Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
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