Fabrication and Evaluation of a pH-Responsive Nanocomposite-Based Colonic Delivery System for Improving the Oral Efficacy of Liraglutide.

PURPOSE: Oral administration of liraglutide, a protein drug, suffers from low intestinal absorption and instability in the gastrointestinal tract, resulting in low bioavailability. The present study aimed to develop a pH-responsive nanocomposite based-colonic delivery system to improve the oral efficacy of liraglutide. METHODS: Nanocomplex (AC-Lira) between aminoclay and liraglutide was prepared by a spontaneous self-assembly. After surface charge reversal using citric acid, AC-Lira was coated with poly(methacrylic acid-co-methyl methacrylate) (1:2). The fabricated nanocomplex underwent various in vitro studies to characterize its physicochemical properties, drug release, and cellular transport. In vivo efficacy studies were also conducted using streptozotocin-induced diabetic rats. RESULTS: Both uncoated (AC-Lira) and coated nanocomplex (EAC-Lira) achieved high entrapment efficiency (> 90%) and showed a narrow size distribution. While exhibiting low drug release at pH 1.2 (approximately 30%), EAC-Lira achieved rapid and extensive drug release (~90%) at pH 7.4, displaying pH-dependent drug release. EAC-Lira showed significant size reduction and surface charge reversal during dissolution at pH 7.4, probably due to the removal of the outer coating layer. Furthermore, EAC-Lira was effective at protecting the entrapped proteins against enzymatic degradation. EAC-Lira also increased the membrane transport of liraglutide by 3.5 folds in Caco-2 cells. Owing to enhanced membrane transport and metabolic stability, EAC-Lira improved in vivo efficacy of orally administered liraglutide, significantly reducing blood glucose concentrations, intake of food and water, and body weight in type 2 diabetes rats. CONCLUSION: These results suggest EAC-Lira is a promising approach to improving the oral bioavailability and efficacy of liraglutide.