JP2014231499A - Fallen hair suppressing agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a fallen hair suppressing agent capable of suppressing fallen hair by inhibiting action of a factor which is thought to provide an action on fallen hair during telogen.SOLUTION: A fallen hair suppressing agent comprises an inhibition factor to a protease degrading an adhesion factor adhering hairs and hair follicle cells.

Description

  The present invention relates to a hair loss inhibitor.

  In general, alopecia is thought to be caused by complex intertwining of various factors such as blood circulation failure, decreased hair matrix cell activity, and sex hormone imbalance. In particular, the modern society is exposed to the risk of hair loss due to various causes, such as aging society and stress society. However, the mechanism and mechanism of hair loss have not been fully elucidated yet.

  Hair grows according to the hair cycle. First, from the growth phase where the metabolic activity is strong and the hair grows, the metabolic activity decreases, and the hair follicle basal layer shifts to the regression phase where it moves upwards over the skin. Later, in the resting period when growth stops completely and the follicular basal layer shrinks near the nap, the new hair that has begun to grow under the resting follicle pushes the old resting hair out of the hair follicle. It is known to come out. Although the mechanism of this hair loss has not yet been clarified, it has been suggested that desmoglein 3 which is an adhesion factor binds the resting hair and the follicular cells (Non-Patent Documents). 1).

Desmoglein 3 anchors telogen hair in the follicle, J Cell Sci, 111, 17, 2529-37 (1998)

  The present inventor has focused on a factor that is considered to act on hair loss during the rest period and has conceived of suppressing hair loss by inhibiting the action. Therefore, the present invention relates to a hair loss inhibitor that can inhibit hair loss by inhibiting the action of the hair loss factor during the rest period.

  The present inventor conducted research while focusing on factors thought to act on hair loss during the rest period, and found that a protease that decomposes the adhesion factor that connects the hair and the hair follicle may be involved. Thus, the present invention was completed by conducting research to inhibit hair loss by inhibiting the action of such protease.

  The present invention provides a hair loss inhibitor containing an inhibitor to a protease that degrades an adhesion factor that connects hair and follicular cells.

  The hair loss inhibitor of the present invention can suppress hair loss by inhibiting a protease that degrades the adhesion factor in the rest period.

It is a figure which shows that the expression level of protease (KLK-11 and KLK-15) is changing before and after hair loss. It is a figure which shows the hair loss suppression effect at the time of administering various protease inhibitors.

  In the present invention, desmoglein 3 is mentioned as one of the adhesion factors that connect hair and follicular cells. In addition, examples of proteases that degrade this include the kallikrein family. As shown in the Examples described later, it has been confirmed that the kallikrein family is expressed before hair loss during the resting period and the expression level decreases after hair loss. From this, it is presumed that protease such as the kallikrein family is involved in hair loss.

  Inhibitors for the protease include 4- (2-aminoethyl) benzenesulfonyl fluoride hydrochloride, aprotinin, (2R) -N'-hydroxy-N-[(2S) -3- (5H-indole Examples include protease inhibitors such as -3-yl) -1-methylamino-1-oxopropan-2-yl] -2- (2-methylpropyl) butanediamide.

  4- (2-Aminoethyl) benzenesulfonyl fluoride hydrochloride is known as the serine protease inhibitor Pefabloc SC. Aprotinin is a serine protease inhibitor derived from bovine pancreas. (2R) -N′-hydroxy-N-[(2S) -3- (5H-indole-3-yl) -1-methylamino-1-oxopropan-2-yl] -2- (2-methylpropyl) ) Butanediamide is known as the MMP inhibitor GM6001.

  The hair loss inhibitor of the present invention contains one or more of the above protease inhibitors. Examples of the form include external preparations, injections, internal preparations, etc., among which external preparations are preferable.

  In the case of an external preparation, the amount of the protease inhibitor is 0.00001% by mass or more, more preferably 0.0001% by mass or more, and further preferably 0.0005% by mass or more from the viewpoint of sufficient hair loss suppressing effect and feeling of use. It is preferably 2% by mass or less, more preferably 0.2% by mass or less, and further preferably 0.1% by mass or less.

  When the hair loss inhibitor of the present invention is used as an external agent for hair loss suppression, in addition to the protease inhibitor, blood circulation promoter, hair follicle activator, polar oil agent, antioxidant, chelating agent, lower alcohol, surfactant Etc. can be blended.

  The blood circulation promoter is blended to promote blood circulation of the scalp and promote hair growth. Examples of the blood circulation promoter include vitamin Es (DL-α-tocopherol, D-α-tocopherol, DL-α-tocopherol acetate, D-α-tocopherol acetate, etc.), nicotinic acids (nicotinic acid, DL-α- Tocopherol nicotinate, nicotinamide, benzyl nicotinate, etc.). Also, acetylcholine, carpronium chloride, spironolactone, vitamin B6 hydrochloride, γ-oryzanol, cerretin, cromakalim, cephalanthin, nicorandil, pinacidil, minoxidil, phthalides, assembly extract, garlic iodide extract, ginkgo biloba extract, kina extract, ginger root extract, Examples include sophora extract, diisopropylamine dichloroacetate, spruce extract, red pepper tincture, cantalis tincture, and ginger tincture. Of these, vitamin E, nicotinic acid, carpronium chloride, cephalanthin, minoxidil, assembly extract, sofa extract, and chili pepper are preferable.

  The blood circulation promoter can be used alone or in combination of two or more, and its content is 0.0001% by mass or more, more preferably 0.001% by mass or more in the total composition, from the viewpoint of sufficient hair-growth effect and suppression of irritation. Moreover, 10 mass% or less, Furthermore, 5 mass% or less is preferable.

  The hair follicle activator is used to activate the hair follicle and promote hair growth. Examples of hair follicle activators include flavonols (such as trans-3,4'-dimethylflavanol), pantothenic acids (such as pantothenic acid, pantothenic acid ester, panthenol, pantothenyl ethyl ether), N-acylamino acids, pentadecane Acid glycerides, 6-benzylaminopurine, procyanidins, adenosines (adenosine, adenosine 5'-phosphate, adenosine 5'-phosphate salts, etc.), potassium aspartate, photosensitizer 301, biotin, scented raffle extract, carrot Extracts (Chickets carrot extract, Panax ginseng extract, etc.), grape extract, apple extract, mononitroguaiacol sodium, yeast extract, garlic component, pearl protein extract, placenta extract, royal jelly and the like. Of these, flavonols, 6-benzylaminopurine, adenosine and carrot extract are preferred.

  The hair follicle activator can be used alone or in combination of two or more, and its content is 0.001% by mass or more, more preferably 0.01% by mass in the total composition from the viewpoint of sufficient hair-growth effect and suppression of irritation. The above is preferable, and it is preferably 10% by mass or less, and more preferably 5% by mass or less.

  Polar oils are blended to solubilize active ingredients to promote penetration into the scalp and to improve feel and stability. Examples of polar oils include aliphatic alcohols, fatty acid alkyl esters, and fatty acid glycerides. Examples of the aliphatic alcohol include linear or branched, saturated or unsaturated aliphatic alcohols having 12 to 28 carbon atoms, particularly lauryl alcohol, stearyl alcohol, oleyl alcohol, isostearyl alcohol, cetostearyl alcohol, and the like. Can be mentioned. Examples of the fatty acid alkyl ester include methyl oleate, ethyl oleate, methyl isostearate, ethyl isostearate, isodecyl isononanoate, isotridecyl isononanoate, and isononyl isononanoate. Examples of the fatty acid glycerides include monoglycerides, diglycerides and triglycerides of fatty acids having 8 to 18 carbon atoms. Among these polar oils, from the viewpoint of preventing the crystallization of active ingredients, dissolving the oil film consisting of lipids on the scalp, and promoting skin penetration, it is liquid at 20 ° C and not more than 100 mPa · s, especially 50 mPa · s. The following are preferred. Specifically, methyl isostearate, ethyl isostearate, isodecyl isononanoate, isotridecyl isononanoate, and isononyl isononanoate are preferred.

  The polar oil agent can be used alone or in combination of two or more, and the content thereof is 0.01% by mass or more, more preferably 0.1% by mass or more in the total composition, from the viewpoint of promoting penetration of active ingredients and improving touch. Moreover, 5 mass% or less, Furthermore, 2 mass% or less is preferable.

  The external preparation for hair loss suppression of the present invention can further contain an antioxidant. Examples of the antioxidant include vitamin C and its derivatives, erythorbic acid, propyl gallate, BHT (di-n-butylhydroxytoluene), BHA (butylhydroxyanisole) and the like. The content of the antioxidant is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, more preferably 0.5% by mass or less, and further preferably 0.3% by mass or less in the total composition.

  The external agent for hair loss suppression of the present invention can further contain a chelating agent. Examples of the chelating agent include edetic acid or a salt thereof, hydroxyethane diphosphonic acid or a salt thereof, and edetate such as disodium edetate, trisodium edetate, and tetrasodium edetate is particularly preferable. These are effective in preventing the occurrence of starch, which is considered to be a modification of component (A), and are particularly effective in improving the storage stability at high temperatures (for example, 50 ° C.). The chelating agent can be used alone or in combination of two or more, and the content thereof is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, more preferably 1% by mass or less, and more preferably 1% by mass or less. 0.5 mass% or less is preferable.

  The external preparation for hair loss suppression of the present invention preferably further contains a lower alcohol. Examples of the lower alcohol include alcohols having 4 or less carbon atoms, such as ethanol, propanol, 1,3-butylene glycol and the like, and ethanol is particularly preferable. A lower alcohol can contain 1 type (s) or 2 or more types, and the content is 30 mass% or more in all compositions, Especially 50 mass% or more is preferable.

  The hair loss inhibitor of the present invention can further contain a surfactant. Examples of the surfactant include a cationic surfactant, an anionic surfactant, and a nonionic surfactant. The surfactant is effective in solubilizing each component and improving the stability.

  Examples of cationic surfactants include cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, aralkyltrimethylammonium chloride, and behenyltrimethylammonium chloride. Particularly, from the viewpoint of smoothness during application, cetyltrimethylammonium chloride, stearyltrimethylchloride Ammonium is preferred.

  Anionic surfactants include alkyl (or alkenyl) sulfates, polyoxyalkylene alkyl (or alkenyl) ether sulfates, alkane sulfonates, olefin sulfonates, alkyl benzene sulfonates, alkyl (or alkenyl) sulfosuccinates. , Dialkyl (or dialkenyl) sulfosuccinate, polyoxyalkylene alkyl (or alkenyl) sulfosuccinate, alkyl (or alkenyl) ether carboxylate, polyoxyalkylene alkyl (or alkenyl) ether carboxylate, polyoxyalkylene alkyl ( Or alkenyl) ether phosphate, fatty acid salt, N-acyl glutamate, N-acyl taurate, N-acyl methyl taurine and the like. Of these, polyoxyalkylene alkyl (or alkenyl) ether phosphate, fatty acid salt, N-acyl glutamate, N-acyl taurate, N-acyl methyl taurine and the like are preferable.

  Nonionic surfactants include polyoxyalkylene alkyl ethers, polyoxyalkylene alkenyl ethers, higher fatty acid sucrose esters, polyglycerin fatty acid esters, higher fatty acid mono- or diethanolamides, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid esters, poly Examples thereof include oxyethylene sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, alkyl polyglycoside, alkylamine oxide, and alkylamidoamine oxide. Of these, polyoxyalkylene alkyl ether, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, and polyoxyethylene hydrogenated castor oil are preferred.

  The surfactant can be used alone or in combination of two or more, and the content thereof is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, more preferably 1% by mass or less, Is preferably 0.5% by mass or less.

  In addition to the above-described components, the external agent for suppressing hair loss can contain various additive components used in normal hair restorers and hair cosmetics depending on the purpose. For example, a moisturizer, an anti-inflammatory agent, an antibacterial agent, a refreshing agent, an antiseborrheic agent, an antiseptic, a salt, a pH adjuster, a propellant, a fragrance, a dye, an ultraviolet absorber and the like can be blended.

  Such an external preparation for hair loss suppression can be in a desired form such as an aqueous solution, ethanol solution, emulsion, suspension, gel, aerosol, etc., for example, hair rinse, hair conditioner, hair treatment, hair lotion, hair pack, It can be in the form of hair cream, conditioning mousse, hair mousse, hair spray, shampoo, leave-on treatment and the like.

Example 1
In order to sample over time, 31-, 33-, 36-, 39-, 43-, 46-, and 48-day-old individuals of C57BL / 6 NCrSlc mice (purchased from Shimizu Experimental Materials Co., Ltd.) were euthanized, and the dorsal skin was excised. Later, it was quickly put into liquid nitrogen and stored at -80 ° C. RNA extraction was performed using the RNeasy Fibrous Tissue Mini Kit manufactured by QIAGEN according to the protocol.
First, an extraction buffer was prepared according to a conventional method. Next, the frozen back skin was quickly set on a cryopress table and struck with an air hammer for about 30 seconds. After crushing, a small amount of liquid nitrogen was added to collect the sample in the corner, and the entire sample was collected with a micro spatula. The crushed material was directly put into a 1.5 mL tube containing RLT + and stored on ice, followed by RNA extraction according to a conventional method. After crushing, when the sample placed in RLT + was not fine enough, it was subdivided by passing about 22G needle attached to a 1 mL syringe about 20 times.
Reverse transcription was performed using a QuantiTect Reverse Transcription kit manufactured by Qiagen, and the operation was performed according to the protocol.
The expression level was measured using a Takara Bio real-time PCR device (Thermal Cycler Dice Real Time System TP800, TP850) and a Takara Bio real-time PCR reagent kit (SYBR Premix Ex Taq II) and operated according to the protocol. .
For data analysis, samples with low reliability were excluded from melting curves and electrophoresis bands or retested, and the final raw data was normalized with β-Actin or GAPDH for comparison.
As a result, a protease was found whose expression level changed before and after hair loss. In particular, the presence of KLK-11 and KLK-15 was confirmed before the hair was removed, but almost disappeared after the hair was removed (FIG. 1).

Example 2
Hair of 4 weeks old Balb / cCrSlc mice (purchased from Shimizu Experimental Materials Co., Ltd.) is trimmed to 3 mm, and the first periodical hair is dyed for 20 minutes with a commercial hair dye (Baoune C6 manufactured by Kao). did. In other words, when new hair grows, the back hair turns white so that it can be compared with old hair that has been dyed.
Various inhibitors were administered every other day from the next day. Pefabloc SC (5 mg / mL) (Roche Applied Science) and GM6001 (10 μg / mL) (Merck) were applied to the back with a 50% ethanol solution each time. Aprotinin (100 ng / mL) (manufactured by Roche Applied Science) was dissolved in a PBS solution and injected at 10 uL × 3 sites with a 29G needle. Similarly, a control group that was not administered was prepared.
At the start of the test, extract numerical information from the digital images taken under the same light source and shooting conditions for the average brightness (Gray value) of the area of about 1 x 1 cm from the digital images taken after 5 days and 8 days. Changes in brightness over time were followed for each individual. The obtained data was averaged for each group, and the relative value with respect to the control group when the starting time was set to 100 was determined, and this was taken as the hair loss inhibiting effect.
As a result, in the group to which the sample was administered, it was shown that, on the fifth day after administration, the hair loss was suppressed and the old hair (the body hair destined to come off) remained without being removed (FIG. 2). This shows that each sample has an effect of delaying (suppressing) hair loss by inhibiting protease.

A hair cosmetic containing the hair loss inhibitor of the present invention is shown below.
Example 3 Hair Loss Suppression Lotion
(mass%)
(1) Eucalyptus extract 1.0
(2) trans-3,4'-dimethyl-3-hydroxy-flavanone 0.2
(3) Nicotinamide 0.1
(4) l-Menthol 0.2
(5) Pefabloc SC 0.01
(6) 95% ethanol 50.0
(7) Purified water remaining

Example 4 Hair Loss Prevention Essence
(mass%)
(1) trans-3,4'-dimethyl-3-hydroxy-flavanone 0.2
(2) Minoxidil 2.0
(3) l-Menthol 0.15
(4) GM6001 0.001
(5) 95% ethanol 50.0
(6) Purified water Remaining propellant (7) Carbon dioxide

Stock solution: propellant = 100: 2 (mass ratio)

Example 5 Hair Loss Shampoo
(mass%)
(1) Assembly extract 1.0
(2) Dipotassium glycyrrhizinate 0.1
(3) l-Menthol 0.2
(4) Pefabloc SC 0.05
(5) Polyoxyethylene (2) sodium lauryl ether sulfate 20.0
(6) Cationic polymer (Polymer JR400, Union Carbide) 0.3
(7) Dibutylhydroxytoluene 0.05
(8) pH adjuster appropriate amount (9) 95% ethanol 5.0
(10) Fragrance Amount (11) Purified Water Remaining

Claims (4)

  A hair loss inhibitor comprising an inhibitor to a protease that degrades an adhesion factor that connects hair and follicular cells.   The hair loss inhibitor according to claim 1, wherein the protease that degrades an adhesion factor that connects hair and hair follicle cells is kallikrein.   Inhibitors for proteases include 4- (2-aminoethyl) benzenesulfonyl fluoride hydrochloride, aprotinin, and (2R) -N′-hydroxy-N-[(2S) -3- (5H-indole-3-yl The hair loss inhibitor according to claim 1 or 2, which is a protease inhibitor selected from) -1-methylamino-1-oxopropan-2-yl] -2- (2-methylpropyl) butanediamide.   The hair loss inhibitor according to any one of claims 1 to 3, which is an external preparation for hair loss suppression.