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 intravenous 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 intravenous 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 less than 3.5% collectively of unsubstituted beta-cyclodextrin (“DS-0”), beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), and beta-cyclodextrin substituted with two hydroxypropyl groups (“DS-2”).
18. The composition of claim 1 , wherein the mixture comprises less than 1.0% collectively of unsubstituted beta-cyclodextrin (“DS-0”), beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”).
19. The composition of claim 18 , wherein the mixture comprises less than 0.5% beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”).
20. The composition of claim 18 , wherein the mixture comprises less than 1.0% beta-cyclodextrin substituted with two hydroxypropyl groups (“DS-2”).
21. The composition of claim 18 , wherein the mixture comprises less than 0.5% beta-cyclodextrin substituted with two hydroxypropyl groups (“DS-2”).
22. The composition of claim 1 , wherein less than 0.1% of the beta-cyclodextrin mixture is DS-0 and DS-1, collectively.
23. The composition of claim 1 , wherein the mixture composition has an osmolality of about 300 to about 450 mOsm/kg.
24. The composition of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.
25. 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.
26. The composition of claim 1 , wherein the composition has a concentration of about 10 mg/mL to about 200 mg/mL.
27. The composition of claim 1 , wherein the wherein the composition is suitable for intravenous administration to patient.
28. The composition of claim 1 , further comprising a pharmaceutically acceptable diluent.
29. A composition comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein the composition is pharmaceutically acceptable for human administration, and the composition comprises less than 0.8 Endotoxin Units (EU) of endotoxins per gram and less than 0.1 ppm of propylene oxide.