Double layer spherical nanoparticles with hyaluronic acid coating to enhance oral delivery of exenatide in T2DM rats

Soybean phospholipid was used as an amphiphilic material to form reverse micelles (RMs) in medium glycerol monolinoleate (Maisine) with Exenatide (EXT.) encapsulated in the polar core formed by the hydrophilic part of phospholipid. Cremopher RH40 and caprylocaproyl macrogol-8 glycerides EP/caprylocaproyl polyoxyl-8 glycerides NF (Labrasol) were added as surfactants to prepare reverse micelle-self emulsifying drug delivery system (RMs-SEDDS). On this basis, oil in water (O/W) emulsion was further prepared. By adding DOTAP, the surface of the emulsion was positively charged. Finally, hyaluronic acid wrapping in the outermost layer by electrostatic adsorption and reverse micelles-O/W-sodium hyaluronate (RMs-O/W-HA) nanoparticles containing Exenatide were prepared. RMs-SEDDS was spherical with an average particle size of 213.6 nm and RMs-O/W-HA was double-layered spherical nanoparticle with an average particle size of 309.2 nm. HA coating enhanced the adhesion of nanoparticles (NPs), and RMs-O/W-HA increased cellular uptake through CD44-mediated endocytosis. Pharmacodynamics results showed that RMs-SEDDS and RMs-O/W-HA could reduce blood glucose in type 2 diabetic rats, protect pancreatic β cells to a certain extent, and relieve insulin resistance and hyperlipemia complications with good safety.