Enhanced Rectal Absorption and Reduced Local Irritation of the Anti-inflammatory Drug Ethyl 4-Biphenylylacetate in Rats by Complexation with Water-Soluble β-Cyclodextrin Derivatives and Formulation as Oleaginous Suppository

Abstract

To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) and heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CyD) was investigated and compared with the use of the parent β-cyclodextrin (β-CyD). Among the three β-CyDs, HP-β-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of β-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and β-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of β-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When β-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-β-CyD (~26% of dose) and DM-β-CyD (~21% of dose), compared with β-CyD (~5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic β-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex. Furthermore, HP-β-CyD significantly reduced the irritation of rectal mucosa in rats caused by BPAA, both for the single and multiple administrations of EBA-β-CyD complexes in the oleaginous suppository. The present data suggest that HP-β-CyD is particularly useful for improving the rectal bioavailability of EBA and reducing local irritation.