Surfactant-free hiv protease inhibitor composition and method of manufacturing thereof

Abstract

Disclosed are pharmaceutical compositions, e.g., in the form of tablets, containing a therapeutically effective amount of an HIV protease inhibitor, e.g., ritonavir, a pharmaceutically acceptable aqueous-soluble polymer, and an erosion-enhancing agent having a particle size distribution in the range of about 1 μm to about 350 μm, wherein the composition is free or substantially free of surfactant. Methods of making the compositions, and methods of using them to treat HIV infection, are also provided.

1 . A pharmaceutical composition containing a therapeutically effective amount of an HIV protease inhibitor, a pharmaceutically acceptable aqueous-soluble polymer, and an erosion-enhancing agent having a particle size distribution in the range of about 1 μm to about 350 μm, wherein the composition is substantially free of surfactant. 
     
     
         2 . The composition of  claim 1 , wherein the HIV protease inhibitor is selected from the group consisting of ritonavir, lopinavir, saquinavir, nelfinavir, amprenavir, atazanavir, fosamprenavir, tipranavir, darunavir, simeprevir and indinavir. 
     
     
         3 . The composition of  claim 2 , wherein the HIV protease inhibitor is ritonavir. 
     
     
         4 . The composition of  claim 1 , wherein the HIV protease inhibitor is present in an amount of about 5 to about 30 wt %, based on the total weight of the composition. 
     
     
         5 . The composition of  claim 4 , wherein the therapeutically effective amount of the HIV protease inhibitor is about 25 mg to about 300 mg. 
     
     
         6 . The composition of  claim 3 , wherein the therapeutically effective amount of ritonavir contained therein is about 100 mg. 
     
     
         7 . The composition of  claim 1 , wherein the aqueous-soluble polymer has a glass transition temperature (Tg) of about 80° C. to about 180° C. 
     
     
         8 . The composition of  claim 1 , wherein the aqueous-soluble polymer is selected from the group consisting of homopolymers and copolymers of N-vinyl lactams, copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, cellulose esters, cellulose ethers, high molecular polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, and polysaccharides. 
     
     
         9 . The composition of  claim 8 , wherein the aqueous-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate. 
     
     
         10 . The composition of  claim 9 , wherein the aqueous-soluble polymer is copovidone. 
     
     
         11 . The composition of  claim 1 , wherein the aqueous-soluble polymer is present in an amount of about 35 wt % to about 80 wt %, based on the total weight of the composition. 
     
     
         12 . The composition of  claim 1 , wherein the erosion-enhancing agent is selected from the group consisting of anhydrous dicalcium phosphate or its hydrate form, sodium chloride, potassium chloride, citric acid, tartaric acid, and succinic acid, and combinations of two or more thereof. 
     
     
         13 . The composition of  claim 12 , wherein the erosion-enhancing agent is anhydrous dicalcium phosphate or its hydrate form. 
     
     
         14 . The composition of  claim 1 , wherein the particle size distribution of the erosion-enhancing agent is about 10 μm to about 150 μm. 
     
     
         15 . The composition of  claim 14 , wherein the particle size distribution of the erosion-enhancing agent is about 150 μm. 
     
     
         16 . The composition of  claim 14 , wherein the particle size distribution of the erosion-enhancing agent is about 60 μm. 
     
     
         17 . The composition of  claim 14 , wherein the particle size distribution of the erosion-enhancing agent is about 12 μm. 
     
     
         18 . The composition of  claim 1 , wherein the erosion-enhancing agent is present in an amount of about 5 wt % to about 20 wt %, based on the total weight of the composition. 
     
     
         19 . The composition of  claim 1 , further comprising a pharmaceutically acceptable excipient. 
     
     
         20 . The composition of  claim 19 , wherein the excipient comprises a lubricant. 
     
     
         21 . The composition of  claim 20 , wherein the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, and glyceryl behenate, and combinations of two or more thereof. 
     
     
         22 . The composition of  claim 19 , wherein the excipient comprises a glidant. 
     
     
         23 . The composition of  claim 22 , wherein the glidant is selected from the group consisting of colloidal silica and calcium silicate, and combinations thereof. 
     
     
         24 . The composition of  claim 1 , which is in the form of a tablet. 
     
     
         25 . The composition of  claim 1 , which is in the form of a capsule. 
     
     
         26 . The composition of  claim 24 , which is coated. 
     
     
         27 . The composition of  claim 1 , which is free of surfactant. 
     
     
         28 . The composition of  claim 1 , which has a dose-adjusted AUC 0-inf  in humans under fasting conditions of about 9305 ng*hr/ml or an AUC 0-inf  in humans under fed conditions of about 4666 ng*hr/ml. 
     
     
         29 . A method of making a pharmaceutical composition, comprising formulating a therapeutically effective amount of an HIV protease inhibitor, a pharmaceutically acceptable aqueous-soluble polymer, and an erosion-enhancing agent having a particle size distribution in the range of about 1 μm to about 350 μm, into the pharmaceutical composition, wherein the composition is substantially free of surfactant. 
     
     
         30 . The method of  claim 29 , comprising subjecting the HIV protease inhibitor and the aqueous-soluble polymer to hot melt extrusion, thus forming an extrudate, milling the extrudate and the erosion-enhancing agent, and compressing the milled extrudate and erosion-enhancing agent into a tablet. 
     
     
         31 . The method of  claim 29 , wherein the HIV protease inhibitor is ritonavir. 
     
     
         32 . The method of  claim 29 , wherein the composition is free of surfactant. 
     
     
         33 . A method of treating a subject infected with HIV, comprising administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of an HIV protease inhibitor, a pharmaceutically acceptable aqueous-soluble polymer, and an erosion-enhancing agent having a particle size distribution in the range of about 1 μm to about 350 μm, wherein the composition is substantially free of surfactant. 
     
     
         34 . The method of  claim 33 , wherein the composition is in the form of a tablet or capsule. 
     
     
         35 . The method of  claim 33 , wherein the HIV protease inhibitor is ritonavir. 
     
     
         36 . The method of  claim 33 , wherein the composition is free of surfactant. 
     
     
         37 . (canceled)