Claims for Patent: 10,040,872

Summary for Patent: 10,040,872

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; lvaro (Loures, PT), Monteiro; Daniel (Loures, PT)
Assignee:	CyDex Pharmaceuticals, Inc. (San Diego, CA)
Application Number:	14/437,439
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,040,872
Patent Claims:	1. A process for preparing an alkylated cyclodextrin composition comprising a sulfoalkyl ether cyclodextrin, the process comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction milieu comprising a sulfoalkyl ether 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 sulfoalkyl ether cyclodextrin and the one or more drug-degrading impurities, wherein the one or more separations are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; (c) preparing a phosphate-free activated carbon having a residual conductivity of 10 .mu.S/cm or less by a process comprising subjecting activated carbon to a first carbon washing process comprising adding water, soaking the carbon in the water for at least 20 minutes, and draining the water; and (d) treating the partially purified solution with the phosphate-free activated carbon having a residual conductivity of 10 .mu.S/cm or less and producing the sulfoalkyl ether cyclodextrin, wherein the treatment is sufficient to produce a sulfoalkyl ether cyclodextrin composition having an absorption of less than 0.5 A.U. due to a drug-degrading agent, as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the sulfoalkyl ether cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 2. The process of claim 1, wherein the first carbon washing process comprises soaking the carbon in water for about 30 minutes. 3. The process of claim 1, wherein the first carbon washing process comprises adding the water in a countercurrent direction. 4. The process of claim 1, further comprising repeating the first carbon washing process at least two times. 5. The process of claim 4, further comprising, after the first carbon washing process, a second carbon washing process comprising flowing water over the carbon in a co-current direction. 6. The process of claim 5, wherein the second carbon washing process comprises flowing water over the carbon in a co-current direction for at least 1 hour. 7. The process of claim 5, wherein the second carbon washing process comprises flowing water over the carbon in a co-current direction for about 3 hours. 8. The process of claim 5, further comprising testing the residual conductivity of the water after the second carbon washing process and, if the residual conductivity of the water is greater than 10 .mu.S/cm, repeating at least one of the first carbon washing process and the second carbon washing process until the residual conductivity of the water is 10 .mu.S/cm or less. 9. The process of claim 5, wherein the sulfoalkyl ether cyclodextrin composition comprises less than 0.5% (w/w) of a chloride. 10. The process of claim 5, wherein the sulfoalkyl ether cyclodextrin composition comprises less than 0.1% (w/w) of a chloride. 11. The process of claim 5, wherein the sulfoalkyl ether cyclodextrin composition comprises less than 0.05% (w/w) of a chloride. 12. A process for preparing at least 8 consecutive lots of a sulfoalkyl ether cyclodextrin composition comprising an alkylated cyclodextrin and less than about 0.05% (w/w) of a chloride, the process for preparing each of the lots comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction milieu comprising a sulfoalkyl ether 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 sulfoalkyl ether 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/cm or less and producing the sulfoalkyl ether cyclodextrin, wherein the sulfoalkyl ether cyclodextrin composition has an absorption of less than 0.5 A.U. due to a drug-degrading agent, as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the sulfoalkyl ether cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 13. The process of claim 12, wherein the at least 15 consecutive lots are prepared. 14. The process of claim 12, wherein the at least 20 consecutive lots are prepared. 15. The process of claim 12, wherein the at least 30 consecutive lots are prepared. 16. The process of claim 12, wherein the consecutive lots are prepared within a period of 10 years. 17. The process of claim 12, wherein the consecutive lots are prepared within a period of 5 years. 18. The process of claim 12, wherein the consecutive lots are prepared within a period of 3 years. 19. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition further comprises less than 500 ppm of a phosphate. 20. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition further comprises less than 125 ppm of a phosphate. 21. The process of claim 1, wherein the residual conductivity is 9 .mu.S/cm or less. 22. The process of claim 1, wherein the residual conductivity is 9 .mu.S/cm or less. 23. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises less than 0.01% (w/w) of a chloride. 24. The process of claim 21, wherein the sulfoalkyl ether cyclodextrin composition comprises less than 0.005% (w/w) of a chloride. 25. The process of any claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises less than 0.0001% (w/w) of a chloride. 26. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition has an average degree of substitution of 2 to 9. 27. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition has an average degree of substitution of 4.5 to 7.5. 28. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition has an average degree of substitution of 6 to 7.5. 29. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition has an absorption of less than 0.2 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 sulfoalkyl ether cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 30. The process of claim 29, wherein the absorption is due to a drug degrading agent. 31. The process of claim 29, wherein the absorption is determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the sulfoalkyl ether cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 32. The process of claim 1, wherein the sulfoalkyl ether 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 sulfoalkyl ether cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 33. The process of claim 1, wherein the sulfoalkyl ether 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 sulfoalkyl ether cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 34. The process of claim 32, wherein the absorption is due to a color forming agent. 35. The process of claim 32, wherein the absorption is determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the sulfoalkyl ether cyclodextrin composition per mL of solution in a cell having a 1 cm path length. 36. The process of claim 26, wherein the phosphate-free activated carbon is washed with a solvent until the eluted solvent has reached the residual conductivity. 37. The process of claim 1, wherein the phosphate-free activated carbon is washed with water until the eluted water has reached the residual conductivity. 38. The process of claim 1, wherein the sulfoalkyl ether 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. 39. The process of claim 38, 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. 40. The process of claim 38, wherein the sulfoalkyl ether cyclodextrin is a sulfobutyl ether cyclodextrin (SBE-CD). 41. The process of claim 1, further comprising combining the sulfoalkyl ether cyclodextrin composition with one or more excipients. 42. The process of claim 1, further comprising combining the sulfoalkyl ether cyclodextrin composition with an active agent. 43. A product prepared by the process of claim 1. 44. A process for preparing a pharmaceutical composition, comprising: preparing a sulfoalkyl ether cyclodextrin according to the process of claim 1 or claim 12; and combining the sulfoalkyl ether cyclodextrin with carfilzomib. 45. A pharmaceutical composition prepared by the process of claim 44. 46. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition further comprises less than 200 ppm of a phosphate. 47. The process of claim 1, wherein the sulfoalkyl ether cyclodextrin composition further comprises less than 150 ppm of a phosphate.