WO2003030844A1

WO2003030844A1 - Long-acting hair growth stimulant preparations

Info

Publication number: WO2003030844A1
Application number: PCT/JP2002/010290
Authority: WO
Inventors: Koji Imamura; Rumi Ochiai; Takako Horie; Susumu Morioka; Shinya Saito
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 2001-10-04
Filing date: 2002-10-02
Publication date: 2003-04-17
Also published as: JP4604489B2; JPWO2003030844A1

Abstract

Long-acting minoxidil preparations showing an excellent hair growth stimulating effect when applied once a day and having a favorable feel in using, characterized by containing: (A) from 0.1 to 5 w/v% of minoxidil based on the whole preparation; (B) polyethylene glycol; and (C) one or two members selected from 1,3-butylene glycol and glycerol. Thus, it becomes possible to provide minoxidil preparations whereby a favorable feel in use can be obtained while saving labor in application.

Description

Specification

Sustained hair growth preparation technology

The present invention relates to a long-lasting hair growth preparation containing minoxidil as an active ingredient. Conventional technology

Minoxidil has the chemical name 6_ (1-piperidinyl) -2,4-pyrimidindiamine-3-oxide, and its application as a hair restorer is described in US Patent No. 4,139,619. There are many reports on hair growth and hair growth.

Although the minoxidil formulation has an excellent hair-growth effect, it has to be applied several times a day to achieve a sufficient effect. In order to reduce the time and effort for such application, JP-A-10-265343, JP-A-200-348314, and the like also disclose a long-acting minoxidil preparation that can obtain a sufficient hair-growth effect by application once a day. There have been reports, but better ones were being sought.

In addition, long-term continuous administration is required to obtain a sufficient hair-growth effect with minoxidil. However, if the user does not have a sufficient feeling of actual use, the user often abandons continuous use, and as a result, a sufficient hair-growth effect cannot be obtained. Therefore, in minoxidil preparations, the feeling of use is very important.

With conventional lotion preparations, a temporary feeling of use due to the volatilization of alcohol was felt immediately after administration, but it was difficult to feel the permeation of the drug gradually, or the feeling that the effect was sustained. Was also difficult to obtain. An object of the present invention is to provide a long-acting minoxidil preparation which can obtain an excellent hair-growth effect by application once a day, and which is excellent in feeling upon use. Disclosure of the invention

The present inventors have studied the conditions for maintaining the penetration of minoxidil into the scalp and the feeling of use from the formulation applied to the scalp from the viewpoint of the composition of the minoxidil formulation. It was found that when used as a solvent, sustained permeability could be maintained.

That is, the present invention comprises (A) 1 to 5 W / V% of the entire preparation, minoxidil (B) polyethylene glycol, and (C) one or two selected from 1,3-butylene glycol and glycerin. It is a long-lasting hair growth preparation characterized by the following.

The amount of minoxidil to be compounded in the present invention is 1 to 5 W / V% of the whole preparation (in the case of an aerosol, in the undiluted solution) (hereinafter “W / V%” may be simply indicated as “%”). And preferably 3 to 5%. If the amount is too small, the hair growth effect is insufficient, and if the amount is too large, minoxidil crystals may precipitate.

In the present invention, it is necessary to use polyethylene glycol in combination with at least one selected from 1,3-butylene glycol and glycerin. The total compounding amount of those polyhydric alcohols is preferably 5 to 20% of the whole preparation, more preferably 9 to 20%, and still more preferably 9 to 15%. If the amount is too small, it is difficult to obtain a sustained effect, and if the amount is too large, the feeling of use is lowered.

In the present invention, the blending amount of the other polyhydric alcohol with respect to 1 part by mass of polyethylene glycol is preferably 0.1 to 10 parts by mass, more preferably 0.5 to 5 parts by mass, and most preferably 1 to 4 parts by mass. .

Further, the mixing amount of 1,3-butylene glycol and glycerin is preferably 0.1 to 5 parts by mass, more preferably 0.25 to 5 parts by mass, and more preferably 0.2 to 5 parts by mass with respect to 1 part by mass of polyethylene glycol. 5 to 2.5 parts by weight are most preferred.

In the present invention, polyethylene glycol, 1,3-butylene glycol and glycerin can be simultaneously added. The content of serine is preferably 4 to 5% of the whole preparation. Within this range, the solubility of minoxidil is high and the feeling of use is excellent, such as reduced stickiness.

Here, the polyethylene glycol used in the present invention preferably has a degree of polymerization of 300 to 4,000, more preferably 300 to 1,000, and particularly preferably polyethylene dalicol having a degree of polymerization of 400. If the degree of polymerization is less than 300, it is difficult to maintain the quality of polyethylene dalicol, and if the degree of polymerization is large, the feeling of use will be poor, and the nature of the preparation will make it difficult to manufacture the preparation.

The glycerin used in the present invention is a concentrated glycerin having a content of about 98%, and when a normally used glycerin having a content of about 85% is used, the amount to be blended is determined in consideration of the water content. There is a need.

In the present invention, when further blending of menthyl lactate, a continuous feeling of infiltration of the drug can be obtained, so that it is easy to continue using the drug and it is effective to bring out a sufficient effect.

In the present invention, the blending amount of menthyl lactate blended for improving the feeling of use is preferably 0.1 to 5% of the whole preparation. If the amount is less than 0.1%, the feeling of penetration imparted at the time of application is insufficient, and even if the amount is more than 5%, no more feeling of penetration can be expected.

As a solvent for the long-lasting hair growth agent of the present invention, ethanol, water or a mixture thereof is preferable. In this case, the amount of ethanol is preferably in the range of about 40 to 82%, and the amount of water is preferably in the range of 5 to 30%. In particular, it is preferable to add ethanol since a good feeling of use can be obtained by volatilization of ethanol immediately after coating.

The long-lasting hair growth preparation of the present invention preferably has a pH of 5.5 to 9.5 from the viewpoint of the stability of the main drug component minoxidil, the feeling of use, the feeling of irritation to the skin during use, the permeability of the drug, and the like. The range of 5.5 to 6.5 is more preferred. Normally used acids and bases can be used to adjust the pH, but citric acid and salts are preferred from the viewpoint of preparation and stability of the preparation. Acids, lactic acid, phosphoric acid, and salts thereof, and the like, more preferably, phosphoric acid and its salts, which have little effect on skin.

In the sustained hair growth preparation of the present invention, other necessary active ingredients and auxiliary ingredients can be added in addition to the essential ingredients. Pharmaceutical ingredients preferably added to and combined with the sustained-growth hair preparation of the present invention include menthol, vitamin E acetate, pantothenyleethyl ether, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, and diphenhydramine hydrochloride. Selected ingredients can be given. Of these optional ingredients, menthol and pantothenylacetyl are preferred from the viewpoint of a sustained effect.

The amount of these optional components to be added is not particularly limited, and can be determined empirically in consideration of the stability of use, the stability of minoxidil, the composition of the solvent system, and the like. For example, a particularly preferred optional ingredient, pantotenyl ester, is formulated in an amount of about 0.5 to 1.0% in the final composition to improve the refreshing sensation during application and improve the usability of the whole preparation. It is preferable to do it.

In the long-acting hair growth preparation of the present invention, in addition to the above-mentioned components, various active ingredients and auxiliary ingredients used in general external preparations such as excipients, vasodilators (carpronium chloride, benzyl nicotinate, Sempuli extract, Panax ginseng extract, Pepper tincture, etc.), antihistamines (isotipendyl hydrochloride, etc.), anti-inflammatory agents (guaiazulene, etc.), keratolytic agents (urea, salicylic acid, etc.), fungicides (chlorhexyl dalconate) , Isopropylmethylphenol, quaternary ammonium salt, pyroctone olamine, etc.), moisturizers (sodium hyaluronate, chondroitin sulfate, etc.), various animals and plants (yew, potampi, kanzo, otogiriso, tsutsuji, bee, potato sprout, Comfrey, Ashitapa, Safran, Sanshishi , Rosemary, sage, mocco, simocco, hops, brassicae, etc.), vitamins (retinol acetate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), Antioxidants (dibutylhydroxytoluene, sodium pyrosulfite, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizers (diisopropyl adipate, isopropyl myristate, polyoxyethylene hydrogenated castor oil , Polysorbates, pull-mouth nicks, various vegetable oils, various animal oils, alkyl glyceryl ethers, hydrocarbons, etc.), metabolic activators, gelling agents (such as water-soluble polymers), adhesives, fragrances, and fresheners Commonly used components such as (heart oil, camphor, etc.) and dyes can be blended within a range that does not impair the effects of the present invention.

Here, a surfactant, which is a component often added to an external preparation, usually affects the skin absorption of minoxidil and may reduce the feeling of use. It is preferable not to substantially add a surfactant.

The essential component of the long-acting hair growth preparation of the present invention and, if necessary, other ingredients are blended, and a suitable external use such as a lotion, aerosol, tonic, cream, ointment, gel or the like is carried out in a usual manner. It can be used as a formulation. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples.

Examples 1-3

According to the formulation shown in the table below, components other than purified water were mixed and dissolved by stirring, and purified water was added to make a total amount of 10 OmL to prepare the lotion preparations of Examples 1 to 3 and Comparative Example 1. . table 1

Test example 1 (blood concentration measurement test)

Wistar rat male (8 weeks old) hair was removed from the abdomen, fixed in a dorsal position under ether anesthesia, and prepared using 14C-minoxidil for a fixed area (2 x 3 cm) of the abdomen 30 L of each of the lotions of Examples 1 to 3 and Comparative Example 1 were applied. Blood is collected from the jugular vein at predetermined times (0.5, 1, 2, 4, 6, 8, 10, 24 hours) with 4 animals per group, and the concentration of minoxidil in the blood is measured by liquid scintillation. The blood minoxidil concentration was measured by measuring with a counter.

The results are shown in Table 2. Figure 1 shows the transition of the results.

Table 2

Changes in blood concentration (unit: ng eq./niL)

Example 4

Mix 1 g of minoxidil, 5 g of 1,3-butyleneglycol, 400 g of macrogol and 70 g of ethanol, stir to dissolve, add purified water to make a total volume of 10 OmL, and mix. A syrup was prepared. Example 5

Minoxidil lg, menthyl lactate lg, macrogol 400 g, glycerin 5 g and ethanol 70 g were mixed and dissolved by stirring, and purified water was added to make a total volume of 10 O mL to prepare a lotion. . Example

In the same manner as in Example 1, the lotions of Examples and Comparative Examples were prepared with the compositions shown in Tables 3 to 8 below.

In the table, “real” indicates an example, and “ratio” indicates a comparative example. Table 3

Fruit 6 Fruit ₇ Fruit 8 Fruit 9 Fruit 1 o Minoxidil 1 g 3 g 5 g 3 g 5 g

1,3-7 'Tylenek 6g 5g 5g

Glycerin 5 g 5 g e. Reethylenek ', Rekor 300 4 g

E. Lithylene lactone, alcohol 400 5 g 5 g 5 g 5 g Ethanol 60.05 g 60.05 g 60.05 g 60.05 g 60.05 g Appropriate amount MM

Lactic acid m

Purified water Total lOOmL Total lOOmL Total lOOmL Total lOOmL Total IGOmL pH 8.4 8. 4 6. O 6. O 6. O

Actual 1 1 Actual 1 2 Actual 1 3 Actual 1 4 Actual 1 5 Minoxidil 3 g 3 g 5 g 5 g 5 g Menthyl lactate 13 g 0.1 g 1 g 1

1,3-F ', CHIRENK', COLOR 5 g 10 g 8 g 5 g 5 g Lithylene ethylene glycol 300 5 g 7 g

E. Liethylenek ', Rekol 400 5 g 5 g 5 gr Ropilenk' Rekol 2.5 g Silicon r ropirene 'Rekol 2.5 g Ethanol 60.05 g 60.05 g 60.05 g 60.05 g 60.05 g Cunic acid Hydrochloric acid Appropriate amount Purified water Total lOOmL total lOOmL total lOOmL total lQOmL total lOOmL pH 8.40 8.6.2 O 6.O 6.2 Table 5

Real 16 Real 17 Real 18 Minoxidil 5 g 5 g 5 g Menthyl lactate 1 g 13 g Glycerin 5 g 5 s 2 g e. Ethylene glycol 'call 400 5

E. Polyethylene glycol 600 5 3 g o Ethanol 60.05 g 60.05 g 60.05 g Cuenoic acid 1 g m

Lactic acid

Sodium hydroxide Weekly Purified water Total lQOmL Total lOOmL Total lOOmL

PH 6.00 5.5 6.5

Table 6

Actual 1 9 Actual 2 0 Minoxidil 1 g 3 σ 1 ε 1 s

1 3 FUJINK "Rikoru et al U U U

E. U Ethylene ゥ -recal 400

Polyethylene poly call 600

Fro. Renk's Recall 10s

Shi ', Rohi "Lenk", Recall 5 et a

Ethanorille 60 05 s 60.05 g

L Thor 0 3 _ε

V-tan E-assembly 0 08 ε 0 08 ^ c. 1 g 1 R hinokitiol 0.05 g 0.05 g 0.1 "g lytyl retinoic acid 0.1 g g fenhydride hydrochloride, lamin 0.1 0.1 g Purified water Total lOOmL Total lOOmL pH 6.0 7.0

Table 7

Table 8

Test example 2

A feeling of use test was conducted for the formulations shown in Table 9 below.

Table 9

Component name Comparative example 9 Comparative example 10 Comparative example 11 Example 21 Minoxidil 3 g 3 g 3 g 3 g

1,3-butylene glycol 3 g 3 g glycerin 3 g 3 g diethylene glycol 400 3 g 3 g ethanol 60.05 g 60.05 g 60.05 g 60.05 Menthyl lactate 5 g 5 g Purification Water Total lQOmL Total lOOmL Total lQOmL Total lOOmL Regarding the feeling of use, a score was given on the feeling of penetration of the drug from the formulation, in a form in which the respondents were asked whether they had a pleasant stimulus.

In the test, 0.5 mL (2 subjects) or 1 mL (1 subject) was applied to one temporal region of the subject and the comparative product to the opposite temporal region, respectively. Subjects were scored every 30 minutes.

The scores were 5: strong permeation, 4: moderate permeation, 3: permeation, 2: slight permeation, 1: no permeation , And were evaluated on a scale of 1.

The results are shown in Table 10, Table 11, FIG. 2 and FIG.

Table 10

(1 mL application)

Experiment 2

Left head Right head Left head Right head

Time Comparative Example 9 Comparative Example 1 0 Comparative Example 1 1 Example 2 1

Immediately after administration 5 5

After 5 minutes 5 5 '

10 minutes later 4 4

2 0 minutes later 3 4

30 minutes later 2 3

4 0 minutes later 2 3

5 0 minutes later 2 3

6 0 minutes later 2 3

9 0 minutes later 2 3 Table 11

(0.5 mL application)

Example 22

30 ml of the lotion agent prepared in Example 4 was filled in an aerosol can, and 70 ml of dimethyl ether was further added to obtain an aerosol agent. In addition, the lotion of Example 5 can be similarly used as an aerosol.

Example

A liquid preparation was obtained by the usual method using the formulation shown in Table 10.

Table 10

Test example 2

The abdomen of a Wistar rat male (8 weeks old) was dehaired, fixed in a dorsal position under ether anesthesia, and a fixed area of the abdomen (2 x 3 cm) was treated with 14C-minoxidil. Each 30 L of the test lotion prepared according to the formulation shown in 1 was applied. Blood is collected from the jugular vein at predetermined times (0.5, 1, 2, 4, 6, 8, 10, 24 hours) with 4 animals per group, and amino acids in the blood are collected. The blood minoxidil concentration was measured by measuring the xyl concentration in a liquid scintillation counter. The results are shown in Table 12 and FIG.

Table 11

Table 1 2

Change in blood concentration (unit: ng eq./mL) Time Comparative Example 1 2 Example 2 5

(h r) Mean SE Mean SE

0 0.00 0.00 0.00 0.00

0.5 2.58 0.38 2.96 0.48

1 5.19 1.12 6.68 1.05

2 8.00 2.96 9.34 1.51

4 4.23 1.56 9.43 2.42

6 3.29 0.66 8.51 2.12

8 3.01 0.47 7.40 1.56

10 2.91 0.47 6.72 1.21

24 2.24 0.33 5.08 1.27 Examples and test examples

Using the formulation shown in Table 13, the concentration of minoxidil in rat blood was measured over time in the same manner as in Test Example 2. The results are shown in Tables 14, 15, 15, and 6.

Table 13

g 1 4

(Unit: ng eq./mL)

Comparative Example 13 Example 26

Time Mean SE Mean SE

0 0 0 0 0

0.5 7.94 5.76 3.77 0.93

1 14.85 8.98 7.40 1.49

2 14.44 5.02 8.83 1.59

4 4.60 1.26 7.77 1.23

6 2.86 0.76 5.89 0.75

8 2.17 0.64 5.24 0.69

10 1.72 0.36 4.73 0.68

24 1.20 0.17 3.39 0.58 Table 15

(Unit: ng eq./mL)

Industrial applicability

According to the present invention, it has become possible to provide a hair restorer which has excellent effects even when applied once a day and has excellent commercial properties that maintains a feeling of actual use. BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 is a graph showing the change in blood minoxidil concentration in the rat. The vertical axis shows the concentration (ng eq./mL), and the horizontal axis shows the elapsed time.

Fig. 2 is a graph showing the results of a usability test with and without the inclusion of menthyl lactate. The vertical axis shows the evaluation results of the usability, and the horizontal axis shows the elapsed time after application. Fig. 3 is a diagram showing the results of a usability test with and without the inclusion of menthyl lactate. The vertical axis shows the evaluation results of the usability and the horizontal axis shows the elapsed time after application. Fig. 4 is a graph showing the change in blood minoxidil concentration in the rat. The vertical axis shows the concentration (ng eq./mL), and the horizontal axis shows the elapsed time.

Fig. 5 is a graph showing the change in blood minoxidil concentration in the rat. The vertical axis shows the concentration (ng eq./mL), and the horizontal axis shows the elapsed time. Fig. 6 is a graph showing the change in blood minoxidil concentration in the rat. The vertical axis shows the concentration (ng eq./mL), and the horizontal axis shows the elapsed time.

Claims

The scope of the claims

1. (_A) 1 to 5 W / V% of the whole preparation containing minoxidil (B) polyethylene glycol and (C) one or two selected from 1,3-butylene glycol and dalyserin A continuous hair growth preparation characterized by the following:

2. The persistent hair restorer according to claim 1, wherein the total amount of the component (B) and the component (C) is 5 to 20 W / V% of the whole preparation.

3. The long-lasting hair growth preparation according to claim 1, further comprising menthyl lactate.

4. The persistent hair restorer according to claim 3, wherein the blending amount of menthyl lactate is 0.1 to 5 W / of the whole preparation.

5. The continuous hair growth preparation according to claim 1, wherein the pH of the preparation is in the range of 5.5 to 9.5.

6. The long-lasting hair growth preparation according to claim 1, further comprising pantothenyl ethyl ether.

7. The long-lasting hair restorer according to claim 6, wherein the amount of the pantotheenyl ester is 0.5 to 1% of the whole preparation.

8. The long-lasting hair restorer according to claim 1, wherein a surfactant is not substantially contained.

9. (A) 1-5 W / V% minoxidil (B) polyethylene A method for treating baldness and thinning hair with a sustained hair growth preparation comprising a glycol, and (C) one or two selected from 1,3-butylendicol and dalyserin.

10. (A) 1-5 W / V% minoxidilyl (B) polyethylene glycol, and (C) 1,3-butyleneglycol and glycerin for the production of a hair restorer or a hair restorer Use of a composition consisting of one or two selected from the group consisting of: