Drug Targeting Organ-Specific Strategies

60 3 Pulmonary Drug Delivery: Delivery To and Through the Lung
The alveolar epithelium consists of so-called Type I and Type II cells. Type I cells cover
over 90% of the alveolar surface, have a large surface, and are thin. Type II cells are larger in
numbers but are small. Therefore, they cover only about 7% of the surface of the alveoli.
Type II cells produce the phospholipids that make up the surfactant layer.
It should be noted that the permeability per surface unit of alveolar epithelium per se is
not particularly high. The significant absorption found for various substances after pulmonary
administration is rather explained by a number of beneficial factors such as the large
surface area of the alveoli, the low volume of the epithelial lining fluid, the relatively thin diffusion
layer, the absence of mucociliary clearance from the alveoli as well as the limited enzymatic
activity in the lining fluids.
Passage over the epithelial membrane from the apical to the basal site may occur via different
routes. The fast absorption found for molecules smaller than 40 kDa is generally explained
by paracellular transport through the tight junctions between the epithelial cells. Although
rather incorrect from a physiological point of view, the estimation of ‘pore sizes’ of
alveolar epithelium on the basis of transport rates of solutes, may help to predict whether or
not a certain molecule can pass the alveolar epithelium. The value of 40 kDa is compatible
with the presence of pore structures with a diameter of about 5 nm. The turnover of epithelial
surface cells may be responsible for the transient existence of larger openings in the alveolar
epithelium. However, whether these pores have any significance to drug absorption is
unknown.
The absorption of molecules that are larger than 40 kDa is generally slow and incomplete.
These molecules probably cannot pass through the tight junctions of the epithelial membrane,
but have to be transported by a transcytotic mechanism in order to be absorbed. Receptor-mediated
endocytosis is a crucial mechanism here. The subsequent transport through
the epithelial cells may occur in coated and non-coated vesicles. The non-coated vesicles are
called caveolae. Macromolecules (after receptor recognition) may be sequestered both in
coated vesicles as well as in caveolae. In the alveolar Type I cells, large numbers of caveolae
are found (about 1.7 million per cell). The caveolae have internal diameters of 50 to 100 nm
which is large enough to contain macromolecules with sizes over 400 kDa. However, in spite
of these well-defined physiological processes the evidence for massive transport of larger
macromolecules via this pathway is scarce. In general it is doubtful whether transcytosis via
caveolae may significantly contribute to the absorption of macromolecules [10,32].
In relation to the above it is obvious that passage of the pulmonary epithelium may depend
on characteristics of a drug molecule. Not only the size, but also its solubility, overall
charge, structural conformation and potential aggregation can have a significant effect on the
absorption rate and bioavailability of the drug after pulmonary deposition.
3.4.1 Systemic Delivery of Peptides and Proteins
Many studies have been carried out regarding the absorption of peptides and proteins after
pulmonary drug delivery. The perspectives of a non-parenteral route of administration for
larger proteins led to studies on the pulmonary absorption of proteins of different size. To
date, over 30 different proteins have been evaluated with regard to absorption rate and