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 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);
wherein the pharmaceutical composition meets one or more bioequivalence criteria when administered to healthy human subjects under fasted conditions as compared to a reference composition administered to the subjects under fasted conditions;
wherein the reference composition is a conventional immediate-release nilotinib formulation comprising crystalline nilotinib monohydrochloride monohydrate;
wherein the amount of nilotinib in the pharmaceutical composition is 50% to 80% less than the amount of nilotinib in the reference composition; and
wherein the one or more bioequivalence criteria is selected from:
(a) a 90% confidence interval for AUC, which is between 80% and 125%; and
(b) a 90% confidence interval for C max , which is between 80% and 125%.
2. The pharmaceutical composition 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%.
3. The pharmaceutical composition of claim 1 , wherein the one or more polymers consists essentially of a hydroxypropyl methylcellulose acetate succinate.
4. The pharmaceutical composition of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib and the one or more polymers.
5. The pharmaceutical composition 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).
6. The pharmaceutical composition 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).
7. The pharmaceutical composition of claim 1 , wherein the amount of nilotinib in the pharmaceutical composition is 60% to 80% less than the amount of nilotinib in the reference composition.
8. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, and comprising 25 mg to 100 mg nilotinib.
9. The pharmaceutical composition of claim 1 , wherein the reference composition comprises 200 mg crystalline nilotinib monohydrochloride monohydrate presented in capsule form.
10. The pharmaceutical composition of claim 1 , wherein the AUC is AUC 0-24h .
11. The pharmaceutical composition of claim 1 , wherein the AUC is AUC last .
12. The pharmaceutical composition of claim 1 , wherein the AUC is AUC inf .
13. 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);
wherein the pharmaceutical composition meets one or more bioequivalence criteria when administered to healthy human subjects under fed conditions as compared to a reference composition administered to the subjects under fasted conditions;
wherein the reference composition is a conventional immediate-release nilotinib formulation comprising crystalline nilotinib monohydrochloride monohydrate;
wherein the amount of nilotinib in the pharmaceutical composition is 50% to 80% less than the amount of nilotinib in the reference composition; and
wherein the one or more bioequivalence criteria is selected from:
(a) a 90% confidence interval for AUC, which is between 80% and 125%; and
(b) a 90% confidence interval for C max , which is between 80% and 125%.
14. The pharmaceutical composition of claim 13 , 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 pharmaceutical composition of claim 13 , wherein the one or more polymers consists essentially of a hydroxypropyl methylcellulose acetate succinate.
16. The pharmaceutical composition of claim 13 , wherein the amorphous solid dispersion consists essentially of nilotinib and the one or more polymers.
17. The pharmaceutical composition of claim 13 , 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).
18. The pharmaceutical composition of claim 13 , 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).
19. The pharmaceutical composition of claim 13 , wherein the amount of nilotinib in the pharmaceutical composition is 60% to 80% less than the amount of nilotinib in the reference composition.
20. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, and comprising 25 mg to 100 mg nilotinib.
21. The pharmaceutical composition of claim 13 , wherein the reference composition comprises 200 mg crystalline nilotinib monohydrochloride monohydrate presented in capsule form.
22. The pharmaceutical composition of claim 13 , wherein the AUC is AUC 0-24h .
23. The pharmaceutical composition of claim 13 , wherein the AUC is AUC last .
24. The pharmaceutical composition of claim 13 , wherein the AUC is AUC inf .