Hydrolyzed cellulose granulations of partial salts of drugs

Abstract

The present invention provides a method for preparing a spray-dried, compressible granular formulation for preparing pharmaceutical tablets in which essentially water-insoluble, acidic, amphoteric, and basic pharmaceutically active agents are converted to more water-soluble salts which are granulated with hydrolyzed cellulose, drug-containing slurries, the resulting granulations, capsules containing granulations, and pharmaceutical tablets compressed from such granules. In these formulations there is employed from 1% to 85% by weight of the pharmaceutically active agent in its salt form, from 5% to 99% of hydrolyzed cellulose, based on the dry weight of the granulation, and optionally, conventional granulation and/or tableting additives such as surfactants, disintegrants, and antiadherents/flow aids. Said tablets have significantly increased dissolution of the pharmaceutically active agent at the pH of the gastrointestinal tract in comparison with the unconverted free pharmaceutically active agent.

We claim:  
     
         1 . A method of improving dissolution of a relatively water-insoluble pharmaceutically active agent comprising the steps of: 
 a) mixing hydrolyzed cellulose with a water of hydration of 30 to 90% with at least one relatively water-insoluble pharmaceutically active agent, and an acid or base that is capable of reacting with said relatively water-insoluble pharmaceutically active agent in an aqueous solvent to form a salt, the amount of said acid or base being sufficient to convert at least 5% but less than 100% of said relatively water-insoluble pharmaceutically active agent to said salt, to form a mixture; and    b) drying the mixture to form granules.    
     
     
         2 . A dry granular composition comprising hydrolyzed cellulose in immixture with at least one relatively water-insoluble pharmaceutically active agent in its more water-soluble form wherein said pharmaceutically active agent in its more water-soluble salt form comprises about 30% to about 80% of said composition and comprises a mixture of ibuprofen and its potassium salt in a ratio of about 3:1 to 1:1; said hydrolyzed cellulose comprises about 20% to about 70% of said composition; said composition additionally comprising about 1% to about 10% of croscarmellose sodium, about 0.5% to about 5% of colloidial silicon dioxide, and about 0.05% to about 0.4% sodium lauryl sulfate; all percentages being by weight of the dry granules.  
     
     
         3 . The method according to  claim 1  wherein said relatively water-insoluble active agent is ibuprofen, ketoprofen, or naproxen.  
     
     
         4 . The method according to  claim 3  wherein said relatively water-insoluble pharmaceutically active agent is ibuprofen.  
     
     
         5 . The method according to  claim 1  wherein said mixture comprises at least about 10% to about 60% solids by weight.  
     
     
         6 . The method according to  claim 1  wherein said granules comprise at least about 97.5% solids by weight.  
     
     
         7 . The product of the method of  claim 1 .  
     
     
         8 . A product according to  claim 7  that comprises more than 97.5% solids by weight.  
     
     
         9 . A product according to  claim 7  wherein said granules comprise: 
 a) about 1% to about 95% by weight of said salt; and  
 b) about 5% to about 99% by weight of said hydrolyzed cellulose.  
 
     
     
         10 . A product according to  claim 9  wherein said granules are substantially porous and substantially spherical.  
     
     
         11 . A compressed pharmaceutical tablet comprising the product according to  claim 10 .  
     
     
         12 . The method of improving dissolution of a relatively water-insoluble pharmaceutically active agent comprising the steps of: 
 a) mixing hydrolyzed cellulose with a water of hydration of 30-90% with at least one relatively water-insoluble pharmaceutically active agent, and an acid or base that is capable of reacting with said relative water-insoluble pharmaceutically active agent to form a salt, the amount of said acid or base being insufficient to convert 100% of said relatively water-insoluble pharmaceutically active agent to said salt, to form a mixture; and    b) drying the mixture to form granules.    
     
     
         13 . The method according to  claim 12  wherein said relatively water-insoluble pharmaceutically active agent is ibuprofen, ketoprofen, or naproxen.  
     
     
         14 . The method according to  claim 12  wherein said mixture comprises at least about 10% to about 60% solids by weight.  
     
     
         15 . The method according to  claim 12  wherein said granules comprise at least about 97.5% solids by weight.  
     
     
         16 . The product of the method of  claim 12 .  
     
     
         17 . A product according to  claim 16  that comprises more than 97.5% solids by weight.