Sustained release dosage forms for a JAK1 inhibitor

1. A method of treating a disease selected from psoriasis, rheumatoid arthritis, primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis in a patient in need thereof, comprising orally administering to said patient a once-daily dose of about 400 mg to about 600 mg on a free base basis of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, wherein the dose comprises one or more sustained release dosage forms each comprising {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, wherein treating refers to inhibiting or ameliorating the disease.

2. A method according to claim 1 , wherein the method comprises administering to said patient the one or more sustained release dosage forms as a once-daily dosage of about 600 mg on a free base basis of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

3. A method according to claim 1 , wherein the one or more sustained release dosage forms are six dosage forms of about 100 mg on a free base basis of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

4. A method according to claim 1 , wherein the one or more sustained release dosage forms are three dosage forms of about 200 mg on a free base basis of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

5. A method according to claim 1 , wherein the one or more sustained release dosage forms are two dosage forms of about 300 mg on a free base basis of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

6. A method according to claim 1 , wherein the one or more sustained release dosage forms is one dosage form of about 600 mg on a free base basis of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

7. A method according to claim 2 , wherein said disease is rheumatoid arthritis.

8. A method according to claim 7 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than about 40%.

9. A method according to claim 7 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than about 50%.

10. A method according to claim 2 , wherein said disease is psoriasis.

11. A method according to claim 10 , wherein the Psoriasis Area and Severity Index-50 score (PASI 50) is greater than about 70%.

12. A method according to claim 2 , wherein said disease is primary myelofibrosis (PMF).

13. A method according to claim 12 , wherein the method results in a reduced total symptom score (TSS) of said patient compared with baseline.

14. A method according to claim 12 , wherein said method results in reduced anemia.

15. A method according to claim 2 , wherein oral administration of one or more sustained release dosage forms to a fasted individual provides a mean time to peak plasma concentration (T max ) of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile of about 0.5 hours to about 3 hours.

16. A method according to claim 2 , wherein oral administration of one or more sustained release dosage forms to a fasted individual provides a ratio of mean peak plasma concentration (C max ) to mean 12-hour plasma concentration (C 12h ) of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile of about 15 to about 30.

17. A method according to claim 2 , wherein oral administration of one or more sustained release dosage forms to an individual after a high-fat meal provides a mean time to peak plasma concentration (T max ) of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile of at least 1.5 hours.

18. A method according to claim 2 , wherein oral administration of one or more sustained release dosage forms to an individual after a high-fat meal provides a ratio of mean peak plasma concentration (C max ) to mean 12-hour plasma concentration (C 12h ) of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile of about 25 to about 45.

19. A method according to claim 2 , wherein oral administration of one or more sustained release dosage forms to an individual after a high-fat meal provides a mean half-life (t 1/2 ) of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile of about 2 hours to about 5 hours.

20. A method according to claim 2 , wherein the one or more sustained release dosage forms are each a tablet.

21. A method according to claim 20 , wherein the one or more sustained release dosage forms are prepared by process comprising wet granulation.

22. A method according to claim 21 , wherein the one or more sustained release dosage forms each comprises one or more hypromelloses.

23. A method according to claim 21 , wherein the one or more sustained release dosage forms each comprises one or more excipients independently selected from hypromelloses and microcrystalline celluloses.

24. A method according to claim 21 , wherein the one or more sustained release dosage forms each comprises one or more excipients independently selected from hypromelloses, microcrystalline celluloses, magnesium stearate, lactose, and lactose monohydrate.

25. A method according to claim 21 , wherein the one or more sustained release dosage forms each comprises a first hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of about 80 cP to about 120 cP and a second hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of about 3000 cP to about 5600 cP.

26. A method according to claim 21 , wherein the one or more sustained release dosage forms each comprises about 10% to about 15% by weight of one or more hypromelloses.

27. A method according to claim 21 , wherein the one or more sustained release dosage forms each comprises about 16% to about 22% by weight of microcrystalline cellulose.

28. A method according to claim 21 , wherein the one or more sustained release dosage forms each comprises about 45% to about 55% by weight of lactose monohydrate.

29. A method according to claim 2 , wherein said salt is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.

30. The method of claim 2 , wherein the disease is post-polycythemia vera myelofibrosis.

31. The method of claim 2 , wherein the disease is post-essential thrombocythemia myelofibrosis.