Enhanced macromolecule bioavailability in rats and pigs using an in situ forming synthetic epithelial lining

Oral delivery of macromolecules is hindered by enzymatic degradation, poor epithelial permeability, and rapid gastric transit, leading to low bioavailability. Existing permeation enhancers (PEs), such as salcaprozate sodium and sodium caprate, improve absorption but do not fully address proteolytic degradation and require high doses due in part to short gastrointestinal residence times. We developed the Peroral Mucosal Epithelium Absorption Enhancer (PERMEATE) system, an orally administered polymer film designed to adhere to the small intestinal mucosa, maximizing contact between therapeutics, PEs, and the absorptive tissue. Utilizing Synthetic Tissue-Lining (SYNT™) technology, PERMEATE triggers endogenous catalase-dependent dopamine polymerization to form an in situ polydopamine coating, creating a temporary depot that enhances co-localization and prolongs exposure to the absorptive mucosa. We assessed PERMEATE's potential to enhance the oral bioavailability of semaglutide (SEMA). High-throughput screening using the GI tissue robotic interface system (GI-ORIS) identified glycocholic acid (GCA) and ammonium carbonate (NHCO) as effective PEs when combined with SYNT. Ex vivo studies (n = 8-24) and in vivo tests in Sprague-Dawley rats (n = 5-11/group) demonstrated a 200-fold increase in bioavailability compared to SEMA alone (P = 0.0001) and a 6-fold increase relative to SEMA+PE without SYNT (P = 0.0011). In Yorkshire pigs (n = 3-4), PERMEATE achieved a 2.4 % absolute bioavailability, a 6-fold improvement over SEMA+PE controls (P = 0.0316). These results suggest PERMEATE as a promising platform for improving oral macromolecule delivery through enhanced mucosal adhesion and prolonged therapeutic contact, supporting further development for clinical application.