Enhanced Oral Bioavailability and Anticoagulant Activity of Dabigatran Etexilate by Self-Micro Emulsifying Drug Delivery System: Systematic Development, In vitro, Ex vivo and In vivo Evaluation

Abstract

Dabigatran etexilate (DE), a prodrug of Dabigatran, is a potent, oral, reversible and direct thrombin inhibitor with low oral bioavailability due to active efflux by intestinal P-glycoprotein receptors. No lipid based oral formulation is marketed for DE till date. Hence, we formulated and evaluated self-micro emulsifying drug delivery system (SMEDDS), by using P-gp modulator excipients to tackle this issue and elevate the systemic availability of DE. The SMEDDS were developed using Capmul MCM C8, Cremophor EL and Transcutol HP as oil, surfactant and co-surfactant respectively. The formulation was optimized using statistical D-optimal design. The globule size of 73.24 nm with 0.085 PDI was achieved upon spontaneous emulsification with >99% Transmittance at 250 times dilution and discrete globules were observed under TEM. The in vitro and ex vivo drug release from DE-SMEDDS was found to be significantly higher in comparison to that from plain drug suspension. The DE-SMEDDS was observed to be non-cytotoxic and safe when assessed by MTT assay on Caco-2 cells. Moreover, a deeper penetration in the Caco-2 cells was observed with DE-SMEDDS when assessed using confocal laser scanning microscopy. Flow-cytometric studies also revealed greater uptake of fluorescent probe in Caco-2 cell-lines from the DE-SMEDDS when compared with drug suspension. Furthermore, the AUC0→t of DE from the optimized DE-SMEDDS formulation was found to be 2.5 times higher and relative bioavailability was enhanced by 3.36 folds than that from drug suspension on oral administration to rats. Moreover, DE SMEDDS exhibited higher anticoagulant activity than drug suspension, further indicating better bioavailability.