title: Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the presence of a chemically modified beta-cyclodextrin.
abstract: OBJECTIVE
  A method for obtaining clear supersaturated aqueous solutions for parenteral administration of the poorly soluble experimental anti-cancer drug silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) has been developed.
  
  
  METHODS
  Equilibrium solubilities of DB-67 were determined in various solvents and pH values, and in the presence of chemically modified water-soluble beta-cyclodextrins. The stoichiometry and binding constants for complexes of the lactone form of DB-67 and its ring-opened carboxylate with sulfobutyl ether and 2-hydroxypropyl substituted beta-cyclodextrins (SBE-CD and HP-CD) were obtained by solubility and circular dichroism spectroscopy, respectively. Kinetics for the reversible ring-opening of DB-67 in aqueous solution and for lactone precipitation were determined by HPLC with UV detection.
  
  
  RESULTS
  Solubilities of DB-67 lactone in various injectable solvent systems were found to be at least one order of magnitude below the target concentration (2 mg/ml). DB-67 forms inclusion complexes with SBE-CD and HP-CD but the solubilization attainable is substantially less than the target concentration. Slow addition of DB-67/ DMSO into 22.2% (w/v) SBE-CD failed to yield stable supersaturated solutions due to precipitation. Stable supersatured solutions were obtained, however, by mixing a concentrated alkaline aqueous solution of DB-67 carboxylate with an acidified 22.2% (w/v) SBE-CD solution. Ring-closure yielded supersaturated solutions that could be lyophilized and reconstituted to clear, stable, supersaturated solutions.
  
  
  CONCLUSIONS
  The method developed provides an alternative to colloidal dispersions (e.g., liposomal suspensions, emulsions, etc.) for parenteral administration of lipophilic camptothecin analogs.
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington 40536-0082, USA.
authors.forename: Tian-Xiang
authors.initials: TX
authors.lastname: Xiang
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D003505:Cyclodextrins / Q000138:chemical synthesis / Q000737:chemistry*; D004355:Drug Stability; D017646:Organosilicon Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D019999:Pharmaceutical Solutions / Q000138:chemical synthesis / Q000737:chemistry; D047392:beta-Cyclodextrins
chemical_list: D003505:Cyclodextrins; D017646:Organosilicon Compounds; D019999:Pharmaceutical Solutions; D047392:beta-Cyclodextrins; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; C031215:betadex; D002166:Camptothecin