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Design, evaluation, and in vitro–in vivo correlation of self-nanoemulsifying drug delivery systems to improve the oral absorption of exenatide

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Title: Design, evaluation, and in vitro–in vivo correlation of self-nanoemulsifying drug delivery systems to improve the oral absorption of exenatide
Authors: Venkatasubramanian, Ramakrishnan, Al-Maghrabi, Passant M., Alavi, Oscar, Lind, Tania, Sassene, Philip Jonas, Kirkensgaard, Jacob J.K., Mota-Santiago, Pablo, Rades, Thomas, Müllertz, Anette
Contributors: Lund University, Faculty of Engineering, LTH, Departments at LTH, Department of Construction Sciences, Solid Mechanics, Lunds universitet, Lunds Tekniska Högskola, Institutioner vid LTH, Institutionen för byggvetenskaper, Hållfasthetslära, Originator
Source: Journal of Controlled Release. 379:440-451
Subject Terms: Medical and Health Sciences, Basic Medicine, Pharmaceutical Sciences, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Farmaceutiska vetenskaper, Medical Biotechnology, Biomaterials Science, Medicinsk bioteknologi, Biomaterialvetenskap
Description: 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.
Access URL: https://doi.org/10.1016/j.jconrel.2025.01.013
Database: SwePub
Description
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.
ISSN:01683659
DOI:10.1016/j.jconrel.2025.01.013