Aerosolizable modified-release particles of montelukast improve retention and availability of the drug in the lungs.

Montelukast, a cysteinyl leukotriene receptor antagonist available as oral tablets, is used as a second-line therapy in asthma. In this study, we sought to enhance the availability of montelukast in the lungs by encapsulating the drug in poly (lactide-co-glycolic acid)-based (PLGA) respirable large porous particles. We determined the oral and lung specific availability of montelukast by assessing metabolic stability of the drug in the lung and liver homogenates, respectively. We similarly measured the oral and inhalational bioavailability by monitoring the pharmacokinetics and disposition of the drug in live animals. After preparing montelukast-loaded particles with various polymers, in the absence or presence of polyethylenimine (PEI-1), we characterized the particles for physical-chemical properties, entrapment efficiency, in vitro release, uptake by alveolar macrophages, deposition in the lungs, and safety after pulmonary administration. When incubated in lung or liver homogenates, the amount of intact drug in the lung homogenates was greater than that in the liver homogenates. Likewise, the extent of montelukast absorption via the lungs was greater than that via the oral route. Compared with smaller non-porous particles, large porous particles (PEI-1) were taken up by the alveolar macrophages at a lesser extent but deposited in the lungs at a greater extent. The levels of injury markers in the bronchoalveolar lavage fluid (BALF), collected from rat lungs treated with PEI-1, were no different from that in BALF collected from saline treated rats. Overall, the retention time and concentration of montelukast in the lungs can be increased by formulating the drug in large porous particles of PLGA.