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
a sustained-release matrix former, which is a cellulosic ether;
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;
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, 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.
2. The oral sustained-release dosage form of claim 1 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 10 mg on a free base basis.
3. The oral sustained-release dosage form of claim 1 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 20 mg on a free base basis.
4. The oral sustained-release dosage form of claim 1 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 30 mg on a free base basis.
5. The oral sustained-release dosage form of claim 1 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 40 mg on a free base basis.
6. The oral sustained-release dosage form of claim 1 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 50 mg on a free base basis.
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 1 to 10.
8. The oral sustained-release dosage form of claim 1 , wherein administration of the sustained-release 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.
9. 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.
10. The oral sustained-release dosage form of claim 1 , wherein the dosage form is a tablet.
11. The oral sustained-release dosage form of claim 1 , wherein the dosage form is a capsule.
12. 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.
13. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 1 once per day.
14. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 2 once per day.
15. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 3 once per day.
16. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 4 once per day.
17. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 5 once per day.
18. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 6 once per day.
19. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 7 once per day.
20. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 8 once per day.
21. The method of claim 13 , wherein the disease is myelofibrosis.
22. The method of claim 21 , wherein the myelofibrosis is primary myelofibrosis (PMF), post_polycythemia vera myelofibrosis (PV-MF), or post-essential thrombocythemia myelofibrosis (post ET-MF).
23. The method of claim 13 , wherein the disease is polycythemia vera.
24. The method of claim 13 , wherein the disease is graft versus host disease.
25. An oral sustained-release dosage form comprising:
ruxolitinib phosphate, and
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;
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, 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.
26. A method of treating a disease selected from myelofibrosis, polycythemia vera, and graft versus host disease in a human patient in need thereof, comprising administering to the patient the oral sustained-release dosage form of claim 25 once per day.
27. The method of claim 26 , wherein the disease is myelofibrosis.
28. The method of claim 27 , wherein the myelofibrosis is primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PV-MF), or post-essential thrombocythemia myelofibrosis (post ET-MF).
29. The method of claim 26 , wherein the disease is polycythemia vera.
30. The method of claim 26 , wherein the disease is graft versus host disease.