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 the effect of additives on insulin absorption. The bioavailability of insulin was estimated from the change in the plasma glucose level. The bioavailability of insulin from dry powder with no additive exceeded that obtained from 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 almost 100%. The bioavailability of dry powder with 0.42 mg/dose of bacitracin was 20% that of the solution with 1.4 mg/dose of bacitracin. The insulin dry powder with 0.21 mg/dose of Span 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 study. While citric acid was more effective in dry powder that in solution to increase the hypoglycemic effect. The pH 5.0 and pH 3.0 solutions containing 0.19 mg of citric acid in 0.1 ml showed absolute bioavailabilities of 43% and 57%, respectively, while the bioavailabilities for dry powders containing 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 at 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 for saline administration, suggesting citric acid is a safe additive. Thus, citric acid appears to be a safe and potent absorption enhancer for insulin in dry powder.