A Hierarchical Dual-barrier Nanoparticle System Combining Solid Lipid Nanoparticles and Enteric Coating for Effective Oral Insulin Delivery

Objective Oral delivery of insulin is limited by enzymatic degradation and instability in the gastrointestinal tract, as well as inefficient intestinal absorption. This study aimed to develop a dual-barrier oral insulin delivery system to protect insulin during gastrointestinal transit. Methods A hierarchical formulation was constructed by integrating dextran-mediated insulin stabilization, solid lipid nanoparticle (SLN) encapsulation, enteric coating, and lyophilization. Insulin was first complexed with dextran and subsequently encapsulated into solid lipid nanoparticles (INS-SLNs) via a double-emulsion solvent evaporation method, followed by coating with Eudragit L100 (INS-SLNs-L100). The physicochemical properties, secondary structure, in vitro release and enzymatic stability, and in vivo hypoglycemic effects were evaluated. Results The optimized INS-SLNs and INS-SLNs-L100 exhibited particle sizes of 221.2 ± 3.2 nm and 288.2 ± 1.1 nm, respectively, with encapsulation efficiencies exceeding 85%. The secondary structure of insulin was largely preserved after formulation and lyophilization. Both formulations improved the resistance of insulin to enzymatic degradation. The L100-coated formulation further enhanced insulin protection under simulated gastric conditions while maintaining efficient release under intestinal conditions. In streptozotocin-induced diabetic rats, oral administration resulted in relative pharmacological availability (rPA) values of 5.69% and 7.66% for INS-SLNs and INS-SLNs-L100, respectively, compared with 1.1% for oral insulin solution. Conclusion The developed dual-barrier oral insulin delivery system provided enhanced gastrointestinal protection and sustained hypoglycemic effects after oral administration, supporting its potential as a formulation strategy for oral delivery of insulin and other peptide therapeutics.