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 Lind, Philip Jonas Sassene, Jacob J.K. Kirkensgaard, Pablo Mota-Santiago, Thomas Rades*, Anette Müllertz

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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.

OriginalsprogEngelsk
TidsskriftJournal of Controlled Release
Vol/bind379
Sider (fra-til)440-451
ISSN0168-3659
DOI
StatusUdgivet - 2025

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