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 comprising beta-cyclodextrins having glucose units of the structure:
wherein R1, R2, and R3, independently for each occurrence, are —H or —HP, wherein HP comprises one or more hydroxypropyl groups, and the percentage of total occurrences of R1 and R2 combined that are HP is at least 5%, and wherein the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
2 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 10%.
3 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 15%.
4 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 20%.
5 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 25%.
6 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 30%.
7 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 35%.
8 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 40%.
9 . The method of claim 1 , wherein the percentage of R1 and R2 combined that are HP is at least 45%.
10 . The method of claim 1 , wherein at least 5% of total occurrences of R3 are HP.
11 . The method of claim 1 , wherein at least 10% of total occurrences of R3 are HP.
12 . The method of claim 9 , wherein at least 5% of total occurrences of R3 are HP.
13 . The method of claim 9 , wherein at least 10% of total occurrences of R3 are HP.
14 . The method of claim 1 , wherein the amount of DS-0 or beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”) is determined by peak height of an electrospray MS spectrum.
15 . The method of claim 1 , wherein the composition comprises no more than 0.5% propylene glycol.
16 . The method of claim 1 , wherein the composition comprises no more than 0.5% propylene glycol as measured by HPLC or by gas chromatography.
17 . The method of claim 1 , wherein the composition comprises no more than 1 ppm propylene oxide.
18 . 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.
19 . 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 comprising beta-cyclodextrins having glucose units of the structure:
wherein R1, R2, and R3, independently for each occurrence, are —H or —HP, wherein HP comprises one or more hydroxypropyl groups, and wherein the average number of occurrences of HP per beta-cyclodextrin is 3 to 7, and wherein the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
20 . The composition of claim 19 , wherein the average number of occurrences of HP per beta-cyclodextrin is 4 to 7.
21 . The composition of claim 19 , wherein the average number of occurrences of HP per beta-cyclodextrin is 4 to 6.
22 . 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 4% beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”) and comprising beta-cyclodextrins having glucose units of the structure:
wherein R1, R2, and R3, independently for each occurrence, are —H or —HP, wherein HP comprises one or more hydroxypropyl groups, and the percentage of total occurrences of R1 and R2 combined that are HP is at least 5%, and wherein the composition comprises less than 5 IU endotoxin per gram of the beta-cyclodextrin mixture.
23 . The method of claim 22 , wherein the percentage of R1 and R2 combined that are HP is at least 10%.
24 . The method of claim 22 , wherein the percentage of R1 and R2 combined that are HP is at least 15%.
25 . The method of claim 22 , wherein the percentage of R1 and R2 combined that are HP is at least 20%.
26 . The method of claim 22 , wherein the percentage of R1 and R2 combined that are HP is at least 25%.
27 . The method of claim 22 , wherein the percentage of R1 and R2 combined that are HP is at least 30%.
28 . The method of claim 22 , wherein the percentage of R1 and R2 combined that are HP is at least 35%.
29 . The method of claim 22 , wherein the percentage of R1 and R2 combined that are HP is at least 40%.
30 . The method of claim 22 , wherein at least about 5% of total occurrences of R3 are HP.