Comparison of Different Chitosan Lipid Nanoparticles for Improved Ophthalmic Tetrandrine Delivery: Formulation, Characterization, Pharmacokinetic and Molecular Dynamics Simulation

Abstract

In this study, three different chitosan, namely carboxymethyl chitosan (CMC), hydroxypropyl chitosan (HPC) and trimethyl chitosan (TMC) were used as cationic materials to prepare tetrandrine lipid nanoparticles (TET-LNPs) for the treatment of glaucoma. In vitro drug release and pre-corneal retention were used to select the optimal chitosan. In vitro drug release curves of three kinds of LNPs showed a sustained release and TMC-TET-LNPs were the slowest. Moreover, compared with CMC-TET-LNPs and HPC-TET-LNPs, TMC-TET-LNPs had longer corneal retention time. Afterwards, the characteristics of TMC-TET-LNPs were investigated. The ocular irritation study revealed no sign of irritation in rabbit eyes. The pharmacokinetic studies showed that the area under the curve of TMC-TET-LNPs was increased by 2.03 times than TET solution (p < 0.01). Furthermore, the drug biofilm interactions were evaluated by molecular dynamics (MD) simulation. In MD simulation, the strong hydrophobic group of TET interacted with the tail of POPC, making it hard to enter the hydrophobic region of the membrane, thereby restricting TET ocular bioavailability. The experiments and MD simulation indicated that TMC-TET-LNPs had great potential for ocular administration and MD simulation could predict transmembrane transport of drugs.