Comparative study of cilnidipine loaded PLGA nanoparticles: process optimization by DoE, physico-chemical characterization and in vivo evaluation.

Abstract

Cilnidipine (CND) 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 PLGA nanoparticles (CND-PLGA-NPs) were prepared with two different grades of PLGA (50:50 and 75:25) by design of experiment. Critical factors affecting particle size and entrapment efficiency (EE%) were assessed by mixed design approach, comprising of Plackett-Burman design followed by rotatable central composite design. Particle size, PDI, zeta potential, and EE% of optimized formulations of CND-PLGA(50:50)-NPs and CND-PLGA(75:25)-NPs were 211.6 ± 1.8nm, 0.21 ± 0.05, - 15.1 ± 1.6mV, and 85.9 ± 1.5% and 243.5 ± 2.4nm, 0.23 ± 0.06, -19.6 ± 1.3mV, and 92.0 ± 1.2% respectively. No significant changes were observed in physical stability of NPs when stored at 25°C/60% RH over a period of 3months. Pharmacokinetic studies revealed that Fabs of CND-PLGA(50:50)-NPs (1.15) and CND-PLGA(75:25)-NPs (2.23) were significantly higher than the free CND (0.26). The Cmax and AUC0-∞ of CND-PLGA(50:50)-NPs (787.42 ± 27.38ng/mL and 9339.37 ± 252.38ng/ml × h) and CND-PLGA(75:25)-NPs (803.49 ± 19.63ng/mL and 18,153.34 ± 543.05ng/ml × h) were significantly higher (p˂0.0001) compared with free CND (367.69 ± 47.22ng/mL and 2107.95 ± 136.40ng/ml × h). MRTOral of CND-PLGA(50:50)-NPs (33.36 ± 0.48h) and CND-PLGA(75:25)-NPs (48.37 ± 0.61h) were significantly higher (p ˂ 0.0001) compared with free CND (4.69 ± 0.58h). CND-PLGA-NPs can provide higher and sustained plasma drug levels of CND and be effective in antihypertensive therapy. Graphical abstract.