Development and optimization of atorvastatin calcium loaded oral biodegradable polymeric nanoparticles using central composite design

Abstract

Atorvastatin calcium (ATR) is a second generation and best selling statin drug for the treatment of hyperlipidemia. Statin inhibits the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A reductase resulting in reduced cholesterol synthesis. Low oral bioavailability (12%) is a major drawback of this blockbuster drug. In this study a biodegradable polymer, poly lactide-co-glycolic acid (PLGA) based polymeric nanoparticles (PNs) of ATR has been attempted to improve its oral bioavailability and to sustain the drug release. PNs has been prepared by nano-precipitation method using vitamin E to copheryl polyethylene glycol 1000 succinate (VitE-TPGS) as a stabilizer and optimized by linear central composite design. The effect of independent variables like polymer content, stabilizer concentration, volume of organic phase and stirring speed has been studied on the mean diameter particle size (PS) and entrapment efficiency (EE) of ATR loaded PNs. The observed responses well matched with the predicted values of the optimization technique. The formulation composition of optimized batch was found to be 125 mg PLGA, 0.31% of stabiliser (VitE-TPGS), 1250 rpm stirring speed and 8.0 ml of organic phase (acetone). PS and EE were found to be 207 nm and 81.3% respectively. The drug polymer compatibility study has been carried out by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses and was observed compatible under normal room temperature condition. DSC and XRD also showed the amorphous nature of drug in PNs formulation. The transmission electron microscopy revealed spherical shape of the PNs. The in vitro drug release study of the optimized batch has shown sustained drug release up to 72 h in phosphate buffer solution (pH 7.4). Pharmacokinetic study exhibited a significant enhancement in drug bioavailability following the oral intake of PNs formulation as compared to the pure drug suspension. © 2014 American Scientific Publishers. All rights reserved.