Claims for Patent: 11,938,136

Summary for Patent: 11,938,136

Title:	Compositions for treating spinal muscular atrophy
Abstract:	The present invention provides pharmaceutical compositions comprising a compound of formula (I)
Inventor(s):	Jochem Alsenz, Olaf Grassmann, Peter Kuehl, Friedrich Metzger, Kathleen Dorothy McCarthy, Eduardo Paulo Morawski Vianna, Marvin Lloyd Woodhouse
Assignee:	Hoffmann La Roche Inc
Application Number:	US16/685,431
Patent Claims:	1. A dry granulated powder blend for an oral solution, said dry granulated powder blend comprising 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharmaceutically acceptable salt thereof; a stabilizer comprising disodium ethylenediaminetetraacetate; an antioxidant comprising ascorbic acid; and an acidifier comprising tartaric acid. 2. The dry granulated powder blend of claim 1, wherein the blend comprises: 1 to 10% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharmaceutically acceptable salt thereof; disodium ethylenediaminetetraacetate at a ratio of 1:20 to 2:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; ascorbic acid at a ratio of 1:10 to 4:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and tartaric acid at a ratio of 1:2 to 15:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 3. The dry granulated powder blend of claim 1, wherein the blend further comprises a diluent selected from the group consisting of lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, isomalt, sorbitol, sucrose, dextrose, dibasic calcium phosphate, calcium sulfate, and combinations thereof. 4. The dry granulated powder blend of claim 3, wherein the diluent is mannitol and isomalt. 5. The dry granulated powder blend of claim 1, wherein the blend further comprises a preservative selected from the group consisting of sorbic acid and sodium benzoate. 6. The dry granulated powder blend of claim 5, wherein the preservative is sodium benzoate. 7. The dry granulated powder blend of claim 1, wherein the blend further comprises a poly(ethylene glycol) lubricant. 8. The dry granulated powder blend of claim 7, wherein the lubricant is PEG 6000. 9. An aqueous oral solution produced from a dry granulated powder blend, wherein said dry granulated powder blend comprises 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharmaceutically acceptable salt thereof; a stabilizer comprising disodium ethylenediaminetetraacetate; an antioxidant comprising ascorbic acid; and an acidifier comprising tartaric acid. 10. The aqueous oral solution of claim 9, wherein the stabilizer is at a ratio of 1:20 to 2:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; the antioxidant is at a ratio of 1:10 to 4:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and the acidifier is at a ratio of 1:2 to 15:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 11. The aqueous oral solution of claim 10, wherein the dry granulated powder blend comprises 1 to 10% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 12. The aqueous oral solution of claim 9, wherein the dry granulated powder blend further comprises: a diluent comprising mannitol and isomalt; a preservative comprising sodium benzoate; and a lubricant comprising poly(ethylene glycol). 13. The aqueous oral solution of claim 12, wherein the poly(ethylene glycol) is PEG 6000. 14. The aqueous oral solution of claim 12, wherein the diluent is at a ratio of 4:1 to 70:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; the preservative is at a ratio of 1:10 to 8:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and the lubricant is at a ratio of 1:20 to 2:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 15. The aqueous oral solution of claim 12, wherein the dry granulated powder blend comprises: disodium ethylenediaminetetraacetate at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; ascorbic acid at a ratio of 1:6 to 3:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; tartaric acid at a ratio of 3:2 to 13:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; mannitol at a ratio of 45:6 to 55:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; isomalt at a ratio of 4:3 to 5:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; sodium benzoate at a ratio of 1:6 to 7:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and poly(ethylene glycol) at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 16. The aqueous oral solution of claim 15, wherein the dry granulated powder blend comprises 2 to 6% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 17. The dry granulated powder blend of claim 1, wherein the blend further comprises: a diluent comprising mannitol or a mixture of mannitol and isomalt; a preservative comprising sodium benzoate; and a lubricant comprising poly(ethylene glycol). 18. The dry granulated powder blend of claim 17, wherein the poly(ethylene glycol) is PEG 6000. 19. The dry granulated powder blend of claim 17, wherein said blend comprises: a mixture of mannitol and isomalt at a ratio of 4:1 to 70:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; sodium benzoate at a ratio of 1:10 to 8:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and poly(ethylene glycol) at a ratio of 1:20 to 2:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 20. The dry granulated powder blend of claim 17, wherein said blend comprises: disodium ethylenediaminetetraacetate at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; ascorbic acid at a ratio of 1:6 to 3:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; tartaric acid at a ratio of 3:2 to 13:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; mannitol at a ratio of 45:6 to 55:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; isomalt at a ratio of 4:3 to 5:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; sodium benzoate at a ratio of 1:6 to 7:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and poly(ethylene glycol) at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 21. The dry granulated powder blend of claim 20, wherein the dry granulated powder blend comprises 2 to 6% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 22. The dry granulated powder blend of claim 17, wherein the stabilizer is at a ratio of 1:8 to 3:4 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; the antioxidant is at a ratio of 1:5 to 7:5 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and the acidifier is at a ratio of 4:3 to 9:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; the diluent is at a ratio of 16:1 to 100:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; the preservative is at a ratio of 1:2 to 13:4 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and the lubricant is at a ratio of 1:5 to 5:4 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 23. The dry granulated powder blend of claim 22, wherein the dry granulated powder blend comprises 1 to 5% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 24. A dry granulated powder blend comprising 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; disodium ethylenediaminetetraacetate; ascorbic acid; and tartaric acid. 25. The dry granulated powder blend of claim 24, wherein the disodium ethylenediaminetetraacetate is a dihydrate. 26. The dry granulated powder blend of claim 24, wherein the blend comprises disodium ethylenediaminetetraacetate at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; ascorbic acid at a ratio of 1:6 to 3:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and tartaric acid at a ratio of 3:2 to 13:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 27. The dry granulated powder blend of claim 26, wherein the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is 2 to 6% wt of the blend. 28. The dry granulated powder blend of claim 24, wherein the blend comprises disodium ethylenediaminetetraacetate at a ratio of 1:8 to 3:4 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; ascorbic acid at a ratio of 1:5 to 7:5 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and tartaric acid at a ratio of 4:3 to 9:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 29. The dry granulated powder blend of claim 28, wherein the dry granulated powder blend comprises 1 to 5% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 30. The dry granulated powder blend of claim 24 further comprising mannitol; isomalt; sodium benzoate; and poly(ethylene glycol). 31. The dry granulated powder blend of claim 30, wherein the poly(ethylene glycol) is PEG 6000. 32. The dry granulated powder blend of claim 30, wherein the blend comprises mannitol at a ratio of 45:6 to 55:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; isomalt at a ratio of 4:3 to 5:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; sodium benzoate at a ratio of 1:6 to 7:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and poly(ethylene glycol) at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 33. The dry granulated powder blend of claim 32, wherein the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is 2 to 6% wt of the blend. 34. The dry granulated powder blend of claim 30, wherein the blend comprises 2 to 6% wt 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; disodium ethylenediaminetetraacetate dihydrate at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; ascorbic acid at a ratio of 1:6 to 3:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; tartaric acid at a ratio of 3:2 to 13:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; mannitol at a ratio of 45:6 to 55:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; isomalt at a ratio of 4:3 to 5:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; sodium benzoate at a ratio of 1:6 to 7:2 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and PEG 6000 at a ratio of 1:12 to 1:1 with 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, and wherein the blend is constituted in water to form an aqueous solution with a pH of about 3.4. 35. An aqueous solution comprising the dry granulated blend of claim 24 constituted in said solution. 36. A kit for the preparation of a pharmaceutical composition comprising 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof, wherein the kit comprises the dry granulated powder blend of claim 1. 37. The kit of claim 36, wherein said kit further comprises a bottle. 38. The kit of claim 36, wherein said kit further comprises water as a solvent for constitution of the dry granulated powder blend of claim 1. 39. The aqueous oral solution of claim 35, wherein the aqueous oral solution has a pH of less than 4. 40. The aqueous oral solution of claim 39, wherein the aqueous oral solution has a pH of about 3.4. 41. The dry granulated powder blend of claim 31, wherein the blend comprises 2 to 6% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 42. The dry granulated powder blend of claim 41, wherein the blend comprises 4 to 15% wt of tartaric acid. 43. The dry granulated powder blend of claim 41, wherein the blend comprises 40 to 70% wt of mannitol. 44. The dry granulated powder blend of claim 41, wherein the blend comprises 1 to 4% wt of ascorbic acid. 45. The dry granulated powder blend of claim 41, wherein the blend comprises 0.2 to 2% wt disodium ethylenediaminetetraacetate. 46. The dry granulated powder blend of claim 41, wherein the blend comprises 0.5 to 2% wt of PEG6000. 47. The dry granulated powder blend of claim 41, wherein the blend comprises 1 to 8% wt of sodium benzoate.