Effect of para-Sulfonato-Calix[n]arenes on the Solubility, Chemical Stability, and Bioavailability of a Water Insoluble Drug Nifedipine

Wenzhan      Yang; Daniel   P.   Otto; Wilna      Liebenberg; Melgardt   M.   de Villiers

Abstract

This study reports the use of para-sulphonato calix[8]arene to produce stable complexes with improved bioavailability for nifedipine, a calcium-channel blocker that is practically insoluble in water. Thermal analysis and electrospray ionisation mass spectroscopy confirmed that nifedipine formed complexes with the calixarenes in a size dependent way. The most stable, soluble complexes was formed with para-sulphonato calix[8]arene. Complexation was weakest with the calix[4]arene while complexation with the calix[6]arene was intermediate. However, the calix[4 and 6]arenes changed the chemical stability of the drug in solution because significant amounts of the nitroso-pyridine derivative was produced, proposing an interaction between the nifedipine bearing a H substituent at the N-1 position and the calixarenes. This oxidative degradation of the drug was greatest when combined with the calix[6]arene. Simultaneous oral ingestion of the calix[6 or 8]arenes significantly increased the bioavailability of the drug after oral administration in male Sprague-Dawley rats while not influencing CYP3A activities in the liver. The pharmacokinetic parameters of the nifedipine: para-sulfonato calix[8]arene complexes showed it was bioequivalent to a nifedipine PEG-solution. The absolute bioavailability for both formulations was ca. 60 %.

Keywords: Para-sulphonato calix[n]arenes, nifedipine, solubility, stability, pharmacokinetics