JAC Advance Access published online on November 12, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg477
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Biochemistry,
Postgraduate Institute of Medical Education & Research,
Chandigarh--160 012;
* Corresponding author. E-mail: gkkhuller{at}yahoo.co.in.
Received 11 July 2003
; revised 27 August 2003
; accepted 6 September 2003
Objectives: To improve the bioavailability
of antitubercular drugs (ATDs) as well as to assess the feasibility of
administering ATDs via the respiratory route, this study reports
the formulation of three frontline ATDs, i.e. rifampicin, isoniazid
and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide)
nanoparticles suitable for nebulization. Methods: Drug-loaded nanoparticles were prepared
by the multiple emulsion technique, vacuum-dried and nebulized to
guinea pigs. The formulation was evaluated with respect to the pharmacokinetics
of each drug and its chemotherapeutic potential in Mycobacterium
tuberculosis infected guinea pigs. Results: The aerosolized particles exhibited
a mass median aerodynamic diameter of 1.88 ± 0.11 µm, favourable for bronchoalveolar lung
delivery. A single nebulization to guinea pigs resulted in sustained
therapeutic drug levels in the plasma for 6-8 days and
in the lungs for up to 11 days. The elimination half-life and mean
residence time of the drugs were significantly prolonged compared
to when the parent drugs were administered orally, resulting in
an enhanced relative bioavailability (compared to oral administration)
for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin,
isoniazid and pyrazinamide, respectively). The absolute bioavailability [compared
to intravenous (iv) administration] was also increased
by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide,
respectively. On nebulization of nanoparticles containing drugs
to M. tuberculosis infected guinea pigs at every
10th day, no tubercle bacilli could be detected in the lung after
five doses of treatment whereas 46 daily doses of orally administered
drug were required to obtain an equivalent therapeutic benefit. Conclusions: Nebulization of nanoparticles-based
ATDs forms a sound basis for improving drug bioavailability and
reducing the dosing frequency for better management of pulmonary
tuberculosis.
Keywords: poly(DL-lactide-co-glycolide),
nanoparticles, antitubercular drugs, nebulization, tuberculosis
Poly (DL-lactide-co-glycolide)
nanoparticle-based inhalable sustained drug delivery system for
experimental tuberculosis
2 EMID,
CSIO, Sector 30, Chandigarh, India
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