Swellable microparticles as carriers for sustained pulmonary drug delivery

In this investigation, novel biodegradable physically crosslinked hydrogel microparticles were developed and evaluated in vitro as potential carriers for sustained pulmonary drug delivery. To facilitate sustained release in the lungs, aerosols must first navigate past efficient aerodynamic filtering to penetrate to the deep lung (requires small particle size) where they must then avoid rapid macrophage clearance (enhanced by large particle size). The strategy suggested in this study to solve this problem is to deliver drug‐loaded hydrogel microparticles with aerodynamic characteristics allowing them to be respirable when dry but attain large swollen sizes once deposited on moist lung surfaces to reduce macrophage uptake rates. The microparticles are based on PEG graft copolymerized onto chitosan in combination with Pluronic® F‐108 and were prepared via cryomilling. The synthesized polymers used in preparation of the microparticles were characterized using FTIR, EA, 2D‐XRD, and differential scanning calorimetry (DSC). The microparticles size, morphology, moisture content, and biodegradation rates were investigated. Swelling studies and in vitro drug release profiles were determined. An aerosolization study was conducted and macrophage uptake rates were evaluated against controls. The microparticles showed a respirable fraction of approximately 15% when prepared as dry powders. Enzymatic degradation of microparticles started within the first hour and about 7–41% weights were remaining after 240 h. Microparticles showed sustained release up to 10 and 20 days in the presence and absence of lysozyme, respectively. Preliminary macrophage interaction studies indicate that the developed hydrogel microparticles significantly delayed phagocytosis and may have the potential for sustained drug delivery to the lung. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2343–2356, 2010