Abstract:
A soft gelatin capsule preparation of a 1α-hydroxy-vitamin D which contains sorbic acid or its salt and a process for preparing the preparation are disclosed. Sorbic acid or its salt which is incorporated in a soft gelatin capsule and/or an oily diluent acts as a preservative for gelatin and as a stabilizer for the vitamin D.

Description:
FIELD OF THE INVENTION 
     This invention relates to a stabilized preparation of a 1α-hydroxy-vitamin D encapsulated in a soft gelatin capsule and a process for preparing the same. 
     BACKGROUND OF THE INVENTION 
     In recent years, a vitamin D having a hydroxy group at 1 α position, for example, 1α-hydroxy-vitamin D 3  or 1α,25-dihydroxy-vitamin D 3  has been given attention due to its strong vitamin D activities. 
     However, since vitamin D is usually used in a very small dose per single administration, it is difficult to give a predetermined exact amount per unit dose in case the vitamin D is formulated in the form of pill or tablet. Further, vitamin D is very sensitive to exposure to light, particularly to ultraviolet light and, therefore, its handling or treatment should be effected under light-intercepted conditions and also a pharmaceutical preparation containing the vitamin D should be stored without exposure to light. 
     From the viewpoint of stability of the vitamin D, the most desirable process for manufacturing a pharmaceutical preparation is to dissolve 1α-hydroxy-vitamin D in an oily diluent and then encapsulate the solution with a soft capsule. 
     The encapsulation in a soft gelatin capsule is advantageous because the press-through-pack can be employed with the use of transparent plastic film capable of intercepting ultraviolet light to reduce the deactivation of the vitamin D due to the exposure to ultraviolet light. 
     However, the inventors of this invention experimentally found that, even in case 1α-hydroxy-vitamin D was dissolved in an oily diluent and encapsulated in a soft gelatin capsule and the capsule preparation was subjected to the press-through-pack to intercept ultraviolet light, a considerable amount of 1α-hydroxy-vitamin D contained in the preparation lost its vitamin D activities. 
     The inventors continued their study on such deactivation phenomenon to find that the phenomenon is induced due to the effect of a p-hydroxybenzoic ester which is conventionally incorporated into a soft gelatin capsule as a preservative for gelatin. On the other hand, since gelatin, the base material for a capsule is putrescible and especially, such putrefaction is accelerated in case a soft gelatin capsule contains a softening agent, such as glycerin, polyethylene glycol, propylene glycol or the like, for preventing the capsule from hardening, a preservative should be present in the capsule. 
     The inventors focused their study on the preservative for gelatin and found that sorbic acid or its salt which is a suitable preservative does not induce the deactivation of a 1α-hydroxy-vitamin D and, besides, heightens its stability. Based on these facts, they finally completed the present invention. 
     SUMMARY OF THE INVENTION 
     According to the present invention, a capsule preparation containing a 1α-hydroxy-vitamin D in a stabilized state and a process for preparing such capsule preparation can be provided. The preparation comprises a soft gelatin capsule filled with a solution of a 1α-hydroxy-vitamin D in an oily diluent. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     A 1α-hydroxy-vitamin D which may be applied to the present invention includes a vitamin D having a hydroxyl group at 1α position, for example, 1α-hydroxy-vitamin D 3 , 1α,25-dihydroxy-vitamin D 3 , 1α,24-dihydroxy-vitamin D 3  or the like. 
     For an oily diluent, any oil which is liquid around room temperature and does not decompose a 1α-hydroxy-vitamin D may be used in the present invention, but a triglyceride of fatty acid, an unsaturated middle chain fatty acid such as linoleic acid, cotton seed oil, olive oil, corn oil and the like are preferable. 
     Sorbic acid may be used as it is or as a pharmaceutically acceptable salt, but sorbic acid, or sodium or potassium sorbate is preferable. It will be understood that a mixture of sorbic acid with one or more salts in any suitable proportion may be used in the present invention. Sorbic acid, its salt or a mixture thereof is preferably present in a soft gelatin capsule in an amount of from 0.2 to 1% by weight based on the total weight of the capsule or preferably present in an amount of from 0.005 to 1% by weight based on the diluent. 
     The thus formulated and encapsulated vitamin D is recognized to be highly stable. 
     The present invention is further illustrated by the following Experiments and Examples, but they are not to be construed as limiting the scope of this invention. 
     Experiment 1 
     For comparison, various capsule preparations containing 1α-hydroxy-vitamin D 3  were prepared as disclosed in the Example 1 hereinbelow except for the use of a capsule containing a different preservative or containing no preservative. These capsule preparations and the capsule preparation prepared in Example 1 were covered by a transparent film capable of intercepting ultraviolet light and exposed to sunbeams for 2 weeks. After the exposure, the amount of active 1α-hydroxy-vitamin D 3  in each of the capsule preparations was determined by the use of high speed liquid chromatography. 
     The test results are shown in Table 1 below. Incidentally, the value shown in Table 1 is the amount of 1α-hydroxy-vitamin D 3  as calculated by assuming the amount of 1α-hydroxy-vitamin D 3  in the preservative free capsule to be 100. 
     
                       Table 1______________________________________Preservative             Value______________________________________not used                 100methyl p-hydroxybenzoate 64ethyl p-hydroxybenzoate  67propyl p-hydroxybenzoate 70butyl p-hydroxybenzoate  70isopropyl p-hydroxybenzoate                    69isobutyl p-hydroxybenzoate                    71sodium tetrahydroxyacetate                    85sodium benzoate          87sorbic acid              115potassium sorbate        124sodium sorbate           122______________________________________ 
    
     Experiment 2 
     By the method similar to that described in Experiment 1, the effect of sorbic acid or its salt for reducing the deactivation of some vitamin D 3  was determined by the use of the capsule preparation prepared in Example 2 hereinbelow. 
     The test results are shown in Table 2 below. In Table 2, the value is the amount of each vitamin D 3  as calculated by assuming the amount of each vitamin D 3  dissolved in the diluent free from sorbic acid or its salt. 
     
                       Table 2______________________________________                       1α,25-                               1α,24-Test    Concent- 1α-hydroxy-                       dihydroxy-                               dihydroxy-Compound   ration   vitamin D.sub.3                       vitamin D.sub.3                               vitamin D.sub.3______________________________________not used   --       100        100     100sorbic acid   0.05%    128        131     120   0.50%    126        136     123potassium   0.005%   108        --      --sorbate 0.02%    124        --      --sodium  0.01%    --         110     --sorbate 0.05%    --         115     --______________________________________ 
    
     Example 1 
     In a triglyceride of middle-chain fatty acid (O.D.O.: manufactured by Nisshin Seiyu Kabushiki Kaisha) was dissolved 1α-hydroxy-vitamin D 3  at a concentration of 10 μg/ml. Separately, the ingredients specified below were blended while warming to form a fusion. 
     
         ______________________________________Ingredients    Proportion (parts by weight)______________________________________Gelatin        10Glycerin       5Preservative   0.08Purified water 14______________________________________ 
    
     The fusion was formed to soft gelatin capsule which was filled with the solution of 1α-hydroxy-vitamin D 3  in an amount of 1 μg per each capsule in a conventional manner by the use of an encapsulating machine. 
     EXAMPLE 2 
     In the triglyceride of middle chain fatty acid (O.D.O.) was dissolved sorbic acid or its salt in a predetermined amount and then to the resulting solution was dissolved a 1α-hydroxy-vitamin D 3  at a concentration of 10 μg/ml. In the same manner as described in Example 1, the above solution was charged in the soft gelatin capsule to form a soft gelatin capsule preparation. The used capsule was the same as that of Example 1 except for containing no preservative therein.