In Situ and in Vivo Methods for Pulmonary Delivery

Abstract

The alveolar region of the mammalian lung seems to offer a promising route for the systemic delivery of certain protein and peptide biopharmaceuticals which otherwise must be injected (Bensch et al., 1967; Byron, 1990; Dominquez et al., 1967; Patton and Platz, 1992). The absorption of these molecules into the systemic circulation is thought to occur by diffusion in the conducting airways (Taylor and Gaar, 1970) and by diffusion and transcytosis in the alveolar region of the lungs (Patton and Platz, 1992). Diffusion of lipid-soluble drugs approximately parallels the lipid/water partition coefficients of the compounds as measured at pH 7.4, which suggests that diffusion is occurring through lipid structures. Drugs with very low lipid solubilities are absorbed at rates inversely related to the size of the molecule. This absorption is driven by a concentration gradient, suggesting the presence of “aqueous pores.” The morphological correlate of aqueous pores is uncertain but may be tight junctions. Molecules greater than 2.3 nm in diameter, corresponding to molecular weights of 10 kDa, cannot diffuse through the tight junctions of the intestinal epithelial cells which are roughly similar to those in the airways (Madara, 1989; Taylor and Gaar, 1970). Transcytosis is a process where cells of the alveolar lining form endocytic sacs that carry fluid and solutes from the alveolar lumen into the interstitium. It is hypothesized that depending on the molecular size, molecules in the interstitium may transcytose through and/or diffuse between the capillary endothelial cells into the bloodstream. If the molecule is greater than 25–50 kDa in size, its transport across the capillary endothelium may be blocked by the basement membrane, and instead it will diffuse into the lymphatic system and eventually ends up in the circulation (Hubbard et al., 1989; Taylor and Gaar, 1970).