Novel dietary lipid-based self-nanoemulsifying drug delivery systems of paclitaxel with p-gp inhibitor: implications on cytotoxicity and biopharmaceutical performance

Abstract

<div><p><b><i>Objectives:</i></b> This work describes the development and characterization of novel self-nanoemulsifying drug delivery systems (SNEDDS) employing polyunsaturated fatty acids for enhancing the oral bioavailability and anticancer activity of paclitaxel (PTX) by coadministration with curcumin (Cu).</p><p><b><i>Methods:</i></b> Preformulation studies endorsed sesame oil, labrasol, and sodium deoxycholate as lipid surfactants and cosurfactants based on their solubility for the drugs and spontaneity of emulsification to produce nanoemulsions. Further, phase titration studies were performed to identify a suitable nanoemulsion region for preparing the SNEDDS formulation.</p><p><b><i>Results:</i></b> The prepared formulations were characterized through <i>in vitro,</i><i>in situ,</i> and <i>in vivo</i> studies to evaluate the biopharmaceutical performance. <i>In vitro</i> drug release studies showed 2.8- to 3.4-fold enhancement in the dissolution rate of both drugs from SNEDDS as compared with the pure drug suspension. Cell line studies revealed 1.5- to 2.7-fold reduction in the cytotoxicity on MCF-7 cells by plain PTX-SNEDDS and PTX-Cu-SNEDDS vis-à-vis the PTX-suspension. <i>In situ</i> intestinal perfusion studies revealed significant augmentation in permeability and absorption parameters of drug from PTX-Cu-SNEDDS over the plain PTX-SNEDDS and PTX-suspension (<i>p</i> < 0.001). <i>In vivo</i> pharmacokinetic studies also showed a remarkable improvement (i.e., 5.8- to 6.3-fold) in the oral bioavailability (<i>C</i>_max and AUC) of the drug from PTX-SNEDDS and PTX-Cu-SNEDDS vis-à-vis the PTX-suspension.</p><p><b><i>Conclusions:</i></b> Overall, the studies corroborated superior biopharmaceutical performance of PTX-Cu-SNEDDS.</p></div