Abstract:
Minoxidil preparations having a sustained action by which a fully satisfactory effect of stimulating hair growth can be obtained when applied once a day.  
     Namely, hair growth stimulant compositions with a sustained action, which comprise (A) 2 to 6% by mass of minoxidil and (B) 5 to 30% by mass of a mixture of 1,3-butylene glycol or dipropylene glycol with glycerol blended at a weight ratio of 10:1 to 1:4, exert an excellent effect of stimulating hair growth.

Description:
TECHNICAL FIELD  
         [0001]    The present invention relates to a hair growth stimulant composition with sustained action (sustained release hair growth composition) comprising minoxidil as an active component, and more particularly to a sustained release hair growth composition possessing a prolonged effect achieved by retaining minoxidil in the dermis of the scalp for a long period of time.  
         BACKGROUND ART  
         [0002]    The chemical name for minoxidil is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide. The adaptation of minoxidil as a hair growth agent is disclosed in U.S. Pat. No. 4,139,619. Due to the excellent hair growth obtained by the topical application of minoxidil, hair growth agents containing minoxidil (hereinafter referred to as “minoxidil preparations”) have been widely accepted and their sales volume is record breaking.  
           [0003]    Because minoxidil preparations have to be applied several times a day, application tends to be forgotten during busy times. As a result, there are instances where a sufficient hair growth effect is not obtained. Research has been conducted to obtain a sustained release minoxidil preparation having a sufficient hair growth effect through a once-per-day application to coincide with the rhythm of human life, however there are currently very few sustained release minoxidil preparations that can satisfactorily accomplish this.  
           [0004]    The present invention was accomplished in light of this situation to obtain a sustained release minoxidil preparation having an excellent hair growth effect through a once-per-day application.  
         DISCLOSURE OF THE INVENTION  
         [0005]    To investigate the conditions under which the percutaneously absorbed minoxidil was stably retained in the dermis of the scalp, the present inventors examined the composition of the minoxidil preparation. As a result, the inventors have discovered that the above objective can be accomplished using a solution of a specific dihydric alcohol and a specific trihydric alcohol, thereby completing the present invention.  
           [0006]    Accordingly, an object of the present invention is to provide a sustained release hair growth composition comprising (A) 2 to 6% by mass of minoxidil and (B) 5 to 30% by mass of a mixture of 1,3-butylene glycol or dipropylene glycol with glycerol blended at a weight ratio of 10:1 to 1:4. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWING  
       [0007]    [0007]FIG. 1 is a graph showing the measurement results of the concentration of minoxidil in the blood for the preparations of the present invention and a comparative preparation. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0008]    The sustained release hair growth composition of the present invention is produced by mixing 5 to 30% by mass (hereinafter simply referred to as “%”) of a mixture of 1,3-butylene glycol or dipropylene glycol with glycerol blended at a weight ratio of 10:1 to 1:4 (component (B)) and 2 to 6% of the active component minoxidil (component (A)), respectively for the total amount of the composition.  
         [0009]    The sustained release hair growth composition even more preferably contains 3 to 6% of the component (A) (minoxidil) In view of sustained release action, the amount of the component (B) is preferably 10% or more and even more preferably 14% or more. In view of feeling during use, the amount is preferably 20% or less. Also, in view of the solubility of minoxidil and feeling during use of the hair growth composition, the incorporated amount of the component (B) (weight ratio; hereinafter the same) in regard to the component (A) is even more preferably in a range of about 1:1 to 1:5.  
         [0010]    In the present invention, a mixture of 1,3-butylene glycol or dipropylene glycol as the dihydric alcohol and glycerol as the trihydric alcohol with a weight ratio of 10:1 to 1:4 must be used as the component (B). 1,3-butylene glycol or dipropylene glycol and glycerol at a weight ratio of 6:1 to 1:1 are even more preferable. The dihydric alcohol of the component (B) may be a mixture of 1,3-butylene glycol and dipropylene glycol.  
         [0011]    The sustained release hair growth composition of the present invention is composed of the above composition, however, when necessary ethanol and water may be combined with the composition. In this instance, a preferable range for the incorporated amount of ethanol is about 40 to 82% and a preferable range for the incorporated amount of water is 5 to 30%.  
         [0012]    The sustained release-hair growth composition of the present invention is preferably adjusted to a pH of 5.5 to 9.5, and even more preferably to a pH of 5.5 to 6.5. An acid and/or base may be used as the pH adjustor for adjusting the pH. As preferable examples of the pH adjustor, citric acid, hydrochloric acid, lactic acid, phosphoric acid, and the like can be given.  
         [0013]    In addition to the above components, other necessary active components and supplementary components may be added to the sustained release hair growth composition of the present invention. As medicinal components that are preferably added to and combined with the sustained release hair growth composition of the present invention, components selected from the group consisting of menthol, vitamin E acetate, pantothenylethylether, hinokitiol, glycyrrhetic acid, and diphenhydramine hydrochloride can be given (hereinafter referred to as “optional components”). Of these optional components, menthol and pantothenylethylether are preferable in view of sustained release action.  
         [0014]    There are no particular limitations to the amount of these optional components to be added. This can be decided experimentally while taking the feeling during use and stability of minoxidil or solvent-type components into consideration. For example, the final composition preferably contains about 0.2 to 0.4% of menthol, a particularly preferable optional component.  
         [0015]    In addition to the above components, the sustained release hair growth composition of the present invention may contain various active components and supplementary components normally used in topical preparations in an amount that does not harm the effect of the present invention. Examples of these components include fillers, vasodilators (carpronium chloride, benzyl nicotinate, swertia herb extract, panax ginseng extract, capsicum tincture, and the like), antihistamines (isothipendyl hydrochloride and the like), anti-inflammatory agents (guaiazulene and the like), keratolytics (urea, salicylic acid, and the like), antimicrobial agents (chlorhexidine gluconate, isopropyl methylphenol, quaternary ammonium salts, piroctone olamine, and the like), humectants (sodium hyaluronate, chondroitin sulfuric acid, and the like), extracts of animals and plants ( Taxus cuspidata, Paeonia suffruticosa, Glycyrrhisa uralensis, Hypericum erectum , aconite root,  Eriobotrya japonica, Artemisia capillaris, Symphytum officinale, Angelica keiskei, Crocus sativus, Gardeniae fructus, Rosmarinus officinalis, Salvia officinalis, Saussurea lappa, Aristolochia debilis, Lupuli strobilus , placenta, and the like), vitamins (retinol acetate, pyridoxine hydrochloride, ascorbic acid, thiamin nitrate, cyanocobalamin, biotin, and the like), anti-oxidants (dibutylhydroxytoluene, sodium pyrosulfite, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, and the like), solubilizers (diisopropyl adipate, isopropyl myristate, vegetable oils, animal oils, alkyl glyceryl ethers, hydrocarbons, and the like), metabolic activators, gelling agents (water-soluble high molecular compounds and the like), adhesives, perfumes, refrigerants (mentha oil, camphor, and the like), dyes, and the like.  
         [0016]    However, since the addition of surfactants affects the cutaneous absorption of minoxidil and decreases the feeling during use, it is preferable that the sustained release hair growth composition of the present invention does not substantially contain surfactants.  
         [0017]    The sustained release hair growth composition of the present invention thus obtained can be used as a suitable topical preparation such as a lotion, aerosol, tonic, cream, ointment, gel, and the like.  
       EXAMPLES  
       [0018]    The present invention will be described in more detail by examples, which should not be construed as limiting the present invention.  
       Example 1  
       [0019]    Sustained Release Hair Growth Lotion:  
         [0020]    2 g of minoxidil, 7 g of 1,3-butylene glycol, 3 g of glycerol, and 60.05 g of ethanol were mixed and stirred until dissolved. Next, purified water was added to the mixture to obtain 100 ml of a lotion (preparation 1).  
       Example 2  
       [0021]    Using the components shown in Tables 1-9, lotion preparations 2-38 (products of the present invention) were prepared in the same manner as in Example 1. Likewise, the lotion preparations 39-41 (comparative products) were prepared using the components shown in Table 10. Using the following test method, the concentration of minoxidil in the blood for the lotion products of the present invention and the comparative lotion products was measured. These results showed that minoxidil in the products of the present invention was released more slowly and retained for a longer period of time.  
         [0022]    (Composition)  
                                                 TABLE 1                                   Preparation 1   Preparation 2   Preparation 3                                    minoxidil      2 g      2 g      2 g       1,3-butylene glycol      7 g      6 g      5 g       glycerol      3 g      4 g      5 g       ethanol   60.05 g   60.05 g   60.05 g       purified water   balance*   balance*   balance*       pH   8.6   8.7   8.7                          
 
         [0023]    [0023]                                                         TABLE 2                                   Preparation 4   Preparation 5   Preparation 6   Preparation 7                                    minoxidil      3 g      3 g      5 g      5 g       1,3-butylene      6 g      5 g     10 g     15 g       glycol       glycerol      4 g      5 g     10 g     15 g       ethanol   60.05 g   60.05 g   51.47 g   42.89 g       purified water   balance*   balance*   balance*   balance*       pH   8.8   8.8   9.0   8.9                            
         [0024]    [0024]                                                                 TABLE 3                                   Prepara-   Prepara-   Prepara-   Prepara-   Prepara-           tion 8   tion 9   tion 10   tion 11   tion 12                                    minoxidil      3 g      3 g      3 g      5 g      5 g       1,3-butylene      7 g      6 g      5 g     17 g     15 g       glycol       glycerol      3 g      4 g      5 g      3 g      5 g       ethanol   60.05 g   60.05 g   60.05 g   51.47 g   51.47 g       citric acid   proper   —   —   —    1.0 g           amount       phosphoric   —   proper   —   —   —       acid       amount       lactic acid   —   —   proper   —   —                   amount       hydrochloric   —   —   —   proper   —       acid               amount       sodium   —   —   —   —   proper       hydroxide                   amount       purified   balance*   balance*   balance*   balance*   balance*       water       pH   6.0   6.0   5.5   5.6   6.5                            
         [0025]    [0025]                                                                 TABLE 4                                   Prepara-   Prepara-   Prepara-   Prepara-   Prepara-           tion 13   tion 14   tion 15   tion 16   tion 17                                    minoxidil      5 g      5 g      5 g      5 g      5 g       1,3-butylene     18 g     15 g     13 g     12 g     10 g       glycol       glycerol      3 g      5 g      7 g      8 g     10 g       ethanol   60.05 g   60.05 g   60.05 g   60.05 g   60.05 g       citric acid   proper   —   —   —   —           amount       phosphoric   —   proper   —   —   —       acid       amount       lactic acid   —   —   proper   —    1.0 g                   amount       hydrochloric   —   —   —   proper   —       acid               amount       sodium   —   —   —   —   proper       hydroxide                   amount       purified   balance*   balance*   balance*   balance*   balance*       water       pH   6.0   6.0   5.5   5.6   6.5                            
         [0026]    [0026]                                                 TABLE 5                                   Preparation 18   Preparation 19   Preparation 20                                    minoxidil      2 g      2 g      2 g       dipropylene glycol      7 g      6 g      5 g       glycerol      3 g      4 g      5 g       ethanol   60.05 g   60.05 g   60.05 g       purified water   balance*   balance*   balance*       pH   8.6   8.7   8.6                            
         [0027]    [0027]                                                         TABLE 6                                   Preparation   Preparation   Preparation   Preparation           21   22   23   24                                    minoxidil      3 g      3 g      5 g      5 g       dipropylene      6 g      5 g     10 g     15 g       glycol       glycerol      4 g      5 g     10 g     15 g       ethanol   60.05 g   60.05 g   51.47 g   42.89 g       purified water   balance*   balance*   balance*   balance*       pH   8.8   8.8   8.9   9.0                            
         [0028]    [0028]                                                                 TABLE 7                                   Prepara-   Prepara-   Prepara-   Prepara-   Prepara-           tion 25   tion 26   tion 27   tion 28   tion 29                                    minoxidil      3 g      3 g      3 g      5 g      5 g       dipropylene      7 g      6 g      5 g     17 g     15 g       glycol       glycerol      3 g      4 g      5 g      3 g      5 g       ethanol   60.05 g   60.05 g   60.05 g   51.47 g   51.47 g       citric acid   proper   —   —   —    1.0 g           amount       phosphoric   —   proper   —   —   —       acid       amount       lactic acid   —   —   proper   —   —                   amount       hydrochloric   —   —   —   proper   —       acid               amount       sodium   —   —   —   —   proper       hydroxide                   amount       purified   balance*   balance*   balance*   balance*   balance*       water       pH   6.0   6.0   5.5   5.6   6.5                            
         [0029]    [0029]                                                                 TABLE 8                                   Prepara-   Prepara-   Prepara-   Prepara-   Prepara-           tion 30   tion 31   tion 32   tion 33   tion 34                                    minoxidil      5 g      5 g      5 g      5 g      5 g       dipropylene     18 g     15 g     13 g     12 g     10 g       glycol       glycerol      3 g      5 g      7 g      8 g      10 g       ethanol   60.05 g   60.05 g   60.05 g   60.05 g   60.05 g       citric acid   proper   —   —   —   —           amount       phosphoric   —   proper   —   —   —       acid       amount       lactic acid   —   —   proper   —    1.0 g                   amount       hydrochloric   —   —   —   proper   —       acid               amount       sodium   —   —   —   —   proper       hydroxide                   amount       purified   balance*   balance*   balance*   balance*   balance*       water       pH   6.0   6.0   5.5   5.6   6.5                            
         [0030]    [0030]                                                         TABLE 9                                   Preparation   Preparation   Preparation   Preparation           35   36   37   38                                    minoxidil     5 g     5 g      5 g      5 g       dipropylene    18 g    15 g     10 g     12 g       glycol       glycerol     3 g     5 g      5 g      6 g       ethanol   60.05 g    60.05 g    60.05 g   60.05 g       citric acid   proper   —   —   —           amount       phosphoric acid   —   —   proper   —                   amount       lactic acid   —   —   —   amount                       amount       hydrochloric   —   0.2 g   —   —       acid       sodium   —   proper   —   —       hydroxide       amount       L-menthol   0.3 g   0.3 g    0.3 g    0.3 g       vitamin E   0.08 g    0.08 g    —   —       acetate       pantothenyl-     1 g     1 g      1 g      1 g       ethylether       hinokitiol   0.05 g    0.05 g    —   —       glycyrrhetic   0.1 g   0.1 g   —   —       acid       di-   0.1 g   0.1 g   —   —       phenhydramine       hydrochloride       purified water   balance*   balance*   balance*   balance*       pH   6.0   6.1   6.0   6.0                            
         [0031]    [0031]                                                 TABLE 10                                   Preparation 39   Preparation 40   Preparation 41                                    minoxidil      2 g      3 g      5 g       1,3-butylene glycol     10 g    12 10 g     10 g       glycerol   —   —   —       ethanol   60.05 g   60.05 g   60.05 g       citric acid   —   —   proper amount       purified water   balance*   balance*   balance*       pH   8.7   8.8   6.0                            
         [0032]    Using the components shown in Table 11, lotion preparations 42 and 43 (products of the present invention) were prepared in the same manner as in Example 1. Likewise, lotion preparation 44 (comparative product) was prepared using the components shown in Table 11. The results of measurement of the concentration of minoxidil in the blood for the lotion products of the present invention and the comparative lotion products using the following test method are shown in FIG. 1. These results confirm that the products of the present invention release minoxidil much slower.  
                                                 TABLE 11                                   Preparation 42   Preparation 43   Preparation 44                                    minoxidil   2 g   2 g   2 g       1,3-butylene glycol   8 g   —   2 g       dipropylene glycol   —   8 g   —       glycerol   8 g   8 g   2 g       ethanol   50 g    50 g    50 g        phosphoric acid   0.1 ml   0.1 ml   —       purified water   balance*   balance*   balance*       pH   6.0   6.0   8.7                          
 
         [0033]    (Test Method)  
         [0034]    Male Wistar rats (8 weeks old), whose abdominal hairs were shaved, were positioned supine under ether anesthesia, and 30 μl of each lotion prepared with  14 C-minoxidil was applied on the defined area (2×3 cm) of the abdomen. At each defined time period (0.5, 1, 2, 4, 6, 8, and 24 hours), blood was collected from the jugular vein, and the concentration of minoxidil in the blood was measured using a liquid scintillation counter.  
       Example 4  
       [0035]    An aerosol was prepared by filling an aerosol can with 30 ml of the lotion prepared in Example 1 and 70 ml of dimethyl ether. In the same manner, an aerosol was prepared using the lotion of Example 2.