By adhering to Lipinski’s rule of 5, small molecules can usually get across the intestine with ease. However, anything larger than a small molecule, including peptides, struggle to pass through. This predicament has therefore sparked interest in oral peptide delivery across the life sciences community.
John Glesson, Associate Principal Scientist at Merck, compared organ-on-a-chip models to the gold standard Caco-2 for predicting intestinal permeability. He noted that Caco-2 is the only cell model that’s been approved in the ICH M9 bio classification guideline. Glesson explained that the scientific industry would like to reduce the number of animal models used so it would be beneficial to investigate using other cell models to predict permeability.
Glesson stated: “The crux of formulation space and models is how can we make these models more physiologically relevant while giving us better clinical predictions, but not necessarily over fine-tuning it so that it's a disease and a dish model necessarily because we don't necessarily need to go to that level of complexity.”
The talk went on to explain the difficulty of translating preclinical absorption enhancer data to clinical outcomes for oral peptide delivery. Glesson suggested that current models often overpredict enhancement compared to what is observed in vivo and in the clinic.
The comparative study between organ-on-a-chip and transwell systems showed that both models can distinguish between highly and poorly permeable molecules but struggle to differentiate moderate from low permeability compounds. Furthermore, the chip model was
found to be more robust than transwell systems when simulating fed-state intestinal conditions, showing less disruption from bile salts and better mimicking clinical scenarios.
Glesson also added that absorption enhancers like sodium caprate and sucrose monolaurate are necessary for oral peptide formulations, but realistic improvements in bioavailability are typically modest (e.g., threefold increases). This aligns more closely with clinical results when using chip models.
Overall, Glesson highlighted how he uses in vitro tools to guide formulation design. Looking ahead, Merck is exploring the use of intestinal organoids and mucus assays to further improve model predictiveness for modified release formulations. Another aim is to better understand the role of mucus in peptide and enhancer absorption.
