Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design

Objective: Nisoldipine (ND) is a potential antihypertensive drug with low oral bioavailability. The aim was to develop an optimal formulation of ND-loaded solid lipid nanoparticles (ND-SLNs) for improved oral bioavailability and pharmacodynamic effect by using a two-factor, three-level central composite design. Glyceryl trimyristate (Dynasan 114) and egg lecithin were selected as independent variables. Particle size (Y-1), PDI (Y-2) and entrapment efficiency (EE) (Y-3) of SLNs were selected as dependent response variables.Methods: The ND-SLNs were prepared by hot homogenization followed by ultrasonication. The size, PDI, zeta potential, EE, assay, in vitro release and morphology of ND-SLNs were characterized. Further, the pharmacokinetic (PK) and pharmacodynamic behavior of ND-SLNs was evaluated in male Wistar rats.Results: The optimal ND-SLN formulation had particle size of 104.42.13nm, PDI of 0.241 +/- 0.02 and EE of 89.84 +/- 0.52%. The differential scanning calorimetry and X-ray diffraction analyses indicated that the drug incorporated into ND-SLNs was in amorphous form. The morphology of ND-SLNs was found to be nearly spherical by scanning electron microscopy. The optimized formulation was stable at refrigerated and room temperature for 3 months. PK studies showed that 2.17-fold increase in oral bioavailability when compared with a drug suspension. In pharmacodynamic studies, a significant reduction in the systolic blood pressure was observed, which sustained for a period of 36h when compared with a controlled suspension.Conclusion: Taken together, the results conclusively demonstrated that the developed optimal ND-SLNs caused significant enhancement in oral bioavailability along with pharmacodynamic effect.