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 an anionic polymer comprising phthalate functionality;
wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 20:80 to 95:5 (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 nilotinib is present in the amorphous solid dispersion as nilotinib free base.
4. The method of claim 1 , wherein the nilotinib is present in the amorphous solid dispersion as nilotinib hydrochloride.
5. The method of claim 1 , wherein the anionic polymer comprising phthalate functionality includes hydroxypropyl methylcellulose phthalate.
6. The method of claim 1 , wherein the anionic polymer comprising phthalate functionality includes polyvinyl acetate phthalate.
7. The method of claim 1 , wherein the amorphous solid dispersion includes one or more functional components selected from the group consisting of antioxidants, wetting agents, and solubilizers.
8. The method of claim 1 , wherein the amorphous solid dispersion includes one or more solubilizers.
9. The method of claim 8 , wherein the one or more solubilizers comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
10. The method of claim 8 , wherein the one or more solubilizers comprises d-α-tocopherol acid polyethylene glycol (PEG) 1000 succinate.
11. The method of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib and the anionic polymer comprising phthalate functionality.
12. The method of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib and hydroxypropyl methylcellulose phthalate.
13. The method of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib and polyvinyl acetate phthalate.
14. The method of claim 1 , wherein the nilotinib and the anionic polymer comprising phthalate functionality are present in the amorphous solid dispersion in a w/w ratio of 25:75 to 90:10 (nilotinib:polymer).
15. The method of claim 1 , wherein the pharmaceutical composition comprises the amorphous solid dispersion and one or more pharmaceutically acceptable additives.
16. The method of claim 15 , wherein the one or more pharmaceutically acceptable additives includes one or more solubilizers.
17. The method of claim 16 , wherein the one or more solubilizers comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
18. The method of claim 16 , wherein the one or more solubilizers comprises d-α-tocopherol acid polyethylene glycol (PEG) 1000 succinate.
19. The method of claim 1 , wherein the conventional immediate-release crystalline nilotinib formulation comprises 200 mg crystalline nilotinib monohydrochloride monohydrate presented in capsule form.