Optimization of pH-responsive carboxymethylated iota-carrageenan/chitosan nanoparticles for oral insulin delivery using response surface methodology

Abstract

In designing an oral delivery method for insulin, we previously reported that pH-responsive carboxymethylated kappa-carrageenan-based microparticles protected insulin from acid degradation during transport through the gastrointestinal tract. However, the low surface-to-volume ratio of these microparticles and the presence of only one sulfate group in each kappa-carrageenan subunit for insulin stabilization may lead to a suboptimal delivery efficiency. To improve the delivery efficiency, we designed a nanoparticle from chitosan (CS) and carboxymethylated iota-carrageenan (CMCi) that possessed two sulfate groups per subunit based on response surface methodology together with multivariate spline interpolation (RSMMSI). The resulting optimized nanoparticles had a zeta potential, mean particle size, loading capacity and entrapment efficiency of 52.5±0.5mV, 613±41nm, 10.7±0.6%, and 86.9±2.6%, respectively. The release of insulin from the optimized nanoparticles was low (4.91±0.24%) in simulated gastric fluid (SGF) and high (86.64±2.2%) in simulated intestinal fluid (SIF) during a 12-h release study, thereby showing a pH-responsive drug release property. The nanoparticles were stable at 4°C and −20°C for at least 90days and for up to 7days at room temperature. The RSMMSI technique successfully expedited the design of the nanoparticles, which could serve as an improved oral insulin drug delivery system.