Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl--cyclodextrin

Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl--cyclodextrin
19 March 2004
Received 12 June 2002; Revised 25 November 2003; accepted 29 November 2003. Available online 28 January 2004.
Jae-Hyun Kim , , Su-Kyung Lee , Min-Hyo Ki , Won-Kyu Choi , Soon-Kil Ahn , Hee-Jong Shin and Chung Il Hong
International Journal of Pharmaceutics
Volume 272, Issues 1-2 , 19 March 2004, Pages 79-89
ScienceDirect
Pharmaceutical Research Labs, CKD Research Institute, Chong Kun Dang Pharm., P.O. Box 74, Chonan 330-600, South Korea
Abstract
The effect of hydroxypropyl--cyclodextrin (HP--CyD) on the aqueous solubility and chemical stability of O-(4-Dimethylaminoethoxycinnamoyl)fumagillol (CKD-732), a new angiogenesis inhibitor, was investigated with an aim of preparing a stable and effective parenteral formulation. The CKD-732/HP--CyD inclusion complex was obtained in solid state by freeze-drying and characterized in solution by proton nuclear magnetic resonance (1H NMR). Then, the pharmacokinetic profile in rats and the in vivo tumor growth inhibitory activity in mice following the parenteral administration of aqueous CKD-732/HP--CyD complex were compared to those of CKD-732?hemioxalate solution having an equivalent concentration. The aqueous solubility of CKD-732 was markedly increased by the combination of pH adjustment and HP--CyD complexation through a soluble 1:1 inclusion complex formation, which was supported by NMR spectroscopy. The hydrolysis of CKD-732 following pseudo first-order kinetics was decelerated moderately but significantly in acidic and basic solutions in the presence of HP--CyD. The stability of lyophilized CKD-732/HP--CyD complex was also drastically improved after storage in various conditions. The intravenous pharmacokinetic profile and the subcutaneous in vivo tumor growth inhibitory activity of aqueous CKD-732/HP--CyD complex were not significantly different from those of CKD-732?hemioxalate solution with the favorable reduction of irritation. These results demonstrate that the CKD-732/HP--CyD complex is an attractive formulation for use in the parenteral delivery of CKD-732.
Author Keywords: Author Keywords: O-(4-Dimethylaminoethoxycinnamoyl)fumagillol (CKD-732); Angiogenesis inhibitor; Hydroxypropyl--cyclodextrin (HP--CyD); Solubilization; Stabilization