Combination formulation of two antiviral compounds

Abstract

Disclosed are pharmaceutical compositions having an effective amount of substantially amorphous ledipasvir and an effective amount of substantially crystalline sofosbuvir.

We claim: 
     
         1 . A pharmaceutical composition comprising:
 a) an effective amount of ledipasvir having the formula:   
       
         
           
           
               
               
           
         
       
       wherein the ledipasvir is substantially amorphous; and
 b) an effective amount of sofosbuvir having the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein the sofosbuvir is substantially crystalline. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein ledipasvir is formulated as a solid dispersion comprising ledipasvir dispersed within a polymer matrix formed by a pharmaceutically acceptable polymer. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the polymer is copovidone. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the weight ratio of ledipasvir to copovidone in the solid dispersion is about 1:1. 
     
     
         5 . The pharmaceutical composition of  claim 3 , comprising
 a) about 40% w/w of sofosbuvir and   b) about 18% w/w of the solid dispersion comprising ledipasvir.   
     
     
         6 . The pharmaceutical composition of  claim 5 , further comprising
 a) about 5 to about 25% w/w lactose monohydrate,   b) about 5 to about 25% w/w microcrystalline cellulose,   c) about 1 to about 10% w/w croscarmellose sodium,   d) about 0.5 to about 3% w/w colloidal silicon dioxide, and   e) about 0.1 to about 3% w/w magnesium stearate.   
     
     
         7 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 1 , comprising about 90 mg of ledipasvir and about 400 mg of sofosbuvir. 
     
     
         8 . The pharmaceutical dosage form of  claim 7 , wherein the ledipasvir is formulated as a solid dispersion within a polymer matrix of copovidone. 
     
     
         9 . The pharmaceutical dosage form of  claim 8 , wherein the amount of copovidone is about 90 mg. 
     
     
         10 . The pharmaceutical dosage form of  claim 9 , further comprising:
 (a) about 165 mg of lactose monohydrate;   (b) about 180 mg of microcrystalline cellulose;   (c) about 50 mg of croscarmellose sodium;   (d) about 10 mg of colloidal silicon dioxide; and   (e) about 15 mg of magnesium stearate.   
     
     
         11 . The pharmaceutical dosage form of  claim 9  which is in the form of a tablet comprising a film coating. 
     
     
         12 . A method of treating a patient infected with hepatitis C virus comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the pharmaceutical composition is administered for about 24 weeks or less. 
     
     
         14 . The method of  claim 12 , wherein the pharmaceutical composition is administered for about 12 weeks or less. 
     
     
         15 . The method of  claim 12 , wherein the pharmaceutical composition is administered for about 8 weeks or less. 
     
     
         16 . The method of  claim 12 , wherein the pharmaceutical composition is administered for about 6 weeks or less. 
     
     
         17 . The method of  claim 12 , wherein the pharmaceutical composition is administered once daily for about 12 weeks or less and wherein the hepatitis C virus is genotype 1, 2, 3, 4, 5, or 6. 
     
     
         18 . The method of  claim 12 , wherein the pharmaceutical composition is administered once daily for about 8 weeks or less and wherein the hepatitis C virus is genotype 1, 2, 3, 4, 5, or 6. 
     
     
         19 . The method of  claim 12 , wherein the pharmaceutical composition is administered once daily for about 6 weeks or less and wherein the hepatitis C virus is genotype 1, 2, 3, 4, 5, or 6. 
     
     
         20 . The method of  claim 17 , wherein the hepatitis C virus is genotype 1a or 1b. 
     
     
         21 . The method of  claim 18 , wherein the hepatitis C virus is genotype 1a or 1b. 
     
     
         22 . The method of  claim 19 , wherein the hepatitis C virus is genotype 1a or 1b. 
     
     
         23 . The method of  claim 12 , wherein the pharmaceutical composition is administered once daily for about 12 weeks and wherein the hepatitis C virus is genotype 1a, 1b, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 3e, 3f, 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 5a, or 6a. 
     
     
         24 . The method of  claim 12 , wherein the pharmaceutical composition is administered once daily for about 8 weeks and wherein the hepatitis C virus is genotype 1a, 1b, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 3e, 3f, 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 5a, or 6a. 
     
     
         25 . The method of  claim 12 , further comprising administering ribavirin. 
     
     
         26 . The method of  claim 12 , wherein the treatment does not include interferon. 
     
     
         27 . The method of  claim 12 , wherein the treatment does not include ribavirin. 
     
     
         28 . The method of  claim 12 , wherein the treatment does not include interferon or ribavirin. 
     
     
         29 . The method of  claim 12 , further comprising administering an NS3 protease inhibitor. 
     
     
         30 . The method of  claim 12 , further comprising administering simeprevir.