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 method of increasing ATG5, VPS15, ATG18, or ATG101 expression levels in a subject in need thereof, comprising administering to the subject a composition comprising a pharmaceutically effective amount of a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein the composition comprises less than 10 International Units (IU) of endotoxins per gram.
2 . The method of claim 1 , wherein the composition comprises less than 8 IU of endotoxins per gram.
3 . The method of claim 1 , wherein the composition comprises less than 6 IU of endotoxins per gram.
4 . The method of claim 1 , wherein the composition comprises less than 5 IU of endotoxins per gram.
5 . The method of claim 1 , wherein the composition comprises less than 4 IU of endotoxins per gram.
6 . The method of claim 1 , wherein the composition comprises less than 3 IU of endotoxins per gram.
7 . The method of claim 1 , wherein the composition comprises less than 1 ppm propylene oxide.
8 . The method of claim 1 , wherein the composition comprises less than 0.8 ppm propylene oxide.
9 . The method of claim 1 , wherein the composition comprises less than 0.6 ppm propylene oxide.
10 . The method of claim 1 , wherein the composition comprises less than 0.5 ppm propylene oxide.
11 . The method of claim 1 , wherein the composition is suitable for intrathecal administration.
12 . The method of claim 1 , wherein the mixture of beta-cyclodextrin molecules comprises less than 1% unsubstituted beta-cyclodextrin (“DS-0”).
13 . The method of claim 1 , wherein the mixture of beta-cyclodextrin molecules comprises 10% to 30% molecules having three hydroxypropyl substitutions (“DS-3”).
14 . The method of claim 1 , wherein the mixture of beta-cyclodextrin molecules comprises at least 75% molecules having three, four, five, and six hydroxypropyl substitutions, collectively (“DS-3”, “DS-4”, “DS-5”, and “DS-6”).
15 . The method of claim 1 , wherein the mixture of beta-cyclodextrin molecules comprises less than 1% molecules having nine and ten hydroxypropyl substitutions, collectively (“DS-9” and “DS-10”).
16 . The method of claim 1 , wherein the mixture of beta-cyclodextrin molecules comprises less than 0.1% molecules having nine and ten hydroxypropyl substitutions, collectively (“DS-9” and “DS-10”).
17 . The method of claim 1 , wherein the composition comprises less than 0.9% propylene glycol.
18 . The method of claim 1 , wherein the composition comprises less than 0.8% propylene glycol.
19 . The method of claim 1 , wherein the composition comprises less than 0.7% propylene glycol.
20 . The method of claim 1 , wherein the composition comprises less than 0.6% propylene glycol.
21 . The method of claim 1 , wherein the composition further comprises sodium chloride.
22 . The method of claim 1 , wherein the composition is suitable for lumbar injection.
23 . A method of increasing ATG5 or VPS15 expression levels in a subject in need thereof, comprising administering to the subject a composition comprising a pharmaceutically effective amount of a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein the composition comprises less than 10 International Units (IU) of endotoxins per gram.
24 . The method of claim 23 , wherein the composition comprises less than 8 IU of endotoxins per gram.
25 . The method of claim 23 , wherein the composition comprises less than 5 IU of endotoxins per gram.
26 . The method of claim 23 , wherein the composition comprises less than 1 ppm propylene oxide.
27 . A method of increasing ATG18 or ATG101 expression levels in a subject in need thereof, comprising administering to the subject a composition comprising a pharmaceutically effective amount of a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein the composition comprises less than 10 International Units (IU) of endotoxins per gram.
28 . The method of claim 27 , wherein the composition comprises less than 8 IU of endotoxins per gram.
29 . The method of claim 27 , wherein the composition comprises less than 5 IU of endotoxins per gram.
30 . The method of claim 27 , wherein the composition comprises less than 1 ppm propylene oxide.