Oral Insulin Delivery Using Poly (Styrene Co-Maleic Acid) Micelles in a Diabetic Mouse Model

The oral delivery of insulin is a convenient and safe physiological route of administration for management of diabetes mellitus. In this study, we developed a poly-(styrene-co-maleic acid) (SMA) micellar system for oral insulin delivery to overcome the rapid degradation of insulin in the stomach, improve its absorption in the intestine, and provide a physiologically-relevant method of insulin to reach portal circulation. The insulin was encapsulated into SMA micelles in a pH-dependent process. The charge and size of the nanoparticles were determined by dynamic light scattering. The insulin loading of the nanoparticles was measured by HPLC. The transport of the SMA-insulin through biological membranes was assessed in vitro using Caco-2 cells, ex vivo rat intestinal section, and in vivo in a streptozotocin-induced diabetes mouse model. SMA-insulin micelles were negatively charged and had a mean diameter of 179.7 nm. SMA-insulin efficiently stimulated glucose uptake in HepG-2 hepatic cells and was transported across the Caco-2 epithelial cells in vitro by 46% and ex vivo across intestinal epithelium by 22%. The animal studies demonstrated that orally-administered SMA-insulin can produce a hypoglycemic effect up to 3 h after administration of one dose. Overall, our results indicate that SMA micelles are capable of the oral delivery of bioactive compounds like insulin and can be effective tools in the management of diabetes.