Fibroblast growth factor-5 production inhibitor

Abstract

To provide a fibroblast growth factor-5 production inhibitor having excellent fibroblast growth factor-5 production inhibitory action and high safety.SOLUTION: The fibroblast growth factor-5 (FGF-5) production inhibitor includes at least one selected from the group consisting of pinobanksin, pinocembrin, quercetin, rutin, isoquercetin, genistein, 6-prenylnaringenin, isosakuranetin, and biochanin A.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for inhibiting the production of fibroblast growth factor (FGF)-5 (hereinafter, sometimes referred to as "FGF-5"). [Background technology]

[0002] Fibroblast growth factors are multifunctional secretory factors that not only have proliferation activity for fibroblasts, but also play important roles as morphogenetic factors that promote cell proliferation and differentiation in various cells, tissue repair factors that act upon tissue damage, and metabolic regulators that maintain homeostasis. There are known to be more than 20 types of FGF family, and of these, FGF-5 is known to be involved in the hair cycle.

[0003] Hair grows and falls out repeatedly according to a cyclical hair cycle consisting of an anagen phase, a catagen phase, and a telogen phase. If the anagen phase is short, the hair does not grow sufficiently and falls out while still thin and short. Furthermore, once the anagen phase is shortened, the next anagen phase will also be short, and the hair will become even thinner and shorter. Here, the above-mentioned FGF-5 is known to have the effect of acting on the hair papilla to cause a transition from the anagen phase to the catagen phase in the hair cycle (see, for example, Non-Patent Document 1).

[0004] Therefore, if the function of FGF-5 can be suppressed, the transition from the growth phase to the regression phase in the hair cycle can be inhibited, thereby extending the growth phase of hair and preventing or improving thinning hair and hair loss, making it useful for hair growth and care. Known ingredients that suppress the function of FGF-5 include, for example, burnet extract (see, for example, Non-Patent Document 2) and phytic acid (see, for example, Patent Document 1).

[0005] However, there remains a strong demand for new materials that are highly safe, naturally derived, and have the effect of inhibiting FGF-5 production, and that can therefore be widely used as ingredients in pharmaceuticals, quasi-drugs, topical compositions such as cosmetics, foods and beverages, and research reagents, and there is currently a need for their rapid development. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2017-043594 [Non-patent literature]

[0007] [Non-Patent Document 1] Cell,1994,vol.78,no.6,pp.1017-1025 [Non-patent document 2] West Japan Dermatology, 2007, Vol. 69, No. 1, pp. 81-86 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to solve the above-mentioned conventional problems and achieve the following object: That is, the present invention aims to provide an inhibitor of fibroblast growth factor-5 production that has excellent inhibitory effect on fibroblast growth factor-5 production and is highly safe. [Means for solving the problem]

[0009] As a result of extensive research, the present inventors have discovered that at least one substance selected from the group consisting of pinobanksin, pinocembrin, quercetin, rutin, isoquercetin, genistein, 6-prenylnaringenin, isosakuranetin, and biochanin A, which are highly safe natural product-derived materials, has an excellent inhibitory effect on fibroblast growth factor-5 production, and have completed the present invention.

[0010] The present invention is based on the above findings of the present inventors, and the means for solving the above problems are as follows: <1> A fibroblast growth factor-5 (FGF-5) production inhibitor characterized by containing at least one selected from the group consisting of pinobanksin, pinocembrin, quercetin, rutin, isoquercetin, genistein, 6-prenylnaringenin, isosakuranetin, and biochanin A. [Effects of the Invention]

[0011] According to the present invention, the above-mentioned problems of the prior art can be solved, the above-mentioned objective can be achieved, and a fibroblast growth factor-5 production inhibitor that has excellent fibroblast growth factor-5 production inhibitory activity and is highly safe can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0012] (Fibroblast growth factor-5 (FGF-5) production inhibitor) The fibroblast growth factor-5 (FGF-5) production inhibitor of this embodiment contains at least one active ingredient selected from the group consisting of pinobanksin, pinocembrin, quercetin, rutin, isoquercetin, genistein, 6-prenylnaringenin, isosakuranetin, and biochanin A, and further contains other ingredients as necessary.

[0013] As used herein, inhibiting the production of fibroblast growth factor-5 means reducing the production of FGF-5 compared to when the FGF-5 production inhibitor is not administered.

[0014] It was not previously known that pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin have excellent FGF-5 production inhibitory effects and are useful as FGF-5 production inhibitors, and this is a new discovery made by the present inventors.

[0015] <At least one selected from the group consisting of pinobanksin, pinocembrin, quercetin, rutin, isoquercetin, genistein, 6-prenylnaringenin, isosakuranetin, and biochanin A> -Pinobanksin- Pinobanksin (CAS Registry Number: 548-82-3) is a compound represented by the following structural formula (1). [ka]

[0016] -Pinocembrin- Pinocembrin (CAS Registry Number: 480-39-7) is a compound represented by the following structural formula (2). [ka]

[0017] -Genistein- Genistein (CAS Registry Number: 446-72-0) is a compound represented by the following structural formula (3). [ka]

[0018] -6-Prenylnaringenin- 6-prenylnaringenin (CAS registration number: 68236-13-5) is a compound represented by the following structural formula (4). [ka]

[0019] -Isosakuranetin- Isosakuranetin (CAS Registry Number: 480-43-3) is a compound represented by the following structural formula (5). [ka]

[0020] -Biochanin A- Biochanin A (CAS Registry Number: 491-80-5) is a compound represented by the following structural formula (6). [ka]

[0021] -Quercetin- Quercetin (CAS Registry Number: 117-39-5) is a compound represented by the following structural formula (7). [ka]

[0022] -Isoquercetin- Isoquercetin (CAS Registry Number: 482-35-9) is a compound represented by the following structural formula (8). [ka]

[0023] -Rutin- Rutin (CAS Registry Number: 153-18-4) is a compound represented by the following structural formula (9). [ka]

[0024] The pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin are known compounds, and commercially available products may be used, or products produced by known methods may be used.

[0025] The pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin are contained in plants, for example, and can also be prepared from plants by extraction methods generally used for plant extraction, etc.

[0026] The pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin may be used singly or in combination of two or more.

[0027] The total content of at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin in the FGF-5 production inhibitor is not particularly limited and can be appropriately selected depending on the purpose. Furthermore, when two or more of the pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin are used in combination, the ratio of the amount of each component to be blended is not particularly limited and can be selected appropriately depending on the purpose.

[0028] The FGF-5 production inhibitor may consist of only at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin, or may be a formulation of at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin.

[0029] At least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin can be formulated into any dosage form, such as powder, granules, tablets, or liquid, according to a conventional method using a pharmaceutically acceptable carrier such as dextrin, cyclodextrin, or any other auxiliary agent. In this case, examples of the auxiliary agent that can be used include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, and odor-correcting agents. The FGF-5 production inhibitor can be used by incorporating it into other compositions (e.g., topical preparations such as topical preparations for hair and skin, or food and beverages), and can also be used as oral preparations such as tablets, powders, capsules, granules, extracts, and syrups; parenteral preparations such as injections, drips, and suppositories; ointments, eye drops, topical liquids, and patches.

[0030] The total content of at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin in the formulated FGF-5 production inhibitor is not particularly limited and can be selected appropriately depending on the purpose.

[0031] <Other ingredients> The other components are not particularly limited as long as they do not impair the effects of the present invention and can be appropriately selected depending on the form of use of the FGF-5 production inhibitor, and examples include the components that can be used in the formulation described above. Furthermore, if necessary, a component having an FGF-5 production inhibitory effect other than at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin may be blended. The other components may be used alone or in combination of two or more.

[0032] The content of the other components in the FGF-5 production inhibitor is not particularly limited and can be appropriately selected depending on the purpose.

[0033] The uses of the FGF-5 production inhibitor are not particularly limited and can be selected appropriately depending on the purpose, and can be used in a wide range of applications, such as pharmaceuticals, quasi-drugs, cosmetics, food and beverages, and research reagents.

[0034] The method of use of the FGF-5 production inhibitor is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include oral, parenteral, and external use.

[0035] The dosage form of the FGF-5 production inhibitor is not particularly limited, and any known dosage form can be appropriately selected depending on the purpose. The method for producing the FGF-5 production inhibitor in any dosage form is not particularly limited, and any known method can be appropriately selected.

[0036] The administration method, dosage, administration site, administration period, and administration interval of the FGF-5 production inhibitor (hereinafter sometimes referred to as "usage method, dosage, administration site, administration period, and administration interval") are not particularly limited and can be selected appropriately depending on the purpose.

[0037] The FGF-5 production inhibitor can inhibit FGF-5 production through the FGF-5 production inhibitory activity of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercitrin, and rutin. This inhibits the function of FGF-5, inhibits the transition from the anagen phase to the catagen phase in the hair cycle, prolongs the anagen phase, and prevents and improves thinning hair and hair loss. However, the FGF-5 production inhibitor of this embodiment can also be used for all other uses where exerting an FGF-5 production inhibitory activity is meaningful.

[0038] The FGF-5 production inhibitor has an excellent FGF-5 production inhibitory effect and is highly safe, and therefore can be incorporated into external preparations such as external preparations for hair and skin, as well as foods and beverages. In this case, at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin may be incorporated as is, or a formulation of at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin may be incorporated.

[0039] The topical preparations are not limited to any particular category and include a wide range of cosmetics, quasi-drugs, pharmaceuticals, etc. that are used transdermally.

[0040] The topical preparations that can be blended with the FGF-5 production inhibitor are not particularly limited and can be selected appropriately depending on the purpose. Examples include topical hair and skin preparations such as hair tonic, hair lotion, hair cream, hair liquid, pomade, shampoo, rinse, and treatment, as well as ointments, creams, emulsions, lotions, skin lotions, beauty serums, gels, beauty oils, packs, jellies, lip balms, lipsticks, foundations, bath additives, soaps, body soaps, and astringents.

[0041] When the FGF-5 production inhibitor is incorporated into an external preparation, the amount to be incorporated is not particularly limited and can be adjusted appropriately depending on the type of external preparation, etc. However, the total amount of at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin is preferably 0.00001% by mass to 20% by mass, more preferably 0.00001% by mass to 10% by mass.

[0042] The topical preparation may contain, in addition to the main ingredient, auxiliary agent, or other ingredient typically used in the manufacture of topical preparations, such as astringents, bactericides / antibacterial agents, whitening agents, ultraviolet absorbers, moisturizers, cell activators, anti-inflammatory / antiallergic agents, antioxidants / active oxygen scavengers, oils and fats, waxes, hydrocarbons, fatty acids, alcohols, esters, surfactants, fragrances, etc., so long as the effects of the present invention are not impaired. Such combinations may result in more general-purpose products, and the synergistic effect with the other active ingredients used in combination may bring about effects superior to those normally expected.

[0043] The method for producing the topical agent is not particularly limited, and any known method can be appropriately selected.

[0044] The administration method, dosage, administration site, administration period, administration interval, etc. of the topical preparation are not particularly limited and can be appropriately selected depending on the purpose.

[0045] The topical preparation can be suitably used for inhibiting FGF-5 production, and for hair growth based on the FGF-5 production inhibitory effect.

[0046] Food and beverage products refer to products that are ingested orally or via gastrointestinal administration in normal social life and are unlikely to be harmful to human health. They are not limited to administrative classifications such as food, medicine, or quasi-drug. Therefore, in this embodiment, "food and beverage products" broadly includes orally ingested general foods, health foods (functional food and beverage products), health functional foods (foods for specified health uses, foods with nutrient functions), quasi-drugs, medicines, etc. Preferably, the food and beverage products are products that can display the favorable effects of the active ingredient according to this embodiment on the food and beverage product or its packaging, and are particularly preferably health functional foods (foods for specified health uses, foods with functional claims, foods with nutrient functions), quasi-drugs, and medicines.

[0047] When the FGF-5 production inhibitor is incorporated into a food or beverage, the amount to be incorporated is not particularly limited and can be adjusted appropriately depending on the type of food or beverage. However, the total amount of at least one selected from the group consisting of pinobanksin, pinocembrin, genistein, 6-prenylnaringenin, isosakuranetin, biochanin A, quercetin, isoquercetin, and rutin is preferably 0.00001% by mass to 20% by mass, and more preferably 0.00001% by mass to 10% by mass.

[0048] The method for producing the food or drink is not particularly limited, and any known method can be appropriately selected.

[0049] The method, amount, period, and interval of ingestion of the food and drink are not particularly limited and can be appropriately selected depending on the purpose.

[0050] The food and drink products can be suitably used for inhibiting FGF-5 production, and for hair growth based on the FGF-5 production inhibitory effect.

[0051] Although the FGF-5 production inhibitor of this embodiment is preferably applied to humans, it can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, etc.) as long as it has the effect of inhibiting FGF-5 production.

[0052] Furthermore, the FGF-5 production inhibitor according to this embodiment can also be suitably used as a reagent for research into the mechanism of FGF-5 production inhibitory action.

[0053] As described above, the FGF-5 production inhibitor of this embodiment has an excellent FGF-5 production inhibitory effect. Therefore, the present invention also relates to a method for inhibiting FGF-5 production, which comprises administering the FGF-5 production inhibitor to an individual. [Example]

[0054] Test examples and formulation examples of the present invention will be explained below, but the present invention is not limited to these test examples and formulation examples.

[0055] (Test Example 1: Fibroblast growth factor-5 (FGF-5) production inhibitory effect test) The following compounds were used as test samples and tested for their inhibitory effect on FGF-5 production by the following test method.

[0056] <Test sample> (1) Pinobanksin (Toronto Research Chemicals) (2) Pinocembrin (manufactured by Chemsheen) (3) Genistein (Fujifilm Wako Pure Chemical Industries, Ltd.) (4) 6-Prenylnaringenin (Cayman Chemical Company) (5) Isosakuranetin (Extra Synthese) (6) Biochanin A (Tokyo Chemical Industry Co., Ltd.) (7) Quercetin (Fujifilm Wako Pure Chemical Industries, Ltd.) (8) Isoquercetin (Fujifilm Wako Pure Chemical Industries, Ltd.) (9) Rutin (Fujifilm Wako Pure Chemical Industries, Ltd.)

[0057] <Test Method> It has been reported that prostaglandin (PG) D2 promotes the production of FGF-5 in hair follicle cells (JP 2023-184345 A). Therefore, the inhibitory effect of PGD2 stimulation on FGF-5 production was tested as follows. Normal human hair papilla cells were cultured in a dermal papilla cell growth medium and then harvested by trypsinization. The harvested cells were 1.67 x 10 4 After diluting with dermal papilla cell growth medium to a concentration of 5.01 x 10 cells / mL, 3 mL of the medium was seeded onto a collagen-coated 60 mm dish. 4 cells / plate) and cultured for 7 days. After culturing, PGD2 (Funakoshi) and the test sample were dissolved in the required concentrations in the dermal papilla cell growth medium (see Tables 1 and 2 below for the final concentrations of the test samples), and 30 μL was added to each Petri dish, followed by culturing for 72 hours at 37° C. in 5% CO2. As controls, dermal papilla cell growth medium without PGD2 or test sample, or dermal papilla cell growth medium with PGD2 but without test sample, was used and cultured in the same manner. After the culture was completed, the amount of FGF-5 in the culture supernatant of each dish was quantified using an FGF-5 ELISA Kit (RayBiotech). From the obtained results, the FGF-5 production inhibition rate was calculated using the following formula. The results are shown in Tables 1 and 2. In the formula below, the FGF-5 production inhibition rate when no test sample and no PGD2 were added was 100%, and the FGF-5 production inhibition rate when no test sample and PGD2 were added was 0%. FGF-5 production suppression rate (%)={1-(AC) / (BC)}×100 In the above formula, A to C respectively represent the following. A: Amount of FGF-5 produced when test sample and PGD2 were added B: Amount of FGF-5 produced without test sample and with PGD2 added C: Amount of FGF-5 produced without the addition of test sample or PGD2

[0058] [Table 1]

[0059] [Table 2]

[0060] The results in Tables 1 and 2 confirmed that the test sample had an excellent inhibitory effect on FGF-5 production.

[0061] (Combination example 1) A hair tonic having the following composition was prepared by a conventional method. Pinobanksin 0.4g Tocopherol acetate (appropriate amount) Cephalatin 0.002g Isopropylmethylphenol 0.1g Sodium hyaluronate 0.15g 15.0g glycerin Ethanol 15.0g · Appropriate amount of fragrance Chelating agent (sodium edetate) appropriate amount Preservative (hinokitiol) appropriate amount Solubilizer (polyoxyethylene cetyl ether) appropriate amount Purified water, balance (total amount 100g)

[0062] (Combination example 2) A shampoo having the following composition was prepared by a conventional method. Pinocembrin 1.0g Genistein 0.5g Plum fruit extract 0.2g Sodium coconut oil fatty acid methyl taurate 10.0g Coconut oil fatty acid amidopropyl betaine 10.0g Sodium polyoxyethylene alkyl ether sulfate 20.0g Coconut oil fatty acid diethanolamide 4.0g Propylene glycol 2.0g · Appropriate amount of fragrance Purified water, balance (total amount 100g)

[0063] (Combination example 3) A rinse having the following composition was prepared by a conventional method. 6-Prenylnaringenin 0.5g 1.5g stearyltrimethylammonium chloride Polyoxyethylene cetyl ether 1.0g Cetyl alcohol 2.0g Octyldodecanol 1.0g Cationic cellulose 0.5g Propylene glycol 5.0g Soapberry extract 0.2g Phellodendron bark extract 0.5g Rosemary extract 0.5g · Fragrance 3.0g Purified water, balance (total amount 100g)

[0064] (Combination example 4) A treatment having the following composition was prepared by a conventional method. Isosakuranetin 0.5% by mass Biochanin A 0.5% by mass 1,3-propylene glycol 0.5% by mass Pentaerythritol tetra-2-ethylhexanate 1.2% by mass 95% ethanol 60.0% by mass · Appropriate amount of fragrance · DME / LPG(95 / 5) appropriate amount Remaining purified water

[0065] (Combination example 5) A hair tonic having the following composition was prepared by a conventional method. Quercetin 0.1g Isoquercetin 0.1g Rutin 0.2g Tocopherol acetate (appropriate amount) Cephalatin 0.002g Isopropylmethylphenol 0.1g Sodium hyaluronate 0.15g 15.0g glycerin Ethanol 15.0g · Appropriate amount of fragrance Chelating agent (sodium edetate) appropriate amount Preservative (hinokitiol) appropriate amount Solubilizer (polyoxyethylene cetyl ether) appropriate amount Purified water, balance (total amount 100g)

Claims

[Claim 1] A fibroblast growth factor-5 (FGF-5) production inhibitor comprising at least one member selected from the group consisting of pinobanksin, pinocembrin, quercetin, rutin, isoquercetin, genistein, 6-prenylnaringenin, isosakuranetin, and biochanin A.