Alkylated cyclodextrin compositions and processes for preparing and using the same

Patent metadata

Field	Value
Publication number	US-9493582-B2
Application number	US-201314381568-A
Country	US
Kind code	B2
Filing date	Feb 27, 2013
Priority date	Feb 28, 2012
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

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 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 contain

Assignees

• Cydex Pharmaceuticals Inc

Inventors

• Antle Vincent D
• Lopes Alvaro
• Monteiro Daniel

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K38/07

  Tetrapeptides · CPC title

• C08L5/16

  Cyclodextrin; Derivatives thereof · CPC title

• C01B32/30

  Active carbon · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title