Formulation and Pharmacokinetics of Self-Assembled Rifampicin Nanoparticle Systems for Pulmonary Delivery
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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