Oversaturated solutions of drug in hydroxypropylcyclodextrins: parenteral preparation of pancratistatin.
The effect of 15 cyclodextrin derivatives (polar-electroneutral, cationic, anionic, and lipophilic) and of three 2-hydroxypropyldigitonins on the solubility of pancratistatin, an anticancer drug, was evaluated. The direct solubilizations into aqueous solutions were invariably low (0.1-1.2 mg/mL compared with 50 micrograms/mL in water). Complexes of pancratistatin with hydroxypropyl-beta-cyclodextrin were more stable (Kapp 153 M-1) than those with hydroxypropyl-gamma-cyclodextrin (Kapp 108 M-1). Acceptable preparations were made by dissolution of pancratistatin in a large excess (50x) of hydroxypropylcyclodextrin by ammonia and then freeze drying to ammonia-free preparations. In these preparations, both the inclusion and interdispersion phenomena were operative, and the preparations dissolved rapidly forming clear solutions of pancratistatin of concentrations up to 9 mg/mL. These solutions were oversaturated and while those based on hydroxypropyl-beta-cyclodextrin precipitated within 1 h; those based on hydroxypropyl-gamma-cyclodextrin were stable for at least 4 h when kept in a plastic container (i.e., time sufficient for potential use in parenteral preparations).
Torres-Labandeira
J J
JJ
National Institutes of Health, NIA/GRC, Baltimore, MD 21224.
Davignon
P
P
Pitha
J
J
D047151:Amaryllidaceae Alkaloids; D000643:Ammonium Chloride; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D011232:Chemical Precipitation; D003505:Cyclodextrins / Q000737:chemistry*; D004072:Digitonin / Q000031:analogs & derivatives / Q000737:chemistry; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage* / Q000737:chemistry; D010592:Pharmaceutic Aids; D012995:Solubility; D012996:Solutions; D014867:Water / Q000737:chemistry
C057235:2-hydroxypropyldigitonin; D047151:Amaryllidaceae Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D003505:Cyclodextrins; D007546:Isoquinolines; D010592:Pharmaceutic Aids; D012996:Solutions; D000643:Ammonium Chloride; D014867:Water; C044997:pancratistatin; D004072:Digitonin