Abstract
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.
Highlights
Diabetes mellitus (DM) is the most common metabolic disease and the seventh leading cause of death globally, according to the World Health Organization [1]
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
Poly-(styrene-co-maleic anhydride), cumene terminated, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC), Hank’s balanced salt solution, advanced Dulbecco’s Modified Eagle’s Medium (DMEM), Roswell Park Memorial Institute (RPMI) 1640 medium, fetal bovine serum (FBS), bovine serum albumin (BSA), and TrypLE Express were purchased from ThermoFisher Scientific (Dubai, United Arab Emirates)
Summary
Diabetes mellitus (DM) is the most common metabolic disease and the seventh leading cause of death globally, according to the World Health Organization [1]. There are two major forms of the disease, T1DM and T2DM, both characterized by hyperglycemia. Subcutaneous insulin injection is commonly used in patients with DM to normalize the blood glucose level (BGL) once or multiple times per day. Subcutaneous injections, are often associated with poor compliance where numerous regular injections can lead to hypertrophy, infections, and lipid deposits at the injection sites as well as skin allergy and production of exogenous insulin antibodies [7]. Oral administration of insulin could improve disease management, enhance patient compliance, and decrease the long-term complications of DM [8]. Several alternative insulin delivery routes involving nanotechnologies have been exploited to overcome the limitations of the standard delivery [10,11]
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