Claims for Patent: 9,255,068

Summary for Patent: 9,255,068

Title:	Crystalline salts of (4S,4AS,5AR,12AS)-4-dimethylamino-3,10,12,12A-tetrahydroxy-7-[methoxy(met- hyl)amino)-methyl] acid amide and methods of using the same
Abstract:	A crystalline mono hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(me- thyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-- 2-carboxylic acid amide is disclosed having improved stability. In addition, a crystalline mono mesylate salt and crystalline mono sulfate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(me- thoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naph- thacene-2-carboxylic acid amide are also disclosed having improved stability. A pharmaceutical composition containing the crystalline salts and methods of treating inflammatory skin disorders and bacterial infections comprising administering the crystalline salts are also disclosed.
Inventor(s):	Coulter; Catherine (Ballymena, GB), Johnston; Sean M. (Doylestown, PA), Seyedi; Farzaneh (Mansfield, MA)
Assignee:	Warner Chilcott Company, LLC (Fajardo, PR) Paratek Pharmaceuticals, Inc. (Boston, MA)
Application Number:	13/471,275
Patent Claims:	1. A crystalline salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(me- thyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-- 2-carboxylic acid amide, wherein the salt is selected from a group consisting of mono hydrochloride, mono mesylate and mono sulfate, and wherein the crystalline salt has a crystal-like internal structural arrangement. 2. The crystalline salt of claim 1, wherein the salt is substantially pure. 3. The crystalline salt of claim 1, wherein the salt is mono hydrochloride. 4. The crystalline salt of claim 3, having an XRPD pattern substantially as illustrated in FIG. 1 after synthesis of the crystalline salt. 5. The crystalline salt of claim 3, having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 13.4, about 20.5 and about 23.3, as measured by XRPD. 6. The crystalline salt of claim 3, having a DSC curve substantially as illustrated in FIG. 2 after synthesis of the crystalline salt. 7. The crystalline salt of claim 3, having a TGA curve substantially as illustrated in FIG. 3 after synthesis of the crystalline salt. 8. The crystalline salt of claim 3, wherein the salt has a .beta.-isomer content at 0 days of about 0.1% peak area to about 7.0% peak area, as measured by HPLC. 9. The crystalline salt of claim 1, wherein the salt is mono mesylate. 10. The crystalline salt of claim 9, having an XRPD pattern substantially as illustrated in FIG. 4 after synthesis of the crystalline salt. 11. The crystalline salt of claim 9, having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 9, about 15 and about 23.8, as measured by XRPD. 12. The crystalline salt of claim 9, having a DSC curve substantially as illustrated in FIG. 5 after synthesis of the crystalline salt. 13. The crystalline salt of claim 9, having a TGA curve substantially as illustrated in FIG. 6 after synthesis of the crystalline salt. 14. The crystalline salt of claim 9, wherein the salt has a .beta.-isomer content at 0 days of about 2.0% peak area to about 10.0% peak area, as measured by HPLC. 15. The crystalline salt of claim 1, wherein the salt is mono sulfate. 16. The crystalline salt of claim 15, having an XRPD pattern substantially as illustrated in FIG. 7 after synthesis of the crystalline salt. 17. The crystalline salt of claim 15, having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 15, about 17.8 and about 23.5, as measured by XRPD. 18. The crystalline salt of claim 15, having a DSC curve substantially as illustrated in FIG. 8 after synthesis of the crystalline salt. 19. The crystalline salt of claim 15, having a TGA curve substantially as illustrated in FIG. 9 after synthesis of the crystalline salt. 20. The crystalline salt of claim 15, wherein the salt has a .beta.-isomer content at 0 days of about 3.0% peak area to about 26.0% peak area, as measured by HPLC. 21. A pharmaceutical composition comprising the crystalline salt of claim 1 and a pharmaceutically acceptable excipient. 22. The pharmaceutical composition of claim 21, wherein the salt is mono hydrochloride. 23. The pharmaceutical composition of claim 21, wherein the salt is mono mesylate. 24. The pharmaceutical composition of claim 21, wherein the salt is mono sulfate. 25. A method for treating acne comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1. 26. The method of claim 25, wherein the salt is mono hydrochloride. 27. The method of claim 25, wherein the salt is mono mesylate. 28. The method of claim 25, wherein the salt is mono sulfate. 29. A method for treating rosacea comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1. 30. The method of claim 29, wherein the salt is mono hydrochloride. 31. The method of claim 29, wherein the salt is mono mesylate. 32. The method of claim 29, wherein the salt is mono sulfate. 33. A method for treating a gram positive bacterial infection, wherein the gram positive bacteria is selected from the group consisting of Propionibacterium acnes, Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile, comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1. 34. The method of claim 33, wherein the salt is mono hydrochloride. 35. The method of claim 33, wherein the salt is mono mesylate. 36. The method of claim 33, wherein the salt is mono sulfate. 37. A crystalline salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(me- thyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-- 2-carboxylic acid amide, wherein the salt is selected from a group consisting of mono hydrochloride, mono mesylate and mono sulfate, and wherein the crystalline salt is substantially free of an amorphous salt. 38. The crystalline salt of claim 37, wherein the salt is substantially pure. 39. The crystalline salt of claim 37, wherein the salt is mono hydrochloride. 40. The crystalline salt of claim 39, having an XRPD pattern substantially as illustrated in FIG. 1 after synthesis of the crystalline salt. 41. The crystalline salt of claim 39, having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 13.4, about 20.5 and about 23.3, as measured by XRPD. 42. The crystalline salt of claim 39, having a DSC curve substantially as illustrated in FIG. 2 after synthesis of the crystalline salt. 43. The crystalline salt of claim 39, having a TGA curve substantially as illustrated in FIG. 3 after synthesis of the crystalline salt. 44. The crystalline salt of claim 39, wherein the salt has a .beta.-isomer content at 0 days of about 0.1% peak area to about 7.0% peak area, as measured by HPLC. 45. The crystalline salt of claim 37, wherein the salt is mono mesylate. 46. The crystalline salt of claim 45, having an XRPD pattern substantially as illustrated in FIG. 4 after synthesis of the crystalline salt. 47. The crystalline salt of claim 45, having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 48, about 15 and about 23.8, as measured by XRPD. 48. The crystalline salt of claim 45, having a DSC curve substantially as illustrated in FIG. 5 after synthesis of the crystalline salt. 49. The crystalline salt of claim 45, having a TGA curve substantially as illustrated in FIG. 6 after synthesis of the crystalline salt. 50. The crystalline salt of claim 45, wherein the salt has a .beta.-isomer content at 0 days of about 2.0% peak area to about 10.0% peak area, as measured by HPLC. 51. The crystalline salt of claim 37, wherein the salt is mono sulfate. 52. The crystalline salt of claim 51, having an XRPD pattern substantially as illustrated in FIG. 7 after synthesis of the crystalline salt. 53. The crystalline salt of claim 51, having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 15, about 17.8 and about 23.5, as measured by XRPD. 54. The crystalline salt of claim 51, having a DSC curve substantially as illustrated in FIG. 8 after synthesis of the crystalline salt. 55. The crystalline salt of claim 51, having a TGA curve substantially as illustrated in FIG. 9 after synthesis of the crystalline salt. 56. The crystalline salt of claim 51, wherein the salt has a .beta.-isomer content at 0 days of about 3.0% peak area to about 26.0% peak area, as measured by HPLC. 57. A pharmaceutical composition comprising the crystalline salt of claim 37 and a pharmaceutically acceptable excipient. 58. The pharmaceutical composition of claim 57, wherein the salt is mono hydrochloride. 59. The pharmaceutical composition of claim 57, wherein the salt is mono mesylate. 60. The pharmaceutical composition of claim 57, wherein the salt is mono sulfate. 61. A method for treating acne comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 37. 62. The method of claim 61, wherein the salt is mono hydrochloride. 63. The method of claim 61, wherein the salt is mono mesylate. 64. The method of claim 61, wherein the salt is mono sulfate. 65. A method for treating rosacea comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 37. 66. The method of claim 65, wherein the salt is mono hydrochloride. 67. The method of claim 65, wherein the salt is mono mesylate. 68. The method of claim 65, wherein the salt is mono sulfate. 69. A method for treating a gram positive bacterial infection, wherein the gram positive bacteria is selected from the group consisting of Propionibacterium acnes, Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile, comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 37. 70. The method of claim 69, wherein the salt is mono hydrochloride. 71. The method of claim 69, wherein the salt is mono mesylate. 72. The method of claim 69, wherein the salt is mono sulfate.