Formulation and Pharmacokinetics of Self-Assembled Rifampicin Nanoparticle Systems for Pulmonary Delivery
To formulate rifampicin, an anti-tuberculosis antibiotic, for aerosol delivery in a dry powder ‘porous nanoparticle-aggregate particle’ (PNAP) form suited for shelf stability, effective dispersibility and extended release with local lung and systemic drug delivery.
Rifampicin was encapsulated in PLGA nanoparticles by a solvent evaporation process, spray dried into PNAPs containing varying amounts of nanoparticles, and characterized for physical and aerosol properties. Pharmacokinetic studies were performed with formulations delivered to guinea pigs by intratracheal insufflation and compared to oral and intravenous delivery of rifampicin.
The PNAP formulations possessed properties suitable for efficient deposition in the lungs. In vitro release showed an initial burst of rifampicin, with the remainder available for release beyond eight hours. PNAPs delivered to guinea pigs by insufflation achieved systemic levels of rifampicin detected for six to eight hours. Moreover, rifampicin concentrations remained detectable in lung tissue and cells up to and beyond eight hours. Conversely, after pulmonary delivery of an aerosol without nanoparticles, rifampicin could not be detected in the lungs at eight hours.
Our results indicate that rifampicin can be formulated into an aggregated nanoparticle form that, once delivered to animals, achieves systemic exposure and extends levels of drug in the lungs.
KEY WORDSaerosols antibiotics nanoparticles pulmonary drug delivery tuberculosis
Fine particle fraction of the total dose less than 5.8 μm
Porous nanoparticle-aggregate particle
PNAPs containing 40% NP by weight
PNAPs containing 80% NP by weight
The authors thank Plastiape for their generous donation of inhaler devices and Shionogi for supplying capsules, Prof. Patrick Couvreur for fruitful discussions and Annalicia Poehler for research assistance. Electron microscopy work was performed at the Center for Nanoscale Systems (CNS), part of the Faculty of Arts and Sciences at Harvard University. This work was supported by a grant from the National Institute of Health/NIAID under Grant Number 5 U01 61336-02 and a National Science Foundation Graduate Research Fellowship.
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