Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A

Abstract

In this study, cyclosporin-A (Cy-A) a highly lipophilic, poorly absorbable drug can be prepared easily and reproducibly as positively and negatively charged nanoparticles with the aim of improving its bioavailability and reducing its inter- and intra-individual variability. The nanoparticles were prepared by emulsification solvent diffusion method, using lecithin and poloxamer 188 as emulsifiers, and chitosan HCl, gelatin-A or sodium glycocholate (SGC) as charge inducing agents. The prepared nanoparticles were evaluated with respect to particle size, zeta potential, drug content and encapsulation efficiency. The bioavailability Cy-A from nanoparticles in comparison with the currently available Cy-A microemulsion (Neoral®) were assessed in beagle dogs. The results obtained revealed that, it was possible to prepare Cy-A as nanoparticles with size range of 104–148 nm. Chitosan HCl and gelatin-A nanoparticles exhibited +31.2 and +23.1 mV zeta potential, respectively; while SGC-nanoparticles exhibited −41.6 mV zeta potential. The in vivo results showed that, chitosan-nanoparticles gave the highest C max (2762.8 ng/ml) of Cy-A after 2.17 h ( T max), while SGC-nanoparticles gave the lowest one (1202.4 ng/ml after 4.0 h). Furthermore, AUC 0–24 of Cy-A from chitosan-nanoparticles was markedly increased by about 2.6-fold when compared with SGC-nanoparticles and increased by about 1.8-fold when compared with the reference Neoral® microemulsion. However, in case of gelatin-nanoparticles the AUC 0–24 of Cy-A increased by about 1.8 and 1.2-fold when compared with SGC-nanoparticles and the reference Neoral® microemulsion, respectively. The relative bioavailability of Cy-A from chitosan-nanoparticles was increased by about 73%, and by about 18% from gelatin nanoparticles, while it was decreased by about 36% from SGC-nanoparticles.