Sustained-release dosage forms of ruxolitinib
The present invention relates to sustained-release formulations and dosage forms of ruxolitinib, or a pharmaceutically acceptable salt thereof, which are useful in the treatment of Janus kinase-associated diseases such as myeloproliferative disorders.
1. A method of treating a disease selected from myelofibrosis, polycythemia vera, or graft versus host disease in a patient in need thereof, comprising administering an oral sustained-release dosage form, comprising:
ruxolitinib phosphate, and
from about 10% to about 30% by weight of a sustained-release matrix former, which is hydroxypropyl methylcellulose,
wherein the ruxolitinib phosphate is present in the dosage form in an amount of 10 to 60 mg on a free base basis;
wherein the dosage form is suitable for oral administration; and
wherein administration of the dosage form to a human results in a ratio of mean peak plasma concentration (C max ) to mean 12-hour plasma concentration (C 12h ) of ruxolitinib of 10 or less.
2. The method of claim 1 , wherein the disease is myelofibrosis.
3. The method of claim 2 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 10 mg on a free base basis.
4. The method of claim 2 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 20 mg on a free base basis.
5. The method of claim 2 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 30 mg on a free base basis.
6. The method of claim 2 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 40 mg on a free base basis.
7. The method of claim 2 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 50 mg on a free base basis.
8. The method of claim 2 , wherein administration of the dosage form to a human results in a mean half-life (t 1/2 ) of from 3.5 hours to 11 hours.
9. The method of claim 2 wherein administration of the dosage form to a human results in a mean half-life (t 1/2 ) of from 4 hours to 8 hours.
10. The method of claim 2 , wherein the myelofibrosis is primary myelofibrosis (PMF).
11. The method of claim 2 , wherein the myelofibrosis is postpolycythemia vera myelofibrosis (PV-MF).
12. The method of claim 2 , wherein the myelofibrosis is post-essential thrombocythemia myelofibrosis (post ET-MF).
13. The method of claim 1 , wherein the disease is polycythemia vera (PV).
14. The method of claim 13 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 10 mg on a free base basis.
15. The method of claim 13 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 20 mg on a free base basis.
16. The method of claim 13 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 30 mg on a free base basis.
17. The method of claim 13 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 40 mg on a free base basis.
18. The method of claim 13 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 50 mg on a free base basis.
19. The method of claim 13 , wherein administration of the dosage form to a human results in a mean half-life (t 1/2 ) of from 3.5 hours to 11 hours.
20. The method of claim 13 wherein administration of the dosage form to a human results in a mean half-life (t 1/2 ) of from 4 hours to 8 hours.
21. The method of claim 1 , wherein the disease is graft versus host disease.
22. The method of claim 21 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 10 mg on a free base basis.
23. The method of claim 21 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 20 mg on a free base basis.
24. The method of claim 21 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 30 mg on a free base basis.
25. The method of claim 21 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 40 mg on a free base basis.
26. The method of claim 21 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 50 mg on a free base basis.
27. The method of claim 21 , wherein administration of the dosage form to a human results in a mean half-life (t 1/2 ) of from 3.5 hours to 11 hours.
28. The method of claim 21 wherein administration of the dosage form to a human results in a mean half-life (t 1/2 ) of from 4 hours to 8 hours.
29. The method of claim 1 , wherein administration of the dosage form to a human results in a mean time to peak plasma concentration (T max ) of ruxolitinib of 1.5 hours to 5 hours.
30. The method of claim 1 , wherein the dosage form is in the form of a tablet or capsule.
31. The method of claim 1 , wherein administration of the dosage form to a human once-daily for 16 weeks results in a mean decrease in mean platelet count from baseline of no more than 100×10 9 /L.
32. The method of claim 1 , wherein administration of the dosage form to a human once-daily for 16 weeks results in a mean decrease in mean hemoglobin from baseline of no more than 15 g/L.
33. The method of claim 1 , wherein administration of the dosage form to a human results in a ratio of mean peak plasma concentration (C max ) to mean 12-hour plasma concentration (C 12h ) of ruxolitinib of 1 to 10.
34. The method of claim 1 , wherein administration of the dosage form to a human patient results in a reduction in thrombocytopenia or anemia relative to an immediate-release dosing regimen.