JPS63192710A - Dissolved composition of (benzo-1,2,4-thiadiazine)-1-dioxide derivative - Google Patents

Abstract

PURPOSE:To provide a drug preparation containing a [benzo-1,2,4-thiadiazine]-1- dioxide derivative, DMSO, water and n-decylmethyl sulfoxide and having excellent trichogenous and hair-nourishing effect. CONSTITUTION:The objective composition contains (A) 0.005-10wt.% compound of formula [R is Cl, CF3, SO2 or NH2; R1 is H, Cl, SO2 or NH2; R2 is H, CnH2n+1 (n is 1-10), CH2OH, COOH or CH2C6H5; R3 is H, CnH2n+1 or CH2C6H5], (B) 1.0-30wt.% DMSO and/or benzyl alcohol, (C) 1.0-70wt.% water and (D) 0.1-10wt.% n-decylmethyl sulfoxide. The pH of the composition may be adjusted to 8.5-11.0 with a pH modifier to improve the solubility of the component A or the composition may be incorporated with 10-85wt.% isopropyl alcohol from the viewpoint of skin safety.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to [benzo-1,2,4-thiadiazine]-1-
This invention relates to a dioxide derivative dissolved composition and a hair growth and hair growth promoter containing the composition as an active ingredient. More specifically, the present invention provides A: one or more [benzo-1,2,/l-thiadiazine]-1-dioxide derivatives (hereinafter referred to as "dioxide"); B: dimethyl sulfoxide (
(hereinafter referred to as DMSO) and/or benzyl alcohol (
A dissolving composition characterized by containing (hereinafter referred to as BA), C: water, and D: n-decyl methyl sulfoxide (hereinafter referred to as n-DeMeSO), and the dissolving composition is blended as an active ingredient. Regarding hair growth and hair growth promoters. The present invention is particularly useful in the pharmaceutical or cosmetic fields.

[Prior Art] Dioxide has conventionally been used as an oral antihypertensive agent, but hirsutism has been reported as a side effect (The Journal Obediatrics [Th
e Journal of Pediatics], Vol. 71, No. 4, pp. 494-505, 1967).

Based on this knowledge, an invention was published in JP-A No. 56-85811 to use dioxide externally as a hair growth and hair growth promoter.
This invention is disclosed in Japanese Patent Application No. 60-256167.

[Problems to be solved by the inventions] In these inventions, the main solvent is JP-A-56-6581.
DMSO in No. 1, B in patent application No. 60-256167.
A has been used, but its effect on promoting hair growth and hair growth is not satisfactory, and there has been a desire to develop a formulation that is even more effective in promoting hair growth and hair growth.

[Means for Solving the Problems] The present inventors further conducted intensive research to obtain a dioxide-dissolving composition that is highly effective in promoting hair growth and hair growth, and as a result, n-
It has been discovered that the effect of promoting hair growth and hair growth is increased by incorporating DeMeSO.

That is, the present invention is a dissolution composition characterized by containing the following four components.

A; One or more kinds of dioxide derivatives B; DM
SO and/or BAC; Water D; n-DeMeS O Furthermore, by incorporating the above-mentioned dissolved composition as an active ingredient, it is possible to develop a hair growth and hair growth promoting agent that is excellent in hair growth and hair growth promoting effects. It was successful.

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

Dioxide used in the present invention is a substance known as a therapeutic agent for hypertension, and is a compound represented by the following general formula. .

RS R3 (in the formula R=CI, CF3, SO□, NF2, R1=I
(, CI, 5O7Nl+2, R2=H% CnH2n+
1: n” integer from 1 to 10, C1f20H,
C00H1CH2C6H5, R3”H, coH2, +,
; n ” an integer from 1 to 10, CH2C6H3) The amount of the dioxide compounded is o, oo in the dissolved composition of the present invention.
It is about s to 10% by weight (hereinafter, % means % by weight). When used as a hair growth and hair growth promoter, the higher the amount, the greater the hair growth and hair growth promoting effect, but considering the occurrence of side effects when used in large amounts, it should be 10% or less. Bye. Preferably it is 0.01 to 7%.
(The blending amount of n-DeMeSO is 0.1% to 10%, preferably 0.5% to
It is 7.0%. If it is less than 0.1%, no effect on promoting hair growth or hair growth will be observed, and if it is more than 10%, skin safety will be poor.

The blending amount of DMSO is 1.0 to 30%, preferably 2%.
．． It is 0-10%. The blending amount of BA is 1.0-30%
The content is preferably 3.0 to 15%. In the present invention, a single or mixed solvent of DMSO and BA is used.

The amount of water blended is 1.0 to 70%, preferably 3.0 to 5%.
It is 0%.

The blending amount of these solvents is appropriately selected according to the blending amount of the dioxide and the combination of solvents.

Furthermore, from the viewpoint of skin safety, it is also possible to add isoglobil alcohol (hereinafter referred to as PA) in addition to the above solvent. The amount of IPA blended can be any amount as long as it does not impair the original effect, but preferably 10 to 8
5%, more preferably 21 to 60%.

Furthermore, in order to improve the solubility of the dioxide, a pH adjuster was added to adjust the pH to 8.
It may be adjusted to 5 to 11.0. As a pH adjuster,
Inorganic salts, organic salts, or buffers containing these may be used as long as they can adjust the pH to 8.5 to 11.0. If the pH is less than 8.5, the solubility of the dioxide may be poor, and on the other hand, if the .H value exceeds 11.0, Ff may not be so good from a safety point of view.

Hair growth and hair growth promoters according to the present invention include Dioxide D and other commonly used hair growth and hair growth promoters such as salicylic acid, resorcinol, and bactericides such as hexachlorophene, nicotinic acid, vitamin E1, vitamin A acid, and pantothene. Agents such as acids, ethinyl estradiol, hinokitiol, glycyrrhetinic acid, piotin and other vitamins, fatty acids, amino acids, retinol, retinyl palmitate and other retinoids can be blended.

If necessary, various ingredients commonly used in pharmaceuticals and cosmetics, such as aqueous ingredients, powder ingredients, oils, surfactants, humectants, thickeners, preservatives, and oxidants, may be added to the extent that does not impair the effects of the present invention. Preventive agents, fragrances, colorants, etc. can be added.

Effects of the Invention The dissolved composition of the present invention is a dissolved composition in which dioxide is dissolved, and the effects of the dioxide are efficiently exhibited.

It is also extremely effective in promoting hair growth and hair growth. Furthermore, by adding a thickener, a transparent gel-like dissolved composition can be obtained. Furthermore, it can be applied to emulsions, creams, aerosols and other dosage forms.

Examples and effects based on the present invention are shown below together with comparative examples, but the present invention is not limited thereto.

Example 1 Transparent liquid composition (1) 7-chloro-3-methyl-283.0%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) BA 13
．． 0(3) IPA
44.0(4) n-DeMe SO7,0(
5) Sodium hydroxide 0.5 (6)
) Purified water Residue U manufacturing method J After adding and dissolving (5) in (6), add (1) and make 50
Warm to °C and stir and disperse (1). Next, (2), (
By sequentially adding 3) and (4) and stirring, mixing and dissolving, a transparent liquid composition is obtained. The pH of this transparent liquid composition is approximately 10.
It is 2.

Comparative Example 1 (1) 7-chloro-3-methyl-283.0%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) BA 13.
0(3) IPA 4
4.0(4) Sodium hydroxide 0
．． 5 (5) Purified water remainder [
Manufacturing method] According to Example 1. The pH of this transparent liquid composition is approximately 10.
．． It is 2.

Comparative example 2 (1) BA 13.0
%(2) IPA 44
．． 0(3) n-DeMe S 0
5.0(4) Sodium hydroxide
Appropriate amount (5) Potassium dihydrogen phosphate
Appropriate amount (6) Purified water Residual [
Manufacturing method] After adding and dissolving (3) in (8), (1) and (2) are added and mixed by stirring. Next, add appropriate amounts of (4) and (5) and p
u was adjusted to about 10.2.

Comparative Example 3 (1) BA 13.
0(2) IPA 44
．． 0(3) Sodium hydroxide appropriate amount (
4) Potassium dihydrogen phosphate appropriate amount (5)
Purified water remainder [! ! Method 1 After adding (1) and (2) to (5) and stirring and mixing, add (5)
) and (6) were added in appropriate amounts to adjust the pH to approximately 10.2.

[Hair growth test] The hair growth tests in Example 1 and Comparative Examples 1 to 3 were conducted using C3H/HeNCrJ mice in the resting phase of the hair cycle using the method of Ogawa et al.
Abnormal Eoidermal 'Dif
frentiation], M, 5eiji and 1. A
, edited by Bernstein, pp. 159-170, 19
An experiment was conducted in 1982 (University of Tokyo Publishing). That is, 10 mice per group, no application, Example 1 and Comparative Example 1.
The mice were divided into groups of ~305, the backs of the mice were pricked with hair clippers and a shaver, and each sample was given 0.00 mg once a day. III
1 was applied.

The hair growth effect of each sample was determined by measuring the hair growth area on the back of the mouse.
Comparisons were made based on area ratio.

(Test Results) No hair growth was observed in any group until the 9th day after sample application. 10
On day 0, the backs of the mice in the group of Example 1 were blackish and had grown hair. On the 144th day of application, about half of the mice in the group of Comparative Example 1 entered the anagen phase, and on the 200th day of application, some mice in the non-application, Comparative Examples 2 and 3 groups transitioned to the anagen phase. Table 1 shows the hair growth rate 25 days after application of each sample.

Table-1 As is clear from Table-1, the effect on hair growth is as follows:
It was found that the Example 1 group had a more significant effect than the Comparative Examples 1 to 30 groups.

Example 2 Transparent liquid composition (1) 7-chloro-3-methyl-283.0%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) BA 10
．． 0(3) IPA
50.0(4) Dipropylene glycol
5.0 (5) n-DeMeSO5,0 (6) Sodium hydroxide 0.5 (
7) Purified water Residue [Production method] After adding and dissolving (6) in (7), add (1) to 50
Heat to 8C and disperse (1) well. Next, (2), (
3), (4), and (5) are added and mixed by stirring, and (1),
(4) was dissolved to obtain a transparent liquid composition. The pH of this transparent liquid composition is about 10.2.

[Effect 1 The transparent liquid composition of Example 2 was administered once to 10 healthy subjects (male, 27 to 49 years old) exhibiting symptoms of androgenetic alopecia and hair loss.
When 2 to 4+nl was applied once or twice a day for 3 months, the results shown in Table 2 were obtained.

Table 2 As is clear from Table 2, the transparent liquid composition of Example 4 was effective against hair loss in all patients, and also showed a high efficacy rate of 70% against hair growth.

Example 3 Transparent liquid composition (1) 7-chloro-3-methyl-281,0%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) BA
7.0 (3) DMSO5,0 (4) IPA
50.0 (5) Polyethylene glycol 4
00 4.0 (6) n-DeMeSO6,0 (7) Potassium hydroxide 0.23
(8) Purified water remainder [Production method] According to Example 2. The pti of this transparent liquid composition is approximately 9.
．． It is 3.

Example 4 Transparent liquid composition (1) 7-chloro-3-methyl-2810,0%-[benzo-1,2,4-thiadiazinko-1-dioxide ('2) BA 20.
0(3) IPA 50
．． 0(4) n-DeMeSo
1.0(5) Sodium hydroxide 0
．． 8(6) Purified water remainder [
Manufacturing method] According to Example 2. The pH of this transparent liquid composition is approximately 10.
．． It is 7.

Example 5 Transparent liquid composition (1) 7-chloro-3-methyl-2H6,0%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) BA 15
．． 0(3) IPA
45.0(4) Dipropylene glycol
4.0(5) Sodium lactate aqueous solution (50%)6.
0(6) n-DeMeSO1,0 (7) Sodium hydroxide 1.05
(8) Trisodium citrate 0.05
(9) Purified water Residue [Manufacturing method] Add and dissolve (7) and (8) in (9), and then follow the same procedure as in Example 4. The pH of this transparent liquid composition is about 10.5.

Example 6 Transparent liquid composition (1) 7-chloro-3-methyl-284.0%-[benzo-1,2,4-thiadiazinoco-1-dioxide (2) DMS O10.0 (3) IPA 45
．． 0(4) Polyethylene glycol 200 5.
0(5) n-DeMeSO3,0 (6) Sodium hydroxide 0.67
(7) Purified water remainder [Production method] Same as Example 4. The pH of this transparent liquid composition is approximately 10.
．． It is 4.

Example 7 Hair tonic (1) 7-chloro-3-methyl-2HO, 02%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) Hinokitiol 0.01
(3) Retinyl palmitate 0.1 (
4) Vitamin E acetate 0.05
(5) Vitamin 860.1 (6) BA 10.
0(7) IPA
25.0(8) Ethyl alcohol
35.0(9) Propylene glycol
5.0 (10) Fragrance
Appropriate amount (11) Polyoxyethylene (15 mol) 4.0 Oleyl alcohol (12) n -DeMeSO0,5(
13) Potassium hydroxide 0.02
(14) Purified Water Residue [Manufacturing Method] After adding and dissolving (13) in (14), add (1) thereto and heat to 50°C. In addition to (6), (7),
Add (9) and (12) and mix with stirring to obtain (1) and (
12) to obtain a transparent liquid composition. Add this to the composition (
A).

Separately, in (8), (2), (3), (4), (5), (1
0) and (11) were sequentially added and dissolved with stirring. This is referred to as composition (B).

Composition (B) is gradually added to composition (A) while stirring, and the mixture is further stirred and mixed, followed by filtration to obtain a transparent liquid hair tonic.

Example 8 Gel-like hair nourishing composition (1) 7-chloro-3-methyl-282.0%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) Hinokitiol 0.0
1(3) Pantothenyl ethyl ether 0.0
5(4) BA 1
0.0 (5) IPA
40.0(6) Dipropylene glycol
10.0(7) Glycerin
5.0(8) Hydroxypropylcellulose
1.0(9) Carboxyvinyl polymer 1
．． 0(10) Polyoxyethylene (60 mol) Hard
2.0 castor oil (11) n-DeMeSO2,0 (12) Sodium hydroxide 0.3 (1
3) Purified water Residue [Production method] After adding and dissolving (12) in a part of (13), add (
Add 1), heat to 50°C, and stir and disperse (1) well. In addition, (6), (7), part of (5), (4
) and (11) are added in order and stirred to dissolve 1) and (11) to obtain a transparent liquid composition (A).

Separately, (2), (3), and (10) are dissolved in a portion of (5), and (8) is dispersed therein to prepare composition (B).

Furthermore, (9) is dispersed and dissolved in a part of (13) to form a composition (C).
Prepare in advance.

While stirring the composition (B), the composition (C) is added thereto and mixed well. Further, composition (A) is gradually added to this mixture and mixed with stirring to obtain a transparent gel-like composition.

Example 9 Gel hair tonic (1) 7-chloro-3-methyl-2HO, 03%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) Ethinyl estradiol 0.002
(3) Vitamin E acetate 0.0
5(4) BA 5
．． 0(5) IPA 2
0.0(6) Ethyl alcohol 25
．． 0(7)1.3-butadiene glycol 5.0(8
) Diethylene glycol 5.0 (9)
Glycerin 4.0 (10)
Hydroxypropyl cellulose 1.2 (11)
Carboxyvinyl polymer 0.8 (12) n
-DeMeSO0,3 (13) Diisoproprobanolamine 0.3(
14) Sodium hydroxide 0.05
(15) Purified water remainder [Production method] According to Example 10.

However, the transparent liquid composition (A) is (IL(4), (5L(
7), (8), (9), (12), (13), (
14), (15), and the composition (
B) is composed of parts of (2), (3), (6), and (10), and composition (C) is composed of parts of (11) and (''15), respectively.

Example 10 Emulsion (1) 7-chloro-3-methyl-2HO, 1%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) BA
5.0(3) IPA
20.0(4) Dipropylene glycol 15. .

(5) Liquid paraffin 3.0 (6
) Cetyl alcohol 0.2 (7)
Carboxyvinyl polymer 0.2 (8) Fragrance appropriate amount (9) n -
D e M e S O0,7 (10) Polyoxyethylene hardened castor 1.0 oil (P, O, E, i 40
mole) (11) Preservative appropriate amount (1
2) Sodium hexametaphosphate'b 0.03
(13) Potassium hydroxide 0.1
9(14) Purified water remainder [
Manufacturing method] After adding and dissolving (13) in a part of (14), (1) was added and heated to 50°C, part of (4), (3), (2
) to dissolve (1), further add (9), and mix and dissolve.

This is referred to as composition (A).

Add a part of (14) and (10) to the remainder of (4) and add 50
Dissolve by heating at 8C. While stirring this with a homomixer, add (6), (8), and (11) to (5), and
The mixture was heated to C and mixed and dissolved, then the mixture was cooled and emulsified. This is referred to as composition (B).

After adding and dissolving (7) and (12) to the remainder of (14),
While stirring this, composition (B) and composition (A) are sequentially added. This was further stirred and mixed using a homomixer, and then cooled to obtain a milky lotion.

Example 11 Cream (1) 7-chloro-3-methyl-2HO, 06%-[benzo-1,2,4-thiadiazine]-1-dioxide (2) Vitamin E acetate) 0.
05(3) BA
5.0 (4) IPA
25.0 (5) Polyethylene glycol 200 1
3.0 (6) Glycerin 4.
0(7) Liquid paraffin 1.0
(8) Castor oil 3.5
(9) Appropriate amount of fragrance (10
) Glycerin monofatty acid ester 1.5 (11)
n-DeMeSO1,0 (12) Preservative appropriate amount (1
3) Clay mineral (bentonite) 6.0 (14) Potassium hydroxide 0.02 (15) Purified water
Residue [Production method] After adding and dissolving (14) in a part of (15), (1) was added and heated to 500C, (3), (4), (5), (
Add 6) and dissolve 1) with stirring, then add (11) and dissolve with stirring. This is referred to as composition (A).

(7), (2), (8), (9), (10), (12
) were sequentially added, heated to 708C, and mixed and dissolved.

This is referred to as composition (B).

While maintaining the temperature at 70'C, composition (B) is gradually added to composition (A) while stirring, pre-emulsified, and then emulsified using a homomixer.

This was added while stirring to a mixture in which (13) had been added and dispersed in the remainder of (15), and the mixture was cooled to obtain a cream.

Example 12 Aerosol 1 Wataru Gorachi (1) 7-chloro-3-methyl-2HO, 6%-Cbenzo 1.2.4-thiadiazine]-1-dioxide (2) Ethinyl estradiol 0.001
(3) Bantothenyl ethyl ether 0.05 (
4), BA 6.0
(5) IPA 37.
0(6) Ethyl alcohol 37.0
(7) Dipropylene glycol 15.0 (
8) Polyoxyethylene hardened castor 1.0 oil (P
, O, E, ; 60 mol) (9) n-DeMeSO2,5 (10) Fragrance appropriate amount (11)
Sodium hydroxide 0.1 (12)
Purified water remaining 155 (13) stock solution 30.0
%(14) Freon 12 42
．． 0 (15) Freon 13 2
8.0 [Production method] A stock solution is prepared according to Example 9.

For filling, the prescribed amount of stock solution (13) is filled into the can, and after the valve is attached, the prescribed amount of gas (14 L (15)) is sequentially filled.

Claims (1)

[Claims] 1. A dissolving composition characterized by containing the following four components. A; one or more kinds of [benzo-1,2,4-thiadiazine]-1-dioxide derivatives B; dimethyl sulfoxide and or benzyl alcohol C; water D; n-decyl methyl sulfoxide 2, Claim 1 A hair growth and hair growth promoter containing the dissolving composition described in 1. as an active ingredient.