title: Novel self-emulsifying formulation of quercetin for improved in vivo antioxidant potential: implications for drug-induced cardiotoxicity and nephrotoxicity.
abstract: Quercetin (QT) was formulated into a novel self-emulsifying drug delivery system (SEDDS) to improve its oral bioavailability and antioxidant potential compared to free drug. Capmul MCM was selected as the oily phase on the basis of optimum solubility of QT in oil. Tween 20 and ethanol were selected as surfactant and cosurfactant from a large pool of excipients, depending upon their spontaneous self-emulsifying ability with the selected oily phase. Pseudoternary-phase diagrams were constructed to identify the efficient self-emulsification regions in various dilution media, viz., water, pH 1.2, and pH 6.8. The ratio of 40:40:20 w/w, Capmul MCM:QT (19:1)/Tween 20/ethanol was optimized based on its ability to form a spontaneous submicrometer emulsion in simulated gastrointestinal fluids. DPPH scavenging assay showed comparable antioxidant activity of QT-SEDDS to free QT. QT-SEDDS was robust in terms of stability against short-term excursion of freeze/thaw cycles and accelerated stability for 6 months as per International Conference on Harmonisation guidelines. A fluorescent dye-loaded SEDDS formulation showed rapid internalization within 1h of incubation with Caco-2 cells as evident by confocal laser scanning microscopy. QT-SEDDS showed a significant increase in cellular uptake by 23.75-fold in comparison with free QT cultured with Caco-2 cells. The SEDDS demonstrated ~5-fold enhancement in oral bioavailability compared to free QT suspension. The in vitro-in vivo relation between in vitro Caco-2 cell uptake and in vivo pharmacokinetics of QT-SEDDS showed a correlation coefficient of ~0.9961, as evident from a Levy plot. Finally, QT-SEDDS showed a significantly higher in vivo antioxidant potential compared to free QT when evaluated as a function of ability to combat doxorubicin- and cyclosporin A-induced cardiotoxicity and nephrotoxicity, respectively.
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), 160062 Punjab, India. Electronic address: sanyogjain@niper.ac.in.
authors.forename: Sanyog
authors.initials: S
authors.lastname: Jain
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), 160062 Punjab, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Jain
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), 160062 Punjab, India.
authors.forename: Milind
authors.initials: M
authors.lastname: Pohekar
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), 160062 Punjab, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Thanki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D000975:Antioxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D066126:Cardiotoxicity / Q000517:prevention & control; D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000009:adverse effects; D004317:Doxorubicin / Q000009:adverse effects; D016503:Drug Delivery Systems / Q000379:methods*; D045703:Emulsifying Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D004655:Emulsions / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D018613:Microscopy, Confocal; D011794:Quercetin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D045703:Emulsifying Agents; D004655:Emulsions; D004317:Doxorubicin; D016572:Cyclosporine; D011794:Quercetin
keywords: 1,1-diphenyl-2-picrylhydrazyl; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Antioxidant activity; BUN; Bioavailability; C-6-QT-SEDDS; CK-MB; CLSM; Caco-2 cells; CyA; DPPH; Dox; Free radicals; GI; IVIVR; LDH; MTT; NIPER; National Institute of Pharmaceutical Education and Research; PDI; PEG-200; PLGA; QT; QT-SEDDS; Quercetin; RH; ROS; SEDDS; SGF; SIF; Self-emulsifying formulation; blood urea nitrogen; confocal laser scanning microscope; coumarin- and quercetin-loaded SEDDS; creatine kinase myocyte B; cyclosporin A; doxorubicin; gastrointestinal; in vitro–in vivo relation; lactate dehydrogenase; poly(lactic-co-glycolic acid); polydispersity index; polyethylene glycol-200; quercetin; quercetin-loaded SEDDS; reactive oxygen species; relative humidity; self-emulsifying drug delivery system; simulated gastric fluid; simulated intestinal fluid