Inhalable Microparticles Containing Large Payload of Anti-tuberculosis Drugs

Abstract

Microparticles containing large payloads of two anti-tuberculosis (TB) drugs were prepared and evaluated for suitability as a dry powder inhalation targeting alveolar macrophages. A solution containing 1 part each of isoniazid and rifabutin, plus 2 parts poly(lactic acid) (L-PLA) was spray-dried. Drug content and in vitro release were assayed by HPLC, and DSC was used to elucidate release behaviour. Particle size was measured by laser scattering and aerosol characteristics by cascade impaction using a Lovelace impactor. Microparticles were administered to mice using an in-house inhalation apparatus or by intra-tracheal instillation. Drugs in solution were administered orally and by intra-cardiac injection. Flow cytometry and HPLC were used to investigate the specificity and magnitude of targeting to macrophages. Microparticles having drug content ~50% wt/wt, particle size ~5μm and satisfactory aerosol characteristics (median mass aerodynamic diameter, MMAD = 3.57 m; geometric standard deviation, GSD=1.41 m; fine particle fraction, FPF<4.6m = 78.91  8.4 %) were obtained in yields of >60%. About 70% of the payload was released in vitro in 10 days. Microparticles targeted macrophages and not epithelial cells on inhalation. Drug concentrations in macrophages were ~20 times higher when microparticles were inhaled rather than drug solutions administered. Microparticles were thus deemed suitable for enhanced targeted drug delivery to lung macrophages. Keywords: dry powder inhalation; respirable microspheres; targeting; macrophages; pulmonary delivery; tuberculosis.