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 treating Niemann Pick disease in a human subject in need thereof comprising intrathecally, intravenously, or intracerebroventricularly administering a composition comprising mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 2.5% beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), wherein the composition is suitable for administration to a patient in need thereof, wherein the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture, and wherein the composition comprises no more than 0.5% propylene glycol.
2 . The method of claim 1 , wherein the mixture comprises less than 2.0% DS-1.
3 . The method of claim 1 , wherein the mixture comprises less than 1.7% DS-1.
4 . The method of claim 1 , wherein the mixture comprises less than 1.5% DS-1.
5 . The method of claim 1 , wherein the mixture comprises less than 1.2% DS-1.
6 . The method of claim 1 , wherein the mixture comprises less than 1.0% DS-1.
7 . The method of claim 1 , wherein the mixture comprises less than 0.8% DS-1.
8 . The method of claim 1 , wherein the mixture has an average molar substitution (“MS”) in the range of 0.40-0.80.
9 . The method of claim 1 , wherein the mixture has an average number of hydroxypropyl groups per beta-cyclodextrin (“DSa”) of about 3 to about 7.
10 . The method of claim 1 , wherein the mixture has an average number of hydroxypropyl groups per beta-cyclodextrin (“DSa”) of 4.06-4.76.
11 . The method of claim 1 , wherein the mixture has an average number of hydroxypropyl groups per beta-cyclodextrin (“DSa”) in the range of 4.2±0.3.
12 . The method of claim 1 , wherein the mixture has an average number of hydroxypropyl groups per beta-cyclodextrin (“DSa”) in the range of 4.3±0.3.
13 . The method of claim 1 , wherein the mixture has an average number of hydroxypropyl groups per beta-cyclodextrin (“DSa”) in the range of 4.7±0.3.
14 . The method of claim 1 , wherein the mixture has an average number of hydroxypropyl groups per beta-cyclodextrin (“DSa”) in the range of 4.8±0.3.
15 . The method of claim 1 , wherein the mixture has a concentration of about 10 mg/mL to about 200 mg/mL.
16 . A method of treating Niemann Pick disease in a human subject in need thereof comprising intrathecally, intravenously, or intracerebroventricularly administering a composition comprising mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 2.0% unsubstituted beta-cyclodextrin (“DS-0”); and wherein the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
17 . The method of claim 16 , wherein the composition comprises no more than 0.5% propylene glycol.
18 . The method of claim 16 , wherein the mixture comprises less than 1.5% DS-0.
19 . The method of claim 16 , wherein the mixture comprises less than 1.2% DS-0.
20 . The method of claim 16 , wherein the mixture comprises less than 1.0% DS-0.
21 . The method of claim 16 , wherein the mixture comprises less than 0.9% DS-0.
22 . The method of claim 16 , wherein the mixture comprises less than 0.8% DS-0.
23 . The method of claim 16 , wherein the mixture comprises less than 0.7% DS-0.
24 . The method of claim 16 , wherein the mixture comprises less than 0.6% DS-0.
25 . The method of claim 16 , wherein the mixture comprises less than 0.5% DS-0.
26 . A method of treating Niemann Pick disease in a human subject in need thereof comprising administering a composition comprising mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 2.5% beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), wherein the composition is suitable for intrathecal, intravenous, or intracerebroventricular administration to a patient in need thereof, wherein the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture, and wherein the composition comprises no more than 0.2% propylene glycol.
27 . A method of treating Niemann Pick disease in a human subject in need thereof comprising administering a composition comprising mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, wherein: the mixture comprises less than 2.0% unsubstituted beta-cyclodextrin (“DS-0”), wherein the composition is suitable for intrathecal, intravenous, or intracerebroventricular administration to a patient in need thereof, wherein the composition comprises no more than 0.5% propylene glycol, and wherein the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
28 . The method of claim 1 , wherein the composition comprises no more than 0.01% propylene glycol.
29 . The method of claim 16 , wherein the composition comprises no more than 0.01% propylene glycol.
30 . The method of claim 27 , wherein the composition comprises no more than 0.01% propylene glycol.