PULMONARY DELIVERY OF THERAPEUTIC PEPTIDES AND PROTEINS

There have been many attempts to improve systemic delivery of peptide and protein drugs by routes of administration other than by injection. Studies in this area of drug delivery have included nasal, rectal, buccal and the transdermal route of administration. There is little research in the area of pulmonary delivery of these compounds. Yet, the lung is unquestionably the most relevant site for delivering anti-asthmatic and mucolytic drugs. The human lung is a complex organ with high enzymatic activity. Yet it is effective for the delivery of locally acting drugs some of which are unstable to metabolizing enzymes. This makes it probable for the lung to become a feasible port for entry of peptide and protein drugs to the body. Being labile and refractory, survival to metabolizing enzymes and influence of airway filtration mechanisms make quantization of lung bioavailability of peptide and protein drugs a formidable effort. Furthermore, the effect of complex biophysical (e.g., inertial impaction) and biochemical factors (e.g., size, charge, permeability, lung clearance mechanisms) causes significant reduction of lower airway drug deposition. Subsequently, the efficiency of drug absorption from the lung is often orders of magnitude lower than it is for other routes. This manuscript reviews data on lung delivery of several peptidic compounds administered for either local or systemic effects. Leuprolide, a nonapeptide and analog of LH-RH is used as a model drug for those peptides administered via lung for a systemic pharmacological effect. A mechanistic approach to describe the bioavailability of leuprolide is described. The paper presents descriptive terms (intrinsic, extrinsic and absolute bioavailability) used to describe the fractional bioavailability of this peptide. Reported data include the estimated bioavailable fractions from bolus dosages of either instillations or inhalation dosages of this nonapeptide, F, based on comparable injectable dosages (i.v. or s.c.). The extent of lung absorption correlated well with depth of drug deposition in the airways. There was quantitative absorption of drug deposited at the bifurcation of the trachea. This peptide has both the C and N terminals blocked. Therefore, it is stable to lung metabolizing enzymes. The discussion includes clinical perspectives and implications for using this method to estimate peptide absorption from the airways.