Development of Oral Self-nanoemulsifying Drug Delivery System Incorporated Insulin-Hydrophobic Ion Pairing Complex

This study aimed to develop an oral self-nanoemulsifying drug delivery system (SNEDDS) using insulin (INS) as a model peptide drug to improve enzymatic stability and epithelial permeability. To enable efficient incorporation of INS into the SNEDDS, a hydrophobic ion pairing (HIP) strategy was employed. Dual counter ions, sodium dodecyl sulfate (SDS) and sodium dodecylbenzenesulfonate (SDBS), were used to enhance its lipophilicity by forming hydrophobic ion pairing complexes (HIPCs). A pseudo-ternary phase diagram and I-optimal mixture design were used to optimize the SNEDDS composition, which was subsequently evaluated for physicochemical properties, enzymatic stability, and in vitro permeability using Caco-2 cell monolayers. The optimized INS-HIPC SNEDDS consisted of Capryol® 90 (14.9%), Tween 80 (56.2%), and Transcutol® P (28.9%), with a droplet size of 29.8 nm, zeta potential of − 9.4 mV, and self-emulsification time of 67 s. In simulated gastric and intestinal fluids, the formulation retained 52.5% and 29.4% of INS at 1 h, respectively. Caco-2 studies demonstrated concentration- and time-dependent increases in the apparent permeability coefficient (Papp) of INS, reaching 9.7 × 10−6 cm/s at 4 h, whereas free INS remained below the limit of detection (LOD) in the basolateral compartment. The developed INS-HIPC SNEDDS improved the enzymatic stability and in vitro epithelial transport of INS. These findings suggest that the system may have potential as a lipid-based oral delivery approach for peptide drugs.