JP3049593B2 - Hair restorer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention has no remarkable side effects on living organisms, such as hormonal agents, etc., and has a hair-growing / hair-growing effect by an excellent function of improving the function of the scalp by enhancing the function of the skin. 13,14-dihydro-15-keto-9 (α), which is a metabolite of prostaglandin F ₂ α and has a therapeutic effect on alopecia by activating hair root cells
11 (α) -dihydroxy-5-cis-13-trans-prostadienoic acid [13,14-dihydro-15-keto-9
(α), 11 (α) -dihydroxy-5-cis-13-trans-prostadienoi
c acid] and its derivatives, and prostaglandin F ₂
(+)-Z-7-[(1R, 2R, 3) which is a homologue of α and is also a metabolic prostaglandin related compound.
R, 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoic acid [(+)-
Z-7-[(1R, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyc
lopentyl] hept-5-enoic acid] and derivatives thereof as active ingredients.

[0002]

2. Description of the Related Art Numerous studies have been made on hormonal agents, blood flow promoting agents, various cell activating components, etc. on the prevention and treatment of alopecia, and on hair growth and hair growth by hyperfunction of the scalp and hair roots. Has been tried and incorporated into a topical hair restorer. However, few are particularly effective and highly safe, and most of the components that are said to have medicinal effects are expressed in preventive effects if the effectiveness is objectively evaluated. That is the current situation.

[0003]

DISCLOSURE OF THE INVENTION The present invention is excellent in safety and stability, and has an effect of treating alopecia by hair growth and hair restoration effects by promoting the function of skin cells, and a method for preventing alopecia from developing. The purpose of the present invention is to develop a hair-growing / hair-growing agent that promotes excellent and healthy hair growth, has a high effect of preventing alopecia, and has an anti-aging effect on the scalp and hair roots.

[0004]

Means for Solving the Problems The hair restorer / hair restorer of the present invention is a metabolite of prostaglandin F ₂ α, which is 13,1.
4-dihydro-15-keto-9 (α), 11 (α) -dihydroxy-5-cis-13-trans-prostadienoic acid and its derivatives, and (+)-Z-7-[(1
R, 2R, 3R, 5S) -3,5-dihydroxy-2
-(3-oxodecyl) cyclopentyl] hept-5-
One or more selected from enic acid and its derivatives are blended. Among the active ingredients of the present invention, (+)-Z-7-[(1R, 2R, 3R,
A derivative of 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoic acid is preferred, and in particular, an isopropyl derivative (+)-isopropyl Z-7-[(1R, 2R, 3R, 5S)-
3,5-Dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoate is preferred. The active ingredient of the present invention is a metabolic prostaglandin homologous compound whose metabolic pathway is similar to the endogenous prostaglandin metabolic pathway and exerts its effects on hair growth and hair restoration.

[0005] Prostaglandins are eicosanoids that are biosynthesized in tissues and organs of living organisms and have various physiological roles, and it is generally thought that their actions are expressed via specific receptors. , Prostaglandin D receptor (DP), prostaglandin E receptor (EP), prostaglandin F receptor (FP), and prostaglandin I receptor (I) depending on the type of prostaglandin.
The presence of P) and the thromboxane receptor (TP) is currently known. Production of these prostaglandins and the presence of receptors have also been reported in the scalp and hair root tissues consisting of epidermal cells and fibroblasts, and are deeply involved in the division and differentiation of scalp and hair root cells. It is clear that.

[0006] The present invention focuses on this point, and has studied the medicinal components of various metabolic prostaglandins on hair growth and hair growth for many years, and has examined the effects of sympathetic nerves and accessory sympathetic nerves on autonomic imbalance. In the imbalance (dominant sympathetic dominance), the occurrence of alopecia is frequently observed clinically. It has been found for the first time that the above-mentioned active ingredient of the present invention, which is a blocker, has an excellent hair-growth / hair-growing effect, and the present invention has been completed.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The active ingredient of the present invention, 13,1
Detailed specific examples of 4-dihydro-15-keto-9 (α), 11 (α) -dihydroxy-5-cis-13-trans-prostadienoic acid and derivatives thereof are shown below. The prostaglandin targeted in the present invention is a prostanoic acid having a hydroxyl group at 9α-position and 11α-position and represented by the following formula (I).

Embedded image In the formula (I), when R ₁ is a hydrogen atom (—H),
13,14-dihydro-15-keto-9 (α), 11
(Α) -Dihydroxy-5-cis-13-trans-
Prostadienoic acid, and as other derivatives, R ₁
Is an n-alkyl group such as a methyl group (—CH ₃ ), an ethyl group (—C ₂ H ₅ ), or a propyl group (—C ₃ H ₇ ), or an iso group such as an isopropyl group (—CH (CH ₃ ) ₂ ). - alkyl base an alkyl group, also include salts shown sodium R ₁ is potassium and the like, or even an aliphatic alcohol such as stearyl alcohol, or may be an ester of a sugar-polyol such as glucose.

As one example, isopropyl 13,14-dihydro-15-keto-9 (α), 11 (α) -dihydroxy-5-cis-where R ₁ is an isopropyl group.
13-trans-prostadienoate (isopropyl metabolized PGF2α, hereinafter abbreviated as IPGF) is represented by the following formula (II):
Is a compound having the structural formula shown below.

Embedded image IPGF can be administered in various dosage forms such as lotions and creams.

(+)-Z-7-[(1R, 2R, 3R,
Specific examples of 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoic acid and its derivatives are shown below. This active ingredient is represented by the following formula (III).

Embedded image In the formula (III), when R ₂ is a hydrogen atom (—H),
Unoprostonic acid, and as other derivatives, R ₁ is an n-alkyl group of a methyl group (—CH ₃ ), an ethyl group (—C ₂ H ₅ ), a propyl group (—C ₃ H ₇ ), or an isopropyl group (− iso such CH (CH _{3) 2)} - alkyl substrate an alkyl group, also sodium, aliphatic alcohols, such as potassium salt indicating, for example, or even stearyl alcohol, and also esters of a sugar-polyhydric alcohol such as glucose Good.

As an example, (+) glucopyranosyl-Z-7-[(1R, 2R, 3R, 5S) -3,5- is a glycoside of unoprostonic acid in which R ₂ is glucose.
Dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoate (generic name: unoprostonic acid glucoside, hereinafter abbreviated as GIP) is a compound having a structural formula represented by the following formula (IV).

Embedded image (In the formula, G represents glucose.) GIP can be administered in various dosage forms such as lotions and creams.

[0011] The active ingredient of the present invention is preferably (+)-isopropyl Z-7- among unoprostonic acid derivatives.
[(1R, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoate (generic name: isopropyl unoprostone, hereinafter abbreviated as IUP) is preferred. It is represented by the following equation (V).

Embedded image IUP is a colorless viscous liquid with a molecular weight of 424.62, has almost no smell or taste, is extremely soluble in ethanol and isopropanol, and is soluble in various oils commonly used in external preparations, such as lotions and creams. It can be administered in various dosage forms. The active ingredient of the present invention is 0.0001 to 20% by weight ratio (W / W) to the hair restorer / hair restorer.
(W / W%), preferably 0.01 to 5.0%.

The details of the mechanism by which the active ingredient of the present invention is effective in the hair growth and hair growth preparation of the present invention are not known at present, but act on the increase in enzyme activities related to cell division and keratinization. , By promoting the metabolic activity of the cell,
The present inventors presume that the effect is a hair restoration effect. Specifically, as described above, the sympathetic nerve β of the active ingredient of the present invention has
Blocking action and promotion of hair growth through the receptor for the active ingredient of the present invention possessed by the cells of the hair root and hair papilla cells, that is, the transition of telogen hair, which is hair that is resting, to anagen hair. It is presumed that this may be due to the promotion and prolongation of the growth period, and the promotion of the division and keratinization of the hair mother cells of the anagen hair. The present inventors have studied alopecia for many years,
At the same time, the effectiveness and mechanism of action of many and many components have been studied to complete the present invention.

The basic study of the present invention uses experimental animals,
The effects on skin cells and hair mother cells were examined. One of the experimental examples is shown below.

Experimental Example C commonly used as an experimental animal for evaluating the effectiveness of hair growth action
Completely fixed area of back hair of 3H mouse ♂ (8 weeks old)
Hair removal (area about 4 cm ² ) by Hand plucking method, 0.05% IPGF in a 60% alcohol aqueous solution,
Each test solution in which GUP was dissolved in 2.0% and IUP was dissolved in 0.1% and a solution containing only a 60% alcohol aqueous solution as a control were used to completely regenerate the entire hair in a total of 10 animals (5 animals per group) in two groups. Until the end, 200 μL was applied once a day for 27 consecutive days. 12 days after the start of application administration after the test,
On the 14th, 16th, 20th, 23rd and 27th days, 20 hairs were collected from each animal, and their length was measured by an actual measurement method. The effectiveness was examined by statistical analysis. The results are shown in Tables 1 to 3.

[0015] * Indicates a significant difference of 1% or less in the risk ratio of the comparison between the alcohol control group and the alcohol control group by statistical analysis (T test). Same in the table below.

[0016]

[0017]

From the results of this experimental example, it can be seen that the component according to the present invention has excellent hair growth and hair growth promoting effects on scalp and hair growth. The mechanism of these results is that the active ingredient of the present invention penetrates into the skin, activates various functions of cells of the scalp and hair roots, promotes the development of capillaries greatly involved in hair growth, and enhances the functions of skin cells. It is thought that it is directly promoted to activate the condition of the scalp and promote hair growth.

The present inventors have proposed a substance already known to have a hair-growing effect in order to enhance the hair-growth / hair-growth promoting effect of the active ingredient of the present invention, for example, “(3-carboxypropyl) -trimethylammonium chloride methyl. ester",
"6-amino-2,2-dihydro-hydroxy-imino-4-piperidinopyridimine", "7-chloro-3-methyl-2H-benzo-1,2,4-thiadiazine-1,
1-oxide "," polyoxyethylene sorbitan monostearate (20 EO) "," assembly extract ",
"Ethinyl estradiol", "extended lifegrass extract",
Combined effects with "Bitter ginseng extract", "Cactus extracts", "Ricaceae plant extract", "Urea" and the like were also examined. As a result, a synergistic effect of promoting hair growth and hair growth by an excellent skin function-enhancing action due to the combination with the active ingredient of the present invention was recognized. In addition, a combination of a known skin stimulating action component having a skin blood circulation promoting action, a cholinergic action mechanism component, an adrenaline inhibitory action component, a vascular smooth muscle relaxation action component, and the like and the active ingredient of the present invention. We also examined the hair-growth promoting effect of, and were able to recognize higher efficacy.

For the purpose of increasing the transdermal absorption rate of the active ingredient of the present invention, a humectant, a keratin softener and a surfactant, which are commonly used in cosmetics, are compounded in the external preparation of the present invention. There was an increase in the effect, which was presumably due to an increase in the rate of absorption into the water. The compounding concentration of the active ingredient of the present invention used as an external preparation for skin in the present invention is desirably about 0.01 to 5.0%. Hair growth containing the active ingredient of the present invention at a concentration of 0.01 to 1.0%.
"(3-Carboxypropyl)-
The concentration of "trimethylammonium chloride methyl ester" is preferably about 0.01 to 5.0%. "6-amino-
The content of "1,2-dihydro-hydroxy-imino-4-piperidinopyridmine" is desirably 0.01 to 5.0%. "7
-Chloro-3-methyl-2H-benzo-1,2,4-thiadiazine-1,1-dioxide has a compounding concentration of 0.01 to
5.0% is desirable. The formulation of "polyoxyethylene sorbitan monostearate (20 EO)" is 1.0 to 6
About 0.0% is desirable. "Assembly extract (dry weight 1)
g is equivalent to 1 g of the extract)) is preferably about 0.01 to 5.0%. The blending concentration of "ethynyl estradiol" is desirably about 0.001 to 0.1%. The blending concentration of “Enmeisou grass extract (1 g dry weight is equivalent to 1 g extract)”
0.01 to 10.0% is desirable. "Ginseng extract (1 g dry weight)
Is equivalent to 1 g of the extract)) is preferably about 0.01 to 10.0%. The concentration of urea is preferably 0.1% to 10.0%.

[0021] Cyclodextrin may be incorporated to enhance the stability of the active ingredient of the present invention in the preparation. Although the concentration of cyclodextrin varies depending on the dosage form, the addition of 0.1 to 50% (W / W) showed excellent active ingredients in the formulation and a stabilizing effect of the activity.

[0022]

EXAMPLES Some examples of the present invention are shown below. In addition to the fried components of the present invention, components which are conventionally useful for the scalp and hair may be further added. Is not limited to these examples. In the examples, the unit of the amount of each component is g (gram).

Example 1 A gel hair nourishing cosmetic having an excellent hair nourishing effect was prepared according to the following formulation by a conventional method. IPGF 0.5 7-chloro-3-methyl-2H 1,2,4-benzothiadiane 1.0-1,1-dioxide concentrated glycerin 2.0 ethylhexanediol 2.0 hinokitiol 0.01 decaglyceryl monolaurate 0.5 carboxyvinyl polymer 0.5 cyclodestrin 1.0 Triethanolamine qs perfume qs Alcohol 30.0 water * total 100.0g (* add water to make total 100.0g)

Example 2 A lotion hair-growth cosmetic having an excellent hair-growth effect was prepared according to the following formulation by a conventional method. GUP 2.0 Concentrated glycerin 5.0 Salicylic acid 0.1 POE hydrogenated castor oil (50E.O.) 0.5 Alcohol 20.0 Fragrance Fine buffer solution Appropriate amount Water * Total amount 100.0g (* Add water to make total amount 100.0g.) POE indicates polyoxyethylene and EO indicates ethylene oxide.

Example 3 A lotion hair-growth cosmetic having an excellent hair-growth effect was prepared by a conventional method according to the following formulation. IUP 0.1 Bitter extract 5.0 Urine 1.0 β-Glycyrrhetinic acid 0.1 N-Lauroylglutamate Sodium 0.5 Fragrance Small amount Buffer solution Appropriate amount Alcohol 50.0 Phenoxytanol 1.0 Water * Total amount 100.0 g (* Add water to make total amount 100.0 g. )

Example 4 IPGF 0.2 (3-carboxypropyl) -trimethylammonium chloride methyl ester 1.0 Concentrated glycerin 3.0 Isopropylmethylferyl 0.3 Decaglyceryl monolaurate 0.5 Salicylic acid 0.5 Fragrance Microbuffer Buffer Alcohol 40.0 Water * Total amount 100.0g (* Add water to make total amount 100.0g.)

Example 5 GUP 2.0 6-amino acid-1,2-dihydrohydroxyimino-4-piperi 1.0 dinopyrimidine concentrated glycerin 25.0 salicylic acid 0.5 polyoxyethylene hydrogenated castor oil (50E.O.) 0.5 isopropylmethylphenol 0.3 fragrance Small volume Buffer solution Alcohol 60.0 Water * Total amount 100.0g (* Add water to make total amount 100.0g.)

Example 6 A hair restoration shampoo having an excellent hair restoration effect was prepared according to the following formulation by a conventional method. IUP 10.0 Lauryl POE (3) sulfate sodium salt 30.0 Lauryl sulfate sodium salt 15.0 Ethylene glycol monostearyl ester 3.0 N-lauroyl diethanolamide 2.0 Lanolin derivative 1.0 Hydrolyzed keratin 3.0 Cyclodextrin 5.0 Fragrance Fine color Water * Total amount 100.0 g (* Add water to make total amount 100.0 g.) In the above, POE indicates polyoxyethylene.

Example 7 A hair-growing rinse having an excellent hair-growing effect was prepared according to the following formulation by a conventional method. IUP 5.0 Stearyltrimethylammonium chloride 2.0 Cetyl alcohol 2.0 Silicone oil 3.0 Oleyl POE (10) alcohol ether 1.0 Glycerin 5.0 Hydrolyzed keratin 2.0 Cyclodextrin 5.0 Fragrance Fine pigment Fine water Water * Total 100.0 g (* Add water to total In the above, POE represents polyoxyethylene.

Test Example 4 to 6 healthy males aged 36 to 51 years, who show symptoms of alopecia areata, are applied as a group once or twice a day for about 3 ml each for 3 months. -The result of the hair growth effect was obtained. (Determination criteria) Three months later, the hair density measurement method for measuring the number of hair shafts of the hard hair per unit area for the generation and growth of new hair on the applied part, and the SCORE determination method for determining by photographing Was evaluated. The criteria for SCORE determination were as follows. SCORE 1 There is little hair and only slight vellus hair is seen. SCORE 2 Many soft hairs and slightly hard hairs are observed at the hair loss site. SCORE 3 There are dense vellus hairs at the hair loss site, and about half of the hard hairs are found. SCORE 4 Although the whole is covered with hard hairs, the scalp can be seen through. SCORE 5 No bald area or thinning hair is seen at all. A case where one or more ranks have been improved by the SCORE determination is regarded as valid.

(Results) The effectiveness of the hair growth / hair restoration promoter containing 0.2% of IPGF in the base 1 was 78.5%, and the effectiveness of the hair growth / growth promoter containing 2.0% of GUP was 75.9%. I
The effective rate of the case containing 0.2% of UP was 80.5%. In base 1, 1.0% of (3-carboxypropyl) -trimethylammonium chloride methyl ester and I
The effective rate of the hair growth and hair growth promoter containing 1.0% GPF is based on the presence of the hair growth and hair growth promoter containing 1.0% of (3-carboxypropyl) -trimethylammonium chloride methyl ester in Base 1. 7.6% higher IGP than efficiency
A synergistic effect due to the addition of F was observed.

The effective rate of a hair growth and hair growth promoting agent containing 1.0% of 6-amino-1,2-dihydrohydroxyimino-4-piperidinopyrimidine and 0.5% of GUP in the base 2 is as follows. The synergistic effect of GUP was recognized by 6.3% higher than the effective rate of the hair growth and hair growth promoting agent containing 1.0% of 6-amino-1,2-hydrohydroxyimino-4-piperidinopyrimidine in Example 2. 7-chloro-3-methyl-2H- [benzo-1,2,4-thiadiazine]-
The effective rate of the hair growth and hair growth promoter containing 1.0% of 1,1-dioxide and 2.0% of IUP is as follows.
10.8% higher than the effective rate of hair growth and hair growth promoter containing 1.0% of 3-methyl-2H- [benzo-1,2,4-thiadiazine] -1,1-dioxide, showing a synergistic effect of IUP. Was done.

The effective rate of the hair growth and hair growth promoting agent containing 50% of polyoxyethylene sorbitan monostearate (20E.O.) and 0.2% of IUP in the base 1 is based on the polyoxyethylene Sorbitan monostearate (20E.O.)
The synergistic effect of IUP was recognized by 7.9% higher than the effective rate of the hair growth and hair growth promoter containing 50%. The water of the base was subtracted by the amount of polyoxyethylene sorbitan monostearate (20E.O.). 1.0% (equivalent to 1 g dry weight) of assembly extract and IUP in base 1
The effective rate of hair growth and hair growth promoter containing 0.2% is based on Base 1
7.6% higher than the effective rate of the hair growth and hair growth promoter containing 1.0% (equivalent to 1 g dry weight) of the assembly extract in IU
A synergistic effect due to P was observed.

Base 1 contains 0.01% of ethinylstradiol
The effective rate of the hair growth and hair growth promoter containing 0.2% of IUP and IUP is 7.5% higher than that of the hair growth and hair growth promoter containing 0.01% of ethynylstradiol in the base 1, and is synergistic with the IUP. The effect was recognized. Prolonged life extract to base 1
The effective rate of the hair growth and hair growth promoter containing 2.0% (corresponding to 2 g of dry weight) and 0.2% of IUP was as follows. Hair growth
The synergistic effect of IUP was recognized by 4.4% higher than the effective rate of the hair growth promoter. 2.0% urea and GUP in Base 1
The effective rate of hair growth and hair growth promoter containing 0.2% is based on Base 1
The synergistic effect of GUP was 6.2% higher than the effective rate of the hair growth and hair growth promoter containing 2.0% urea.

Base 1 (unit: g) Concentrated glycerin 3.0 Isopropylmethylphenol 0.3 Decaglyceryl monolaurate 0.5 Salicylic acid 0.5 Perfume Minor alcohol 40.0 Water * Total amount 100.0 g (* Add water to make total amount 100.0 g. the same.)

Base 2 (unit: g) Condensed glycerin 25.0 Isopropyl methylphenol 0.3 Polyoxyethylene hydrogenated castor oil 0.5 (50E.O.) Salicylic acid 0.5 Fragrance Fine alcohol 60.0 Water * Total 100.0 g

Base 3 (Unit: g) Concentrated glycerin 2.0 Isopropyl methylphenol 0.3 Decaglyceryl monolaurate 0.5 Carboxyvinyl polymer 0.5 Triethanolamine Fine amount Ethyl hexanediol 2.0 Flavor Fine amount Alcohol 30.0 Water * Total amount 100.0 g

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 7/06 A61K 31/557

Claims (6)

(57) [Claims] 1. A hair growth-promoting active ingredient comprising 13,1
4-dihydro-15-keto-9 (α), 11 (α) -dihydroxy-5-cis-13-trans-prostadienoic acid and its derivatives, and (+)-Z-7-[(1
R, 2R, 3R, 5S) -3,5-dihydroxy-2
-(3-oxodecyl) cyclopentyl] hept-5-
A hair restorer / hair restorer comprising one or more selected from enic acid and its derivatives. 2. As a hair growth promoting active ingredient, 13,1
Mixing one or more selected from 4-dihydro-15-keto-9 (α), 11 (α) -dihydroxy-5-cis-13-trans-prostadienoic acid and derivatives thereof. The hair restorer / hair restorer according to claim 1, characterized in that: 3. The hair growth promoting active ingredient (+)-
One or more selected from Z-7-[(1R, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoic acid and derivatives thereof 2. The composition according to claim 1, wherein
The hair restorer / hair restorer described. 4. The hair growth promoting active ingredient is (+)-Z-
Derivatives of 7-[(1R, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoic acid, especially (+)-isopropyl Z-7- [(1R, 2R, 3R, 5S) -3,5
-Dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoate. 5. The method according to claim 1, further comprising, in addition to the hair growth-promoting active ingredient, other ingredients known to be added to a hair growth / hair restoration agent. The hair restorer / hair restorer according to the item. 6. The hair restorer / hair restorer according to claim 1, wherein cyclodextrin is compounded to improve the stability of the active ingredient for promoting hair growth.