Effer-vescent bisphosphonate formulation

Abstract

An effervescent formulation of alendronate contains an acid source, a carbonate source, a binder, a lubricant and optionally, flavoring agents, colorants and sweeteners.

What is claimed is:  
     
         1 . An effervescent pharmaceutical formulation comprising as an active ingredient a bisphosphonate selected from the groups consisting of: alendronate, cimadronate, clodronate, EB-1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, pharmaceutically acceptable salts and esters of the foregoing, and mixtures of the foregoing; and 
 an acid source selected from the group consisting of: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid; an anhydride of said acids; an acid salt selected from the group consisting of sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate and sodium acid sulfite; and mixtures of the acids, anhydrides and acid salts; a carbonate source selected from the group consisting of: sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, and mixtures thereof;    a binder selected from the group consisting of a non-reducing sugar, polyvinyl pyrrolidone, sodium chloride, sodium benzoate and sodium sulfate;    a lubricant selected from the group consist of stearic acid salts, powdered sodium benzoate, L-leucine, sodium laurel sulfate and PEG; and    optionally, one or more additional agents selected from the group consisting of flavoring agents, colorants, and sweeteners.    
     
     
         2 . An effervescent pharmaceutical formulation according to  claim 1  wherein the active ingredient comprises alendronate or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising: an acid source selected from the group consisting of: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid; an anhydride of said acids; an acid salt selected from the group consisting of sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate and sodium acid sulfite; and mixtures of the acids, anhydrides and acid salts; a carbonate source selected from the group consisting of: sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, and mixtures thereof; 
 wherein the acid source is present in an equal or excess amount compared to the carbonate source, based on molecular equivalent amounts;  
 a binder selected from the group consisting of mannitol, sorbitol, polyvinyl pyrrolidone, lactose, sodium chloride, sodium benzoate and sodium sulfate;  
 a lubricant selected from the group consist of stearic acid salts, powdered sodium benzoate, L-leucine, sodium laurel sulfate and PEG; and  
 optionally, one or more additional agents selected from the group consisting of flavoring agents, colorants, and sweeteners.  
 
     
     
         3 . A formulation according to  claim 2  wherein the amount of alendronate or salt thereof is from 1-80 mg.  
     
     
         4 . A formulation according to  claim 3  wherein the acid source is citric acid, tartaric acid or mixtures thereof.  
     
     
         5 . A formulation according to  claim 3  wherein the carbonate source is sodium bicarbonate, sodium carbonate, and mixtures thereof.  
     
     
         6 . A formulation according to  claim 5  wherein the mole ratio of citric acid to bicarbonate is from 1:1 to 1:3.  
     
     
         7 . A formulation according to  claim 5  wherein the binder is mannitol, lactose, dextrose or sorbitol.  
     
     
         8 . A formulation comprising (in mg):  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Alendronate sodium 
                    5-10 mg 
                 
                     
                   (in mg alendronic acid) 
                 
                     
                   citric acid 
                   600-750 
                 
                     
                   sodium bicarbonate 
                   300-500 
                 
                     
                   sodium carbonate 
                    20-60 
                 
                     
                   sodium benzoate 
                    5-15 
                 
                     
                   water 
                    0-5. 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         9 . A formulation according to  claim 8 , further comprising a flavoring agent or a colorant.  
     
     
         10 . A formulation comprising (in mg):  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Alendronate sodium 
                    5-10 
                 
                     
                   (in mg alendronic acid) 
                 
                     
                   citric acid 
                   450-650 
                 
                     
                   sodium bicarbonate (total) 
                   800-1150. 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A formulation comprising (in mg):  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Alendronate sodium 
                   2.5-10  
                 
                     
                   (in mg alendronic acid) 
                 
                     
                   citric acid 
                   400-800 
                 
                     
                   sodium bicarbonate 
                   1000-2000 
                 
                     
                   sodium carbonate 
                   20-80 
                 
                     
                   sodium benzoate 
                    25-175 
                 
                     
                   xylitol 
                    100-300. 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . A formulation made by the process of combining:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Alendronate sodium 
                   2.5-10  
                 
                     
                   (in mg alendronic acid) 
                 
                     
                   citric acid 
                   400-800 
                 
                     
                   sodium bicarbonate 
                   1000-2000 
                 
                     
                   sodium carbonate 
                   20-80 
                 
                     
                   sodium benzoate 
                    25-175 
                 
                     
                   xylitol 
                    100-300.