Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the presence of a chemically modified beta-cyclodextrin.

Abstract

PURPOSE:

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: Tian-Xiang Xiang, Bradley D Anderson
• Journal: Pharmaceutical research (Pharm Res) Vol. 19 Issue 8 Pg. 1215-22 (Aug 2002) ISSN: 0724-8741 [Print] United States
• PMID: 12240949 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclodextrins
• Organosilicon Compounds
• Pharmaceutical Solutions
• beta-Cyclodextrins
• 7-tert-butyldimethylsilyl-10-hydroxycamptothecin
• betadex
• Camptothecin

Topics

• Camptothecin (analogs & derivatives, chemical synthesis, chemistry)
• Cyclodextrins (chemical synthesis, chemistry)
• Drug Stability
• Organosilicon Compounds (chemical synthesis, chemistry)
• Pharmaceutical Solutions (chemical synthesis, chemistry)
• beta-Cyclodextrins