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

Introduction

Upon oral administration, peptides are labile to acid and enzymatic hydrolysis and show poor permeability across the intestinal epithelium due to their large size and hydrophilicity. Self-nanoemulsifying drug delivery systems (SNEDDS) potentially improve absorption of peptides [1] as they may provide proteolytic protection and have innate permeation enhancing abilities [[2], [3], [4], [5], [6]] to facilitate either paracellular or transcellular transport [[7], [8], [9]]. However, the hydrophilicity of therapeutic peptides makes it challenging to load them into the lipophilic SNEDDS preconcentrate (i.e. a SNEDDS formulation before dispersion).

One approach to improve the lipophilicity of peptides is via complexation with phospholipids, such as soybean phosphatidylcholine (SPC). Insulin has previously been complexed with SPC using freeze-drying prior to loading into SNEDDS preconcentrates. Complexation of insulin with SPC improved its lipophilicity [10], and loading the complex into SNEDDS protected insulin against proteolytic enzymes, enabled a better transport across cell monolayers, and improved intestinal absorption compared to an aqueous insulin solution [10,11].

Despite the considerable potential of SNEDDS in overcoming the challenges associated with oral peptide delivery, the design and optimization of these systems remain empirically driven. While prior research has demonstrated the capacity of SNEDDS to enhance peptide bioavailability through various mechanisms such as permeability [2,7], and proteolytic protection [[12], [13], [14]], the underlying properties that govern these effects have not been systematically elucidated. This represents a significant gap in the development of rational, peptide-specific SNEDDS formulations.
In the present study, an optimized exenatide (Ex) (a 39-amino acid GLP-1 analogue, with a molecular weight of 4.2 kDa) complex with SPC (Ex:SPC complex) was prepared and added to various SNEDDS preconcentrates. For the SNEDDS preconcentrates medium chain (C8-C10) triglycerides (MCT), medium chain (C8-C10) mono-diglycerides (MGDG), and monoacyl-phosphatidylcholine (MAPC), were selected as excipients for a design of experiments (DoE) based formulation approach [4,11,14]. Protection of Ex from proteolysis was evaluated by an in vitro proteolysis assay. The initial droplet size and rate and extent of digestion were investigated by dynamic light scattering, in vitro lipolysis and small -angle X-Ray scattering (SAXS). The ability of the DoE designed SNEDDS to open tight junctions was evaluated in Caco 2 cell monolayers.

The objective of this study was to assess the ability of the above mentioned in vitro methods applied on the DoE designed Ex:SPC complex containing SNEDDS to predict the absorption of Ex after oral gavage in rats.

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Materials

Ex was gifted from Bachem (Basel, Switzerland). SPC (Lipoid S 100 (phosphatidylcholine from soybean; not less than 94.0 % pure) and MAPC (Lipoid P LPC 80 (lyso-phosphatidylcholine (LPC) from soybean, containing 80.0 % LPC) were donated by Lipoid (Ludwigshafen, Germany). Medium chain (C8-C10) triglycerides (MCT; Captex 300 EP/NF) and C8-C10 mono-diglycerides (Capmul MCM EP/NF; MGDG)) were gifted from Abitec (Janesville, WI, USA). Polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40) was donated by BASF (Ludwigshafen, Germany). Calcium chloride anhydrous was purchased from Merck KGaA (Darmstadt, Germany). α-Chymotrypsin (α–CT) from bovine pancreas (type II, lyophilized powder, ≥40 units/mg protein), bovine bile, fluorescein isothiocynate dextran-4 (4 kDa; FD4), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), t-octylphenoxypoly-ethoxyethanol (Triton™ X-100) and porcine pancreatin extract were obtained from Sigma-Aldrich (St Louis, MO, USA). Lithium heparin coated plasma tubes were purchased from Sarstedt (Nümbrecht, Germany). Deionized water was obtained from an SG Ultraclear water system (SG Water GmbH, Barsbüttel, Germany). All other reagents used were of analytical grade. The compositions of lipid excipients is described in Table S1.

Ramakrishnan Venkatasubramanian, Passant M. Al-Maghrabi, Oscar Alavi, Tania Lind, Philip Jonas Sassene, Jacob J.K. Kirkensgaard, Pablo Mota-Santiago, Thomas Rades, Anette Müllertz, Design, evaluation, and in vitro–in vivo correlation of self-nanoemulsifying drug delivery systems to improve the oral absorption of exenatide, Journal of Controlled Release, Volume 379, 2025, Pages 440-451, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2025.01.013.

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