期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 485, 期 1-2, 页码 138-151出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2015.02.050
关键词
Lipidic nanoparticles; Rifampicin; Acute toxicity; Repeat dose toxicity; Pharmacokinetics
资金
- Department of Biotechnology, Government of India
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.
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