Alkylated cyclodextrin compositions and processes for preparing and using the same

Patent metadata

Field	Value
Publication number	US-10040872-B2
Application number	US-201314437439-A
Country	US
Kind code	B2
Filing date	Oct 21, 2013
Priority date	Oct 22, 2012
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

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.

First claim

What is claimed is:

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

Assignees

• Cydex Pharmaceuticals Inc

Inventors

• Antle Vincent D
• Lopes Álvaro
• Monteiro Daniel

Classifications

• B01D39/2058

  the material being particulate · CPC title

• B01D39/2055

  Carbonaceous material (solid sorbent compositions comprising free carbon B01J20/20) · CPC title

• A61K38/07 Primary

  Tetrapeptides · CPC title

• A61K47/40

  Cyclodextrins; Derivatives thereof · CPC title

• C08B37/0012 Primary

  Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof · CPC title