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 comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 1% unsubstituted beta-cyclodextrin (“DS-0”) and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”); and, the mixture comprises no more than 25% beta-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”) and no more than 20% beta-cyclodextrin substituted with five hydroxypropyl groups (“DS-5”).
2. A composition comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 1% unsubstituted beta-cyclodextrin (“DS-0”) and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”); and, the mixture comprises no more than 25% beta-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”), no more than 20% beta-cyclodextrin substituted with five hydroxypropyl groups (“DS-5”), and no more than 15% beta-cyclodextrin substituted with six hydroxypropyl groups (“DS-6”).
3. The composition of claim 1 , wherein less than 0.1% of the beta-cyclodextrin mixture is DS-0 and DS-1, collectively.
4. The composition of claim 1 , wherein less than 0.01% of the beta-cyclodextrin mixture is DS-0 and DS-1, collectively.
5. The composition of claim 1 , wherein the amount of DS-0 or DS-1 is determined by peak height of an electrospray MS spectrum.
6. The composition of claim 1 , wherein the mixture has an average molar substitution (“MS”) in the range of 0.40-0.80.
7. The composition of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.
8. The composition of claim 1 , wherein the composition comprises no more than 0.01% propylene glycol as measured by the HPLC.
9. The composition of claim 1 , wherein the composition comprises no more than 0.01% propylene glycol as measured by gas chromatography.
10. The composition of claim 1 , wherein the composition comprises no more than 0.01% propylene glycol as measured by PG/EG-ratio of propylene glycol to ethylene glycol.
11. The composition of claim 1 , wherein the composition purified by absorption chromatography alumina, solvent precipitation, or a combination thereof.
12. The composition of claim 1 , wherein the composition comprises no more than 1 ppm propylene oxide.
13. 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.
14. The composition of claim 1 , wherein the composition has a concentration of about 10 mg/mL to about 200 mg/mL.
15. The composition of claim 1 , wherein the wherein the composition is suitable for administration to a pediatric patient.
16. The composition of claim 1 , wherein the wherein the composition is suitable for administration to an adult patient.
17. The composition of claim 1 , further comprising a pharmaceutically acceptable diluent.
18. The composition of claim 1 , wherein the composition is capable of solubilizing lipids in an aqueous medium.
19. The composition of claim 18 , wherein lipids that are solubilized comprise unesterified or esterified cholesterol.
20. The composition of claim 18 , wherein the solubilization is determined by UV spectrometry or by HPLC.
21. The composition of claim 1 , wherein about 200 mg of the composition is capable of solubilizing 2 mg of unesterified cholesterol in distilled water at room temperature after 24 hours.
22. The composition of claim 1 , wherein the composition has increased affinity for unesterified cholesterol.
23. The composition of claim 1 , wherein the mixture comprises from 5% to 25% beta-cyclodextrin substituted with six hydroxypropyl groups (“DS-6”).
24. The composition of claim 1 , wherein the composition comprises no more than (“NMT”) 5 EU of endotoxins per gram of beta-cyclodextrin mixture.
25. The composition of claim 24 , wherein the composition comprises no more than (“NMT”) 1.5 EU of endotoxins per gram of beta-cyclodextrin mixture.
26. The composition of claim 24 , wherein the composition comprises no more than (“NMT”) 0.5% propylene glycol.
27. The composition of claim 24 , wherein the composition comprises no more than (“NMT”) 0.01% propylene oxide.
28. The composition of claim 24 , wherein the composition comprises no more than (“NMT”) 0.010% propylene glycol.
29. A composition comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 1% unsubstituted beta-cyclodextrin (“DS-0”) and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”); and, the mixture comprises no more than 25% beta-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”), and no more than 15% beta-cyclodextrin substituted with six hydroxypropyl groups (“DS-6”).
30. A composition comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 1% unsubstituted beta-cyclodextrin (“DS-0”) and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”); and, the mixture comprises no more than 20% beta-cyclodextrin substituted with five hydroxypropyl groups (“DS-5”), and no more than 15%, beta-cyclodextrin substituted with six hydroxypropyl groups (“DS-6”).