Hydroxypropyl Beta-Cyclodextrin Compositions and Methods

Abstract

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 mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, wherein:
 the mixture comprises less than 1% unsubstituted beta-cyclodextrin (“DS-0”) and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively;   the mixture comprises at least 85% beta-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”), beta-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”), beta-cyclodextrin substituted with five hydroxypropyl groups (“DS-5”), and beta-cyclodextrin substituted with six hydroxypropyl groups (“DS-6”), collectively;   the mixture comprises less than 1% beta-cyclodextrin substituted with nine hydroxypropyl groups (“DS-9”) and beta-cyclodextrin substituted with ten hydroxypropyl groups (“DS-10”), collectively,   as determined by peak heights of an electrospray MS spectrum.   
     
     
         2 . The mixture of  claim 1 , wherein less than 0.1% of the beta-cyclodextrin mixture is DS-0 and DS-1, collectively. 
     
     
         3 . The mixture of  claim 2 , wherein less than 0.01% of the beta-cyclodextrin mixture is DS-0 and DS-1, collectively. 
     
     
         4 . The mixture of  claim 1 , wherein at least 87% of the beta-cyclodextrin mixture is DS-3, DS-4, DS-5, and DS-6, collectively. 
     
     
         5 . The mixture of  claim 4 , wherein at least 90% of the beta-cyclodextrin mixture is DS-3, DS-4, DS-5, and DS-6, collectively. 
     
     
         6 . The mixture of  claim 1 , wherein less than 0.1% of the beta-cyclodextrin mixture is DS-9 and DS-10, collectively. 
     
     
         7 . The mixture of  claim 6 , wherein less than 0.01% of the beta-cyclodextrin mixture is DS-9 and DS-10, collectively. 
     
     
         8 . A mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, wherein:
 the mixture comprises less than 1% unsubstituted beta-cyclodextrin (“DS-0”) and beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), collectively;   the mixture comprises less than 1% beta-cyclodextrin substituted with nine hydroxypropyl groups (“DS-9”) and beta-cyclodextrin substituted with ten hydroxypropyl groups (“DS-10”), collectively, as determined by peak heights of an electrospray MS spectrum; and   the mixture has an average molar substitution (“MS”) in the range of 0.50 to 0.80.   
     
     
         9 . The mixture of  claim 8 , wherein less than 0.1% of the beta-cyclodextrin mixture is DS-0 and DS-1, collectively. 
     
     
         10 . The mixture of  claim 9 , wherein less than 0.01% of the beta-cyclodextrin mixture is DS-0 and DS-1, collectively. 
     
     
         11 . The mixture of  claim 8 , wherein less than 0.1% of the beta-cyclodextrin mixture is DS-9 and DS-10, collectively. 
     
     
         12 . The mixture of  claim 11 , wherein less than 0.01% of the beta-cyclodextrin mixture is DS-9 and DS-10, collectively. 
     
     
         13 . The mixture of  claim 8 , wherein the MS is in the range of 0.60 to 0.70. 
     
     
         14 . The mixture of  claim 13 , wherein the MS is in the range of 0.64 to 0.68. 
     
     
         15 . The mixture of  claim 14 , wherein the MS is about 0.66-0.67. 
     
     
         16 . A pharmaceutical composition comprising the beta-cyclodextrin mixture of  claim 1 , and a pharmaceutically acceptable diluent. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the composition comprises no more than (“NMT”) 5 EU of endotoxins per gram of beta-cyclodextrin mixture. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the composition comprises NMT 1.5 EU of endotoxins per gram of beta-cyclodextrin mixture. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the composition comprises no more than 0.5% propylene glycol, as measured by the HPLC method set forth in the USP Hydroxypropyl Betadex monograph. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the composition comprises no more than 0.01% propylene glycol, as measured by the HPLC method set forth in the USP Hydroxypropyl Betadex monograph. 
     
     
         21 . The pharmaceutical composition of  claim 16 , wherein the composition comprises no more than 1 ppm propylene oxide, determined according to the USP Hydroxypropyl Betadex monograph. 
     
     
         22 . The pharmaceutical composition of any one of  claim 16 , wherein the composition is suitable for intrathecal or intracerebroventicular administration. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the composition has an osmolality of about 300 to about 450 mOsm/kg. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the composition comprises about 10 mg/mL to about 200 mg/mL of the beta-cyclodextrin mixture. 
     
     
         25 . A pharmaceutical composition comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, and a diluent that is pharmaceutically acceptable for intrathecal, intracerebroventricular, or intravenous administration, wherein:
 the composition comprises no more than (“NMT”) 5 EU of endotoxins per gram of beta-cyclodextrin mixture;   the composition comprises no more than 0.5% propylene glycol, as measured by the HPLC method set forth in the USP Hydroxypropyl Betadex monograph;   the composition comprises no more than 1 ppm propylene oxide, determined according to the USP Hydroxypropyl Betadex monograph.   
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the composition comprises NMT 1.5 EU of endotoxins per gram of beta-cyclodextrin mixture. 
     
     
         27 . The pharmaceutical composition of  claim 25 , wherein the composition comprises no more than 0.01% propylene glycol, as measured by the HPLC method set forth in the USP Hydroxypropyl Betadex monograph. 
     
     
         28 . The pharmaceutical composition of  claim 25 , wherein:
 the mixture comprises less than 3% unsubstituted beta-cyclodextrin (“DS-0”), beta-cyclodextrin substituted with one hydroxypropyl group (“DS-1”), and beta-cyclodextrin substituted with two hydroxypropyl groups (“DS-2”), collectively;   the mixture comprises at least 65% beta-cyclodextrin substituted with five hydroxypropyl groups (“DS-5”), beta-cyclodextrin substituted with six hydroxypropyl groups (′DS-6″), and beta-cyclodextrin substituted with seven hydroxypropyl groups (′DS-7″), collectively;   the mixture comprises less than 3% beta-cyclodextrin substituted with nine hydroxypropyl groups (“DS-9”) and beta-cyclodextrin substituted with ten hydroxypropyl groups (“DS-10”), collectively,   as determined by peak heights of an electrospray MS spectrum.   
     
     
         29 . A method of treating Niemann-Pick disease Type C, comprising administering to a patient with Niemann-Pick disease Type C a therapeutically effective amount of the pharmaceutical composition of  claim 16 . 
     
     
         30 . The method of  claim 29 , wherein the administering is by intrathecal or intracerebroventricular administration. 
     
     
         31 . The method of  claim 29 , comprising administering about 300 mg to about 2000 mg of the beta-cyclodextrin mixture to the patient. 
     
     
         32 . The method of  claim 29 , wherein the administering occurs once every week, once every two weeks, once every three weeks, once every month, once every two months, or once every three months. 
     
     
         33 . The method of  claim 29 , comprising administering about 900 mg to about 1800 mg of the beta-cyclodextrin mixture to the patient once every two weeks. 
     
     
         34 . The method of  claim 33 , comprising administering about 900 mg of the beta-cyclodextrin mixture to the patient once every two weeks. 
     
     
         35 . The method of  claim 29 , comprising administering an amount of the beta-cyclodextrin mixture sufficient to modulate the level in cerebrospinal fluid of one or more of: tau protein, amyloid peptide, neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), sterol, oxysterol, chitotriosidase activity, calbindin, lysosomal-associated membrane protein 1 (LAMP-1), GM2 or GM3 ganglioside, sphingosine, and sphingosine-1-phosphate (S1P). 
     
     
         36 . The method of  claim 29 , comprising administering an amount of the beta-cyclodextrin mixture sufficient to modulate the level in plasma of one or more of: 7-ketocholesterol, 7-ketocholesterol, 7β-hydroxycholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, and cholestane-3β,5α,6β-triol. 
     
     
         37 . The method of  claim 29 , comprising administering an amount of the beta-cyclodextrin mixture sufficient to modulate the level in urine of one or more of 3β-sulfoxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid (SNAG-Δ 5 -CA), glycine-conjugated 3β-sulfoxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid (SNAG-Δ 5 -CG), and taurine-conjugated 3β-sulfoxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid (SNAG-Δ 5 -CT). 
     
     
         38 . The method of  claim 29 , comprising administering the beta-cyclodextrin mixture in an amount sufficient to maintain or reduce one or more domain scores of the NPC Severity Scale selected from: ambulation, fine motor skills, cognition, speech, swallowing, eye movement, memory, hearing, and seizures. 
     
     
         39 . A process for preparing the beta-cyclodextrin mixture of  claim 1 , comprising: treating Kleptose® HBP with absorption chromatography on alumina. 
     
     
         40 . A process of  claim 39 , further comprising: treating Kleptose® HBP with solvent precipitation. 
     
     
         41 . The process of  claim 40 , wherein the solvent precipitation is performed using water with acetone as precipitating agent. 
     
     
         42 . The process of  claim 40 , wherein the solvent precipitation is performed using methanol with acetone as precipitating agent. 
     
     
         43 . A mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, made by the process of  claim 39 . 
     
     
         44 . A method of qualifying a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, for use in a pharmaceutical composition for intrathecal or intracerebroventricular administration, the method comprising:
 a) performing electrospray MS analysis of the mixture;   b) measuring heights of all peaks; and   c) calculating the percentage of each beta-cyclodextrin species in the entire mixture, wherein the mixture is qualified for use if   the mixture comprises less than 1% DS-0 and DS-1, collectively;   the mixture comprises at least 85% DS-3, DS-4, DS-5, and DS-6, collectively;   the mixture comprises less than 1% DS-9 and DS-10, collectively.