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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

Venkatasubramanian, Ramakrishnan ; Al-Maghrabi, Passant M. ; Alavi, Oscar ; Lind, Tania LU ; Sassene, Philip Jonas ; Kirkensgaard, Jacob J.K. ; Mota-Santiago, Pablo LU ; Rades, Thomas and Müllertz, Anette (2025) In Journal of Controlled Release 379. p.440-451
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... (More)

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.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Design of experiments, Exenatide, In vitro- in vivo correlation, Oral bioavailability, Oral peptide drug delivery, Self-nanoemulsifying drug delivery systems (SNEDDS)
in
Journal of Controlled Release
volume
379
pages
12 pages
publisher
Elsevier
external identifiers
  • pmid:39805462
  • scopus:85214962019
ISSN
0168-3659
DOI
10.1016/j.jconrel.2025.01.013
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024
id
f9b75795-6c59-47c4-b70d-1fdcd8dc076e
date added to LUP
2025-03-20 14:11:57
date last changed
2025-07-10 22:54:46
@article{f9b75795-6c59-47c4-b70d-1fdcd8dc076e,
  abstract     = {{<p>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.</p>}},
  author       = {{Venkatasubramanian, Ramakrishnan and Al-Maghrabi, Passant M. and Alavi, Oscar and Lind, Tania and Sassene, Philip Jonas and Kirkensgaard, Jacob J.K. and Mota-Santiago, Pablo and Rades, Thomas and Müllertz, Anette}},
  issn         = {{0168-3659}},
  keywords     = {{Design of experiments; Exenatide; In vitro- in vivo correlation; Oral bioavailability; Oral peptide drug delivery; Self-nanoemulsifying drug delivery systems (SNEDDS)}},
  language     = {{eng}},
  month        = {{03}},
  pages        = {{440--451}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Controlled Release}},
  title        = {{Design, evaluation, and in vitro–in vivo correlation of self-nanoemulsifying drug delivery systems to improve the oral absorption of exenatide}},
  url          = {{http://dx.doi.org/10.1016/j.jconrel.2025.01.013}},
  doi          = {{10.1016/j.jconrel.2025.01.013}},
  volume       = {{379}},
  year         = {{2025}},
}