NASAL ADMINISTRATION OF GLUCAGON COMBINED WITH DIMETHYL-BETA-CYCLODEXTRIN - COMPARISON OF PHARMACOKINETICS AND PHARMACODYNAMICS OF SPRAY AND POWDER FORMULATIONS

The effect of increasing amounts of dimethyl-beta-cyclodextrin (DM bet a CD) on the nasal absorption and consequent plasma glucose levels of glucagon as spray solution or powder has been examined in rabbits. Nas al spray was prepared by dissolving commercial glucagon in the manufac turer's solvent containing 2 or 5% w/v DM beta CD. Powders were obtain ed by freeze drying of the spray solutions. In general, glucagon was s lightly absorbed in the absence of DM beta CD. Increasing the enhancer concentration was shown to increase plasma glucagon and glucose level s while decreasing the times for maximum glucagon peaks (t(max) glucag on) in both spray and powder formulations. Spray solutions produced fa ster and higher plasma glucagon peaks (C-max glucagon) at any enhancer concentration compared to powders, however the AUC(0-60 min) glucagon and glucose concentrations were not significantly different. The 5% w /v DM beta CD resulted in a more pronounced glucagon absorption with c orresponding higher plasma glucose levels. The percentage bioavailabil ity of glucagon from formulations containing 2% w/v enhancer were betw een 42.78 and 44.61% with corresponding AUC plasma glucose of between 78.89 and 80.47% compared to subcutaneous injection. The values for th e 5% w/v DM beta CD formulations were about 82% with corresponding AUC plasma glucose between 95 and 97% for spray and powder, respectively. Nasal administration was found to initiate serum glucagon and plasma glucose concentrations earlier than those of subcutaneous injection, b ut the effect of the latter was more sustained. Spray solution and fre eze dried powder were equally effective.