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 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 μS 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 μS or less.
5. The process of claim 1 , wherein the residual conductivity in (c) is 8 μS 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):
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.
23. The process of claim 22 , 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.
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):
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.
34. The alkylated cyclodextrin composition of claim 33 , 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.
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):
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.
43. The alkylated cyclodextrin composition of claim 42 , 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.
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.