PENETRATION ENHANCEMENT FOR POLYPEPTIDES THROUGH EPITHELIA .D. ROUTES OF DELIVERY - CASE-STUDIES .2. PULMONARY DELIVERY OF PEPTIDES AND PROTEINS FOR SYSTEMIC ACTION

The columnar epithelium of the gastrointestinal tract, nasal and pulmonary airways is virtually impermeable to most peptides, proteins and other macromolecules- However, the very thin (0.1-0.2-mu-m) alveolar epithelium of the deep lung appears to be unique among the body's ports of entry in that it is permeable to some peptides and proteins. A dense network of endocytic vesicles in the type-1 alveolar epithelial cells offers a possible mechanism to explain how the airsacs remain nearly free of fluid and how macromolecules are subsequently absorbed. Three therapeutic peptides (leuprolide: nine amino acids, insulin: 51 amino acids and growth hormone: 192 amino acids) are absorbed in biologically active form from the lungs with bioavailabilities of 10%-25%. Inefficient aerosol delivery, aggregation and enzymatic degradation reduce bioavailability. Long-term safety remains a concern, although no serious effects have been observed in studies to date.