Hydroxypropyl beta-cyclodextrin compositions and methods
This disclosure provides mixtures of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, for use as a pharmaceutically active ingredient; methods of making such mixtures; methods of qualifying such mixtures for use in a pharmaceutical composition suitable for intrathecal or intracerebroventricular administration; pharmaceutical compositions suitable for intrathecal or intracerebroventricular administration comprising such mixtures; and methods of using the pharmaceutical compositions for treatment of Niemann-Pick disease Type C.
1. A composition for intrathecal injection comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein the composition is pharmaceutically acceptable for intrathecal administration, the composition comprises less than 2 Endotoxin Units (EU) of endotoxins per gram, no more than 0.5% propylene glycol, and less than 1 ppm of propylene oxide.
2. The composition of claim 1 , wherein the composition comprises less than 1.5 EU of endotoxins per gram.
3. The composition of claim 1 , wherein the composition comprises less than 1.0 EU of endotoxins per gram.
4. The composition of claim 1 , wherein the composition comprises less than 0.8 EU of endotoxins per gram.
5. The composition of claim 1 , wherein the composition comprises less than 0.5 EU of endotoxins per gram.
6. The composition of claim 1 , wherein the composition comprises less than 0.3 EU of endotoxins per gram.
7. The composition of claim 1 , wherein the composition comprises less than 0.1 EU of endotoxins per gram.
8. The composition of claim 1 , wherein the composition comprises less than 0.05 EU of endotoxins per gram.
9. The composition of claim 1 , wherein the composition comprises less than 0.8 ppm propylene oxide.
10. The composition of claim 1 , wherein the composition comprises less than 0.5 ppm propylene oxide.
11. The composition of claim 1 , wherein the composition comprises less than 0.1 ppm propylene oxide.
12. The composition of claim 1 , wherein the composition comprises less than 0.05 ppm propylene oxide.
13. The composition of claim 1 , wherein the composition comprises sodium chloride to 0.9% w/v.
14. The composition of claim 1 , wherein the composition comprises a pH of 6.0-8.0.
15. The composition of claim 1 , wherein the composition is sterile filtered.
16. The composition of claim 1 , wherein the composition can be stored at 15-25° C.
17. The composition of claim 1 , wherein the mixture comprises at least 75% collectively of beta-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”), beta-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”), beta-cyclodextrin substituted with five hydroxypropyl group (“DS-5”), and beta-cyclodextrin substituted with six hydroxypropyl groups (“DS-6”).
18. The composition of claim 1 , wherein the mixture comprises less than 1.0% collectively of unsubstituted beta-cyclodextrin (“DS-0”).
19. The composition of claim 18 , wherein the mixture comprises less than 3.0% beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”).
20. The composition of claim 18 , wherein the mixture comprises less than 30% beta-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”).
21. The composition of claim 18 , wherein the mixture comprises less than 25% beta-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”).
22. The composition of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.
23. The composition of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of 4 to 5.
24. The composition of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of 4.06 to 4.76.
25. The composition of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of 4.5 to 5.
26. The composition of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of 4.3±0.3.
27. The composition of claim 1 , wherein the total amount of other unspecified impurities is less than or equal to 0.05% as measured by HPLC.
28. The composition of claim 1 , wherein the composition has a concentration of about 10 mg/mL to about 200 mg/mL.
29. A composition for intrathecal injection comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein the composition is pharmaceutically acceptable for intrathecal administration, the composition comprises less than 4 Endotoxin Units (EU) of endotoxins per gram, no more than 1% propylene glycol.
30. The composition of claim 29 , comprising less than 1 ppm of propylene oxide.