PULMONARY ABSORPTION ENHANCEMENT OF PEPTIDES BY ABSORPTION ENHANCERS AND PROTEASE INHIBITORS

The effects of absorption enhancers and protease inhibitors on the pul monary absorption of insulin and (Asu(1,7))eel-calcitonin (ECT) were e xamined by means of an in vivo pulmonary absorption experiment. Absorp tion enhancers used in this study were sodium-glycocholate (Na-GC), li noleic acid-surfactant mixed micelles (MM), N-lauryl-beta-D-maltopyran oside (LM), ethylenediamine tetraacetic acid disodium salts (EDTA), so dium caprate (Na-Cap) and sodium salicylate (Na-Sal) whereas aprotinin , bacitracin, soybean trypsin inhibitor (STI) were used as protease in hibitors. The absorption of insulin and ECT from the lung was evaluate d by their hypoglycemic and hypocalcemic effects, respectively. We fou nd significant and continuous hypoglycemic or hypocalcemic effects aft er the insulin or ECT administration with these additives. Of these ad juvants, 10 mM LM appeared to be more effective for enhancing the pulm onary absorption of these peptides than the same concentration of othe r adjuvants. In addition, the protease inhibitors were effective in en hancing the pulmonary absorption of insulin due to their inhibitory ac tion of the insulin degradation. Furthermore, these adjuvants did not cause severe mucosal damage of rat lung, as determined by the leakage of Evans blue from the systemic circulation. These findings suggest th at the use of absorption enhancers and protease inhibitors would be a useful approach for improving the pulmonary absorption of biologically active peptides.