SEDDS for intestinal absorption of insulin: Application of Caco-2 and Caco-2/HT29 co-culture monolayers and intra-jejunal instillation in rats.

To face the challenges of oral delivery of peptide and protein drugs (P/P drugs), self-emulsifying drug delivery systems (SEDDSs) containing monoacyl phosphatidylcholine (MAPC), Labrasol (LAB) and medium-chain (MC) monoglycerides as permeation enhancers (PEs) were evaluated for their effect on intestinal absorption of insulin. In this study, insulin was complexed with phosphatidylcholine (SPC) to form an insulin-SPC complex (ins-SPC) with increased lipophilicity. The following three SEDDS: MCT(MAPC) (MC glycerides with MAPC and LAB), MCT(RH40) (MC glycerides with Kolliphor® RH40) and LCT(MAPC) (long-chain glycerides with MAPC and LAB) were loading with ins-SPC (4% or 8% w/w SPC). Three SEDDSs generated emulsions with droplet sizes between 50 to 470 nm and zeta potentials between -5 to -25 mV in a simulated intestinal medium. Mucus-secreting Caco-2/HT29-MTX-E12 co-culture and Caco-2 monolayers were used as in vitro cell transport models to investigate insulin permeability. In comparison to insulin HBSS solution, MCT(MAPC) significantly increased insulin permeability (2.0-2.5×10-7 cm/s) across co-culture and Caco-2 monolayers. In an intra-jejunal (i.j.) instillation model in rats, MCT(RH40) significantly decreased the rat blood glucose after 0.5 h by 17.0 ± 2.5% and for MCT(MAPC), it was 23.6 ± 10.6%. Furthermore, lipase inhibitor orlistat was incorporated into MCT(MAPC) to evaluate the effect of lipid digestion on insulin absorption. Results indicated that the incorporation of orlistat did not significantly alter the in vivo insulin absorption. The in vitro cell model cannot identify the best formulation or fully extrapolate the in vivo performance. Overall, the SEDDS MCT(MAPC) composed of natural PEs (MAPC and MC glycerides) and synthetic PE (LAB) significantly increased the intestinal absorption of insulin upon i.j. instillation. Although it is not possible to conclude if a single PE is dominating insulin absorption, MCT(MAPC) seems to have the potential for oral insulin delivery.