Positively-charged microemulsion for improving the oral bioavailability of alendronate: in-vitro and in-vivo assessment

Objectives Alendronate is a poorly absorbed bisphosphonate with an oral bioavailability of 0.7%. In this study, a positively-charged microemulsion was prepared with the aim of improving the bioavailability of alendronate. Methods The positively-charged microemulsion was evaluated for physical stability, cellular uptake and permeability enhancement on Caco-2 monolayers. The bioavailability of alendronate from the microemulsion was compared with the commercially available tablet (Fosmax) for beagle dogs. Key findings The 2.0, 0.4 and 0.2% positively-charged microemulsion, stable for 4 h after preparation, promoted alendronate transport across the Caco-2 cells by a factor of 194, 146,and 45.1, respectively, compared with the alendronate solution, though no significant cellular uptake enhancement of alendronate was observed. The permeability enhancement was parallel to the reduction in transendothelial electrical resistance, which indicated the microemulsion modulated the tight junctions and widened the paracellular pathway. In-vivo results showed that the microemulsion gave the highest alendronate plasma concentration at 502 ng/ml (C-max) after 0.563 h (T-max), while tablets gave a C-max of 152 ng/ml after 0.750 h (T-max). Furthermore, the AUC(0-infinity) of alendronate from the microemulsion increased by 2.82-fold when compared with the tablets. Conclusions Based on the results, the oral bioavailability of alendronate could be significantly improved by the positively-charged microemulsion, which opened the tight junctions and thus increased absorption through the paracellular route.