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 one or more sustained release tablets, each comprising:

(i) {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;

(ii) a first hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of 80 cP to 120 cP;

(iii) a second hypromellose, characterized by having an apparent viscosity at a concentration of 2% in water of 3000 cP to 5600 cP,

wherein the tablet comprises 8% to 20% by weight of the first and second hypromelloses;

(iv) 16% to 22% by weight of microcrystalline cellulose; and

(v) 45% to 55% by weight of lactose monohydrate;

wherein oral administration of one or more of the sustained release tablets 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-(trifluoromethy)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile of 9 to 40.

2. The method of claim 1 , wherein oral administration of the one or more of the sustained release tablets to a fasted patient provides a ratio of mean peak plasma concentration (C max ) to mean 12-hour plasma concentration (C 12 h) 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 15 to 30.

3. The method of claim 1 , wherein oral administration of the one or more of the sustained release tablets to a patient 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 10 to 70.

4. The method of claim 1 , wherein oral administration of the one or more of the sustained release tablets to a patient 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 15 to 50.

5. The method of claim 1 , wherein oral administration of the one or more of the sustained release tablets to a patient 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 25 to 45.

6. The method of claim 1 , wherein each of the one or more sustained release tablets comprises 10% to 15% by weight of the first and second hypromelloses.

7. The method of claim 1 , 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.

8. The method of claim 1 , wherein the disease is psoriasis.

9. The method according to claim 8 , wherein the Psoriasis Area and Severity Index-50 score (PASI 50) is greater than about 70%.

10. The method of claim 1 , wherein the disease is rheumatoid arthritis.

11. The method according to claim 10 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than about 40%.

12. The method according to claim 10 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than 50%.

13. The method of claim 1 , wherein the disease is primary myelofibrosis (PMF).

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

15. The method according to claim 13 , wherein said method results in reduced anemia.

16. The method of claim 1 , wherein the disease is post-polycythemia vera myelofibrosis.

17. The method of claim 1 , wherein the disease is post-essential thrombocythemia myelofibrosis.

18. 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 one or more sustained release tablets, 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; and at least one sustained release matrix former, wherein:

(a) oral administration of one or more of the sustained release tablets to a fasted individual provides a mean peak plasma concentration (C 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 0.191 μM±0.10 μM; or

(b) oral administration of one or more of the sustained release tablets 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 0.5 hours to 3 hours; or

(c) oral administration of one or more of the sustained release tablets to a fasted individual 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 1 hour to 20 hours; or

(d) oral administration of one or more of the sustained release tablets 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 1 hour to 7 hours; or

(e) any combination of (a)-(d).

19. The method of claim 18 , wherein oral administration of one or more of the sustained release tablets to a patient 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 2 hour to 5 hours.

20. The method of claim 18 , wherein oral administration of one or more of the sustained release tablets to a fasted patient 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 4.9 h±2.6 h.

21. The method of claim 18 , wherein oral administration of one or more of the sustained release tablets to a fasted patient provides a mean peak plasma concentration (C 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 0.191 μM±0.10 μM.

22. The method of claim 18 , wherein oral administration of one or more of the sustained release tablets to a fasted patient 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 0.5 hours to 3 hours.

23. The method of claim 18 , wherein oral administration of one or more of the sustained release tablets to a fasted patient 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 1 hour to 20 hours.

24. The method of claim 18 , wherein oral administration of one or more of the sustained release tablets to a patient 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 1 hour to 7 hours.

25. The method of claim 18 , wherein the at least one sustained release matrix former is a first hypromellose and a second hypromellose, and wherein each sustained release tablet comprises 10% to 15% by weight of the first and second hypromelloses.

26. The method of claim 18 , 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.

27. The method of claim 18 , wherein the disease is psoriasis.

28. A method according to claim 27 , wherein the Psoriasis Area and Severity Index-50 score (PASI 50) is greater than 70%.

29. The method of claim 18 , wherein the disease is rheumatoid arthritis.

30. The method according to claim 29 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than about 40%.

31. The method according to claim 29 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than 50%.

32. The method of claim 18 , wherein the disease is primary myelofibrosis (PMF).

33. The method according to claim 32 , wherein the method results in a reduced total symptom score (TSS) of said patient compared with baseline.

34. The method according to claim 32 , wherein said method results in reduced anemia.

35. The method of claim 18 , wherein the disease is post-polycythemia vera myelofibrosis.

36. The method of claim 18 , wherein the disease is post-essential thrombocythemia myelofibrosis.

37. 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 one or more sustained release tablets, each comprising:

(i) {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;

(ii) a first hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of 80 cP to 120 cP;

(iii) a second hypromellose, characterized by having an apparent viscosity at a concentration of 2% in water of 3000 cP to 5600 cP,

wherein the tablet comprises 10% to 15% by weight of the first and second hypromelloses;

(iv) 16% to 22% by weight of microcrystalline cellulose; and

(v) 45% to 55% by weight of lactose monohydrate;

wherein:

(a) oral administration of one or more of the sustained release tablets to a fasted patient 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 15 to 30; or

(b) oral administration of one or more of the sustained release tablets to a fasted patient 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 0.5 hours to 3 hours; or

(c) oral administration of one or more of the sustained release tablets to a fasted patient 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 1 hour to 20 hours; or

(d) any combination of (a), (b), and (c).

38. The method of claim 37 , 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.

39. The method of claim 37 , wherein the disease is psoriasis.

40. The method according to claim 39 , wherein the Psoriasis Area and Severity Index-50 score (PASI 50) is greater than 70%.

41. The method of claim 37 , wherein the disease is rheumatoid arthritis.

42. The method according to claim 41 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than 40%.

43. The method according to claim 41 , wherein the American College of Rheumatology-70 score (ACR70) of said patient is greater than about 50%.

44. The method of claim 37 , wherein the disease is primary myelofibrosis (PMF).

45. The method according to claim 44 , wherein the method results in a reduced total symptom score (TSS) of said patient compared with baseline.

46. The method according to claim 44 , wherein said method results in reduced anemia.

47. The method of claim 37 , wherein the disease is post-polycythemia vera myelofibrosis.

48. The method of claim 37 , wherein the disease is post-essential thrombocythemia myelofibrosis.