Macromolecule Delivery

As pointed out earlier, one of the main drivers for improvements in pulmonary delivery performance has been the desire to deliver proteins and peptides noninvasively. The pulmonary route offers an ideal opportunity for systemic absorption because its surface area is large and the pulmonary epithelium is thin. In fact, the first attempt to deliver insulin through the lung took place as long ago as 1925. However, putting this sparse early study aside, it wasn't until the beginning of the 1990s, when recombinant technology made protein therapeutics widely available, that researchers really began to tackle the issues related to pulmonary macromolecule delivery. The main challenges were to understand the delivery requirements and to come to grips with the factors that influence and control efficient absorption.

Early work identified deep lung deposition as an imperative to absorption efficiency, and a number of studies have demonstrated higher bioavailabilites (absorption efficiencies) for peripherally deposited aerosols [51]. However, despite a decade of work, the absorption mechanisms that facilitate transfer from the pulmonary epithelium to the blood are still not well understood. Two mechanisms are believed to operate, transcellular and pericellular. There is some evidence that small invaginations called caveolae may be involved in transcellular transport, whereas pericellular transport is via leaky tight junctions.

Numerous macromolecules have been investigated in preclinical models [52]; delivery to and through the lung appears to be generally safe [53], and a large number of molecules have made it to trials in man. Figure 8 summarizes the majority of these investigations by clinical development phase. It will be noted that rhDNAse, a topical lung therapy for the treatment of cystic fibrosis, is the only approved pulmonary protein and that a number of other molecules have progressed as far as Phase III studies. At the time of writing, systemic inhaled insulin was in late Phase III trials.

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