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Last Updated: October 22, 2019

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Claims for Patent: 10,137,127

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Summary for Patent: 10,137,127
Title:Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyri- midin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
Abstract: A liquid formulation of (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyri- midin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, pharmaceutically acceptable salts thereof, or a combination thereof and the use of the liquid formulation in the treatment of pain, cancer, inflammation, and certain infectious diseases are disclosed.
Inventor(s): Reynolds; Mark (Stamford, CT), Smith; Steven A. (Stamford, CT)
Assignee: Loxo Oncology, Inc. (Stamford, CT)
Application Number:15/622,544
Patent Claims: 1. A liquid formulation comprising: (S)--N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyr- imidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I): ##STR00034## a pharmaceutically acceptable salt thereof, or a combination thereof; a .beta.-cyclodextrin; and a base; wherein: the formulation has a pH of about 2.5 to about 5; and the compound of formula (I), the pharmaceutically acceptable salt thereof, or the combination thereof, has a concentration of about 15 mg/mL to about 35 mg/mL in the liquid formulation.

2. The liquid formulation of claim 1, wherein the .beta.-cyclodextrin is hydroxypropyl-.beta.-cyclodextrin.

3. The liquid formulation of claim 1, wherein the .beta.-cyclodextrin is present in an amount of about 5 wt % to about 35 wt %.

4. The liquid formulation of claim 3, wherein the .beta.-cyclodextrin is present in an amount of about 13 wt % to about 17 wt %.

5. The liquid formulation of claim 1, wherein the base is a citrate.

6. The liquid formulation of claim 5, wherein the base comprises at least one of sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, or calcium citrate heptahydrate.

7. The liquid formulation of claim 6, wherein the base comprises sodium citrate dihydrate.

8. The liquid formulation of claim 1, wherein the base is present in an amount of about 0.1 wt % to about 5 wt %.

9. The liquid formulation of claim 1, wherein the formulation has a pH of about 3 to about 4.

10. The liquid formulation of claim 1, wherein the liquid formulation further comprises a sweetener.

11. The liquid formulation of claim 10, wherein the sweetener is present in an amount of about 30 wt % to about 70 wt %.

12. The liquid formulation of claim 11, wherein the sweetener is present in an amount of about 45 wt % to about 55 wt %.

13. The liquid formulation of claim 1, wherein the liquid formulation further comprises a bitterness masking agent.

14. The liquid formulation of claim 13, wherein the bitterness masking agent is present in an amount of about 0.01 wt % to about 2 wt %.

15. The liquid formulation of claim 14, wherein the bitterness masking agent is present in an amount of about 0.2 wt % to about 0.5 wt %.

16. The liquid formulation of claim 1, wherein the formulation further comprises a flavoring agent.

17. The liquid formulation of claim 16, wherein the flavoring agent is present in an amount of about 0.01 wt % to about 2 wt %.

18. The liquid formulation of claim 17, wherein the flavoring agent is present in an amount of about 0.01 wt % to about 0.1 wt %.

19. The liquid formulation of claim 1, wherein the liquid formulation is prepared from a pharmaceutically acceptable salt of the compound of formula (I).

20. The liquid formulation of claim 19, wherein the liquid formulation is prepared from the hydrogen sulfate salt of the compound of formula (I).

21. The liquid formulation of claim 1, wherein the liquid formulation is prepared from a crystalline form of the compound of formula (I).

22. The liquid formulation of claim 1, wherein the liquid formulation is prepared from a crystalline form of the compound of formula (I) having the formula (I-HS): ##STR00035##

23. The liquid formulation of claim 22, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 18.4.+-.0.2, 20.7.+-.0.2, 23.1.+-.0.2, and 24.0.+-.0.2.

24. The liquid formulation of claim 22, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 10.7.+-.0.2, 18.4.+-.0.2, 20.7.+-.0.2, 23.1.+-.0.2, and 24.0.+-.0.2.

25. The liquid formulation of claim 22, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 10.7.+-.0.2, 18.4.+-.0.2, 19.2.+-.0.2, 20.2.+-.0.2, 20.7.+-.0.2, 21.5.+-.0.2, 23.1.+-.0.2, and 24.0.+-.0.2.

26. The liquid formulation of claim 22, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 10.7.+-.0.2, 15.3.+-.0.2, 16.5.+-.0.2, 18.4.+-.0.2, 19.2.+-.0.2, 19.9.+-.0.2, 20.2.+-.0.2, 20.7.+-.0.2, 21.5.+-.0.2, 22.1.+-.0.2, 23.1.+-.0.2, 24.0.+-.0.2, 24.4.+-.0.2, 25.6.+-.0.2, 26.5.+-.0.2, 27.6.+-.0.2, 28.2.+-.0.2, 28.7.+-.0.2, 30.8.+-.0.2, and 38.5.+-.0.2.

27. A liquid formulation comprising: (S)--N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyr- imidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I): ##STR00036## a pharmaceutically acceptable salt thereof, or a combination thereof; a .beta.-cyclodextrin; a base; a sweetener; a bitterness masking agent; and a flavoring agent, wherein: the formulation has a pH of about 2.5 to about 5.5; and the compound of formula (I), the pharmaceutically acceptable salt thereof, or the combination thereof, has a concentration of about 15 mg/mL to about 35 mg/mL in the liquid formulation.

28. The liquid formulation of claim 27, wherein the base comprises sodium citrate dihydrate.

29. A liquid formulation comprising: (S)--N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyr- imidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I): ##STR00037## a pharmaceutically acceptable salt thereof, or a combination thereof; a .beta.-cyclodextrin present in an amount of about 5 wt % to about 35 wt %; a base present in an amount of about 0.1 wt % to about 5 wt %; wherein: the formulation has a pH of about 2.5 to about 5.5; and the compound of formula (I), the pharmaceutically acceptable salt thereof, or the combination thereof has a concentration of about 20 mg/mL to about 30 mg/mL in the liquid formulation.

30. A liquid formulation comprising: (S)--N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyr- imidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I): ##STR00038## a pharmaceutically acceptable salt thereof, or a combination thereof; a .beta.-cyclodextrin present in an amount of about 5 wt % to about 35 wt %; a base present in an amount of about 0.1 wt % to about 5 wt %; a sweetener present in an amount of about 30 wt % to about 70 wt %; a bitterness masking agent present in an amount of about 0.2 wt % to about 0.5 wt %; and a flavoring agent present in an amount of about 0.01 wt % to about 2 wt %, wherein: the formulation has a pH of about 3 to about 4; and the compound of formula (I), the pharmaceutically acceptable salt thereof, or the combination thereof, has a concentration of about 20 mg/mL to about 30 mg/mL in the liquid formulation.

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