Slow Release Formulations of Inhaled Rifampin

Abstract

Rifampin microspheres were prepared by spray drying using either polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) polymers in different drug to polymer ratios (90:10 to 5:95, w/w). The in-vitro release characteristics, particle-size distribution, and cytotoxicity (in an alveolar macrophage cell line) and pharmacokinetics in rats after pulmonary instillation were evaluated. Increasing the polymer content from 10% to 95% slowed down the in vitro drug release with PLGA particles showing a steeper change with increasing polymer content (100% to 20% drug release over 6 h) than PLA particles (88% to 42% drug release over 6 h). PLA microsphere formulations revealed lack of cytotoxicity and a mass median aerodynamic diameter (MMDA) of 2.22-2.86 mum, while PLGA particles were larger (MMDA of 4.67-5.11 mum). Pharmacokinetics differed among the formulations with the 10% PLA formulation showing a distinct sustained release (t (max) of 2 h vs 0.5 h of free drug) and a systemic bioavailability similar to that of free drug. Formulations with high polymer content showed a lower relative bioavailability (30%). This suggested that an optimal release rate existed for which a distinct amount of drug was delivered over an extended period of time.