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. 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 said ruxolitinib phosphate is present in said 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 oral sustained-release dosage form of claim 1 , wherein administration of the dosage form to a human results in a mean peak plasma concentration (C max ) of ruxolitinib of 700 nM or less.
3. The oral sustained-release dosage form of claim 1 , wherein administration of the dosage form to a human results in a mean peak plasma concentration (C max ) of ruxolitinib of 200 to 700 nM.
4. The oral sustained-release dosage form of claim 1 , wherein administration of the dosage form to a human results in a mean peak plasma concentration (C max ) of ruxolitinib of 300 to 400 nM.
5. The oral sustained-release dosage form of claim 1 , wherein administration of the dosage form to a human state results in a mean time to peak plasma concentration (T max ) of ruxolitinib of 1.5 hours or more.
6. The oral sustained-release dosage form 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.
7. The oral sustained-release dosage form 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 4 or less.
8. The oral sustained-release dosage form of claim 1 , 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.
9. The oral sustained-release dosage form of claim 1 , wherein administration of a single dose of the dosage form to a human results in mean bioavailability (AUC 0-∞ ) of ruxolitinib of 3000 to 4000 nM*h.
10. The oral sustained-release dosage form of claim 1 , wherein administration of a single dose of the dosage form to a human results in mean bioavailability (AUC 0-∞ ) of ruxolitinib of 3100 to 3800 nM*h.
11. The oral sustained-release dosage form of claim 1 , which is in the form of a tablet or capsule.
12. The oral sustained-release dosage form of claim 1 , wherein administration to a human results in a ruxolitinib plasma level of 75 to 500 nM for 8 hours.
13. The oral sustained-release dosage form of claim 1 , wherein administration to a human results in a ruxolitinib plasma level of 75 to 500 nM for 12 hours.
14. The oral sustained-release dosage form of claim 1 , wherein administration of said 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 100×109/L.
15. The oral sustained-release dosage form of claim 14 , wherein administration of said 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 80×109/L.
16. The oral sustained-release dosage form of claim 14 , wherein administration of said 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 60×109/L.
17. The oral sustained-release dosage form of claim 14 , wherein administration of said 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 40×109/L.
18. The oral sustained-release dosage form of claim 1 , wherein administration of said 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.
19. The oral sustained-release dosage form of claim 18 , wherein administration of said dosage form to a human once-daily for at least 16 weeks results in a mean decrease in mean hemoglobin from baseline of no more than 10 g/L.
20. The oral sustained-release dosage form of claim 18 , wherein administration of said dosage form to a human once-daily for 16 weeks results in a mean decrease in mean hemoglobin from baseline of no more than 8 g/L.
21. The oral sustained-release dosage form of claim 18 , wherein administration of said dosage form to a human once-daily for 16 weeks results in a mean decrease in mean hemoglobin from baseline of no more than 6 g/L.
22. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 10 mg on a free base basis.
23. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 12.5 mg on a free base basis.
24. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 20 mg on a free base basis.
25. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 30 mg on a free base basis.
26. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 37.5 mg on a free base basis.
27. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 40 mg on a free base basis.
28. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 50 mg on a free base basis.
29. The oral sustained-release dosage form of claim 1 , wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in the dosage form in an amount of 60 mg on a free base basis.
30. The oral sustained-release dosage form 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 6 or less.
31. The oral sustained-release dosage form 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 5 or less.
32. The oral sustained-release dosage form 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.
33. The oral sustained-release dosage form 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 2 to 7.
34. An oral sustained-release oral dosage form, comprising:
ruxolitinib phosphate, and
from 10% to 30% by weight of a sustained-release matrix former, which is hydroxypropyl methylcellulose,
wherein said ruxolitinib phosphate is present in said dosage form in an amount of 10 to 60 mg on a free base basis;
wherein the dosage form is suitable for oral administration;
wherein administration of said 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; and
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.
35. The oral sustained-release dosage form of claim 34 , 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 2 to 7.
36. The oral sustained-release dosage form of claim 35 , 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.