Mechanics of small intestine motility for oral macromolecular delivery: modelling segmentation versus peristalsis

Intestinal motility, including peristalsis and segmentation, drives complex fluid movements critical for the oral delivery of biologics and other macromolecules. Despite advances, oral delivery remains commercially limited by low bioavailability, often attributed to poor epithelial permeability. However, variability in motility patterns may also play a critical role, influencing intraluminal distribution and thus absorption, yet this aspect remains underexplored. Here, we combine computational fluid dynamics and machine learning to evaluate how motility type, intensity, pocket size, contractility, and fluid composition affect the delivery of a model macromolecule (insulin) and a permeation enhancer (sodium caprate, C10). We find that segmentation, especially at light intensity, consistently enhances epithelial colocalisation over peristalsis. Under segmentation, smaller pocket sizes (2 mL versus 10 mL) and stronger contractility (occlusion ratio 0.3) yielded optimal performance. Our extreme gradient boosting regression model identified pocket volume, contractility, and motility type as dominant predictors of colocalisation. In a comparative analysis, segmentation led to 128% and 137% higher maximum normalised concentrations of insulin and C10, respectively, than moderate peristalsis with a nutritional drink. Overall, segmentation achieved 6.7-fold and 8.0-fold higher average maximum normalised concentrations for insulin and C10, respectively. These results emphasise segmentation, characteristic of the fed state, as a superior motility pattern for macromolecular absorption compared to peristalsis during the migrating motor complex (MMC). By elucidating the interplay between motility and transport, our findings may guide the design of more effective oral formulations and support personalised strategies for drug delivery based on individual motility profiles.