Novel pharmaceutical dosage forms comprising valganciclovir hydrochloride

Abstract

The present invention provides novel solid pharmaceutical dosage forms for oral administration, after being constituted in water. The solid dosage forms comprise a therapeutically effective amount of valganciclovir hydrochloride and a non-hygroscopic organic acid present in an amount sufficient to stabilize the valganciclovir hydrochloride in a predetermined amount of water. The present invention also provides novel liquid pharmaceutical dosage forms for oral administration after constituting the solid pharmaceutical dosage form with water. A non-hygroscopic bulking agent may optionally be included in the above dosage form. These novel pharmaceutical dosage forms are useful in the treatment or control of viruses such as herpes simplex virus and cytomegalovirus. The present invention also provides a method for treating these diseases employing the solid and liquid pharmaceutical dosage forms and a method for preparing these pharmaceutical dosage forms.

1 . A solid pharmaceutical dosage form for oral administration, after being constituted in water, comprising:
 (a) a therapeutically effective amount of valganciclovir hydrochloride; and   (b) a non-hygroscopic organic acid present in an amount sufficient to stabilize the valganciclovir hydrochloride in a predetermined amount of water.   
     
     
         2 . The solid dosage form according to  claim 1 , wherein valganciclovir hydrochloride is present in an amount from about 10% to about 90%, by weight of the total composition. 
     
     
         3 . The solid dosage form according to  claim 1 , wherein the non-hygroscopic organic acid is selected from the group consisting of fumaric acid, succinic acid, and adipic acid. 
     
     
         4 . The solid dosage form according to  claim 4 , wherein the non-hygroscopic organic acid is fumaric acid. 
     
     
         5 . The solid dosage form according to  claim 1 , wherein the non-hygroscopic organic acid is aspartic acid or glutamic acid. 
     
     
         6 . The solid dosage form according to  claim 1 , further comprising an effective amount of a non-hygroscopic bulking agent. 
     
     
         7 . The solid dosage form according to  claim 7 , wherein the non-hygroscopic bulking agent is selected from the group consisting of mannitol and lactose. 
     
     
         8 . The solid dosage form according to  claim 8 , wherein the non-hygroscopic bulking agent is mannitol. 
     
     
         9 . The solid dosage form according to  claim 7 , wherein the non-hygroscopic bulking agent is present in an amount up to about 90% by weight of the total composition. 
     
     
         10 . The solid dosage form according to  claim 1 , wherein the dosage form has the following composition: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                   Unit Weight 
                 
                     
                   Components 
                   mg/120 mg 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Valganciclovir HCl 
                   55.15 1   
                 
                     
                   Povidone K30 
                   2.00 
                 
                     
                   Fumaric Acid 
                   2.00 
                 
                     
                   Sodium Benzoate 
                   1.00 
                 
                     
                   Sodium Saccharin 
                   0.25 
                 
                     
                   Mannitol 
                   57.80 
                 
                     
                   Tutti-Frutti Flavor 
                   1.80 
                 
                     
                     
                 
                     
                     1 Equivalent to 50 mg of valganciclovir (as free base) on a dry basis 
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A liquid pharmaceutical dosage form for oral administration comprising:
 (a) a therapeutically effective amount of valganciclovir hydrochloride;   (b) a predetermined amount of water; and   (c) a non-hygroscopic organic acid present in an amount sufficient to stabilize the valganciclovir hydrochloride in the predetermined amount of water.   
     
     
         12 . The liquid dosage form according to  claim 12 , wherein valganciclovir hydrochloride is present in an amount from about 10 mg/mL to about 90 mg/mL. 
     
     
         13 . The liquid dosage form according to  claim 12 , wherein the non-hygroscopic organic acid is selected from the group consisting of fumaric acid, succinic acid, and adipic acid. 
     
     
         14 . The liquid dosage form according to  claim 14 , wherein the non-hygroscopic organic acid is fumaric acid. 
     
     
         15 . The liquid dosage form according to  claim 12 , wherein the non-hygroscopic organic acid is an amino acid. 
     
     
         16 . The liquid dosage form according to  claim 12 , wherein the non-hygroscopic organic acid is present in the liquid dosage form in an amount sufficient to lower the pH to 3.8 or below. 
     
     
         17 . The liquid dosage form according to  claim 12 , further comprising an effective amount of a non-hygroscopic bulking agent. 
     
     
         18 . The liquid dosage form according to  claim 18 , wherein the non-hygroscopic bulking agent is selected from the group consisting of mannitol and lactose. 
     
     
         19 . The liquid dosage form according to  claim 19 , wherein the non-hygroscopic bulking agent is mannitol. 
     
     
         20 . The liquid dosage form according to  claim 18 , wherein the non-hygroscopic bulking agent is present in an amount up to about 90% by weight of the total composition. 
     
     
         21 . The liquid dosage form according to  claim 12 , wherein the dosage form has the following composition: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                   Constituted Soln 
                 
                     
                   Components 
                   Per mL 
                 
                     
                     
                 
                     
                 
                 
                 
                 
                 
               
                     
                   Valganciclovir HCl 
                   55.15 
                   mg 1   
                 
                     
                   Povidone K30 
                   2.00 
                   mg 
                 
                     
                   Fumaric Acid 
                   2.00 
                   mg 
                 
                     
                   Sodium Benzoate 
                   1.00 
                   mg 
                 
                     
                   Sodium Saccharin 
                   0.25 
                   mg 
                 
                     
                   Mannitol 
                   57.80 
                   mg 
                 
                     
                   Tutti-Frutti Flavor 
                   1.80 
                   mg 
                 
                     
                   Purified Water 
                   0.91 
                   mL 
                 
                     
                     
                 
                     
                     1 Equivalent to 50 mg of valganciclovir (as free base) on a dry basis 
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         22 . A method of treating a subject infected with a virus selected from the group consisting of herpes simplex virus and cytomegalovirus comprising administering to a patient, in need thereof, a therapeutically effective amount of a liquid pharmaceutical dosage form for oral administration comprising:
 (a) a therapeutically effective amount of valganciclovir hydrochloride;   (b) a predetermined amount of water; and   (c) a non-hygroscopic organic acid present in an amount sufficient to stabilize the valganciclovir hydrochloride in the predetermined amount of water.   
     
     
         23 . The method according to  claim 23 , wherein valganciclovir hydrochloride is present in an amount from about 10 mg/mL to about 90 mg/mL and the non-hygroscopic organic acid is present in the liquid dosage form in an amount sufficient to lower the pH to 3.8 or below. 
     
     
         24 . The method according to  claim 23  wherein the non-hygroscopic organic acid is fumaric acid. 
     
     
         25 . The method according to  claim 23 , further comprising an effective amount of a non-hygroscopic bulking agent selected from the group consisting of mannitol and lactose.