Nano-formulation of rifampicin with enhanced bioavailability: Development, characterization and in-vivo safety

Rifampicin (RIF) was encapsulated into solid lipid nanoparticles (SLNs) to overcome its poor and unreliable oral bioavailability. Novel microemulsification method with high drug loading (50%) and entrapment efficiency (similar to 67%) was developed (Indian Patent Application 3356/DEL/2013). RIF-SLNs were characterized using TEM, AFM, DSC and XRD. Near neutral SLNs (zeta -3.5 +/- 0.8), with average particle size of 130.0 +/- 22.6 nm showed 70.12% release in phosphate buffer pH 6.8 in 9 days. Single oral dose (50 mg/kg) pharmacokinetic studies in Wistar rats indicated 8.14 times higher (in comparison to free RIF) plasma bioavailability with sustained levels for 5 days. Pharmacodynamic parameters viz. T-MIC (120 h; time for which plasma levels were above MIC of 0.2 mu g/ml), AUC(0-infinity)/MIC (1868.9 h) and C-max/MIC (75.6) for RIF-SLNs were greater than free RIF by 2.5, 8.2 and 6.6 times, respectively. Similar LD50 (1570 mg/kg) and absence (or reversal in satellite group) of adverse events in repeat dose (three doses; highest dose was up to 50 times the human therapeutic dose) toxicity studies confirmed safety of RIF-SLNs. Improved pharmacokinetic profile of RIF-SLNs can be translated to a reduced dose and dosage frequency of RIF, thus resulting in lower or no hepatotoxicity commonly associated with its use. (C) 2015 Elsevier B.V. All rights reserved.