Pharmaceutical microspheres containing valproic acid for oral administration

Abstract

The subject of the invention is pharmaceutical microspheres containing, as active principle, a mixture of valproic acid and of one of its pharmaceutically acceptable salts in combination with a matrix vehicle selected from glycerol esters, hydrogenated oils, esterified polyethylene glycols, waxes and their mixtures.

1 . Pharmaceutical microspheres, containing, as active principle, a mixture of valproic acid and of one of its pharmaceutically acceptable salts in combination with a matrix vehicle selected from glycerol esters, hydrogenated oils, esterified polyethylene glycols or waxes and their mixtures.  
     
     
         2 . Pharmaceutical microspheres according to  claim 1 , wherein the pharmaceutically acceptable salt is an alkali metal salt or an alkaline-earth metal salt.  
     
     
         3 . Pharmaceutical microspheres according to  claim 1  or  2 , wherein the alkali metal salt is the sodium salt.  
     
     
         4 . Pharmaceutical microspheres according to  claim 1  or  2 , wherein the alkaline-earth metal salt is the calcium or magnesium salt.  
     
     
         5 . Pharmaceutical microspheres according to one of  claims 1  to  4 , wherein the active principle is composed of at least 5% by weight either of valproic acid or of pharmaceutically acceptable salt of this acid.  
     
     
         6 . Microspheres according to one of  claims 1  to  5 , wherein the active principle is composed of a mixture of 15% to 60% by weight of valproic acid and of 40% to 85% by weight of pharmaceutically acceptable salt of this acid.  
     
     
         7 . Microspheres according to one of  claims 1  to  6 , wherein the active principle is composed of a mixture of 25% to 35% by weight of valproic acid and of 65% to 75% by weight of pharmaceutically acceptable salt of this acid.  
     
     
         8 . Microspheres according to one of  claims 1  to  7 , containing at most 35% by weight of active principle.  
     
     
         9 . Microspheres according to one of  claims 1  to  8 , containing from 30% to 35% by weight of active principle.  
     
     
         10 . Pharmaceutical microspheres according to one of  claims 1  to  9 , wherein: 
 the glycerol esters are saturated or unsaturated fatty acid glycerides containing up to 80 carbon atoms  
 the esterified polyethylene glycols are saturated polyglycolysed glycerides.  
 
     
     
         11 . Pharmaceutical microspheres according to  claim 10 , wherein the saturated polyglycolysed glycerides are mixtures of glycerol monoesters, diesters and triesters and of polyethylene glycol mono- and diesters.  
     
     
         12 . Pharmaceutical microspheres according to one of  claims 1  to  11 , wherein: 
 the glycerol ester is glyceryl tribehenate, glyceryl palmitate/stearate, glyceryl monostearate, glyceryl monooleate or caprylic/capric glycerides,  
 the hydrogenated oil is hydrogenated castor oil  
 the wax is natural beeswax or synthetic beeswax or a paraffin.  
 
     
     
         13 . Pharmaceutical microspheres according to one of  claims 1  to  12 , wherein the matrix vehicle is natural beeswax.  
     
     
         14 . Pharmaceutical microspheres according to one of  claims 1  to  13 , wherein the melting point of the matrix vehicle is between 50° C. and 120° C.  
     
     
         15 . Pharmaceutical microspheres according to  claim 14 , wherein the melting point of the matrix vehicle is between 70° C. and 90° C.  
     
     
         16 . Pharmaceutical microspheres according to one of  claims 1  to  15 , containing from 30% to 35% of active principle in combination with a matrix vehicle composed of beeswax.  
     
     
         17 . Pharmaceutical microspheres according to  claim 16 , wherein the active principle is formed of 25% to 35% of valproic acid and of 65% to 75% of a pharmaceutically acceptable salt of valproic acid.  
     
     
         18 . Pharmaceutical microspheres according to  claim 16  or  17 , wherein the pharmaceutically acceptable salt is the sodium salt.  
     
     
         19 . Process for the preparation of pharmaceutical microspheres according to one of  claims 1  to  18 , wherein: 
 valproic acid and the pharmaceutically acceptable salt of this acid are added to the matrix vehicle in the molten form and the resulting mixture is maintained with stirring until a clear fluid is obtained,  
 the mixture in the clear form thus obtained is forced through a nozzle which is subjected to vibration, whereby droplets are formed at the outlet of the nozzle and carried by gravity into a tower in which a cold gas moves in a counter-currentwise direction,  
 the microspheres are collected in the bottom of the tower.  
 
     
     
         20 . Pharmaceutical forms for oral administration, containing microspheres according to one of  claims 1  to  18 .  
     
     
         21 . Pharmaceutical forms according to  claim 20 , corresponding to tablets, capsules, including hard gelatin capsules, or powders packaged in chartulas or in systems for dispensing unit doses.  
     
     
         22 . Pharmaceutical forms according to  claim 20  or  21 , containing agents which facilitate flow, lubricants, inorganic fillers and/or sweeteners.