Effect of additives on insulin absorption from intratracheally administered dry powders in rats

The lungs are useful for administration of macromolecules, which are poorly absorbed from the intestine. In the present study, we prepared several dry powder formulations of insulin using a spray drying technique to examine t he effect of additives on insulin absorption. The bioavailability of insuli n was estimated from the change in the plasma glucose level. The bioavailab ility of insulin from dry powder with no additive exceeded that obtained fr om pH 7.4 solution. The absolute bioavailability of insulin administered as a solution with 1.4 mg/dose of bacitracin or 1.0 mg/dose of Span 85 was al most 100%. The bioavailability of dry powder with 0.42 mg/dose of bacitraci n was 20% that of the solution with 1.4 mg/dose of bacitracin. The insulin dry powder with 0.21 mg/dose of Spall 85 showed a bioavailability less than that for the insulin solution with 0.1 mg/dose of Span 85. Bacitracin and Span 85 were not as effective in dry powder as in solution in the present s tudy. While citric acid was more effective in dry powder that in solution t o increase the hypoglycemic effect. The pH 5.0 and pH 3.0 solutions contain ing 0.19 mg of citric acid in 0.1 ml showed absolute bioavailabilities of 4 3% and 57%, respectively, while the bioavailabilities for dry powders conta ining 0.025 and 0.036 mg/dose citric acid were 42%, and 53%, respectively. In addition, the hypoglycemic effect of dry powders continued for a longer period and remained at 240 min with the dry powders, while it disappeared a t 180 min with the solutions. When the insulin dry powder containing 0.036 mg/dose of citric acid was administered, the lactate dehydrogenase activity , a sensitive indicator of acute toxicity to lung cells, in bronchoalveolar lavage was as low as that fur saline administration, suggesting citric aci d is a safe additive. Thus, citric acid appears to be a safe and potent abs orption enhancer for insulin in dry powder. (C) 2001 Elsevier Science B.V. All rights reserved.