Claims for Patent: 9,493,582

Summary for Patent: 9,493,582

Title:	Alkylated cyclodextrin compositions and processes for preparing and using the same
Abstract:	The present invention related to low-chloride alkylated cyclodextrin compositions, along with processes for preparing and using the same. The processes of the present invention provide alkylated cyclodextrins with low levels of drug-degrading agents and chloride.
Inventor(s):	Antle; Vincent D. (Olathe, KS), Lopes; Alvaro (Loures, PT), Monteiro; Daniel (Loures, PT)
Assignee:	Cydex Pharmaceuticals, Inc. (San Diego, CA)
Application Number:	14/381,568
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,493,582
Patent Claims:	1. A process for preparing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, the process comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction milieu comprising an alkylated cyclodextrin, one or more unwanted components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove the one or more unwanted components from the reaction milieu to form a partially purified solution comprising the alkylated cyclodextrin and the one or more drug-degrading impurities, wherein the one or more separations are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; and (c) treating the partially purified solution with a phosphate-free activated carbon having a residual conductivity of 10 .mu.S or less and producing the alkylated cyclodextrin. 2. The process of claim 1, wherein the alkylated cyclodextrin composition further comprises less than 500 ppm of a phosphate. 3. The process of claim 1, wherein the alkylated cyclodextrin composition further comprises less than 125 ppm of a phosphate. 4. The process of claim 1, wherein the residual conductivity in (c) is 9 .mu.S or less. 5. The process of claim 1, wherein the residual conductivity in (c) is 8 .mu.S or less. 6. The process of claim 1, wherein the alkylated cyclodextrin composition further comprises less than 0.5% (w/w) of a chloride. 7. The process of claim 1, wherein the alkylated cyclodextrin composition further comprises 0.1% (w/w) of a chloride. 8. The process of claim 1, wherein the alkylated cyclodextrin composition further comprises 0.05% (w/w) or less of a chloride. 9. The process of claim 1, wherein the alkylated cyclodextrin composition has an average degree of substitution of 2 to 9. 10. The process of claim 1, wherein the alkylated cyclodextrin composition has an average degree of substitution of 4.5 to 7.5. 11. The process of claim 1, wherein the alkylated cyclodextrin composition has an average degree of substitution of 6 to 7.5. 12. The process of claim 1, wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 13. The process of claim 1, wherein the alkylated cyclodextrin composition has an absorption of less than 0.5 A.U., as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 14. The process of claim 12, wherein the absorption is due to a drug degrading agent. 15. The process of claim 1, wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 16. The process of claim 1, wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 17. The process of claim 1, wherein the alkylated cyclodextrin composition has an absorption of less than 0.5 A.U., as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 18. The process of claim 16, wherein the absorption is due to a color forming agent. 19. The process of claim 1, wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 20. The process of claim 1, wherein the phosphate-free activated carbon is washed with a solvent until the eluted solvent has reached the residual conductivity in (c). 21. The process of claim 1, wherein the phosphate-free activated carbon is washed with water until the eluted water has reached the residual conductivity in (c). 22. The process of claim 1, wherein the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of Formula (II): ##STR00011## wherein p is 4, 5, or 6, and R.sub.1 is independently selected at each occurrence from --OH or --O--(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.--T, wherein T is independently selected at each occurrence from pharmaceutically acceptable cations, provided that at least one R.sub.1 is --OH and at least one R.sub.1 is O--(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.--T. 23. The process of claim 22, wherein R.sub.1 is independently selected at each occurrence from --OH or --O--(C.sub.4 alkylene)-SO.sub.3.sup.--T, and -T is Na.sup.+at each occurrence. 24. The process of claim 1, further comprising combining the alkylated cyclodextrin composition with one or more excipients. 25. The process of claim 1, further comprising combining the alkylated cyclodextrin composition with an active agent. 26. A product prepared by the process of claim 1. 27. An alkylated cyclodextrin composition, comprising: an alkylated cyclodextrin having an average degree of substitution of 2 to 9; less than 500 ppm of a phosphate; and 0.07% (w/w) or less of a chloride; wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 28. The alkylated cyclodextrin composition of claim 27, wherein the alkylated cyclodextrin composition has an absorption of 0.5 A.U. or less as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 29. The alkylated cyclodextrin composition of claim 27, wherein the alkylated cyclodextrin composition has an absorption of 0.2 A.U. or less as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 30. The alkylated cyclodextrin composition of claim 27, wherein the absorption is due to a drug degrading agent. 31. An alkylated cyclodextrin composition comprising: an alkylated cyclodextrin having an average degree of substitution of 2 to 9; less than 500 ppm of a phosphate; and 0.07% (w/w) or less of a chloride; wherein the alkylated cyclodextrin composition has an absorption of 0.5 A.U. or less as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 32. The alkylated cyclodextrin composition of claim 27, wherein the average degree of substitution is 6 to 7.5. 33. The alkylated cyclodextrin composition of claim 27 wherein the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of Formula (II): ##STR00012## wherein p is 4, 5, or 6, and R.sub.1 is independently selected at each occurrence from --OH or --O--(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.--T, wherein T is independently selected at each occurrence from pharmaceutically acceptable cations, provided that at least one R.sub.1 is --OH and at least one R.sub.1 is O--(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.--T. 34. The alkylated cyclodextrin composition of claim 33, wherein R.sub.1 is independently selected at each occurrence from --OH or --O--(C.sub.4 alkylene)-SO.sub.3.sup.--T, and -T is Na.sup.+ at each occurrence. 35. The alkylated cyclodextrin composition of claim 27, wherein the alkylated cyclodextrin is a sulfobutyl ether cyclodextrin. 36. An alkylated cyclodextrin composition, comprising: an alkylated cyclodextrin having an average degree of substitution of 2 to 9; less than 500 ppm of a phosphate; and 0.07% (w/w) or less of a chloride; wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 37. The alkylated cyclodextrin composition of claim 36, wherein the alkylated cyclodextrin composition has an absorption of 0.5 A.U. or less as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 38. The alkylated cyclodextrin composition of claim 36 wherein the alkylated cyclodextrin composition has an absorption of 0.2 A.U. or less as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 39. The alkylated cyclodextrin composition of claim 36, wherein the absorption is due to a color forming agent. 40. An alkylated cyclodextrin composition comprising: an alkylated cyclodextrin having an average degree of substitution of 2 to 9; less than 500 ppm of a phosphate; and 0.07% (w/w) or less of a chloride; wherein the alkylated cyclodextrin composition has an absorption of 0.5 A.U. or less as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 41. The alkylated cyclodextrin composition of claim 36, wherein the average degree of substitution is 6 to 7.5. 42. The alkylated cyclodextrin composition of claim 36, wherein the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of Formula (II): ##STR00013## wherein p is 4, 5, or 6, and R.sub.1 is independently selected at each occurrence from --OH or --O--(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.--T, wherein T is independently selected at each occurrence from pharmaceutically acceptable cations, provided that at least one R.sub.1 is --OH and at least one R.sub.1 is O--(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.--T. 43. The alkylated cyclodextrin composition of claim 42, wherein R.sub.1 is independently selected at each occurrence from --OH or --O--(C.sub.4 alkylene)-SO.sub.3.sup.--T, and -T is Na.sup.+ at each occurrence. 44. The alkylated cyclodextrin composition of claim 36, wherein the alkylated cyclodextrin is a sulfobutyl ether cyclodextrin. 45. A pharmaceutical composition, comprising the alkylated cyclodextrin composition of claim 27 and an active pharmaceutical agent. 46. The pharmaceutical composition of claim 45, wherein the active pharmaceutical agent is a chloride sensitive active agent selecting from the group consisting of bortezomib, disulfiram, epigallocatchin-3-gallate, salinosporamide A, and carfilzomib. 47. The pharmaceutical composition of claim 46, wherein the chloride sensitive active agent is carfilzomib. 48. The process of claim 25, wherein active agent is a chloride sensitive active agent selecting from the group consisting of bortezomib, disulfiram, epigallocatchin-3-gallate, salinosporamide A, and carfilzomib. 49. The process of claim 48, wherein the chloride sensitive active agent is carfilzomib. 50. The process of claim 1, wherein the alkylated cyclodextrin composition further comprises less than 200 ppm of a phosphate. 51. The process of claim 1, wherein the alkylated cyclodextrin composition further comprises 0.07% (w/w) or less of a chloride. 52. The process of claim 1, wherein the alkylated cyclodextrin composition has no detectable levels of a chloride as determined by charged aerosol detection. 53. The composition of claim 27, wherein the alkylated cyclodextrin composition further comprises less than 200 ppm of a phosphate. 54. The composition of claim 27, wherein the alkylated cyclodextrin composition comprises 0.05% (w/w) or less of a chloride. 55. The composition of claim 27, wherein the alkylated cyclodextrin composition has no detectable levels of a chloride as determined by charged aerosol detection. 56. The composition of claim 31, wherein the alkylated cyclodextrin composition further comprises less than 200 ppm of a phosphate. 57. The composition of claim 31, wherein the alkylated cyclodextrin composition comprises 0.05% (w/w) or less of a chloride. 58. The composition of claim 31, wherein the alkylated cyclodextrin composition has no detectable levels of a chloride as determined by charged aerosol detection. 59. The composition of claim 36, wherein the alkylated cyclodextrin composition further comprises less than 200 ppm of a phosphate. 60. The composition of claim 36, wherein the alkylated cyclodextrin composition comprises 0.05% (w/w) or less of a chloride. 61. The composition of claim 36, wherein the alkylated cyclodextrin composition has no detectable levels of a chloride as determined by charged aerosol detection. 62. The composition of claim 40, wherein the alkylated cyclodextrin composition further comprises less than 200 ppm of a phosphate. 63. The composition of claim 40, wherein the alkylated cyclodextrin composition comprises 0.05% (w/w) or less of a chloride. 64. The composition of claim 40, wherein the alkylated cyclodextrin composition has no detectable levels of a chloride as determined by charged aerosol detection.