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JAC Advance Access originally published online on April 5, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1146-1152; doi:10.1093/jac/dkl128
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Oral nanoparticle-based antituberculosis drug delivery to the brain in an experimental model

Rajesh Pandey and G. K. Khuller*

Department of Biochemistry, Postgraduate Institute of Medical Education & Research Chandigarh–160 012, India

Received 2 December 2005; returned 10 February 2006; revised 19 February 2006; accepted 13 March 2006

*Corresponding author. Tel: +91-0172-2744401; Fax: +91-0172-2745078; E-mail: gkkhuller{at}yahoo.co.in

Objectives: To evaluate the potential of orally administered poly-lactide-co-glycolide (PLG, a synthetic polymer) nanoparticle encapsulated antituberculosis drugs (ATDs) (rifampicin + isoniazid + pyrazinamide + ethambutol) for cerebral drug delivery in a murine model.

Methods: The formulation was prepared using the multiple emulsion technique and administered orally to mice for biodistribution, pharmacokinetic and chemotherapeutic studies.

Results: A single oral dose of the formulation to mice could maintain sustained drug levels for 5–8 days in the plasma and for 9 days in the brain. There was a significant improvement in the pharmacokinetic parameters such as mean residence time and relative bioavailability as compared with free drugs. The pharmacodynamic parameters such as the ratio of area under the curve to minimum inhibitory concentration (AUC/MIC) and the time up to which MIC levels were maintained in plasma (TMIC) were also improved. In Mycobacterium tuberculosis H37Rv infected mice, five oral doses of the nanoparticle formulation administered every 10th day resulted in undetectable bacilli in the meninges, as assessed on the basis of cfu and histopathology.

Conclusions: Polymeric nanoparticles bear significant potential for ATD delivery to the brain.

Keywords: poly-lactide-co-glycolide , bioavailability , pharmacodynamics , chemotherapy


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