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 patient 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 unsubstituted beta-cyclodextrin (“DS-0”), beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), and less than 10.0% beta-cyclodextrin substituted with seven hydroxypropyl groups (“DS-7”), and wherein the composition comprises less than 5 International Units (IU) of endotoxins per gram.
2 . The method of claim 1 , wherein the mixture comprises less than 0.2% DS-0.
3 . The method of claim 1 , wherein the mixture comprises less than 0.1% DS-0.
4 . The method of claim 1 , wherein the mixture comprises less than 4.0% DS-1.
5 . The method of claim 1 , wherein the mixture comprises less than 3.0% DS-1.
6 . The method of claim 1 , wherein the composition comprises less than 4 International Units (IU) of endotoxins per gram.
7 . The method of claim 1 , wherein the composition comprises less than 2 International Units (IU) of endotoxins per gram.
8 . The method of claim 1 , wherein the composition comprises less than 1 International Units (IU) of endotoxins per gram.
9 . The method of claim 1 , wherein the mixture has an average molar substitution (“MS”) in the range of 0.40-0.80.
10 . The method of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of about 3 to about 7.
11 . The method of claim 1 , wherein the mixture has an average degree of substitution (“DS a ”) of about 6 to about 7.
12 . The method of claim 1 , wherein the composition comprises no more than 1 ppm propylene oxide.
13 . The method of claim 1 , wherein the total amount of other unspecified impurities is less than or equal to 0.05%.
14 . The method of claim 1 , wherein the composition has a concentration of about 10 mg/ml to about 200 mg/mL.
15 . The method of claim 1 , wherein the patient is a pediatric patient.
16 . The method of claim 1 , wherein the patient is an adult patient.
17 . The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable diluent.
18 . The method of claim 1 , wherein the mixture comprises less than 9% DS-7.
19 . The method of claim 1 , wherein the mixture comprises less than 8% DS-7.
20 . The method of claim 1 , wherein the mixture comprises less than 7% DS-7.
21 . A method of treating Niemann Pick in a human patient 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 unsubstituted beta-cyclodextrin (“DS-0”), beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), and from 1% to 10% beta-cyclodextrin substituted with seven hydroxypropyl groups (“DS-7”), and wherein the composition comprises less than 5 International Units (IU) of endotoxins per gram.
22 . The method of claim 21 , wherein the mixture comprises less than 0.2% DS-0.
23 . The method of claim 21 , wherein the mixture comprises less than 0.1% DS-0.
24 . The method of claim 21 , wherein the mixture comprises less than 4.0% DS-1.
25 . The method of claim 21 , wherein the mixture comprises less than 3.0% DS-1.
26 . The method of claim 21 , wherein the composition comprises less than 4 International Units (IU) of endotoxins per gram.
27 . The method of claim 21 , wherein the composition comprises less than 2 International Units (IU) of endotoxins per gram.
28 . The method of claim 21 , wherein the composition comprises less than 1 International Units (IU) of endotoxins per gram.
29 . A method of treating Niemann Pick in a human patient 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 0.2% unsubstituted beta-cyclodextrin (“DS-0”), less than 10.0% beta-cyclodextrin substituted with seven hydroxypropyl groups (“DS-7”); wherein the composition comprises less than 0.2% propylene glycol; and, wherein the composition comprises less than 5 International Units (IU) of endotoxins per gram.