Abstract:
A pharmaceutical preparation for endermic application is disclosed which comprises indomethacin and at least one solubilizer selected from the group consisting of a C 10  terpenoid and a C 10  phenol.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to a novel preparation of indomethacin for endermic application. 
     2. Description of the Prior Art 
     Indomethacin is an excellent non-steroidal, analgesic and antiphlogistic agent. It can however be hardly dissolved in water nor in various solvents which are generally usable as bases for endermic application. Indomethacin is slightly dissolvable in benzyl alcohol,tetrahydrofuran, dimethylsulfoxide, dimethylformamide and the like. The indomethacin solutions thus dissolved suffer some problems in the formation of a preparation suitable for endermic application, from both viewpoints of the concentration and potency of indomethacin. Therefore, indomethacin has been heretofore administered in the form of an oral preparation. 
     The present inventors have made many studies of preparations of indomethacin for endermic application and have already succeeded in obtaining an endermically-applicable preparation having excellent absorptivity through the skin by incorporating indomethacin in an alcohol-water system and then forming the resultant mixture into a gelated ointment, as disclosed in Japanese Patent Publication No. 10886/1981. Such gelated ointment has been recently marketed and has been found highly valuable in its clinical application. 
     The present inventors have conducted continuous research with a view toward developing new dosable forms of the endermically-applicable indomethacin preparation and bases therefor. As a result, it has been discovered that certain types of terpenoids and phenols can enhance the solubiliy and stability of indomethacin in bases and hence permit indomethacin to be incorporated in a variety of bases for endermic application. This discovery has led to the present invention. 
     SUMMARY OF THE INVENTION 
     This invention provides a pharmaceutical preparation for endermic application, which comprises indomethacin and one or more solubilizers selected from the group consisting of C 10  terpenoids and C 10  phenols. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Eligible terpenoids having 10 carbon atoms and useful as solubilizers in the practice of the invention include hydrocarbonaceous terpenes such as limonene, pinene, camphene and cymene; alcoholic terpenes such as citronellol, geraniol, nellol, linalol, menthol, terpineol, rosinol, borneol and iso-borneol; and ketone-type terpenes such as menthone and camphor. On the other hand, eligible phenols having 10 carbon atoms include thymol, safrole, iso-safrole, eugenol, iso-eugenol and the like. These solubilizers may be used singly or in combination. The content of such solubilizers when used either alone or in combination may vary depending on the content of indomethacin and the type and amount of a solvent utilized. However, the solubilizers are capable of producing satisfactory results when incorporated in a total amount of 0.3-10% by weight. 
     Eligible solvents useful in dissolving indomethacin include alcohols such as ethanol and propanol; mixed alcohol-water systems; glycols such as butylene glycol and propylene glycol; vegetable oils such as olive oil and soybean oil; liquid higher fatty acids such as oleic acid, linoleic acid and linolenic acid; higher alcohols such as octyl alcohol and hexadecyl alcohol; hydrocarbons such as paraffin and squalane; esters of C 4  -C 14  monocarboxylic acids and C 1  -C 5  alcohols; and diesters of C 4  -C 10  dicarboxylic acids and C 1  -C 3  alcohols. 
     A pharmaceutical preparation for endermic application according to the invention may be produced by dissolving indomethacin together with at least one solubilizer in one or more of the above-described solvents, or by further incorporating the thus formed solution in another base for endermic application. Preferably, indomethacin is added in an amount of 0.1-5% by weight. 
     Eligible forms of the pharmaceutical preparation for endermic application which are obtainable in such manner include, for example, a liquid preparation, an ointment, a gelated ointment, cream, a plaster and the like. 
     Since the addition of one or more of these solubilizers in a small amount can significantly increase the solubility and stability of indomethacin in various solvents, the resultant indomethacin solutions may be incorporated in a wide variety of bases for endermic application, thus providing endermically-applicable preparations of various forms. Thus, the solubilizers contemplated by the invention are extremely effectively useful. 
     The invention will now be described in further detail with reference to certain specific experiment and preparation examples which are provided for illustration purposes only and are not construed to be limiting. 
     Experiment 1: 
     Solubility Test on Indomethacin 
     A large excess of indomethacin was added to each of a variety of solvents, followed by addition of one of the solubilizers given in Table 1. The resultant mixture was shaken for 24 hours at 25° C. and then subjected to centrifugal separation. The supernatant was collected. The content of indomethacin in the supernatant was determined by the UV method or the HPLC method and compared with that in a supernatant having no stabilizer added thereto. The results are shown in Tables 1 and 2. 
     
                                           TABLE 1__________________________________________________________________________   Solubilizer   None   (Weight dissolved)             l-Menthol                   l-Menthol                         l-MentholSolvent (mg/ml)   3%    5%    10%__________________________________________________________________________100% Ethanol   100       130   140   150   (17.4) 80% Ethanol   100       140   200   270   (8.0) 60% Ethanol   100       160   350   440   (2.4) 50% Ethanol   100       350   x     x    (0.75)Isopropyl   100       210   x     xmyristate   (1.3)Octylodecyl   100       190   x     xmyristate   (0.5)Propanol   100       180   x     x   (7.5)__________________________________________________________________________ Note: The figures are expressed in terms of percentage to the weight of indomethacin dissolved without any solubilizer added in their corresponding solvents. The symbol x indicates that the solubilizer was not dissolved in the solvent. 
    
     
                                           TABLE 2__________________________________________________________________________       SolventSolubilizer 100% Ethanol               80% Ethanol                      60% Ethanol                             50% Ethanol__________________________________________________________________________None (weight dissolved)       100     100    100    100(mg/ml)     (17.4)  (8.0)  (2.4)  (0.75)dl-Camphor 3%       120     150    170    270dl-Camphor 5%       160     190    230    400dl-Camphor 10%       200     230    390    xEugenol 3%  140     160    170    xEugenol 5%  400     190    250    xD-limonene 3%       140     170    x      xD-limonene 5%       250     200    x      x__________________________________________________________________________ Note: The figures and the symbol x have the same significance as given in Table 1. 
    
     Preparation Example 1: (Ointment) 
     
         ______________________________________Indomethacin         0.5    (wt. %)Geraniol             5.0Eugenol              5.0Vaseline             80.5Solid paraffin       5.0Cetanol              2.0Isopropyl myristate  2.0______________________________________ 
    
     Preparation Example 2: (Gelated Preparation) 
     
         ______________________________________Indomethacin         1.0    (wt. %)l-Menthol            3.0Propylene glycol     12.0Carboxyvinyl polymer 1.0(CARBOPOLE 934)Diisopropanol amine  1.0Ethanol              40.0Purified water       Balance to 100.0______________________________________ 
    
     Preparation Example 3: (Liquid Preparation) 
     
         ______________________________________Indomethacin          2.0    (wt. %)l-Menthol             10.0Ethanol               45.0Aqueous ammonia (10%) 0.2Purified water        Balance to 100.0______________________________________ 
    
     Preparation Example 4: (O/W Cream) 
     
         ______________________________________Indomethacin          0.8    (wt. %)Camphor               2.0Diisopropyl adipate   20.0Chrotamiton           2.0Glyceryl monostearate 10.0Polyoxyethylene cetyl ether                 3.0Methylparaben         0.1Propylparaben         0.1Purified water        Balance to 100.0______________________________________ 
    
     Preparation Example 5: (Plaster) 
     
         ______________________________________Indomethacin        1.0    (wt. %)Methyl salicylate   2.0l-Menthol           3.0Diethyl sebacate    5.0Raw rubber          40.0Zinc flower         20.0Rosin               29.0______________________________________ 
    
     This invention now being fully described, it should be noted that various changes and modifications may be made thereto without departing from the spirit or scope of the invention as set forth herein.