JP2019085345A - Hair growth factor production promoter and/or cell adhesion molecule production promoter - Google Patents

Abstract

To provide a hair growth factor production promoter and/or a cell adhesion molecule production promoter.SOLUTION: According to the present invention, provided is a hair growth factor production promoter and/or cell adhesion molecule production promoter containing an organic acid and/or a salt thereof. Furthermore, prepared and provided are a cell activator, an adhesive force enhancing agent, a hair regeneration agent and/or a hair loss inhibiting agent containing an organic acid and/or a salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a hair growth factor production promoter and / or a cell adhesion molecule production promoter.

  Hair is reborn in a certain cycle, which is called a hair cycle. The hair cycle is roughly divided into a growth phase (2 to 6 years), a regression phase (2 weeks), and a rest phase (3 to 4 months). Thin hair is in a state where the growing season is shortened to several months to 1 year, and in order to improve thin hair, it is necessary to restore the shortened growing season and restore the hair cycle to a normal state. The hair cycle is controlled by various factors secreted from the dermal papilla cells, outer hair root sheath cells and the like, and as such factors, hepatocyte growth factor (HGF), vascular endothelial cell growth factor (VEGF), fibroblasts Cell growth factors (FGF), GLI transcription factors, Wnt proteins and the like are known (Non-patent documents 1 and 2). In addition, in order to improve thin hair, it is also important to suppress hair loss, and it is known that desmoglein, which is a cell adhesion molecule, plays a role in fixing hair to hair follicles (Non-patent Document 3).

  Here, Patent Document 1 discloses that taurine is excellent in the hair growth promoting effect because it extends the hair growth period.

  Patent Document 2 discloses that the rice extract promotes the production of a hepatocyte growth factor and therefore is excellent in the hair growth promoting effect.

  Patent Document 3 discloses that a bamboo shoot extract is effective in promoting hair growth since it activates dermal papilla cells and promotes the production of vascular endothelial cell growth factor and fibroblast growth factor.

  Patent Document 4 discloses that peptides showing Wnt protein activity are useful for promoting hair growth and preventing hair loss.

  Patent Document 5 discloses that the intercellular adhesion inhibitor promotes hair loss because it reduces the amount of desmoglein in cells.

Japanese Patent Application Laid-Open No. 2002-097116 Unexamined-Japanese-Patent No. 2004-099503 JP, 2013-180999, A Japanese Patent Application Publication No. 2014-521685 JP 2001-261538 A

Karoline Krause and Kerstin Foitzik (2006) Biology of the Hair Follicle: The Basics. Seminars in Cutaneous Medicine and Surgery 25 (1): 2-10. Rishikaysh et. Al., (2014) Signaling Involved in Hair Follicle Morphogenesis and Development. Int. J. Mol. Sci. 15: 1647-1670. Yasushi Hanakawa et al. (2004) Desmogleins 1 and 3 in the Companion Layer Anchor Mouse Anagen Hair to the Follicle. Journal of Investigative Dermatology. 123 (5): 817-822.

  An object of the present invention is to provide a hair growth factor production promoter and / or a cell adhesion molecule production promoter.

  As a result of intensive studies to solve the above problems, the present inventors have found that an organic acid and / or a salt thereof enhances expression of a hair growth factor and enhances its production, and completes the present invention. did.

  The present inventors have also found that organic acids and / or salts thereof enhance gene expression of cell adhesion molecules and promote their production, and further enhance mitochondrial activity of hair papilla cells, and the present invention completed.

  That is, the present invention provides a hair growth factor production promoter containing the following organic acid and / or a salt thereof, a cell adhesion molecule production promoter, a hair papilla cell activator, an adhesion enhancer between hair and hair follicle, A hair regenerating agent and / or a hair loss inhibitor is provided.

Item 1.
A hair growth factor production promoter containing an organic acid and / or a salt thereof.
Item 2.
The hair growth factor is one or more selected from hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), GLI transcription factor, and Wnt protein, Item 2. The hair growth factor production promoter according to Item 1.
Item 3.
Item 3. The hair growth factor production promoter according to Item 1 or 2, wherein the organic acid is a hydroxy acid.
Item 4.
A cell adhesion molecule production promoter containing an organic acid and / or a salt thereof.
Item 5.
Item 5. The cell adhesion molecule production promoter according to Item 4, wherein the cell adhesion molecule is desmoglein.
Item 6.
The cell adhesion molecule production promoter according to claim 4 or 5, wherein the organic acid is a hydroxy acid.
Item 7.
A dermal papilla cell activator containing an organic acid and / or a salt thereof.
Item 8.
Item 8. The dermal papilla cell activator according to Item 7, wherein the organic acid is a hydroxy acid.
Item 9.
Adhesive force enhancer with hair and hair follicle containing organic acid and / or its salt.
Item 10.
10. The adhesion enhancer according to item 9, wherein the organic acid is a hydroxy acid.
Item 11.
Hair regenerating agent and / or hair loss inhibitor comprising an organic acid and / or a salt thereof as an active ingredient.
Item 12.
Item 12. The hair regenerating agent and / or hair loss inhibitor according to item 11, wherein the organic acid is a hydroxy acid.

The present invention also relates to the following method.
Item 13.
A method of imparting a hair growth factor production promoting effect by containing an organic acid and / or a salt thereof in an external use composition.
Item 14.
A method of imparting a cell adhesion molecule production promoting effect by containing an organic acid and / or a salt thereof in an external use composition.
Item 15.
A method for providing a dermal papilla cell activating effect by containing an organic acid and / or a salt thereof in an external composition.
Item 16.
A method of imparting an adhesion enhancing effect between hair and hair follicle by containing an organic acid and / or a salt thereof to an external composition.
Item 17.
A method for imparting a hair regrowth and / or hair loss suppression effect by containing an organic acid and / or a salt thereof in an external composition.

  In the above method, the hair growth factor is one or two selected from hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), GLI transcription factor, and Wnt protein. It may be a species or more.

  In the above method, the organic acid may be a hydroxy acid.

  According to the present invention, the hair growth factor production promotion and / or cell adhesion molecule production promotion action of the organic acid and / or the salt thereof can induce a good state of hair.

FIG. 1 is a graph showing the results of culturing human hair hair papilla cells in the presence or absence of L-tartaric acid at different concentrations and measuring the amount of each gene encoding multiple hair growth factors. is there. FIG. 2 is a graph showing the results of culturing human hair hair papilla cells in the presence or absence of L-tartaric acid at different concentrations and measuring the amount of production of FGF-7, which is a fibroblast growth factor. . FIG. 3 is a graph showing the results of culturing human outer root sheath cells in the presence or absence of L-tartaric acid at different concentrations, and measuring the expression levels of the respective genes encoding multiple hair growth factors. is there. FIG. 4 is a graph showing the results of culture of human outer root sheath cells in the presence or absence of L-tartaric acid at different concentrations and measurement of the amount of production of vascular endothelial growth factor GLI. FIG. 5 is a graph showing the results of culture of human outer root sheath cells in the presence or absence of L-tartaric acid at different concentrations and measurement of GLI transcription factor production. FIG. 6 is a photograph showing cells stained for GLI transcription factor and cell nucleus after culturing human outer root sheath cells in the presence of L-tartaric acid. FIG. 7 is a photograph showing cells stained for GLI transcription factor and cell nucleus after culturing human outer root sheath cells in the absence of L-tartaric acid. FIG. 8 is a graph showing the results of culturing human hair hair papilla cells in the presence or absence of L-tartaric acid at different concentrations and measuring the mitochondrial activity of the cells. FIG. 9 is a graph showing the results of measuring the expression level of the gene encoding desmogren 3 (DSG-3) by culturing human normal epidermal keratinocytes in the presence or absence of L-tartaric acid at different concentrations. It is. FIG. 10 is a graph showing the results of culturing human normal epidermal keratinocytes in the presence or absence of L-tartaric acid at different concentrations and measuring the amount of desmoglen 3 (DSG-3) produced. FIG. 11 is a photograph showing cells stained with desmogren 3 and cell nuclei after culturing human normal epidermal keratinocytes in the presence of L-tartaric acid. FIG. 12 is a photograph showing cells stained with desmogren 3 and cell nuclei after culturing human normal epidermal keratinocytes in the absence of L-tartaric acid.

  The present invention relates to a hair growth factor production promoter, a cell adhesion molecule production promoter, a hair papilla cell activator, or an adhesion enhancer containing an organic acid and / or a salt thereof. The present invention also relates to a hair regenerating agent and / or a hair loss inhibitor containing an organic acid and / or a salt thereof as an active ingredient.

  As used herein, the term "hair growth" includes an action that promotes the development of new hair in the hair follicle, or advantageously works to promote hair growth and growth. The term "hair" as used herein refers to any hair that grows in the body of animals including humans, for example, all hair types such as hair (hair), eyebrows, eyebrows, mustaches, beards, chest hair, and back hair. Mainly means hair, eyebrows or eyebrows.

  As used herein, the term "hair regeneration" means regenerating hair that has been lost once by waking up the hair growth factor gene that sleeps in hair follicles and regenerating disturbed hair cycles. "Hair regeneration" means regenerating hair that has been lost once by waking up the hair growth factor gene that sleeps in hair follicles and regenerating disturbed hair cycles. In the context of the present invention, hair regeneration especially includes hair regeneration.

[Organic acid and / or its salt]
The organic acid and / or salt thereof used in the present invention may be any organic acid and / or salt thereof known to those skilled in the art. Without limitation, specifically, the organic acid may be a linear or branched saturated or unsaturated fatty acid. Alternatively, an alicyclic carboxylic acid is mentioned as an example.

  Among them, as the organic acid used in the present invention, a hydroxy acid having both a hydroxyl group and a carboxylic acid is preferable, and among them, an aliphatic hydroxy acid is more preferable. Specific examples of aliphatic hydroxy acids include tartaric acid, citric acid, lactic acid, gluconic acid, glycolic acid, talthronic acid, glyceric acid, hydroxybutyric acid, malic acid, citramaric acid, isocitric acid, leucine acid, mevalonic acid, pantoin 1 type, or 2 or more types selected from the group which consists of an acid, ricinoleic acid, a ricineridiic acid, a cerebronic acid, quinic acid, and a shikimic acid are mentioned. Among these, preferred are tartaric acid, citric acid, lactic acid and gluconic acid, and particularly preferred is tartaric acid. These may be D-form or L-form, but are preferably L-form. These salts include alkali metal salts such as sodium, potassium and lithium, alkaline earth metal salts such as calcium and magnesium, trimethylamine salts, triethylamine salts, tributylamine salts, monoethanolamine salts, diethanolamine salts, triethanolamine salts And organic ammonium salts such as lysine salt, arginine salt and choline salt.

  Here, "containing as an active ingredient" refers to an organic acid and / or a salt thereof alone or with other active ingredients regardless of including an active ingredient other than the organic acid and / or the salt thereof. It is meant that it is clearly shown that hair regeneration, hair loss suppression, hair growth factor production promotion, cell adhesion molecule production promotion, hair growth related cell activation, and cell adhesion enhancement are exerted by the combined action. Hair regrowth and hair loss suppression effects are induced by actions such as promoting hair growth factor production, cell adhesion molecule production promotion, activation of cells related to hair growth such as hair papilla cells, and enhancement of cell adhesion. The active ingredient is not directly related to whether or not it is displayed as an active ingredient on the display of the actual product.

[Hair growth factor]
The hair growth factor is not particularly limited, but preferably is one or two selected from the group consisting of hepatocyte growth factor, vascular endothelial cell growth factor, fibroblast growth factor, GLI transcription factor, and Wnt protein. It is above. Among these, although not limited thereto, particularly preferably, hepatocyte growth factor, vascular endothelial cell growth factor, VEGF-A, VEGF-B, fibroblast growth factor, FGF-2, FGF-7, FGF -10, one or more selected from the group consisting of GLI transcription factors, GLI-1, GLI-2, Wnt proteins, Wnt-1, Wnt-5a, and Wnt-10a.

  Hepatocyte growth factor (HGF) is one of the liver regeneration factors that promote the growth of hepatocytes and support the regeneration capacity of the liver. Hepatocyte growth factor is also known to act in the hair root to bring the resting hair follicles into the growth phase and to further stimulate the development of the growth phase. In the present specification, hepatocyte growth factor and HGF are used interchangeably as terms that can be used interchangeably.

  Vascular endothelial growth factor (VEGF) is a group of glycoproteins involved in angiogenesis and angiogenesis and several types are known. Vascular endothelial growth factor A (VEGF-A) and various other vascular endothelial growth factors have the effect of increasing new blood vessels under the scalp, and increasing the branching of existing blood vessels, thereby providing more nutrition. By giving to cells, it has an effect on promoting hair regeneration and hair growth. More specifically, vascular endothelial cell growth factor is excellent in the effect of extending the growth phase of the hair cycle. Herein, vascular endothelial growth factor and VEGF are used interchangeably as interchangeable terms.

  Fibroblast growth factor (FGF) is a type of growth factor related to angiogenesis, wound healing and embryonic development, and many types are known. Among them, in particular, fibroblast growth factor 7 (FGF-7) and fibroblast growth factor 10 (FGF-10) are also known as keratinocyte growth factors KGF and KGF-2, respectively, and proliferation of epithelial cells, Stimulate migration and differentiation to promote repair and regeneration of skin and mucosal tissues. Fibroblast growth factor is also known to act in hair roots to guide the resting hair follicles to the growth phase and to further stimulate the development of the growth phase. In the present specification, fibroblast growth factor and FGF are used interchangeably as interchangeable terms.

  The GLI transcription factor is a transcription factor involved in the hedgehog (Hh) signal transduction system, which plays a central role in somatic formation in mammalian fetal development. Although at least three GLI transcription factors are known (GLI-1, GLI-2, GLI-3), GLI-1 and GLI-2 are known to promote the activity of Hh signal. GLI-1 is involved in hair follicle formation.

  Wnt proteins are secreted glycoproteins in which multiple (19) genes have been identified in humans. In addition to changing skin cells in the fetal stage into hair follicles, stimulate hair follicle cells to induce hair growth. Among these, Wnt-5a is known to be involved in hair follicle formation.

  In the present invention, the hair growth factor production promoter containing an organic acid and / or a salt thereof increases the expression level of the hair growth factor protein itself or the expression level of the gene encoding the hair growth factor protein. Encourage one or both of

[Cell adhesion molecule]
As a cell adhesion molecule, although not limited, desmoglein (DSG) is known, and these molecules play a role of fixing growing hair to hair follicles and have an effect on hair loss suppression. In the present specification, desmogren and DSG are used interchangeably as terms that can be used interchangeably.

  In the present invention, the cell adhesion molecule promoter containing an organic acid and / or a salt thereof is either an increase in the expression level of cell adhesion molecules or an increase in the expression level of a gene encoding a protein of cell adhesion molecules. Encourage one or both.

[Hair-growth related cell activation]
The hair growth process involves cells such as hair papilla cells, outer hair root sheath cells, inner hair root sheath cells, hair matrix cells, adipocytes, hair follicle stem cells, pigment stem cells, melanocytes and the like. Among these, dermal papilla cells play a role in controlling signal transduction substances that carry out the process of hair growth, and activation of dermal papilla cells leads to normalization of the hair cycle. Hairy papillary cell activation can typically be measured by mitochondrial activity.

[Hair regenerating agent and / or hair loss inhibitor]
In the present invention, there are provided a hair regenerating agent and / or a hair loss inhibitor containing an organic acid and / or a salt thereof as an active ingredient. In the present invention, in particular, a hair regenerating agent is provided as a hair regenerating agent containing an organic acid and / or a salt thereof as an active ingredient. That is, according to the present invention, the organic acid and / or the salt thereof enhances the expression of the gene encoding the hair growth factor and promotes their production, thereby transitioning from the telogen to the anagen of the hair matrix. Can promote the growth period to be maintained for an appropriate period of time, and can regenerate the hair cycle to a normal state, so that hair can be regenerated or the progress of hair loss can be prevented. Can. Further, according to the present invention, the organic acid and / or the salt thereof enhances the expression of cell adhesion molecules and promotes the production thereof, whereby the adhesion between hair and hair follicle can be enhanced, thereby suppressing hair loss. can do. Furthermore, since the organic acid and / or the salt thereof induces activation of cells related to hair growth such as dermal papilla cells, hair regeneration and hair loss suppression can be effectively promoted.

[Composition for external use]
The composition for external use of the present invention is preferably prepared as a product for hair regeneration, a product for hair regeneration, a product for hair growth, a product for hair growth, a product for hair loss suppression or the like. Among them, as the application of the composition for external use of the present invention, scalp hair cosmetics (for example, shampoo, hair conditioner, hair treatment, hair essence, hair mist, scalp lotion, scalp cream, hair tonic), particularly preferably Cosmetics (eg, lotions, creams, face creams, face lotions, emulsions, packs, liquid face wash, soap, eyelash cosmetic liquids), makeup cosmetics (eg, eyeliner, eyebrows) are exemplified, and most preferably, It may be, but is not limited to, shampoo, hair conditioner, hair treatment, hair essence, scalp lotion, scalp cream, hair tonic, eyelash cosmetic solution, eyeliner, eyebrow.

  Thus, the dosage form of the composition for external use of the present invention is not particularly limited, and examples include solutions, suspensions, emulsions, creams, gels, liniments, lotions, and aerosols. Moreover, when it contains water to such an extent that the organic acid and / or its salt can be dissolved, it can also be an ointment. Among them, solutions, suspensions, emulsions, lotions and aerosols are preferable, and solutions, lotions and aerosols are more preferable. The dosage form of the composition for external use according to the present invention may be of W / O type when it comprises an oily base and an aqueous base such as a cream, an emulsion, and optionally an ointment, an aerosol etc. Although it may be of the W / W type, the O / W type is preferable in that it has a good feeling in use. The preparation can be produced by mixing the respective components according to or in accordance with the 17th revised Japanese Pharmacopoeia General Rules.

  The concentration of the organic acid and / or the salt thereof in the composition for external use is not particularly limited depending on the product, but from the viewpoint of the effect, 0.0001% by mass or more is preferable as the organic acid, and 0.001% % Or more is more preferable, 0.005% by mass or more is more preferable, 5% by mass or less is preferable, 1% by mass or less is more preferable, and 0.5% by mass or less is more preferable. As a specific range, 0.0001-5 mass% is preferable, 0.001-1 mass% is more preferable, 0.005-0.5 mass% is more preferable.

Base / Carrier In the present invention, the composition for external use includes, in addition to the organic acid and / or the salt thereof, a pharmaceutical external drug, quasi-drug, pharmaceutical or physiological for cosmetics, to the extent that the effect of the present invention is not impaired. May contain an acceptable base or carrier.

Such bases or carriers include water, ethanol, liquid paraffin, squalane, petrolatum, gelled hydrocarbon (such as plastibase), ozokerite, a-olefin oligomers, and hydrocarbons such as light liquid paraffin; methylpolysiloxane Highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone / alkyl chain co-modified polyether modified silicone, silicone / alkyl chain co-modified polyglycerin modified silicone, Silicone oils such as polyether modified branched silicone, polyglycerin modified branched silicone, acrylic silicone, phenyl modified silicone, and silicone resin; coconut oil, olive oil, rice kernel Oils and oils such as shea butter; Waxes such as jojoba oil, mirows, candelilla wax, and lanolin; Setanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyl dodecanol, isostearyl alcohol, phytosterol, and cholesterol Higher alcohols such as: cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; polyvinyl pyrrolidone; carrageenan; polyvinyl butylate; polyethylene glycol; dioxane; butylene glycol adipate polyester; isopropyl myristate, octyldodecyl myristate, Isopropyl palmitate, cetyl palmitate, isononyl isononanoate, and tetet Esters such as 2-ethylhexanoic acid pentaerythritol; polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymers and alkyl-modified carboxyvinyl polymers; methanol, propanol, isopropyl alcohol, Lower (C1-C4) alcohols such as butanol, isobutyl alcohol, sec-butyl alcohol, test-butyl alcohol and the like; and ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, Diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, pro Glycol ethers such as pyrene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether; glycerin, diglycerin, polyglycerin, polyethylene glycol, propylene glycol, dipropylene glycol, Polypropylene glycol, sorbitol, mannitol, trehalose, erythritol, polyols such as xylitol and the like can be mentioned.
The base or carrier can be used alone or in combination of two or more.

Additives In the present invention, the composition for external use can include pharmaceutically or physiologically acceptable additives for external use for pharmaceuticals, quasi-drugs and cosmetics. Examples of such additives include antioxidants, surfactants, thickeners, preservatives, pH adjusters, stabilizers, irritation reducing agents, preservatives, coloring agents, flavors, and solubilizing agents. . As surfactant, an anionic surfactant, a cationic surfactant, an amphoteric surfactant, a nonionic surfactant etc. are mentioned, for example.

  Examples of the anionic surfactant include carboxylic acid type anionic surfactant, sulfonic acid type anionic surfactant, phosphoric acid type anionic surfactant, protein hydrolyzate type anionic surfactant and the like. Examples of carboxylic acid anionic surfactants include fatty acid salts, ether carboxylates, amide ether carboxylates and the like. Examples of fatty acid salts include salts of fatty acids such as C8 to C22, and specific examples include caprylic acid, pelargonic acid, capric acid, capric acid, lauric acid, myristic acid, pentadecyl acid, palmitic acid, palmitoleic acid, margaric acid, stearin. Salts of acids, oleic acid, bacenic acid, linoleic acid, arachidic acid, behenic acid and the like are mentioned. Examples of the ether carboxylate include salts of polyoxyethylene alkyl ether carboxylate, polyoxyethylene cocoyl ether carboxylate, polyoxyethylene lauryl ether carboxylate, polyoxyethylene myristyl ether carboxylate and the like. As a sulfonic acid type anionic surfactant, for example, alkyl sulfate (C8 to C22 alkyl sulfate such as lauryl sulfate), alkyl sulfonate (C8 to C22 alkyl sulfonate such as lauryl sulfonate), alkyl Oxyalkyl sulfonate (alkyloxy C8 to C22 alkyl sulfonate), alkyl aryl sulfate (C8 to C22 alkyl aryl sulfate such as lauryl phenyl sulfate), alkyl benzene sulfonate (C8 such as lauryl benzene sulfonate) C22 alkyl benzene sulfonate), alkyl polyoxyethylene sulfate, glyceryl sulfate, acyl alkyl taurine (C8 to C 22 alkanoyl alkyl taurine such as cocoyl methyl taurine), acyl alkyl taurine taurine (cocoy Mixtures of C8-C22 alkanoyl alkyl taurines such as methyl methyl taurine and taurine salts), acyl isethionate (C8-C22 alkanoyl cethionates such as lauroyl isethionate), polyoxyethylene alkyl ether sulfate Ethylene alkyl ether sulfate triethanolamine etc), polyoxyalkylene fatty acid amide ether sulfate, sulfosuccinate (C8 to C22 alkyl sulfosuccinate, polyoxyethylene C8 to C22 alkyl sulfosuccinate, polyoxyethylene polyoxypropylene sulfosuccinate And the like. As a phosphoric acid type anionic surfactant, a monoalkyl phosphate, a polyoxyethylene alkyl ether phosphate, a polyoxyethylene polyoxypropylene alkyl ether phosphate etc. are mentioned, for example. Examples of amino acid based anionic surfactants include acyl glutamate (C8 to C22 alkanoyl glutamate such as cocoyl glutamate), acyl glycine salt (C8 to C22 alkanoyl glycine such as cocoyl glycine salt), acyl alanine salt (cocoyl C8 to C22 alkanoyl alanine salt such as alanine salt), acyl alkyl alanine salt (C8 to C22 alkanoyl alkyl alanine salt such as lauroyl methyl alanine salt), acyl aspartate (C8 to C22 alkanoyl aspartate such as lauroyl aspartate) And monoalkyl phosphates (C8 to C22 alkyl phosphates and the like), acyl sarcosine salts (C8 to C22 alkanoyl sarcosine salts such as cocoyl sarcosine salts) and the like. Examples of protein hydrolyzate type anionic surfactants include alkyl hydrolyzed collagen salts, coconut oil fatty acid hydrolyzed collagen salts, alkyl hydrolyzed silk salts and the like.

  Examples of cationic surfactants include alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, alkyl benzyl dimethyl ammonium salts and the like. Examples of these salts include hydrochlorides, sulfates and the like.

  Examples of amphoteric surfactants include carbobetaine, sulfobetaine, imidazolinium betaine, amidobetaine and the like. Specifically, fatty acid amidopropyl betaine, hydroxypropyl sulfobetaine, secondary imidazolinium betaine desalted, and the like can be mentioned.

As the nonionic surfactant, for example, amine oxide, glycerin fatty acid ester, sorbitan fatty acid ester, alkyl polyglucoside, sucrose fatty acid ester, alkyl sugar amide, polyglycerin fatty acid ester, polyoxyalkylene alkyl ether, fatty acid alkanolamide, poly Examples include oxyalkylene hydrogenated castor oil, alkyl monoglyceryl ether and the like. Specifically, lauryldimethylamine oxide, lauric acid diethanolamide, myristyl dimethylamine oxide, myristate monoethanolamide, myristate dinoethanolamide, monoglyceride mono-glyceride of isostearic acid, monoethanolamide laurate, monoglyceride oleate, sorbitan monolaurate And sorbitan monooleate, sorbitan sesquioleate, sorbitan monoisostearate, sorbitan trioleate, alkyl polyglucoside, coconut oil fatty acid monoethanolamide, coconut oil fatty acid diethanolamide and the like.
The additives may be used alone or in combination of two or more.

Pharmacologically Active Component / Physiological Active Component In the present invention, the composition for external use can contain a pharmaceutical active, a quasi-drug, a pharmacologically active component or a physiologically active component for cosmetics other than the organic acid and / or a salt thereof. . Such components include circulation promoting components, angiogenesis promoting factors, moisturizing components, anti-inflammatory components, antibacterial components, vitamins, peptides or derivatives thereof, amino acids or derivatives thereof, cell activation components, anti-aging components, keratin softening Or a keratolytic component, a whitening component, an astringent component, a vasodilator component, an antihistamine component, an antioxidant component, a metabolic activator, a refreshing agent, etc. are mentioned. In addition, for example, hair growth components other than organic acids such as spyranolactone, semen extract, capsaicinoid, keratinocyte growth factor (KGF, etc.), ginseng extract, minoxidil and the like and / or salts thereof can also be included.
The pharmacologically active ingredient or the physiologically active ingredient can be used singly or in combination of two or more.

pH
In the present invention, the pH of the composition for external use is not particularly limited. Preferably, about 4.0 to 8.0, about 4.0 to 7.5, about 4.0 to 7.0, about 5.0 to 8.0, about 5.0 to 7.5, about 5 0 to 7.0, about 6.0 to 8.0, about 6.0 to 7.5, about 6.0 to 7.0.

If it is the said range, irritation to the scalp by high pH is avoidable. In addition, the organic acid and / or the salt thereof is easily dissolved.
The adjustment of pH may be performed using a pH adjuster such as inorganic acid such as phosphoric acid, hydrochloric acid and sulfuric acid. In addition, if necessary, a pH adjuster such as an organic base such as triethanolamine, diisopropanolamine or triisopropanolamine; an inorganic base such as potassium hydroxide or sodium hydroxide may be used.
The pH adjusters can be used alone or in combination of two or more.

[container]
In the present invention, the container filled with the composition for external use is not particularly limited. It may be used as a container for external medicine, quasi drug, and cosmetics.
As such a container material, for example, part or all, preferably all, of the contact surface with the composition for external use is polyolefin, acrylic resin, terephthalic acid ester, 2,6-naphthalene dicarboxylic acid ester, polycarbonate, polymethyl Composed of at least one material selected from the group consisting of terpene, fluorocarbon resin, polyvinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, aluminum, and glass Containers are included.

[how to use]
In the present invention, the method of using the composition for external use varies depending on the condition of the hair to be used, the condition of the scalp, age, sex and the like, and may be, for example, the following method.
That is, a suitable amount (eg, about 0.5 to 2 g, or 0.5 to 2 ml) is applied to the skin (eg, scalp) several times a day (eg, about 1 to 5 times, preferably 1 to 3 times). Just do it. In addition, the composition may be applied to the skin (for example, scalp) such that the daily usage amount of the organic acid and / or the salt thereof is, for example, about 0.1 to 50 mg. The application method may be application, spraying or the like according to the dosage form. The application period may be, for example, about 7 days or more. Also, it may be applied until the effect of the present invention is sufficiently obtained, for example, within 6 months, at least 4 months.
The topical composition of the present invention can be used for hair regrowth and / or hair loss control.

[Methods for promoting hair growth factor production, etc.]
The present invention also provides a method for imparting a hair growth factor production promoting action by containing an organic acid and / or a salt thereof to an external composition, a method for imparting cell adhesion molecule production promoting action, and hair papilla cell activating action The present invention relates to a method of imparting an adhesion-promoting effect between hair and hair follicles, and a method of imparting a hair-regeneration and / or hair loss-suppressing effect.

  In these methods, the organic acid and / or the salt thereof, the hair growth factor and the like are the same as the contents described in the composition for external use.

  Next, the present invention will be specifically described by way of examples, but the present invention is not limited to the following examples.

The following tests were conducted to examine the effect of L-tartaric acid on the production of a hair growth promoting factor. In the following tests, cell culture was performed in a CO ₂ (5%) incubator. In addition, it is confirmed that there is no change in the pH of the culture medium by the addition of the test sample (L-tartaric acid) to the culture medium.

  The gene expression amount represented as a result of the test example is a correction value, and in Test Examples 1 and 2, YWHAZ is used as a housekeeping gene, and in Test Example 3, ACTB is used as a housekeeping gene. It was.

<Test 1: Effect of L-tartaric acid on hair growth factor production>
<Test 1-1: Production of a hair growth factor in dermal papilla cells>
(1) Measurement of gene expression level of hair growth factor Total RNA was extracted from dermal papilla cells according to the following procedure, and gene expression levels of FGF-7, HGF, Wnt-5a and GLI-1 were analyzed.

Hair papilla cell growth medium (PCGM, Code No. TMTPGM-250, Toyobo Co., Ltd.) so that human hair hair papilla cells (HFDPC) (made by Toyobo Co., Ltd.) become 3.5 × 10 ⁵ cells / well The cells were seeded in the 12-well plate (CellBIND Surface) used and cultured overnight at 37 ° C. After confirming by microscopic observation that there is no problem in cell growth, L-tartaric acid was added to the medium to a final concentration of 0.01 mM or 0.1 mM, and incubated at 37 ° C. for 6 hours. After removing the medium and washing the cells with PBS (−), the cells were lysed in 0.35 ml of RLT (manufactured by Qiagen, Inc.). The cell lysate was collected in a 1.5 ml tube and 0.35 mL of 70% ethanol was added. The whole solution was applied to a spin column attached to RNeasy Mini Kit (manufactured by Qiagen, Inc.), and total RNA was purified according to a protocol recommended by the manufacturer. Using 50 ng of total RNA as a template, cDNA was synthesized using ReverTra Ace (registered trademark) qPCR RT Master Mix (manufactured by Toyobo Co., Ltd.). Using 2 μl of this reaction solution (synthesized cDNA) as a template, mRNA expression by real-time PCR using Premix EX Taq II (manufactured by Takara Bio Inc.) and QuantStudio 7 Flex Real-Time PCR System (manufactured by Life Technologies Inc.) The amount was determined. In addition, what did not add L-tartaric acid was used as a control.

(2) Measurement of Hair Growth Factor Production Amount FGF-7 produced by dermal papilla cells was measured according to the following procedure.

Human hair hair papilla cells (HFDPC) (manufactured by Toyobo Co., Ltd.) were seeded at 1 × 10 ⁴ cells / well in a 96-well plate (CellBIND Surface) and cultured overnight at 37 ° C. After confirming by microscopic observation that there is no problem in cell growth, L-tartaric acid was added to the culture medium to a final concentration of 0.01 mM or 0.1 mM, and cultured at 37 ° C. for 2 days. The culture supernatant was collected in a 1.5 ml tube, and the FGF-7 concentration in each sample was measured using a Human FGF-7 ELISA kit (manufactured by RayBiotech; ELH-FGF-7). In addition, what did not add L-tartaric acid was used as a control.

  The measurement results of the expression level of the gene encoding FGF-7, HGF, Wnt-5a, and GLI-1, and the production amount of FGF-7 are shown in FIGS. 1 and 2, respectively.

  As shown in FIG. 1, L-tartaric acid promotes gene expression of FGF-7, HGF, Wnt-5a, and GLI-1 in dermal papilla cells at 0.01 to 0.1 mM, and the concentration is high. It became clear that the expression level of the gene increased as the higher. Moreover, as shown in FIG. 2, it became clear that L-tartaric acid promotes the production of FGF-7 in dermal papilla cells at 0.01 to 0.1 mM.

  These results suggest that L-tartaric acid promotes hair cycle regeneration by promoting the production of a hair growth factor in dermal papilla cells and promotes hair regeneration.

<Test 1-2: Gene expression of hair growth factor in outer hair root sheath cells>
(1) Measurement of gene expression level of hair growth factor According to the following procedure, total RNA is extracted from outer hair root sheath cells, and gene expression levels of VEGF-A, FGF-7, HGF and Wnt-5a are analyzed The

  Instead of human hair hair papilla cells (HFDPC), using human hair follicle outer hair root sheath cells (HFORSC) (ScienCell), change to a special growth medium (PCGM) for hair papilla cells, use only outer hair root tree cells As described in Test 1-1 except using growth medium (MSCM, Cat No. 7501, ScienCell Research Laboratories) and changing the concentration of L-tartaric acid added to the medium to 0.01 mM, 0.1 mM or 1 mM The test was performed according to the method.

(2) Measurement of Hair Growth Factor Production Amount VEGF-A and GLI-1 produced by outer hair root sheath cells were measured according to the following procedure.

Human outer root sheath cells were seeded at 1 × 10 ⁴ cells / well in a 96-well plate (CellBIND Surface) and cultured at 37 ° C. for 2 days. After confirming by microscopic observation that there is no problem in cell growth, L-tartaric acid was added to the culture medium to a final concentration of 0.01 mM, 0.1 mM or 1 mM, and cultured at 37 ° C. for 2 days.

  For VEGF-A, the culture supernatant was collected in a 1.5 ml tube, and the VEGF concentration was measured using a Human VEGF-A ELISA kit (manufactured by RayBiotech; ELH-VEGF). In addition, what did not add L-tartaric acid was used as a control.

  In addition, GLI-1 is stained by immunostaining using an anti-GLI-1 antibody (manufactured by Abcam), and the cell nucleus is stained using Hoechest 33342 (manufactured by Dojin Chemical Research Laboratory), and then ImageXpress (Molecular Devices, Inc.) The area of staining, the intensity and the number of nuclei were measured to make the amount of GLI-1 produced. In addition, what did not add L-tartaric acid was used as a control.

  The gene expression level of VEGF-A, FGF-7, and GLI-1, the production level of VEGF-A, and the production level of GLI-1 are shown in FIGS. 3, 4 and 5, respectively. Here, in FIG. 5, the staining intensity of the immunostained image is quantified, and the value divided by the number of cells is taken as the vertical axis. Also, photographs of cells stained for GLI-1 and cell nuclei are shown in FIGS. 6 (1 mM L-tartrate) and 7 (control).

  As shown in FIG. 3, L-tartaric acid promotes gene expression of VEGF-A, FGF-7, and GLI-1 in outer hair root root cells at 0.01 to 1 mM, and the higher the concentration, the higher It became clear that the expression level of the gene increased. Also, as shown in FIGS. 4 and 5, L-tartaric acid promotes the production of VEGF-A and GLI-1 in outer hair root sheath cells at 0.01 to 1 mM, and the higher the concentration, the higher the production amount. It became clear to increase. FIG. 6 shows immunostaining 48 hours after adding L-tartaric acid at 1 mM. Compared to the stained image of L-tartaric acid-free cells in FIG. 7, enhanced production of GLI-1 in the nucleus and in the cytoplasm was confirmed.

  These results suggest that L-tartaric acid promotes hair cycle regeneration by promoting the production of a hair growth factor in outer root sheath cells and promotes hair regeneration.

<Test 2: Effect of L-tartaric acid on the activity of dermal papilla cells>
Mitochondrial activity of dermal papilla cells was examined according to the following procedure.

Seed human hair hair papilla cells (HFDPC) (manufactured by Toyobo Co., Ltd.) at 1 × 10 ⁴ cells / well on a 96-well plate (CellBIND Surface), and use dedicated growth medium (PCGM) for hair papilla cells Culture at 37 ° C. under 5% CO ₂ for 1 day. After confirming by microscopic observation that there is no problem in cell growth, L-tartaric acid was added to the culture medium to a final concentration of 0.01 mM or 0.1 mM, and cultured at 37 ° C. for 2 days. Thereafter, lactate activity is measured as mitochondrial activity using Cell Counting Kit-8 (manufactured by Dojin Chemical Laboratory Co., Ltd.), and the number of cell nuclei is stained by Hoechest 33342 (manufactured by Dojin Chemical Laboratory), and then ImageXpress (Molecular The measurement results of the mitochondrial activity and the number of cell nuclei are shown in FIG.

  As shown in FIG. 8, L-tartaric acid was found to increase mitochondrial activity of dermal papilla cells at 0.1 to 1 mM.

  The results suggest that L-tartaric acid promotes hair cycle regeneration by activating dermal papilla cells and promotes hair regeneration.

<Test 3: Effect of L-tartaric acid on the production of cell adhesion molecules>
Total RNA was extracted from epidermal keratinocytes according to the following procedure, and the gene expression level of DSG-3 was analyzed.
(1) Measurement of gene expression amount of cell adhesion molecule Human normal epidermal keratinocytes (NHEK) (manufactured by Kurashiki Spinning Co., Ltd.) are seeded on a 24-well plate (CellBIND Surface) so as to be 4 × 10 ⁴ cells / well. And cultured at 37 ° C. for 2 days. After confirming by microscopic observation that there is no problem in cell growth, L-tartaric acid was added to the medium to a final concentration of 0.1 mM, 1 mM, or 10 mM, and cultured at 37 ° C. for 24 hours. After removing the medium and washing the cells with PBS (−), the cells were lysed with 0.35 ml of RLT (manufactured by Qiagen, Inc.). The cell lysate was collected in a 1.5 ml tube and 0.35 mL of 70% ethanol was added. The whole solution was applied to a spin column attached to RNeasy Mini Kit (manufactured by Qiagen, Inc.), and total RNA was purified according to a protocol recommended by the manufacturer. Using 50 ng of total RNA as a template, cDNA was synthesized using ReverTra Ace (registered trademark) qPCR RT Master Mix (manufactured by Toyobo Co., Ltd.). Using 2 μl of this reaction solution (synthesized cDNA) as a template, mRNA expression by real-time PCR using Premix EX Taq II (manufactured by Takara Bio Inc.) and QuantStudio 7 Flex Real-Time PCR System (manufactured by Life Technologies Inc.) The amount was determined.

(2) Measurement of Cell Adhesion Molecule Production Amount The DSG-3 produced by epidermal keratinocytes was measured according to the following procedure. As shown in FIG. It has been revealed that the expression of DSG-3 in the gene is promoted, and the higher the concentration, the higher the expression level of the gene. Moreover, as shown in FIG. 10, it became clear that L-tartaric acid promotes the production of DSG-3 in epidermal keratinocytes at 1 mM. FIG. 11 shows immunostaining after 120 hours of addition of 1 mM L-tartaric acid. Compared to the stained image of L-tartaric acid-free cells in FIG. 12, enhanced production of DSG-3 between cells was confirmed.

  These results suggest that L-tartaric acid enhances the adhesion between hair and hair follicles and suppresses hair loss by promoting the production of cell adhesion molecules.

[Formulation example]
Examples of formulations are shown in Tables 1 to 3 below. The numerical value which shows content in a formulation example is mass% all.

Claims (12)

  A hair growth factor production promoter containing an organic acid and / or a salt thereof.   The hair growth factor is one or more selected from hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), GLI transcription factor, and Wnt protein, The hair growth factor production promoter according to claim 1.   The hair growth factor production promoter according to claim 1 or 2, wherein the organic acid is a hydroxy acid.   A cell adhesion molecule production promoter containing an organic acid and / or a salt thereof.   The cell adhesion molecule production promoter according to claim 4, wherein the cell adhesion molecule is desmoglein.   The cell adhesion molecule production promoter according to claim 4 or 5, wherein the organic acid is a hydroxy acid.   A dermal papilla cell activator containing an organic acid and / or a salt thereof.   The dermal papilla cell activator according to claim 7, wherein the organic acid is a hydroxy acid.   Adhesive force enhancer with hair and hair follicle containing organic acid and / or its salt.   The adhesion promoter according to claim 9, wherein the organic acid is a hydroxy acid.   Hair regenerating agent and / or hair loss inhibitor comprising an organic acid and / or a salt thereof as an active ingredient.   The hair regenerating agent and / or the hair loss inhibitor according to claim 11, wherein the organic acid is a hydroxy acid.