Assessment of pectin-ethyl cellulose coated pellets for bacterially enhanced colonic drug delivery in progressively complex in vitro and in vivo models

Microbially triggered drug delivery technologies have long been recognized for their potential to achieve targeted site-specific drug release in the colon. Yet, despite extensive research and ever-increasing knowledge of the role of gut microbiome, few microbially-tiggered formulations have successfully transitioned to the clinic. A major challenge lies in the poor translation of promising in vitro results to in vivo performance, compounded by the lack of physiologically relevant preclinical models that can reliably guide formulation optimization. In this study, a comprehensive evaluation was conducted using a toolkit of in vitro and in vivo models of increasing complexity and biorelevance to investigate polysaccharide-based pellets as a microbiota-responsive material for targeted colonic drug release. Theophylline pellets were coated with a pectin-ethylcellulose film and tested in vitro in the presence of microbial enzymes or bacteria. Pectin-ethylcellulose, ethylcellulose alone coated and uncoated pellets were further assessed in both healthy pigs and microbiota-depleted porcine models in a cross over design. While pectin-ethylcellulose coatings demonstrated microbially enhanced drug release in vitro, this effect was not replicated in vivo. The lack of in vivo response is likely attributable to the low pectinase activity observed in pig faecal samples. This study underscores the need for more predictive, compendial in vitro systems to better anticipate drug release behaviour prior to animal testing. Notably, this study is the first to demonstrate the utility of a porcine microbiota-depletion model for investigating the impact of microbiome alterations on drug pharmacokinetics, using a crossover design that allows comparisons between healthy and microbiota-depleted pigs.