Claims for Patent: 12,083,227

Summary for Patent: 12,083,227

Title:	Solid pharmaceutical formulations for treating endometriosis, uterine fibroids, polycystic ovary syndrome or adenomyosis
Abstract:	The present disclosure relates to pharmaceutical compositions comprising a gonadotropin-releasing hormone (GnRH) antagonist and methods of preparing and using such compositions. The disclosure also relates to methods of facilitating release of a GnRH antagonist from a pharmaceutical composition.
Inventor(s):	Yihong Qiu, Yuchuan Gong, Alexander RUGGLES, Jared A. Baird, Hui Zu, Gregory A. McClelland, Anna V. Stepanenko
Assignee:	Neurocrine Biosciences Inc , AbbVie Inc
Application Number:	US16/105,440
Patent Claims:	1. A high drug load, stable tablet comprising sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate (“elagolix sodium”); wherein the high drug load, stable tablet comprises from about 50% to about 90% of elagolix sodium by weight of the tablet and from about 0.1% to about 20% of a pharmaceutically acceptable meltable binder by weight of the tablet, wherein about 310 mg elagolix sodium is present in the tablet and wherein the pharmaceutically acceptable meltable binder is selected from the group consisting of a polyethylene glycol (PEG), a cellulose derivative, a poloxamer, and combinations thereof; and wherein the high drug load, stable tablet controls degradation of elagolix sodium to within pharmaceutically acceptable levels for at least 1 month when said tablet is stored at 40° C./75% relative humidity. 2. The tablet of claim 1, wherein the elagolix sodium is present in an amount from about 55% to about 60% by weight of the tablet. 3. The tablet of claim 1, wherein the pharmaceutically acceptable meltable binder is present in an amount from about 2% to about 10% by weight of the tablet. 4. The tablet of claim 1, wherein the elagolix sodium is present in an amount from about 55% to about 60% by weight of the tablet and the pharmaceutically acceptable meltable binder is present in an amount from about 2% to about 10% by weight of the tablet. 5. The tablet of claim 1, wherein not more than about 0.5% of a lactam degradant is present in the tablet following storage for at least 1 month at 40° C./75% relative humidity. 6. The tablet of claim 1, wherein the pharmaceutically acceptable meltable binder is selected from the group consisting of polyethylene glycol 3350, hydroxypropylcellulose, poloxamer 188, and combinations thereof. 7. The tablet of claim 1, wherein the pharmaceutically acceptable meltable binder is polyethylene glycol 3350. 8. The tablet of claim 1, further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of a disintegrant, a glidant, a pH modifying agent, and a combination thereof. 9. The tablet of claim 1, further comprising a disintegrant, wherein the disintegrant is selected from the group consisting of cross-linked modified starches, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, and combinations thereof. 10. The tablet of claim 9, further comprising a disintegrant, wherein the disintegrant is present in an amount from about 2% to about 8% by weight of the tablet. 11. The tablet of claim 1, further comprising a glidant, wherein the glidant is colloidal silicon dioxide. 12. The tablet of claim 1, further comprising a glidant, wherein the glidant is present in an amount from about 0.5% to about 3% by weight of the tablet. 13. The tablet of claim 1, further comprising a pH modifying agent, wherein the pH modifying agent is present in an amount from about 25% to about 35% by weight of the tablet. 14. The tablet of claim 13, wherein the pH modifying agent is an alkali or alkaline earth metal hydroxide or an alkali or alkaline earth metal salt. 15. The tablet of claim 13, wherein the pH modifying agent is sodium carbonate. 16. The tablet of claim 1, wherein the tablet comprises a first solid phase and the first solid phase comprises elagolix sodium and the pharmaceutically acceptable meltable binder. 17. A high drug load, stable tablet comprising: (a) from about 55% to about 60% by weight of sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate (“elagolix sodium”); (b) from about 4% to about 6% by weight of a pharmaceutically acceptable meltable binder, wherein the pharmaceutically acceptable meltable binder is selected from the group consisting of polyethylene glycol 3350, hydroxypropylcellulose, poloxamer 188, and combinations thereof; (c) from about 4% to about 6% by weight of a disintegrant; (d) from about 0.1% to about 2% by weight of a glidant; and (e) from about 25% to about 35% by weight of a pH modifying agent; wherein said high drug load, stable tablet controls degradation of elagolix sodium to within pharmaceutically acceptable levels for at least 1 month when said tablet is stored at 40° C./75% relative humidity. 18. The tablet of claim 17, wherein about 310 mg elagolix sodium is present in the tablet. 19. The tablet of claim 17, wherein the pharmaceutically acceptable meltable binder is polyethylene glycol 3350. 20. A method of treating endometriosis, the method comprising administering the tablet of claim 1 to a patient in need thereof. 21. The method according to claim 20, wherein the tablet comprises: (a) from about 55% to about 60% by weight of elagolix sodium; (b) from about 4% to about 6% by weight of the pharmaceutically acceptable meltable binder; (c) from about 4% to about 6% by weight of a disintegrant; (d) from about 0.1% to about 2% by weight of a glidant; and (e) from about 25% to about 35% by weight of a pH modifying agent. 22. A method of treating uterine fibroids, the method comprising administering the tablet of claim 1 to a patient in need thereof. 23. The method according to claim 22, wherein the tablet comprises: (a) from about 55% to about 60% by weight of elagolix sodium; (b) from about 4% to about 6% by weight of the pharmaceutically acceptable meltable binder; (c) from about 4% to about 6% by weight of a disintegrant; (d) from about 0.1% to about 2% by weight of a glidant; and (e) from about 25% to about 35% by weight of a pH modifying agent. 24. A high drug load, stable tablet comprising sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate (“elagolix sodium”); wherein the high drug load, stable tablet comprises from about 50% to about 90% of elagolix sodium by weight of the tablet and from about 0.1% to about 20% of a pharmaceutically acceptable meltable binder by weight of the tablet, wherein the pharmaceutically acceptable meltable binder is suitable for use in melt processing techniques for tablet preparation and wherein the tablet comprises a solid matrix, the solid matrix comprising a molecular dispersion of elagolix sodium and the pharmaceutically acceptable meltable binder; and wherein the high drug load, stable tablet controls degradation of elagolix sodium to within pharmaceutically acceptable levels for at least 1 month when said tablet is stored at 40° C./75% relative humidity. 25. The tablet of claim 24, wherein the pharmaceutically acceptable meltable binder is a polyalkylene glycol. 26. The tablet of claim 24, wherein the pharmaceutically acceptable meltable binder has a melting point of less than 124° C. 27. The tablet of claim 24, wherein the pharmaceutically acceptable meltable binder is selected from the group consisting of a polyethylene glycol (PEG), a cellulose derivative, a poloxamer, and combinations thereof. 28. The tablet of claim 24, wherein the pharmaceutically acceptable meltable binder is a polyethylene glycol (PEG). 29. The tablet of claim 24, wherein the pharmaceutically acceptable meltable binder is polyethylene glycol 3350. 30. The tablet of claim 24, wherein the pharmaceutically acceptable meltable binder is a poloxamer. 31. The tablet of claim 24, wherein the pharmaceutically acceptable meltable binder is poloxamer 188. 32. The tablet of claim 24, further comprising a disintegrant, wherein the disintegrant is selected from the group consisting of cross-linked modified starches, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, and combinations thereof. 33. The tablet of claim 24, further comprising a disintegrant, wherein the disintegrant is present in an amount from about 2% to about 8% by weight of the tablet. 34. A high drug load, stable tablet comprising sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate (“elagolix sodium”); wherein the high drug load, stable tablet comprises from about 50% to about 90% of elagolix sodium by weight of the tablet, from about 0.1% to about 20% of a pharmaceutically acceptable meltable binder by weight of the tablet, and a disintegrant selected from the group consisting of cross-linked modified starches, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, and combinations thereof; and wherein the high drug load, stable tablet controls degradation of elagolix sodium to within pharmaceutically acceptable levels for at least 1 month when said tablet is stored at 40° C./75% relative humidity. 35. The tablet of claim 34, wherein the disintegrant is present in an amount from about 2% to about 8% by weight of the tablet. 36. The tablet of claim 34, wherein the pharmaceutically acceptable meltable binder has a melting point of less than 124° C. 37. The tablet of claim 34, wherein the pharmaceutically acceptable meltable binder is selected from the group consisting of a polyethylene glycol (PEG), a cellulose derivative, a poloxamer, and combinations thereof. 38. The tablet of claim 34, wherein the pharmaceutically acceptable meltable binder is a polyalkylene glycol. 39. The tablet of claim 34, wherein the pharmaceutically acceptable meltable binder is polyethylene glycol 3350. 40. The tablet of claim 34, the tablet comprising: (a) from about 55% to about 60% by weight of elagolix sodium; (b) from about 4% to about 6% by weight of the pharmaceutically acceptable meltable binder; (c) from about 4% to about 6% by weight of the disintegrant; (d) from about 0.1% to about 2% by weight of a glidant; and (e) from about 25% to about 35% by weight of a pH modifying agent. 41. A high drug load, stable tablet comprising: from about 55% to about 60% by weight of sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate (“elagolix sodium”); and from about 4% to about 6% by weight of a pharmaceutically acceptable meltable binder, wherein the pharmaceutically acceptable meltable binder is selected from the group consisting of polyethylene glycol 3350, hydroxypropylcellulose, poloxamer 188, and combinations thereof, wherein said high drug load, stable tablet controls degradation of elagolix sodium to within pharmaceutically acceptable levels for at least 1 month when said tablet is stored at 40° C./75% relative humidity. 42. The tablet of claim 41, wherein about 310 mg elagolix sodium is present in the tablet. 43. The tablet of claim 41, wherein the pharmaceutically acceptable meltable binder is polyethylene glycol 3350. 44. The tablet of claim 41, wherein about 310 mg elagolix sodium is present in the tablet and wherein the pharmaceutically acceptable meltable binder is polyethylene glycol 3350. 45. The tablet of claim 41, further comprising a disintegrant, wherein the disintegrant is present in an amount from about 2% to about 8% by weight of the tablet. 46. The tablet of claim 45, wherein the disintegrant is selected from the group consisting of cross-linked modified starches, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, and combinations thereof.