it is a granular, tablet, capsule, jelly, or liquid supplement that the intake person can easily grasp the intake amount of the active ingredient This is preferable.

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).

It is preferable that the display act is one in which the consumer can directly recognize the use. Specifically, 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.

On the other hand, the displayed content (display 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.

For example, 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. . In particular, 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 worried 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.

In addition to the indication of the use, 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 be produced by a known method by blending a rophenol compound as an active ingredient. The food / beverage products of this invention can be manufactured by mixing the said compound with food-drinks raw material, and processing, for example.

Moreover, when the form of the food or drink of the present invention is a granular, tablet, capsule, jelly, or liquid supplement, the compound as an active ingredient is, for example, lactulose, maltitol, and lactitol And other sugars such as dextrin and starch; proteins such as gelatin, soy protein and corn protein; amino acids such as alanine, glutamine and isoleucine; polysaccharides such as cellulose and gum arabic; soybean oil, medium It is also preferable to formulate together with fats and oils such as chain fatty acid triglycerides.

The food and drink of the present invention can also be in the form of animal feed, and the form is not particularly limited. For example, 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. Animal feeds; yeasts such as torula yeast and beer yeast; mineral feeds such as tricalcium phosphate and calcium carbonate; fats and oils; simple amino acids; sugars and the like. Examples of the form of the feed include pet food, livestock feed, and fish feed.

(Food additive of the present invention)
In the form using the fibroblast activator of the present invention as a food additive (referred to as “the food additive of the present invention”), the food additive is added to food and drink, and the extracellular matrix component by fibroblasts is added. It can be used to prevent and / or ameliorate a disease or condition involving production. Examples of such 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. In addition, 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. Such an emulsifier is not particularly limited as long as it can be used for food. For example, it is preferable to use glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, lecithin and the like which are approved as food additives in Japan.
By containing 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.

There is no restriction | limiting in particular in the form of the food additive of this invention, The normal form of food additives, such as a powder, a granule, a tablet, a liquid, can be taken.
When 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. By setting it as such a dosage form, the dispersibility with respect to the water-soluble food-drinks of a rophenol compound further improves.

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.

In addition, 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”.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

[1] Preparation of test substance 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 β-sitosterol (all manufactured by Tama Seikagaku Co., Ltd.) were similarly prepared as positive controls as substances known to have a fibroblast activation effect.

[2] Culture of fibroblasts Human fibroblasts HDF-a (manufactured by Science Cell Research Laboratories: obtained from Cosmo Bio) was used at 37 ° C. using FM medium containing 10% FCS (manufactured by Sigma). Pre-cultured in a 5% CO ₂ incubator. After the culture, the cells were collected, prepared with a medium so that the number of cells was 1.5 × 10 ⁴ cells / mL, and seeded at 1 mL each in a 6-well plate (Becton Dickinson). After culturing for 24 hours, the medium was removed, and a medium containing a test substance or positive control dissolved in DMSO was added, followed by further culturing for 48 hours. Moreover, what added the culture medium containing DMSO of the same quantity as the culture medium containing a to-be-tested substance and culture | cultivated similarly was used as a negative control. After the culture, the culture supernatant was collected, and collagen and hyaluronic acid contained in the culture supernatant were measured.

[3] Measurement of collagen and hyaluronic acid As an index for activating fibroblasts, the ability to produce extracellular matrix components (collagen and hyaluronic acid) was evaluated.
The measurement of collagen was performed as follows using a Sarkor Collagen Assay Kit (manufactured by Biocolor: obtained from Funakoshi).
Add 1000μL of the dye reagent to 1000μL of the collected culture supernatant or 1000μL of the reference standard reagent (bovine skin collagen 12.5-50μg / mL), mix for 30 minutes, and then centrifuge at 1200rpm to remove the supernatant that did not bind to the dye did. Next, 750 μL of an alkali washing reagent was added and allowed to stand for 5 minutes, and then centrifuged at 12000 rpm to remove the supernatant. Next, an alkali reagent was added and mixed, and the absorbance at 555 nm was measured. The amount of collagen 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 12.5-50μg / mL (concentration of reference standard reagent)

The measurement of hyaluronic acid was performed as follows using a hyaluronic acid quantitative ELISA kit (manufactured by Biotech Trading Partners: obtained from Funakoshi).
100 μL of the collected culture supernatant or 100 μL 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 μL of horseradish peroxidase (HRP) -labeled HABP was added and reacted at room temperature for 30 minutes. After the reaction, each well of the microplate was washed again with a washing buffer, 100 μL of enzyme substrate was added, and then allowed to stand at room temperature for 30 minutes in the dark. Thereafter, 100 μL 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)

[4] Measurement results of collagen and hyaluronic acid Table 1 shows the measurement results of collagen, and Table 2 shows the measurement results of hyaluronic acid. A measurement result is the average value of a triple measurement.
For the significant difference test, Student's t-test was performed to calculate the p-value. It was judged that there was a significant difference at p <0.05.

[5] Discussion 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. In addition, when compared with a positive control to which 0.2 μg / mL of stigmasterol, campesterol and β-sitosterol, which are known to have a fibroblast activation effect, was compared, 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.

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.

Further, not only rophenol compounds but also plant sterols such as β-sitosterol, stigmasterol and campesterol are well known to exert medicinal effects on the skin by transdermal administration (Japanese Patent Laid-Open No. 2013-040113, Special JP 2007-284417 and JP 2001-163764), and the percutaneous administration of pharmaceuticals, quasi-drugs, external preparations for skin, and cosmetics containing these compounds also exhibit the same fibroblast activation effect as described above. Is obvious.

[Production Example 1]
<Cream>
A cream exhibiting the effects of collagen production and hyaluronic acid production was prepared according to the following formulation.
(Prescription)
Stearic acid 5.0% by mass
Stearyl alcohol 4.0% by mass
Isopropyl myristate 18.0% by mass
Glycerin monostearate 3.0% by mass
Propylene glycol 10.0% by mass
Rophenol compound mixture 0.0002 mass%
Caustic potash 0.2% by mass
Sodium bisulfite 0.01% by mass
Preservative Appropriate amount Perfume Appropriate amount Ion-exchanged water Residue (Process)
Propylene glycol, a rophenol compound mixture and caustic potash were added to ion-exchanged water and dissolved, and the mixture was heated and maintained at 70 ° C. to prepare an aqueous layer portion. Further, apart from the aqueous layer part, all the remaining components were mixed, melted by heating and kept at 70 ° C. to prepare an oil layer part. Next, the oil layer portion was gradually added to the aqueous layer portion, and after the addition was completed, the temperature was maintained for a while, and then the mixture was uniformly emulsified with a homomixer and cooled to 30 ° C. while mixing well to prepare a cream.

[Production Example 2]
<Emulsion>
An emulsion exhibiting the effects of collagen production and hyaluronic acid production was prepared according to the following formulation.
(Prescription)
Stearic acid 2.5% by mass
Cetyl alcohol 1.5% by mass
Vaseline 5.0% by mass
Liquid paraffin 10.0% by mass
Polyoxyethylene (10 mol) monooleate 2.0% by mass
Polyethylene glycol 1500 3.0% by mass
Triethanolamine 1.0% by mass
Carboxyvinyl polymer 0.05% by mass
Rophenol compound mixture 0.00002 mass%
Sodium bisulfite 0.01% by mass
Ethylparaben 0.3% by mass
Perfume Appropriate amount Ion exchange water Residue
Carboxyvinyl polymer was dissolved in a part of ion-exchanged water to make one solution. Further, separately from the first solution, 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.

[Production Example 3]
<Yogurt>
A yogurt exhibiting the effects of collagen production and hyaluronic acid production was produced by the following production method.
(Formulation example)
Nonfat dry milk 12.5% by mass
45% cream 6.5% by mass
Granulated sugar 10% by mass
Rophenol compound mixture 0.00002 mass%
Water residue (Manufacturing method)
The whole raw material was prepared so as to be 10 kg, and the solution was homogenized at 70 ° C. and then sterilized by being held at 90 ° C. for 10 minutes. After sterilization, the mixture was cooled to 40 ° C., and 1 g of a commercially available starter for yogurt was added and mixed uniformly. This was fermented to pH 4.8 at 37 ° C., and then quickly cooled to 10 ° C. to produce yogurt.

[Production Example 4]
<Health drink>
A health drink exhibiting the effects of collagen production and hyaluronic acid production was produced by the following production method.
(Formulation example)
Soy protein 0.1% by mass
Rophenol compound mixture 0.002% by mass
Vitamin C 0.001% by mass
Vitamin E 0.001% by mass
Fructose 0.3% by mass
Water residue (Manufacturing method)
All ingredients were mixed, heated to 50 ° C., homogenized with a homogenizer, and sterilized to produce a health drink.

[Production Example 5]
<Supplement>
The tablet-like supplement which exhibits the effect of collagen production and hyaluronic acid production was manufactured by the manufacturing method shown below.
Reduced maltose 35% by mass
Rophenol compound mixture 0.02% by mass
Vitamin C 1% by mass
Vitamin E 1% by mass
Cellulose 2% by mass
2% by mass of silicon dioxide
Calcium stearate 1% by mass
(Manufacturing method)
All raw materials are mixed uniformly, filled in the die of a tableting machine, and the mixed powder is continuously compression-molded (tablet) at a tableting speed of 800 tablets / minute and a pressure of 1 t / m ² . A tablet-like supplement was produced.

Since 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. For example, since 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. , Gloss and / or reduced elasticity, wrinkles, tarmi, cuts, tears, split wounds, abrasions, crush wounds, sores, burns, pressure ulcers, gingivitis, periodontitis, alveolar effusion, keratitis, dry eye, Can prevent, ameliorate or treat diseases or conditions such as hyperemia, corneal erosion, flying mosquito disease, arthritis, osteoarthritis, spondyloarthropathy, scleroderma, Raynaud, skin ulcer, etc. It can be widely used in the form of external preparations for skin, cosmetics, foods and drinks, food additives and the like.

Claims

Fibroblast activator containing rophenol compound.
The fibroblast activator according to claim 1 for promoting collagen production.
The fibroblast activator according to claim 1 for promoting hyaluronic acid production.
The rophenol compound is selected from 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 claims 1 to 3.
A food or drink containing the fibroblast activator according to any one of claims 1 to 4.
A food additive containing the fibroblast activator according to any one of claims 1 to 4.
An external preparation for skin containing the fibroblast activator according to any one of claims 1 to 4.
Cosmetics containing the fibroblast activator according to any one of claims 1 to 4.