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

Abstract

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.