Design, evaluation, and in vitro–in vivo correlation of self-nanoemulsifying drug delivery systems to improve the oral absorption of exenatide
Ramakrishnan Venkatasubramanian, Passant M. Al-Maghrabi, Oscar Alavi, Tania Kjellerup Lind, Philip Sassene, Jacob J. K. Kirkensgaard, Pablo Mota‐Santiago, Thomas Rades, Anette Müllertz
Abstract
The ability to predict the absorption of exenatide (Ex), a GLP-1 analogue, after oral dosing to rats in self-nanoemulsifying drug delivery systems (SNEDDS), using in vitro methods, was assessed. Ex was complexed with soybean phosphatidylcholine (SPC) prior to loading into SNEDDS. A design of experiments (DoE) approach was employed to develop SNEDDS incorporating medium-chain triglycerides (MCT), medium-chain mono- and diglycerides (MGDG), Kolliphor® RH40, and monoacyl phosphatidylcholine. SNEDDS with higher proportions of MGDG and Kolliphor® RH40 demonstrated a 9-fold reduction in droplet size (230 to 26 nm), a 1.5-fold decrease in lipolysis (0.23 to 0.34 mmol of FFA), and a 2-fold enhancement in exenatide protection against proteolysis (73 % to 38 %) compared to those with higher MCT content. Permeability studies in Caco-2 cells showed that SNEDDS with higher proportion of MGDG displayed a 40-fold increase in apparent permeability of FD4, when compared to SNEDDS with higher proportion of MCT. An oral gavage study in rats revealed a 1.8-fold higher absorption of Ex in SNEDDS with a higher proportion of MGDG and Kolliphor®RH40 compared to SNEDDS with higher MCT. These results establish a clear in vitro–in vivo correlation, demonstrating that the selected in vitro methods effectively differentiated formulations with high and low absorption of exenatide after oral dosing in rats. • Enhanced Absorption : SNEDDS with higher MGDG led to a 1.8-fold increase in exenatide absorption compared to higher MCT. • Improved in vitro performance : SNEDDS with higher MGDG and Kolliphor®RH40 showed smaller droplets, less lipolysis, and better protection. • Predictive Efficacy : In vitro studies showed SNEDDS with higher MGDG had the highest exenatide permeation and predicted oral absorption.