Self-Nanoemulsifying Lipid Carrier System for Enhancement of Oral Bioavailability of Etoposide by <I>P</I>-Glycoprotein Modulation: <I>In Vitro</I> Cell Line and <I>In Vivo</I> Pharmacokinetic Investigation

Abstract

The purpose of this work is intended to investigate the potential of self-nanoemulsifying (SNE) drug delivery system for enhanced oral bioavailability of etoposide by P-glycoprotein (P-gp) modulation. The components of SNE formulation were optimized by their solubilization and emulsification efficiency. The ternary phase diagrams provided nanoemulsion existence ranges and the corresponding formulations were developed and evaluated via thermodynamic and dispersibility tests. The successful formulations were characterized for various parameters including time required for self-emulsification, percentage transmittance, droplet size, surface morphology, zeta potential and in vitro release. The etoposide loaded SNE9 formulation showed 2.6- and 11-fold higher permeability coefficient in apical to basolateral direction across Caco-2 monolayers as compared to the Etosid and plain drug solution, respectively. The etoposide loaded SNE9 formulation showed a higher cytotoxicity at the highest tested concentration compared to the blank SNE9 formulation and the free etoposide. Furthermore, an in vivo pharmacokinetic study of etoposide in SNE9 formulation showed 3.2- and 7.9-fold increase in relative oral bioavailability compared with that of etoposide in Etosid and drug suspension, respectively. Thus, the developed SNE drug delivery system could be a valuable tool for the effective oral delivery of etoposide.

The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients

“…The poor solubility of such drugs does not only give low oral bioavailability, but also leads to interand intra-subject variability and lack of dose proportionality [23]. The selected excipients used in this study were reported as solubilizing agents for lipophilic candidates as well as permeation enhancers in emulsifying formulations [3][4][5]10]. The solubility of VP-16 was improved in the presence of selected pharmaceutical excipients and the maximum solubility was found to be in Solutol HS 15, Transcutol-P and Labrasol.…”

“…Sha et al [27] reported that oral bioavailability of gentamycin in rats was significantly enhanced when it was co-administered with Labrasol. The study of Akhtar et al [3] concluded that the improved oral bioavailability of VP-16 in the presence of surfactant could be explained by the significantly improved solubility of VP-16 by surfactant solubilization which could keep the drug as the soluble form during the gastrointestinal permeation process, and the inhibition of P-gp efflux of VP-16 by solution surfactants. Hence, feasibility of oral administration of VP-16 with P-gp inhibitory excipients was considerably improved.…”

“…The design of effective formulation for P-gp substrate drugs has long been a major challenge, because drug efficacy can be severely limited by instability or insufficient solubility in the vehicle. Consequently, more attention is now being paid to pharmaceutical excipients as efflux pump inhibitors in improving oral drug delivery [3][4][5]. Several pharmaceutical excipients are emerging as different classes of P-gp inhibitors owing to many advantages including that they are safe, not being absorbed from the gut and pharmaceutically acceptable [6,7].…”

Emerging Trends in Oral Bioavailability Enhancement

“…(101) In our laboratory, SMEDD formulations for different anticancer drugs, based on Pgp modulation by using excipient having P-gp modulation activity, have been developed and showed many fold higher oral bioavailability. (108)(109) These studies revealed that the bioavailability of drugs can be improved by pgp modulation.…”

Improved oral efficacy of epirubicin through polymeric nanoparticles: pharmacodynamic and toxicological investigations

“…Recently, nanoformulations like nanoemulsion (Verma et al, 2015), self nanoemulsifying drug-delivery system (Akhtar et al, 2013;Negi et al, 2013), solid lipid nanoparticles (Yuan et al, 2013) polymeric micelles (Yao et al, 2011), Dendrimer (Ke et al, 2008), layersomes (Jain et al, 2012), polymeric NPs (Jain et al, 2011b;Fatma et al, 2014;Katiyar et al, 2015), protein NPs (Golla et al, 2013) etc. have gained considerable attention for successful oral delivery of anticancer agents.…”