The complexation of insulin with sodium N‐[8‐(2‐hydroxybenzoyl)amino]‐caprylate for enhanced oral delivery: Effects of concentration, ratio, and pH

Permeation enhancers (PEs), such as N-[8-(2-hydroxybenzoyl)amino]-caprylate (SNAC), have been reported to improve the oral absorption of various macromolecules. However, the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes, pH and other gastrointestinal barriers. In this study, we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration (insulin ≥ 40 µg/mL)-, ratio (SNAC/insulin ≥ 20:1)- and pH (≥ 6.8)-dependent manner, thus contributing to a significantly high efficacy of oral insulin delivery. Specifically, absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol. Furthermore, the complexes accelerated the exocytosis of insulin to the basolateral side, thereby enhancing its intestinal mucosal permeability. EudragitⓇ S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient (Papp) that was 6.6-fold higher than that of the insulin solution. In diabetic rats, hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into enteric-coated capsules. Further pharmacokinetic studies revealed an approximately 6.3% oral bioavailability in both the fasted and fed states, indicating a negligible food effect. Collectively, this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.