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 means for sustained release of the ruxolitinib phosphate,
wherein the ruxolitinib phosphate is present in the dosage form in an amount ranging from 10 mg to 60 mg on a free base basis,
wherein the dosage form is suitable for oral administration,
wherein the administration of the dosage form results in a ratio of mean peak to plasma concentration (C max ) to mean 12-hour plasma concentration (C 12h ) of ruxolitinib of 10 or less, and
wherein the 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 12.5 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 20 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 25 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 30 mg on a free base basis.
7. The oral sustained release dosage form of claim 1 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 37.5 mg on a free base basis.
8. 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.
9. 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.
10. The oral sustained release dosage form of claim 1 , wherein the ruxolitinib phosphate is present in the dosage form in an amount of 60 mg on a free base basis.
11. 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.
12. 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.
13. 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.
14. The oral sustained-release dosage form of claim 1 , wherein the sustained-release dosage form has a mean relative bioavailability based on AUC of from 65% to 110% relative to an immediate release formulation comprising the same amount of ruxolitinib phosphate in humans.
15. The oral sustained-release dosage form of claim 1 , wherein the dosage form is a tablet.
16. The oral sustained-release dosage form of claim 1 , wherein the dosage form is a capsule.
17. 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.
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 1 once per day.
19. The method of claim 18 , wherein the disease is myelofibrosis.
20. The method of claim 19 , wherein the myelofibrosis is primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (PV-MF), or post-essential thrombocythemia myelofibrosis (post ET-MF).
21. The method of claim 18 , wherein the disease is polycythemia vera.
22. The method of claim 18 , wherein the disease is graft versus host disease.
23. The method of claim 18 , 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.