Oral delivery of therapeutic peptides remains a pharmaceutical challenge because peptides are susceptible to gastrointestinal degradation and have poor permeability across the intestinal epithelium. Permeation enhancers (PEs), such as sodium caprate (C10), can improve intestinal uptake, but oral bioavailability remains low and variable. Even among structurally related peptides, the extent of absorption may differ following co-administration with the same PE, and the underlying mechanisms remain incompletely understood.

This thesis aimed to determine how peptide molecular properties and interactions with C10 impact intestinal absorption. The translational relevance of used in vitro and ex vivo permeability models were assessed. The effects of backbone modification and lipidation on peptide stability and absorption were studied. Peptide self-assembly, peptide–C10 interactions; and peptide interactions with a model cell membrane were examined. Four GLP-1 peptide analogues were evaluated: non-lipidated J211, mono-lipidated J229 and semaglutide, and bis-lipidated MEDI7219.

Comparative studies in Caco-2 monolayers, rat jejunal Ussing chambers, rats, and pigs showed that C10-mediated enhancement in vivo was concentration dependent and transient. In contrast, the in vitro and ex vivo models did not reproduce this pattern at physiologically relevant C10 concentrations, reflecting limitations including the absence of vascular clearance and epithelial recovery.

In rat intraduodenal studies, C10 significantly increased absorption of four peptides, but the extent varied markedly. MEDI7219 achieved the highest absolute bioavailability (17.3%), compared with 7.5% for J211, 4.0% for J229, and 2.0% for semaglutide. Extensive backbone modification conferred resistance to pancreatin-mediated degradation, whereas semaglutide was degraded. C10 partially improved semaglutide stability, indicating limited protection against luminal proteolysis in addition to enhanced epithelial transport.

Biophysical characterisation and molecular-dynamics simulations showed that the peptides differed in self-association, interaction with C10 aggregates, and membrane engagement. MEDI7219 showed the weakest apparent association with C10 aggregates and retained the highest apparent mobility, consistent with a greater freely available or rapidly exchanging fraction. It also exhibited the deepest and most stable lipid-tail insertion into the model cell membrane. These properties were consistent with its superior intestinal absorption.

C10-enabled oral peptide absorption is governed not only by epithelial permeabilisation, but also by peptide stability, self-assembly, peptide–enhancer interactions, and membrane association.