Adaptation of Quality by Design-Based Development of Isradipine Nanostructured-Lipid Carrier and Its Evaluation for In Vitro Gut Permeation and In Vivo Solubilization Fate

The present study demonstrated the systematic adaptation of quality by design-integrated approach for the development of novel nanostructured lipid carrier (NLC) of an anti-hypertensive drug isradipine (ISD) to address the inherent challenges such as low solubility and low oral bioavailability. Plackett-Burman design was used for preliminary screening of significant process and formulation variables (p < 0.05), which were further processed using Box-Behnken design for the attainment of optimization goal that is, mean particle size (85.7 +/- 7.3 nm), drug entrapment efficiency (87.4 +/- 3.29%), and in vitro drug release characteristics (92.89 +/- 5.47%). The optimized ISD-NLC formulation also demonstrated well-dispersed uniform-shaped particles (polydispersity index 0.207 +/- 0.029), high gastrointestinal fluid stability (zeta potential -10.17 +/- 0.59 mV), and higher in vitro gut permeation (21.69 +/- 2.38 mu g/cm(2) of ISD-NLC as compared to 11.23 +/- 1.74 mu g/cm(2) in ISD suspension). Furthermore, lipolysis studies were performed for the purpose of in vivo fate, and significantly higher drug content of ISD from ISD-NLC in aqueous phase was found (72.34 +/- 4.62%) as compared to drug suspension (3.01 +/- 0.91%). Relative bioavailability of ISD-NLC and ISD suspension was increased by 4.2-fold and 1.78-fold in the absence and presence of cycloheximide which is a lymphatic uptake inhibitor revealing lymphatic uptake of ISD-NLC in bioavailability improvement. Hence, systematic adaptation of quality by design integrated approach improved gut permeation and potential solubilizaton fate (dynamic lipolysis) of ISD-NLC, which further improved the lymphatic uptake and biodistribution of drug thereby promisingits in vivo prospect and clinical efficacy. (c) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.