title: Nano-formulation of rifampicin with enhanced bioavailability: development, characterization and in-vivo safety.
abstract: 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 (∼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 (50mg/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. TMIC (120 h; time for which plasma levels were above MIC of 0.2 μg/ml), AUC0-∞/MIC (1868.9h) and Cmax/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.
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors.forename: Sahil
authors.initials: S
authors.lastname: Jindal
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Singh
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sharma
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India. Electronic address: indupalkaur@yahoo.com.
authors.forename: Indu Pal
authors.initials: IP
authors.lastname: Kaur
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D019540:Area Under Curve; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004655:Emulsions; D007928:Lethal Dose 50; D008055:Lipids / Q000737:chemistry*; D008657:Metabolic Clearance Rate; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine; D053758:Nanoparticles; D010316:Particle Size; D033362:Powder Diffraction; D017208:Rats, Wistar; D012293:Rifampin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D000904:Antibiotics, Antitubercular; D004337:Drug Carriers; D004655:Emulsions; D008055:Lipids; D012293:Rifampin
keywords: Acute toxicity; Lipidic nanoparticles; Pharmacokinetics; Repeat dose toxicity; Rifampicin