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Claims for Patent: 8,410,077

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Claims for Patent: 8,410,077

Title:Sulfoalkyl ether cyclodextrin compositions
Abstract: SAE-CD compositions are provided, along with methods of making and using the same. The SAE-CD compositions comprise a sulfoalkyl ether cyclodextrin 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 SAE-CD composition per mL of solution in a cell having a 1 cm path length.
Inventor(s): Antle; Vincent (Olathe, KS)
Assignee: CyDex Pharmaceuticals, Inc. (La Jolla, CA)
Application Number:12/613,103
Patent Claims: 1. A sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfoalkyl ether cyclodextrin having an average degree of substitution of 4.5 to 7.5 and less than 100 ppm of a phosphate, wherein the SAE-CD 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 SAE-CD composition per mL of solution in a cell having a 1 cm path length.

2. A SAE-CD composition comprising a sulfoalkyl ether cyclodextrin having an average degree of substitution of 4.5 to 7.5 and less than 100 ppm of a phosphate, wherein the SAE-CD 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 500 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length.

3. A SAE-CD composition comprising a sulfoalkyl ether cyclodextrin and less than 100 ppm of a phosphate, wherein the sulfoalkyl ether cyclodextrin is sulfobutyl ether cyclodextrin, and wherein the SAE-CD 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 SAE-CD composition per mL of solution in a cell having a 1 cm path length.

4. A SAE-CD composition comprising a sulfoalkyl ether cyclodextrin and less than 100 ppm of a phosphate, wherein the sulfoalkyl ether cyclodextrin is sulfobutyl ether cyclodextrin, and wherein the SAE-CD 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 500 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length.

5. The SAE-CD composition of any of claims 1-4, wherein the SAE-CD composition has an absorption of less than 0.2 A.U. due to the drug-degrading agent as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm.

6. The SAE-CD composition of any of claims 1-4, wherein the SAE-CD composition has an absorption of less than 0.2 A.U., due to a color-forming agent, as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length.

7. The SAE-CD composition of any of claims 1-4, wherein the SAE-CD composition further comprises: less than 20 ppm of a sulfoalkylating agent; less than 0.5% wt. of an underivatized cyclodextrin; less than 1% wt. of an alkali metal halide salt; and less than 0.25% wt. of a hydrolyzed sulfoalkylating agent.

8. The SAE-CD composition of any of claims 1-4, wherein the sulfoalkyl ether cyclodextrin is a compound of Formula (1): ##STR00005## 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.

9. The SAE-CD composition of claim 8, wherein R.sub.1 is independently selected at each occurrence from --OH or --O--(C.sub.4alkylene)-SO.sub.3 .sup.--T, and -T is Na.sup.+ at each occurrence.

10. The SAE-CD composition of claim 8, wherein the pharmaceutically acceptable cation is: H.sup.+, an alkali metal cation, an alkaline earth metal cation, an ammonium ion, or an amine cation.

11. The SAE-CD composition of claim 10, wherein the pharmaceutically acceptable cation is an alkali metal cation which is Li.sup.+, Na.sup.+, or K.sup.+.

12. The SAE-CD composition of claim 10, wherein the pharmaceutically acceptable cation is an alkaline earth metal cation which is Ca.sup.2+ or Mg.sup.2+.

13. The SAE-CD composition of claim 10, wherein the pharmaceutically acceptable cation is an amine cation which is the cation of: (C1-C6)-alkylamine, piperidine, pyrazine, (C1-C6) alkanolamine, ethylenediamine, or (C4-C8)-cycloalkanolamine.

14. The SAE-CD composition of any of claims 1-4, wherein the SAE-CD composition comprises: less than 50 ppm of a phosphate; less than 10 ppm of a sulfoalkylating agent; less than 0.2% wt. of an underivatized cyclodextrin; less than 0.5% wt. of an alkali metal halide salt; and less than 0.1% wt. of a hydrolyzed sulfoalkylating agent; wherein the SAE-CD composition has an absorption of less than 0.2 A.U., due to a color-forming agent, as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length.

15. The SAE-CD composition of any of claims 1-4, wherein the SAE-CD composition comprises: less than 10 ppm of a phosphate; less than 2 ppm of a sulfoalkylating agent; less than 0.1% wt. of an underivatized cyclodextrin; less than 0.2% wt. of an alkali metal halide salt; and less than 0.08% wt. of a hydrolyzed sulfoalkylating agent; wherein the SAE-CD composition has an absorption of less than 0.1 A.U., due to a color-forming agent, as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length.

16. The SAE-CD composition of any of claims 1-4, wherein the SAE-CD composition comprises: less than 5 ppm of a phosphate; less than 250 ppb of a sulfoalkylating agent; less than 0.1% wt. of an underivatized cyclodextrin; less than 0.05% wt. of an alkali metal halide salt; and less than 0.08% wt. of a hydrolyzed sulfoalkylating agent.

17. The SAE-CD composition of any of claims 1-4, wherein the average degree of substitution of the SAE-CD is 6 to 7.1.

18. The SAE-CD composition of claim 17, wherein the average degree of substitution of the SAE-CD is 6.5 to 7.

19. A sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfobutyl ether cyclodextrin having an average degree of substitution of 6 to 7.1 and less than 100 ppm of a phosphate, wherein the SAE-CD composition has an absorption of less than 0.2 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 SAE-CD composition per mL of solution in a cell having a 1 cm path length.

20. A sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfobutyl ether cyclodextrin having an average degree of substitution of 6 to 7.1 and less than 100 ppm of a phosphate, wherein the SAE-CD composition has an absorption of less than 0.2 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 500 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length.

21. A SAE-CD composition produced by a process comprising: (a) mixing in an aqueous medium a cyclodextrin with a sulfoalkylating agent in the presence of an alkalizing agent to form an aqueous 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 aqueous milieu to form a partially purified aqueous solution comprising the sulfoalkyl ether cyclodextrin and the one or more drug-degrading impurities, wherein the one or more separations include a process selected from the group consisting of: ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, and dialysis; and (c) treating the partially purified aqueous solution with a phosphate-free activated carbon two or more times to provide the SAE-CD composition, wherein the SAE-CD 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 SAE-CD composition per mL of solution in a cell having a 1 cm path length.

22. The SAE-CD composition of claim 21, wherein the treating comprises: adding a phosphate-free particulate or powdered activated carbon to the partially purified aqueous solution while mixing, separating the activated carbon from the solution, and repeating the adding and the separating at least once until the amount of drug-degrading agent in the solution is reduced to a target level; or passing and recycling the partially purified aqueous solution through a mass of phosphate-free activated carbon in a flow-through apparatus until the amount of drug-degrading agent in the solution is reduced to a target level.

23. The SAE-CD composition of claim 22, wherein the treating comprises passing and recycling the partially purified aqueous solution through the mass of phosphate-free activated carbon two or more times, wherein each passing is with a different mass of phosphate-free activated carbon.

24. The SAE-CD composition of claim 23, wherein the activated carbon present during, the treating is about 12% by weight of the sulfoalkyl ether cyclodextrin, and the treating is performed for at least 2 hours.

25. The SAE-CD composition of claim 21, wherein the weight ratio of the SAE-CD to the activated carbon is 8.3:1 to 8.5:1.

26. The SAE-CD composition of claim 21, wherein the composition is produced by a process further comprising degrading excess sulfoalkylating agent by exposing the reaction milieu to a temperature of 60.degree. C. to 80.degree. C. for 6 hours to 72 hours.

27. The SAE-CD composition of claim 21, wherein the composition is produced by a process further comprising degrading excess sulfoalkylating agent by exposing the reaction milieu to a temperature of 75.degree. C. to 80.degree. C. for 6 hours to 72 hours.

28. The SAE-CD composition of claim 21, wherein the one or more separations include ultrafiltration with a molecular weight cutoff of about 1,000 Da.

29. A composition comprising the SAE-CD composition of claim 1 and an excipient.

30. The composition of claim 29, further comprising an active agent.

31. The composition of claim 30, wherein the composition is a pharmaceutical composition.

32. A composition comprising the SAE-CD composition of claim 1 and an active agent.

33. The composition of claim 32, wherein the composition is a pharmaceutical composition.

34. A composition comprising the SAE-CD composition of claim 2 and an excipient.

35. The composition of claim 34, further comprising an active agent.

36. The composition of claim 35, wherein the composition is a pharmaceutical composition.

37. A composition comprising the SAE-CD composition of claim 2 and an active agent.

38. The composition of claim 37, wherein the composition is a pharmaceutical composition.

39. A composition comprising the SAE-CD composition of claim 3 and an excipient.

40. The composition of claim 39, further comprising an active agent.

41. The composition of claim 40, wherein the composition is a pharmaceutical composition.

42. A composition comprising the SAE-CD composition of claim 3 and an active agent.

43. The composition of claim 42, wherein the composition is a pharmaceutical composition.

44. A composition comprising the SAE-CD composition of claim 4 and an excipient.

45. The composition of claim 44, further comprising an active agent.

46. The composition of claim 45, wherein the composition is a pharmaceutical composition.

47. A composition comprising the SAE-CD composition of claim 4 and an active agent.

48. The composition of claim 47, wherein the composition is a pharmaceutical composition.

49. A composition comprising the SAE-CD composition of claim 19 and an excipient.

50. The composition of claim 49, further comprising an active agent.

51. The composition of claim 50, wherein the composition is a pharmaceutical composition.

52. A composition comprising the SAE-CD composition of claim 19 and an active agent.

53. The composition of claim 52, wherein the composition is a pharmaceutical composition.

54. A composition comprising the SAE-CD composition of claim 20 and an excipient.

55. The composition of claim 54, further comprising an active agent.

56. The composition of claim 55, wherein the composition is a pharmaceutical composition.

57. A composition comprising the SAE-CD composition of claim 20 and an active agent.

58. The composition of claim 57, wherein the composition is a pharmaceutical composition.

59. A composition comprising the SAE-CD composition of claim 21 and an excipient.

60. The composition of claim 59, further comprising an active agent.

61. The composition of claim 60, wherein the composition is a pharmaceutical composition.

62. A composition comprising the SAE-CD composition of claim 21 and an active agent.

63. The composition of claim 62, wherein the composition is a pharmaceutical composition.

64. A SAE-CD composition produced by a process comprising: (a) mixing in an aqueous medium a cyclodextrin with a sulfoalkylating agent in the presence of an alkalizing agent to form an aqueous 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 aqueous milieu to form a partially purified aqueous solution comprising the sulfoalkyl ether cyclodextrin and the one or more drug-degrading impurities, wherein the one or more separations include a process selected from the group consisting of: ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, and dialysis; and (c) treating the partially purified aqueous solution with a phosphate-free activated carbon two or more times to provide the SAE-CD composition, wherein the SAE-CD 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 500 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length.

65. The SAE-CD composition of claim 64, wherein the treating comprises: adding a phosphate-free particulate or powdered activated carbon to the partially purified aqueous solution while mixing, separating the activated carbon from the solution, and repeating the adding and the separating at least once until the amount of drug-degrading agent in the solution is reduced to a target level; or passing and recycling the partially purified aqueous solution through a mass of phosphate-free activated carbon in a flow-through apparatus until the amount of drug-degrading agent in the solution is reduced to a target level.

66. The SAE-CD composition of claim 65, wherein the treating comprises passing and recycling the partially purified aqueous solution through the mass of phosphate-free activated carbon two or more times, wherein each passing is with a different mass of phosphate-free activated carbon.

67. The SAE-CD composition of claim 66, wherein the activated carbon present during the treating is about 12% by weight of the sulfoalkyl ether cyclodextrin, and the treating is performed for at least 2 hours.

68. The SAE-CD composition of claim 64, wherein the weight ratio of the SAE-CD to the activated carbon is 8.3:1 to 8.5:1.

69. The SAE-CD composition of claim 64, wherein the composition is produced by a process further comprising degrading excess sulfoalkylating agent by exposing the reaction milieu to a temperature of 60.degree. C. to 80.degree. C. for 6 hours to 72 hours.

70. The SAE-CD composition of claim 64, wherein the composition is produced by a process further comprising degrading excess sulfoalkylating agent by exposing the reaction milieu to a temperature of 75.degree. C. to 80.degree. C. for 6 hours to 72 hours.

71. The SAE-CD composition of claim 64, wherein the one or more separations include ultrafiltration with a molecular weight cutoff of about 1,000 Da.

72. A composition comprising the SAE-CD composition of claim 64 and an excipient.

73. The composition of claim 72, further comprising an active agent.

74. The composition of claim 73, wherein the composition is a pharmaceutical composition.

75. A composition comprising the SAE-CD composition of claim 64 and an active agent.

76. The composition of claim 75, wherein the composition is a pharmaceutical composition.
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