Inclusion complexes of noscapine in β-cyclodextrin offer better solubility and improved pharmacokinetics

Abstract

Purpose 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 β-cyclodextrin (β-CD) and evaluated its physico-chemical characteristics. Method and results Our phase-solubility analysis shows a 1:1-complexation (K c ~0.454 mM−1) of NOS with β-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 β-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 β-CD inclusion complex state as compared to free NOS. Furthermore, the complex retains the anticancer attributes of NOS. Conclusion Our studies propose for the first time a stable NOS–β-CD inclusion complex as an effective approach to enhance the solubility and bioavailability of NOS for anticancer therapy.