Abstract: The purpose of this study was to prepare, optimize, and characterize a cationic lipid nanoparticle (CLN) system containing multicomponent drugs using a molecular dynamics model as a novel method of evaluating formulations. Puerarin (PUE) and scutellarin (SCU) were used as model drugs. CLNs were successfully prepared using melt-emulsion ultrasonication and low temperature-solidification technique. The properties of CLNs such as morphology, particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), and drug release behavior were investigated. The CLNs were evaluated by corneal permeation, preocular retention time, and pharmacokinetics in the aqueous humor. Additionally, a molecular dynamics model was used to evaluate the formulation. Electron microscopy results showed that the nanoparticles were approximately spherical in shape. The EE (%) and DL (%) values of PUE and SCU in the optimal formulation were 56.60±3.73, 72.31±1.96 and 1.68±0.17, 2.44±1.14, respectively. The pharmacokinetic study in the aqueous humor showed that compared with the PUE and SCU solution, the area under the concentration–time curve (AUC) value of PUE was enhanced by 2.33-fold for PUE-SCU CLNs (p <0.01), and the SCU AUC was enhanced by 2.32-fold (p <0.01). In the molecular dynamics model, PUE and SCU passed through the POPC bilayer, with an obvious difference in the free energy well depth. It was found that the maximum free energy required for PUE and SCU transmembrane movement was ~15 and 88 kJ·mol^-1, respectively. These findings indicated that compared with SCU, PUE easily passed through the membrane. The diffusion coefficient for PUE and SCU were 4.1×10^-3±0.0027 and 1.0×10^-3±0.0006 e^-5cm²·s^-1, respectively. Data from the molecular dynamics model were consistent with the experimental data. All data indicated that CLNs have a great potential for ocular administration and can be used as an ocular delivery system for multicomponent drugs. Moreover, the molecular dynamics model can also be used as a novel method for evaluating formulations.
Keywords: cationic lipid nanoparticle, molecular dynamics model, microdialysis, pharmacokinetic, preocular retention time, ocular delivery