noscapine and betadex

Noscapine (NOS) is a unique class of tubulin-binding anticancer agents. Their potential usefulness as anticancer drugs is however limited by the poor bioavailability, thus necessitating administration of a higher dose regime in the range of 300-600 mg/kg for tumor growth inhibition. To augment bioavailability, we prepared an inclusion complex of NOS in beta-cyclodextrin (beta-CD) and evaluated its physico-chemical characteristics.. Our phase-solubility analysis shows a 1:1-complexation (Kc approximately 0.454 mM(-1)) of NOS with beta-CD that offers better dissolution properties. We confirmed complex formation in solid state by differential scanning calorimetry, powder X-ray diffractometry, Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, rotating frame Overhauser enhancement spectroscopy and by molecular modeling methods. Based upon theoretical calculations in gas phase, we propose O-CH2-O- in orientation of NOS in the beta-CD cavity. The thermal behavior data also provides complementary evidences of complex formation. The pharmacokinetic studies showed a 1.87-fold increase in bioavailability of NOS upon complexation in the beta-CD inclusion complex state as compared to free NOS. Furthermore, the complex retains the anticancer attributes of NOS.. Our studies propose for the first time a stable NOS-beta-CD inclusion complex as an effective approach to enhance the solubility and bioavailability of NOS for anticancer therapy.

Topics: Administration, Oral; Animals; Area Under Curve; beta-Cyclodextrins; Biological Availability; Calorimetry, Differential Scanning; Cell Line, Tumor; Chromatography, High Pressure Liquid; Drug Compounding; Drug Stability; Humans; Magnetic Resonance Spectroscopy; Male; Metabolic Clearance Rate; Mice; Models, Molecular; Molecular Structure; Noscapine; Solubility; Spectroscopy, Fourier Transform Infrared; Temperature; X-Ray Diffraction