Claims for Patent: 11,389,450

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Summary for Patent: 11,389,450

Title:	Amorphous nilotinib microparticles and uses thereof
Abstract:	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.
Inventor(s):	Christian F. Wertz, Tzehaw Chen, Joseph McTarsney
Assignee:	Flex Pharma LLC
Application Number:	US17/238,869
Patent Claims:	1. A method of safely delivering nilotinib to a patient suffering from a proliferative disorder, the method comprising: (a) 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; and (b) administering a meal to the patient; wherein steps (a) and (b) occur within less than two hours of each other; 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 60 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 proliferative disorder is chronic phase Philadelphia chromosome positive chronic myeloid leukemia resistant or intolerant to prior tyrosine kinase inhibitor therapy. 4. 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%. 5. The method of claim 1, wherein the one or more polymers consists essentially of a hydroxypropyl methylcellulose acetate succinate. 6. The method of claim 1, wherein the amorphous solid dispersion comprises one or more antioxidants that are present in an amount of 0.001% to 2% by weight of the amorphous solid dispersion. 7. The method of claim 6, wherein the one or more antioxidants comprises butylated hydroxytoluene. 8. The method of claim 1, wherein the amorphous solid dispersion consists essentially of nilotinib and the one or more polymers. 9. 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). 10. 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). 11. The method of claim 1, comprising the amorphous solid dispersion and one or more pharmaceutically acceptable additives. 12. The method of claim 1, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration. 13. The method of claim 1, wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, and comprising 25 to 100 mg nilotinib. 14. A method of delivering a therapeutically relevant exposure of nilotinib to a patient suffering from a proliferative disorder without regard to whether the patient is in a fasted state or a fed state, comprising administering to the patient 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 60 to 80% less than a dose required for delivering a therapeutically relevant exposure of nilotinib in the fasted state using a conventional immediate-release crystalline nilotinib formulation. 15. The method of claim 14, wherein administration of the pharmaceutical composition to the patient in a fed state results in plasma Cmax of nilotinib that is within 30% of the plasma Cmax of nilotinib resulting from administration of the pharmaceutical composition to the patient in a fasted state. 16. The method of claim 14, wherein administration of the pharmaceutical composition to the patient in a fed state results in plasma AUC of nilotinib that is within 30% of the plasma AUC of nilotinib resulting from administration of the pharmaceutical composition to the patient in a fasted state. 17. The method of claim 14, wherein administration of the pharmaceutical composition to the patient in a fed state results in plasma Cmax of nilotinib that is within 25% of the plasma Cmax of nilotinib resulting from administration in a fasted state of the dose of the immediate-release crystalline nilotinib formulation. 18. The method of claim 14, wherein administration of the pharmaceutical composition to the patient in a fed state results in plasma AUC of nilotinib that is within 25% of the plasma AUC of nilotinib resulting from administration in a fasted state of the dose of the immediate-release crystalline nilotinib formulation. 19. The method of claim 14, 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%. 20. The method of claim 14, wherein the one or more polymers consists essentially of a hydroxypropyl methylcellulose acetate succinate. 21. The method of claim 14, wherein the amorphous solid dispersion comprises one or more antioxidants that are present in an amount of 0.001% to 2% by weight of the amorphous solid dispersion. 22. The method of claim 21, wherein the one or more antioxidants comprises butylated hydroxytoluene. 23. The method of claim 14, wherein the amorphous solid dispersion consists essentially of nilotinib and the one or more polymers. 24. The method of claim 14, 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). 25. The method of claim 14, 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). 26. The method of claim 14, wherein the pharmaceutical composition comprises the amorphous solid dispersion and one or more pharmaceutically acceptable additives. 27. The method of claim 14, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration. 28. The method of claim 14, wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, and comprising 25 to 100 mg nilotinib.