A hybrid design to optimize preparation of lopinavir loaded solid lipid nanoparticles and comparative pharmacokinetic evaluation with marketed lopinavir/ritonavir coformulation.
OBJECTIVE
To prepare stearic acid-based lopinavir (LPV) loaded solid lipid nanoparticles (SLNs) using a hybrid design and compare in-vivo performance of optimized formulation with marketed LPV/ritonavir (RTV) coformulation.


METHODS
LPV SLNs were prepared by hot melt emulsion technique and optimized using Plackett-Burman design and Box-Behnken design. Physical characterization studies were conducted for the optimized SLNs. Comparative oral pharmacokinetic studies and tissue distribution studies of optimized SLNs and LPV/RTV coformulation were done in Wistar rats. In-vitro metabolic stability and intestinal permeability studies for LPV SLNs were undertaken to elucidate the mechanism involved in the pharmacokinetic improvement of LPV.


RESULTS
Optimized SLNs exhibited nanometeric size (223 nm) with high entrapment efficiency (83%). In-vitro drug release study of SLNs showed biphasic sustained release behaviour. Significant increase in oral bioavailability of LPV from LPV SLNs (5 folds) and LPV/RTV coformulation (3.7 folds) was observed as compared with free LPV. LPV SLNs showed better tissue distribution of LPV in HIV reservoirs than LPV/RTV coformulation. In-vitro studies demonstrated that SLNs provided metabolic protection of LPV and were endocytosized during absorption.


CONCLUSIONS
SLNs enhanced oral bioavailability and improved distribution profile of LPV to HIV reservoirs and hence could be better alternative to LPV/RTV coformulation.
Pharmacy Department, BITS-Pilani Hyderabad Campus, Hyderabad, Andhra Pradesh, India.
Punna Rao
PR
Ravi
Rahul
R
Vats
Vikas
V
Dalal
Aditya Narasimha
AN
Murthy
D000818:Animals; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004355:Drug Stability; D004705:Endocytosis; D006678:HIV; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D008055:Lipids / Q000493:pharmacokinetics; D061466:Lopinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D053758:Nanoparticles; D017208:Rats, Wistar; D019438:Ritonavir / Q000493:pharmacokinetics*; D013229:Stearic Acids / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D003692:Delayed-Action Preparations; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D008055:Lipids; D013229:Stearic Acids; D061466:Lopinavir; C031183:stearic acid; D019438:Ritonavir
design of experiments; lopinavir; solid lipid nanoparticles; stearic acid; wistar rats