Amorphous nilotinib microparticles and uses thereof
Amorphous solid dispersions and pharmaceutical compositions of the protein kinase inhibitor nilotinib. The pharmaceutical compositions may be used in methods of treating a proliferative disorder such as cancer. In some embodiments, the pharmaceutical compositions can be administered without regard to food consumption. In other embodiments, the pharmaceutical compositions can be administered at a significantly lower dose as compared to a commercially available immediate-release nilotinib formulation, while providing a comparable therapeutic effect.
1. A method of delivering nilotinib to a patient suffering from a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising an amorphous solid dispersion, the amorphous solid dispersion comprising nilotinib and one or more polymers;
wherein the one or more polymers comprises a hydroxypropyl methylcellulose acetate succinate that exhibits pH-dependent solubility;
wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 35:65 to 80:20 (nilotinib:polymer); and
wherein the administered amount of nilotinib is 50% to 80% less than a dose required for delivering a therapeutically effective amount of nilotinib in the fasted state using a conventional immediate-release crystalline nilotinib formulation.
2. The method of claim 1 , wherein the proliferative disorder is Philadelphia chromosome positive chronic myeloid leukemia.
3. The method of claim 1 , wherein the one or more polymers comprise a hydroxypropyl methylcellulose acetate succinate characterized by an acetyl substitution of 7% to 11% and a succinyl substitution of 10% to 14%.
4. The method of claim 1 , wherein the one or more polymers consists essentially of a hydroxypropyl methylcellulose acetate succinate.
5. The method of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib and the one or more polymers.
6. The method of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib and hydroxypropyl methylcellulose acetate succinate.
7. The method of claim 1 , wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 40:60 to 70:30 (nilotinib:polymer).
8. The method of claim 1 , wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 50:50 (nilotinib:polymer).
9. The method of claim 1 , wherein the administered amount of nilotinib is 60% to 80% less than the dose required for delivering a therapeutically effective amount of nilotinib in the fasted state using the conventional immediate-release crystalline nilotinib formulation.
10. The method of claim 1 , wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, wherein the solid dosage form comprises 25 mg to 100 mg nilotinib per dosage unit.
11. The method of claim 1 , wherein the conventional immediate-release crystalline nilotinib formulation comprises crystalline nilotinib monohydrochloride monohydrate presented in capsule form.
12. A method of delivering nilotinib to a patient suffering from a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising an amorphous solid dispersion, the amorphous solid dispersion comprising nilotinib free base and one or more polymers;
wherein the one or more polymers comprises a hydroxypropyl methylcellulose acetate succinate that exhibits pH-dependent solubility;
wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 35:65 to 80:20 (nilotinib:polymer); and
wherein the administered amount of nilotinib is 50% to 80% less than a dose required for delivering a therapeutically effective amount of nilotinib in the fasted state using a conventional immediate-release crystalline nilotinib formulation.
13. The method of claim 12 , wherein the proliferative disorder is Philadelphia chromosome positive chronic myeloid leukemia.
14. The method of claim 12 , wherein the one or more polymers comprise a hydroxypropyl methylcellulose acetate succinate characterized by an acetyl substitution of 7% to 11% and a succinyl substitution of 10% to 14%.
15. The method of claim 12 , wherein the one or more polymers consists essentially of a hydroxypropyl methylcellulose acetate succinate.
16. The method of claim 12 , wherein the amorphous solid dispersion consists essentially of nilotinib free base and the one or more polymers.
17. The method of claim 12 , wherein the amorphous solid dispersion consists essentially of nilotinib free base and hydroxypropyl methylcellulose acetate succinate.
18. The method of claim 12 , wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 40:60 to 70:30 (nilotinib:polymer).
19. The method of claim 12 , wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 50:50 (nilotinib:polymer).
20. The method of claim 12 , wherein the administered amount of nilotinib is 60% to 80% less than the dose required for delivering a therapeutically effective amount of nilotinib in the fasted state using the conventional immediate-release crystalline nilotinib formulation.
21. The method of claim 12 , wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, wherein the solid dosage form comprises 25 mg to 100 mg nilotinib per dosage unit.
22. The method of claim 12 , wherein the conventional immediate-release crystalline nilotinib formulation comprises crystalline nilotinib monohydrochloride monohydrate presented in capsule form.