Design for optimization of nanoparticles integrating biomaterials for orally dosed insulin

Design of nanoparticles integrating biomaterials that govern the functional behavior of orally dosed insulin is focused on improving insulin stability and absorption by facilitating its uptake and translocation throughout the intestinal membrane, while providing protection from acidic and enzymatic degradation in the gastrointestinal tract. The purpose of the study was to optimize a nanoparticle formulation by investigating the relationship between design factors and experimental data by response surface methodology. Designed nanoparticles consisting of calcium crosslinked alginate, dextran sulfate, poloxamer 188 and chitosan followed by an outermost coating of albumin are described as multilayer complex retaining insulin within the nanoparticle. A 3-factor 3-level Box–Behnken design was used to optimize nanoparticle formulation. The screened independent variables were the concentration of calcium chloride, chitosan and albumin, and the dependent variables were particle size, polydispersity index, zeta potential, entrapment efficiency and insulin release in enzyme-free simulated digestive fluids. Experimental responses of a total of 15 formulations resulted in mean nanoparticle diameters ranging from 394 to 588 nm, with polydispersity index from 0.77 to 1.10, zeta potential values ranging from −36.6 to −44.5 mV, and entrapment efficiency of insulin was over 85%. Insulin release from nanoparticles in enzyme-free digestive fluids was prevented during 120 min in gastric conditions, and over 80% of insulin was released after 180 min in simulated intestinal fluid. Based on the experimental responses and the criteria of desirability defined by constraints, solutions of 0.20% calcium chloride, 0.04% chitosan and 0.47% albumin constitute the optimum formulation of nanoparticles for orally dosed insulin.