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

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 (RSM^MSI). The resulting optimized nanoparticles had a zeta potential, mean particle size, loading capacity and entrapment efficiency of 52.5 ± 0.5 mV, 613 ± 41 nm, 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 90 days and for up to 7 days at room temperature. The RSM^MSI technique successfully expedited the design of the nanoparticles, which could serve as an improved oral insulin drug delivery system.