Sustained-release dosage forms of ruxolitinib

Patent metadata

Field	Value
Publication number	US-10874616-B2
Application number	US-201816190883-A
Country	US
Kind code	B2
Filing date	Nov 14, 2018
Priority date	Nov 15, 2012
Publication date	Dec 29, 2020
Grant date	Dec 29, 2020

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Incyte Corp
• Incyte Holdings Corp

Inventors

• Ni Yong
• Parikh Bhavnish
• Yeleswaram Krishnaswamy
• Erickson-Viitanen Susan
• Williams William V

Classifications

• A61K9/2054 Primary

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title