Alkylated cyclodextrin compositions and processes for preparing and using the same
View Patent ↗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.
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 μS/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 μS/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 μS/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 μS/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 μS/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 μS/cm or less.
22. The process of claim 1 , wherein the residual conductivity is 9 μS/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):
wherein p is 4, 5, or 6, and R 1 is independently selected at each occurrence from —OH or —O—(C 2 -C 6 alkylene)-SO 3 − -T, wherein T is independently selected at each occurrence from pharmaceutically acceptable cations, provided that at least one R 1 is —OH and at least one R 1 is O—(C 2 -C 6 alkylene)-SO 3 − -T.
39. The process of claim 38 , wherein R 1 is independently selected at each occurrence from —OH or —O—(C 4 alkylene)-SO 3 − -T, and -T is Na + 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.