Surfactant-free HIV protease inhibitor composition and method of manufacturing thereof
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 substantially free or free of surfactant. Methods of making the compositions, and methods of using them to treat HIV infection are also provided.
1. A pharmaceutical composition comprising: a melt extrudate and an extragranular component, wherein the melt extrudate comprises a solid dispersion comprising a therapeutically effective amount of amorphous ritonavir, and a pharmaceutically acceptable aqueous-soluble polymer, and the extragranular component comprises an erosion-enhancing agent having a particle size D 50 of about 60 μm or less, wherein the composition is free of surfactant, and wherein the therapeutically effective amount of amorphous ritonavir is about 100 mg.
2. The composition of claim 1 , wherein the amorphous ritonavir is present in an amount of about 5 to about 30 wt %, based on the total weight of the composition.
3. The composition of claim 1 , wherein the aqueous-soluble polymer has a glass transition temperature (Tg) of about 80° C. to about 180° C.
4. 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 weight polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, and polysaccharides.
5. The composition of claim 1 , wherein the aqueous-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate.
6. The composition of claim 5 , wherein the aqueous-soluble polymer is copovidone.
7. 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.
8. 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.
9. The composition of claim 8 , wherein the erosion-enhancing agent is anhydrous dicalcium phosphate or its hydrate form.
10. The composition of claim 1 , wherein the erosion-enhancing agent has a particle size D 50 of about 12 μm or less.
11. 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.
12. The composition of claim 1 , further comprising a pharmaceutically acceptable excipient.
13. The composition of claim 12 , wherein the excipient comprises a lubricant.
14. The composition of claim 13 , 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.
15. The composition of claim 12 , wherein the excipient comprises a glidant.
16. The composition of claim 15 , wherein the glidant is selected from the group consisting of colloidal silica, calcium silicate, and a combination thereof.
17. The composition of claim 1 , which is in the form of a tablet or a capsule.
18. The composition of claim 17 , which is coated.
19. The composition of claim 17 , which comprises a) copovidone, and b) anhydrous dicalcium phosphate or its hydrate form.
20. The composition of claim 1 , wherein the ritonavir is in a stable amorphous form.
21. A method of making the pharmaceutical composition of claim 1 , comprising formulating a therapeutically effective amount of ritonavir, a pharmaceutically acceptable aqueous-soluble polymer, and an erosion-enhancing agent having a particle size D 50 of about 60 μm or less, into the pharmaceutical composition, wherein the composition is free of surfactant, and wherein the therapeutically effective amount of ritonavir is about 100 mg.
22. The method of claim 21 , comprising subjecting ritonavir 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.
23. A method of treating a subject infected with HIV, comprising administering to said subject the pharmaceutical composition of claim 1 .
24. The method of claim 23 , wherein the composition is in the form of a tablet or capsule.
25. A pharmaceutical composition comprising an intragranular component and an extragranular component, wherein the intragranular component comprises a therapeutically effective amount of amorphous ritonavir, and a pharmaceutically acceptable aqueous-soluble polymer, and the extragranular component comprises an erosion-enhancing agent having a particle size D 50 of about 60 μm or less, wherein the composition is free of surfactant, and wherein the therapeutically effective amount of amorphous ritonavir is about 100 mg.
26. The composition of claim 25 , wherein the aqueous-soluble polymer has a glass transition temperature (Tg) of about 80° C. to about 180° C.
27. The composition of claim 25 , 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 weight polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, and polysaccharides.
28. The composition of claim 25 , wherein the ritonavir is in a stable amorphous form.
29. The composition of claim 25 , wherein the extragranular component is free of a HIV protease inhibitor.
30. The composition of claim 25 , wherein the extragranular component consists essentially of an erosion-enhancing agent having a particle size D 50 of about 60 μm or less, and at least one excipient.
31. The composition of claim 25 , wherein the intragranular component comprises a solid dispersion comprising a therapeutically effective amount of amorphous ritonavir.
32. The composition of claim 25 , wherein the erosion-enhancing agent has a particle size D 50 of about 12 μm or less.
33. A pharmaceutical composition comprising: a melt extrudate and an extragranular component, wherein the melt extrudate comprises an amorphous solid dispersion comprising about 100 mg of ritonavir in a stable amorphous form, and a pharmaceutically acceptable aqueous-soluble polymer 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 weight polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, and polysaccharides and mixtures thereof, present in an amount of about 35 wt % to about 80 wt %, based on the total weight of the composition, and the extragranular component comprises an erosion-enhancing agent 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, present in an amount of about 5 wt % to about 20 wt %, based on the total weight of the composition and having a particle size D 50 of about 60 μm or less, wherein the composition is free of surfactant.
34. The composition of claim 33 , wherein the erosion-enhancing agent has a particle size D 50 of about 12 μm or less.
35. A pharmaceutical composition comprising: a melt extrudate and an extragranular component, wherein the melt extrudate comprises a solid dispersion comprising a therapeutically effective amount of amorphous ritonavir, and a pharmaceutically acceptable aqueous-soluble polymer, and the extragranular component comprises an erosion-enhancing agent having a particle size D 50 of about 60 μm or less, wherein the composition is free of surfactant, the therapeutically effective amount of amorphous ritonavir is about 100 mg, and the composition maintains the ritonavir in a state of supersaturation when in contact with aqueous fluids in the gastrointestinal tract.
36. The composition of claim 35 , wherein the erosion-enhancing agent has a particle size D 50 of about 12 μm or less.