JP2555389B2 - Hair restorer - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel hair nourishing agent.

[Conventional technology]

Conventionally, the causes of baldness and hair loss are activation of elastic hormones in organs such as hair roots and sebaceous glands, decrease in blood flow to hair follicles, excessive secretion of sebum, production of oxides, etc. Abnormalities, genetic factors, neurosis due to stress, etc., secondary ones due to diseases, and aging are considered.

Therefore, a conventional hair nourishing agent is generally blended with a compound having an action of removing or reducing the above-mentioned causes. For example, vitamins such as vitamin B, amino acids such as methionine, vasodilators such as acetylcholine derivatives, anti-inflammatory agents such as purple root extract, female hormone agents such as estradiol, and skin function-enhancing agents such as cepharanthin are blended, It is used for the prevention and treatment of alopecia.

[Problems to be solved by the invention]

However, the mechanism of hair loss and hair growth is very complicated, and baldness and hair loss cannot be sufficiently prevented by merely inhibiting the activation of male hormones or increasing the blood flow rate of the hair follicle. Conventional hair nourishing agents only for some people,
Although the effect of preventing or improving dandruff, itchiness, and hair loss has been recognized, no one has yet achieved a satisfactory effect on hair growth, hair growth promotion or hair loss prevention.

In view of the above circumstances, the present inventors have conducted extensive studies to obtain a substance that is effective for hair loss and has an excellent hair-growth effect, and as a result, has an excellent hair-growth effect for sialic acid and sialic acid derivatives. The present invention has been completed and the present invention has been completed.

[Means for solving problems]

That is, the present invention provides a hair nourishing agent containing one or more selected from the group consisting of sialic acid and sialic acid derivatives.

 Hereinafter, the configuration of the present invention will be described in detail.

The sialic acid used in the present invention is a known substance, and is a generic term for N-acyl and N-acyl, O-acyl derivatives of polyhydroxymonoaminocarboxylic acid (neuraminic acid), and is also called sialic acid.

Sialic acid is contained in various organisms and normally constitutes cell surface saccharides and is present by glycosidic bonds to the ends of sugar proteins and glycolipids. Especially the brain, nerves, blood, submandibular gland, mucinous,
Most are present in colostrum, but are also liberated and present in serum, body fluids, and urine. The most representative sialic acid found in the living world is N-acetylneuraminic acid (NANA: molecular weight 3
09), melting point 185-187 ℃, ▲ [α] ²⁰ _D ▼ −32 ° ± 2 °
It is a white powder of.

The biological pharmacological actions of sialic acid and sialic acid derivatives are known to contribute to the negative charge on the cell surface, participate in the specific recognition mechanism of cells, hemagglutination reaction by viruses, homing phenomenon of blood proteins, etc. There is. Recently, expectorant activity on sialic acid has been disclosed (Japanese Patent Application Laid-Open No. 61-6841).
8), anti-inflammatory effect (JP-A-62-145015) and nutritional effect of sialic acid-linked oligosaccharide (JP-A-61-152233).

However, it has not yet been known to have a hair-feeding effect. In the present specification, the "hair nourishing effect" or "hair nourishing action" means hair loss prevention, promotion of hair growth and hair growth, and hair growth.

A method for producing sialic acid and a sialic acid derivative is a synthetic method,
Natural extraction method (raw material: egg white, submandibular gland mucin, placenta extract,
Colominic acid and the like obtained from E. coli)
The milk raw material extraction method (Patent No. 1191212, Patent No. 125)
2988, JP-A-59-184197, etc.) are particularly preferable.

The production examples of the compound according to the present invention by the milk extraction method are shown below. Milk used in the milk extraction method can be freely selected from raw milk, sheep milk, breast milk, and the like, and the concentration of sialic acid can be adjusted depending on the degree of purification.Therefore, the production method is selected according to the application, usage, dosage form, and purpose. It is possible. The present invention is not limited to this.

(Production Example I) Sialic acid 10 kg of cheese whey was added with 28 kg of hydrochloric acid to adjust the pH to 2, and then heated at 92 ° C for 60 minutes for hydrolysis. The obtained whey was hydrolyzed by heating with a screw decanter to remove proteins coagulated by heating to obtain a sialic acid-containing liquid. Then, the sialic acid-containing solution was put into desalted sugar of the electrolytic dialysis apparatus to desalt the conductivity to 2 mS / cm, and then the dialysis was stopped once and the concentrated sugar solution was discarded. Then add 30 distilled water to the concentration tank.
Then, dialysis was carried out again by adding l to a conductivity of 50 μS / cm. After the dialysis, the concentrated sugar solution was concentrated and dried to obtain 600 g of white powder. The powder thus obtained has a free sialic acid purity of about 97.
%Met.

(Example 2) Sialic acid salt The above-mentioned free sialic acid was adjusted with caustic soda to prepare sialic acid.
Get Na. In addition, salts such as Mg, K, phosphoric acid, and amino acid salts can be freely selected and produced according to the purpose.

(Production Example 3) Sialic acid-bound oligosaccharide The filtrate prepared by ultrafiltration of milk or cheese whey was concentrated under reduced pressure to a total solid content of 20%. This solution (25 kg) was electrodialyzed to an electric conductivity of 20 μS / cm, and then passed through a column packed with Dowex 1 × 2 (2 kg) to adsorb oligosaccharides. Then, 20 kg of water was passed through the column,
After removing the neutral sugar, the oligosaccharide adsorbed on the column was eluted with 0.5 M hydrochloric acid. After adjusting the pH of the obtained eluate to pH 7.0 with 30% caustic soda, the electrical conductivity was again 150 μS / cm.
Electrodialysis was performed until. The obtained dialysate was concentrated and dried to obtain 100 g of white powder. The powder thus obtained had a sialic acid-linked oligosaccharide purity of 90%.

(Production Example 4) 300 L of sialic acid-bonded protein rennet gazein curd waste liquid was sterilized by heating in a Fordora tank at 75 ° C for 30 minutes, and then cooled to 40 ° C.
The pH was adjusted to 4.6 with concentrated hydrochloric acid. The mixture was allowed to stand for about 30 minutes, the liquid in which a precipitate was generated was passed through a clarifier to return the pH to 7.0, and then the clear liquid was concentrated and desalted with an RO membrane. After concentrating up to 10 times, water was added to the concentrated solution to concentrate up to 10 times again. The obtained concentrated liquid was dried to obtain 1.3 kg of white powder. The sialic acid-binding protein of the powder thus obtained has a purity of about 80%.
there were.

(Production Example 5) Sialic acid-bonded lipid 15 kg of buttermilk powder was mixed with 100 l of a chloroform-methanol mixture (1: 1) and stirred at room temperature for 30 minutes for extraction. Next, the chloroform-methanol mixed solution was collected and passed through an ion exchange resin (DEAE-Toyopearl acetate type) 1 to adsorb the sialic acid-bound lipid, and then the resin was washed with 2 l of a chloroform-methanol mixed solution (1: 1), and then 0.5 The sialic acid-bound lipid was eluted with 4 L of M sodium acetate-methanol solution. The eluate was concentrated to remove methanol, 5 l of water was added, and desalting and concentration of sialic acid-bound lipid were performed by ultrafiltration. After the concentrated solution containing sialic acid-bound lipid was dried with an evaporator, it was passed through a silica gel column (4.0 x 50 cm) to adsorb the sialic acid-bound lipid, and then washed sequentially with chloroform 1 and chloroform-methanol mixture (4: 1) 1. After that, the sialic acid-bound lipid was eluted with a mixed solution of chloroform-methanol mixed solution (2: 8). The eluate was evaporated to dryness with an evaporator to obtain 15 g of a white powder.

The purity of the sialic acid-bound lipid in the powder thus obtained was 90% or more by thin layer chromatography (resorcinol method).

Next, the safety test of sialic acid and sialic acid derivatives was carried out, and the results are shown.

Acute toxicity test Using sialic acid, Na sialic acid, sialic acid-binding oligosaccharide, sialic acid-binding protein, and sialic acid-binding lipid produced in Production Examples 1 to 5 as test substances, ICR female mice (6 weeks old, 1 (Group of 5 animals) was intraperitoneally administered by suspending 0.5% sodium carboxymethylcellulose / physiological saline solution to a concentration of 2% by weight of each test substance using a 22 1 / 2G injection needle. Oral administration was carried out by suspending 5% by weight of each test substance in olive oil using an oral needle, and intraperitoneally administered at 60 ml / kg and orally administered at 30 ml / kg. As a result, no deaths, weight loss, or notable toxic symptoms were not observed during the 7-day observation period for all test substances, and no abnormalities were observed in the biopsy performed for 7 days.

As is clear from these results, the acute toxicity value (LD ₅₀ ) of sialic acid and sialic acid derivatives is 1200 mg / kg after intraperitoneal administration.
As mentioned above, it was proved to be highly safe with oral administration of 1500 mg / kg or more.

Next, formulation for applying sialic acid and a sialic acid derivative as a hair nourishing agent will be described.

The hair nourishing agent of the present invention can be used in the form of a mixture containing pharmaceutically acceptable additives and other agents in addition to sialic acid and sialic acid derivatives. However, since sialic acid has a problem with stability to acid, alkali and light and is not suitable for long-term storage, it is preferable to use a sialic acid derivative having good stability.

Examples of the additives include vasodilators such as carpronium chloride, minoxidil and diazoxide, female hormone agents such as estradiol, amino acids such as methionine, vitamins such as B vitamins, herbs such as Cordyceps sinensis, pentadecanoic acid. , And skin function enhancers such as triglycerides, male androgen agents such as oxendron, hinokitiol, hexachlorophene, phenol, ZPT, tocopheryl retinoate, vitamin E
Quaternary ammonium salts such as nicotinic acid ester, vitamin E / acetic acid ester, selenium sulfide, thioxolone, sulfur, resorcinol, tetrachlorosalicylanilide, octadecyltrimethylammonium chloride, hexadecyldimethylbenzylammonium chloride, benzalkonium chloride, cetylpyridinium Antidandruff agents such as chloride, undecylenic acid, trichlorocarbanilide and bithionol, derivatives of glycyrrhizinic acid and its ammonium salt, anti-inflammatory or cooling agents such as allantoin and menthol, salicylic acid, zinc and its compounds, lactic acid and its alkyl Drugs such as esters, vitamins, herbal medicines, olive oil, macadamia nut oil, animal and vegetable oils such as squalane, hydrocarbon oils represented by liquid paraffin, isopropyl myristate, se Louis Seo octanoate, ester oils such as 2-ethylhexyl palmitate, waxes such as beeswax, higher fatty acids, higher alcohols such as oil,
Water, derivatives such as lactic acid and its ethyl ester, polyhydric alcohols such as polyethylene glycol and sorbitol, lower alcohols such as ethanol, mucopolysaccharides (chondroitin sulfate, hyaluronic acid and salts thereof, etc.), pyrrolidone carboxylate, proteoglycan, Examples thereof include humectants such as collagen and glycerin, surfactants, fragrances, antioxidants, ultraviolet absorbers, pigments, and the like, and these are used alone or in combination of two or more.

As the dosage form of the hair nourishing agent of the present invention, any form can be used as long as it is suitable for obtaining a medicinal effect, and for example, powder, granules, powders, tablets, capsules, syrups, suppositories, injections, ointments. Etc. Of these, external preparations are preferred from the viewpoint of ease of use, and may be in any form as long as they can be applied externally, for example, lotions, liniments, external preparations such as emulsions, creams, ointments, pasta, paps, jellies, sprays and the like. An external semi-solid type agent and the like can be mentioned.

In the hair nourishing agent of the present invention, the total amount of sialic acid and sialic acid derivative as an active ingredient is 0 based on the total amount of the composition.
It is 0001 to 50% by weight, preferably 0.001 to 5% by weight.
If it is less than 0.0001% by weight, it tends to be difficult to obtain a sufficient effect, and conversely, if it exceeds 50% by weight, it is difficult to expect a large increase in the effect.

In the case of external use, the hair nourishing agent of the present invention is administered by transdermal administration, which is directly applied to or sprayed on the skin. Further, the dose of the hair nourishing agent of the present invention can be administered in an amount outside the following range depending on age, individual difference, medical condition, etc., and thus it is not clearly limited, but when generally intended for humans, sialic acid or sialic acid is used. Oral dose and transdermal dose of all acid derivatives are 1kg
And 0.001 to 2000 mg per day, preferably 0.01 to 100
It is 0 mg, and this amount can be administered once or several times a day.

Hereinafter, the method for formulating the hair nourishing agent and the hair nourishing effect according to the present invention will be specifically described with reference to Examples. The present invention is not limited to this. Below, the blending amount is% by weight
Is.

(Method for producing hair nourishing agent) Add sodium sialic acid and hydrogenated castor oil ethylene oxide (40 mol) adduct to 95% ethanol, stir and dissolve,
Next, ion-exchanged water was added and mixed to obtain the liquid hair nourishing agent of Example 1. Examples 2 to 5 and Comparative Example 1 are also Example 1
Was obtained in the same manner as. The sodium sialic acid and the sialic acid derivative used were those produced in Production Examples 2-5.

(Hair nourishing agent effect test) Next, in order to investigate the hair nourishing effect of the hair nourishing agent of the present invention, (1) trichogram test and (2) end hair conversion rate test were conducted on the hair nourishing agents of Examples 1 to 5 and Comparative Example 1.

(1) Trichogram test The hair roots of the removed hair before and after the use of the hair tonic were observed under a microscope, the number of resting hair roots was counted from the form of the hair root, and the hair-restoring effect of the hair tonic was compared by increasing or decreasing the ratio. . Resting hair roots are hair roots of hairs that have stopped growing, and people who complain of hair loss have a higher proportion of resting hair roots than normal people. Therefore, the hair nourishing effect was evaluated from the reduction of resting hair roots.

Each of the hair nourishment test solutions of Examples 1 to 5 and Comparative Example 1 was applied to the scalp of 10 male subjects twice a day, 2 ml each, continuously for 6 months, immediately before and immediately after the application for 6 months. 100 hairs were removed from each subject and the hair roots were examined. The change rate of the ratio of resting hair roots after the use of the hair nourishing agent was calculated, and the effective rate was calculated when the reduction rate was 15% or more. The results are shown in Table-2.

(2) End hair conversion rate test 30 heads of each of the 30 male pattern baldness subjects
In each place, the conversion rate from downy hair to terminal hair was compared before and after the application of each test solution (Examples 1 to 5 and Comparative Example 1). End hair is hair other than downy, that is, length 14
It means hair of mm or more, and the conversion from downy hair to terminal hair means a hair nourishing effect. The test solution was divided into 6 groups of 5 people per group, and each test solution was applied to each group twice a day (morning and evening) for 4 months. Immediately before the application of each test solution and immediately after application for 4 months, the conversion of the above-mentioned head fluff portion was taken by taking a close-up photograph, and the conversion rate to the terminal hair was shown as an average of the three positions in percentage. For the determination of the hair nourishing effect, the average terminal hair conversion rate of 10% or more is effective,
Less than 10% was judged invalid. The results are shown in Table-3.

(Results) From the test results of Tables 2 and 3, sialic acid and sialic acid derivatives have an excellent hair-growth effect, and when two or more kinds of sialic acid and sialic acid derivatives are combined, a synergistic effect can be obtained. Admitted. In both tests, there were no subjects who complained of side effects, and many subjects reported that dandruff and itchiness were suppressed. Therefore, it was proved to be a highly safe hair nourishing agent.

Next, various embodiments will be shown. In the following, the blending amount will be% by weight.

Example 6 W / 0 Emulsifying hair nourishing agent (% by weight) Polyoxyethylene (60 mol) Additive hydrogenated castor oil 2.0 Glycerin 10.0 Dipropylene glycol 10.0 1,3-Butylene glycol 5.0 Polyethylene glycol 1500 5.0 Cetyl isooctanate 10.0 Squalane 5.0 Vaseline 2.0 Propyl paraben 2.0 Carboxyvinyl polymer 1% aqueous solution 30.0 Sodium hexametaphosphate 0.03 Causticari 0.12 Na sialic acid 1.0 Ion-exchanged water Residual Example 7 Cream hair nourishing agent (% by weight) Sialic acid-binding oligosaccharide 5.0 Sialic acid-binding protein 2.0 Sial-binding lipid 0.0001 Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Glyceryl monostearate 3.0 EO (20 mol) -2-octyldodecyl ether 3.0 Propylparaben 0.3 Perfume 0.1 Glycerin 8.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 F Sodium xametaphosphate 0.005 Ion-exchanged water Residual Example 8 Tablets Tablets containing 50 mg of sialic acid Ca, 50 mg of sialic acid-bound oligosaccharide, 50 mg of sialic acid-bound lipid, 50 mg of sialic acid-bound protein and 100 mg of microcrystalline cellulose were prepared according to a conventional method. Then
Syrup gelatin-precipitated calcium carbonate was sugar coated. The tablets are used in a single dose of 1 to 10 tablets.

Example 9 Granules 20 g of sialic acid-bound oligosaccharide, 80 g of lactose, 10 g of water and 90 g of microcrystalline cellulose were uniformly mixed, crushed and granulated, dried,
Sieve to obtain granules. This granule is 0.5 per dose
Used at ~ 10g.

Example 10 Capsule 100 mg of sialic acid-bound protein, 100 mg of microcrystalline cellulose and 200 mg of lactose were uniformly mixed. This capsule is used in a single dose of 1 to 10 capsules.

Example 11 Ointment 47.5 g of plastic base 50W composed of liquid paraffin (95%) and polyethylene (5%) was added to sialic acid-bound oligosaccharide.
2.5 g was kneaded and deaerated under reduced pressure to obtain an ointment. This ointment is 1
It is applied to the executives 4-5 times a day.

〔The invention's effect〕

The hair nourishing agent of the present invention is a highly safe hair nourishing agent having excellent effects on hair growth, hair loss prevention and dandruff / itchiness.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Yukio Togawa Yukio Togawa 157 Idogaya Yanaka-cho, Minami-ku, Yokohama-shi Kanagawa 703 Diamond Palace Idogaya 703 (72) Inventor Kenkichi Ahiko 2-688-18 Hanakoganei, Kodaira-shi, Tokyo ( 72) Inventor Eike Eiki 2-23-5 Irumagawa, Sayama City, Saitama Prefecture 102

Claims (4)

(57) [Claims] 1. A hair nourishing agent containing one or more selected from the group consisting of sialic acid and sialic acid derivatives. 2. A sialic acid derivative is a sialic acid-linked oligosaccharide,
The hair nourishing agent according to claim (1), which is a sialic acid-binding protein, a sialic acid-binding lipid or a sialic acid salt. 3. The hair nourishing agent according to claim (1) or (2), which uses sialic acid or a sialic acid derivative obtained by extraction from milk. 4. The sialic acid is N-acetylneuraminic acid. Claims (1), (2) or (3).
The hair restorer according to the item.