Pharmacodynamic, pharmacokinetic and physical characterization of cilnidipine loaded solid lipid nanoparticles for oral delivery optimized using the principles of design of experiments

摘要

Cilnidipine (CND), an anti-hypertensive drug, is known to have low oral bioavailability due to its poor aqueous solubility, low dissolution rate and high gut wall metabolism. In the present study, CND loaded compritol based nanoparticles (CND-CMP-NPs) were prepared by emulsification-solvent evaporation method applying the concepts of design of experiments. Critical factors affecting particle size and loading efficiency (LE%) were assessed by hybrid design approach, comprising of Mini Run Resolution IV design followed by Box-Behnken design. Particle size, PDI, zeta potential and LE% of optimized formulations of CND-CMP-NPs were 207.1 +/- 2.9 nm, 0.27 +/- 0.1, -22.2 +/- 1.9 mV and 15.9 +/- 1.3% respectively. No significant changes were observed in physical stability of NPs when stored at 25 degrees C/60% RH over a period of three months. Pharmacokinetic studies revealed that F-abs of CND-CMP-NPs (0.66) was significantly higher than the free CND (0.27). The C-max and AUC(0-infinity) of CND-CMP-NPs (572.4 +/- 25.3 ng/mL and 5588.6 +/- 229.5 ng/mL x h) were significantly higher (P-cal< 0.0001) as compared to free CND (363.6 +/- 23.5 ng/mL and 2316.1 +/- 163.6 ng/mL x h). MRT of CND-CMP-NPs (9.8 +/- 0.9 h) was significantly higher (P-cal< 0.0001) as compared to free CND (5.7 +/- 0.5 h). Pharmacodynamic studies showed a maximum of 38% decrease in systolic blood pressure with more than 20% drop in systolic blood pressure sustained for a total duration of 64 h in the case of CND-CMP-NPs as compared to free CND. CNDCMP-NPs not only provide higher and sustained plasma levels of CND but also higher and sustained antihypertensive therapy as compared to free CND.