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 in a human subject in need thereof comprising administering 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 2% unsubstituted beta-cyclodextrin (“DS-0”); and, the mixture comprises beta-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”); and the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
2 . The method of claim 1 , wherein less than 3.0% of the beta-cyclodextrin mixture is DS-0 and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively.
3 . The method of claim 1 , wherein less than 2.0% of the beta-cyclodextrin mixture is DS-0 and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively.
4 . The method of claim 1 , wherein the amount of DS-0 is determined by peak height of an electrospray MS spectrum.
5 . The method of claim 1 , wherein at least 20% of the beta-cyclodextrin mixture is DS-4.
6 . The method of claim 1 , wherein the mixture has an average molar substitution (“MS”) in the range of 0.40-0.80.
7 . The method of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.
8 . The method of claim 1 , wherein the composition comprises no more than 0.5% propylene glycol.
9 . The method of claim 1 , wherein no more than 40% of the beta-cyclodextrin mixture is DS-4.
10 . The method of claim 1 , wherein the composition comprises no more than 1 ppm propylene oxide.
11 . The method of claim 1 , wherein the mixture of beta-cyclodextrin molecules has an aqueous concentration of about 10 mg/ml to about 200 mg/mL.
12 . The method of claim 1 , wherein the composition is administered to a pediatric patient.
13 . The method of claim 1 , wherein the composition is administered to an adult patient.
14 . A method of treating Niemann Pick in a human subject in need thereof comprising administering 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 2% unsubstituted beta-cyclodextrin (“DS-0”); and, the mixture comprises at least 10% beta-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”); and the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
15 . The method of claim 14 , wherein less than 3.0% of the beta-cyclodextrin mixture is DS-0 and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively.
16 . The method of claim 14 , wherein less than 2.0% of the beta-cyclodextrin mixture is DS-0 and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively.
17 . The method of claim 14 , wherein at least 20% of the beta-cyclodextrin mixture is DS-4.
18 . The method of claim 14 , wherein no more than 40% of the beta-cyclodextrin mixture is DS-4.
19 . The method of claim 14 , wherein the mixture has an average molar substitution (“MS”) in the range of 0.40-0.80.
20 . The method of claim 14 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.
21 . A method of treating Niemann Pick in a human subject in need thereof comprising administering 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 2% unsubstituted beta-cyclodextrin (“DS-0”); and, the mixture comprises no more than 30% beta-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”); and the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
22 . The method of claim 21 , wherein less than 3.0% of the beta-cyclodextrin mixture is DS-0 and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively.
23 . The method of claim 21 , wherein less than 2.0% of the beta-cyclodextrin mixture is DS-0 and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively.
24 . The method of claim 21 , wherein at least 20% of the beta-cyclodextrin mixture is DS-4.
25 . The method of claim 21 , wherein no more than 40% of the beta-cyclodextrin mixture is DS-4.
26 . The method of claim 21 , wherein the mixture has an average molar substitution (“MS”) in the range of 0.40-0.80.
27 . The method of claim 21 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.
28 . A method of treating Niemann Pick in a human subject in need thereof comprising administering 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 2% unsubstituted beta-cyclodextrin (“DS-0”); and, the mixture comprises 10 to 30% beta-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”), and 20 to 40% beta-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”); and the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
29 . The method of claim 28 , wherein the mixture has an average molar substitution (“MS”) in the range of 0.40-0.80.
30 . The method of claim 28 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.