IN-VIVO EVALUATION OF SPRAY FORMULATIONS OF HUMAN INSULIN FOR NASAL DELIVERY

There are many ongoing investigations to improve the nasal bioavailability of peptide and protein formulations. The presence of bioadhesive polymers in nasal formulations may increase the residence time of the drugs in the nasal cavity. A combination of bioadhesive polymers with permeation enhancers would seem to further improve nasal bioavailability. In this study, insulin spray formulations containing two bioadhesive polymers (1.5% w/v microcrystalline cellulose (MCC) and 70% w/w Plastoid L50) alone or in combination with the enhancers such as sodium taurocholate (ST), ammonium glycyrrhizinate (AG) or glycyrrhetinic acid (GA) at 1% w/v level, were evaluated in diabetic rabbits. A total volume of 100 mu l of freshly prepared insulin formulation was sprayed into the nasal cavity of each diabetic rabbit. Glucose levels were monitored using a blood glucose assay and serum insulin levels were analyzed using RIA. 5 U/kg insulin in the MCC suspension alone resulted in an absolute bioavailability of 1.96% while Plastoid L50 alone resulted in 2.25% absolute bioavailability. Insulin in the MCC suspension and ST, AG or GA resulted in 8.36, 7.83 and 2.15% bioavailability, respectively. The same formulations produced a hypoglycemic effect in terms of total glucose reductions of 39.12, 15.96 and 9.36% and the maximal decreases in glucose levels were 58.37, 21.8 and 18.61%, respectively. The Plastoid formulation containing 1% ST provided nasal insulin bioavailability of 5.9% with a total glucose reduction of 17.03% and a maximal glucose decrease of 26.56%. Insulin spray formulations containing 1% ST alone and 1% AG alone resulted in bioavailabilities of 7.25 and 3.57%, respectively. These same sprays provided total glucose reductions of 25.08 and 16.97% with maximal glucose decreases of 44.56 and 19.81%, respectively. The presence of benzalkonium chloride and 2-phenylethanol as preservatives in the MCC suspension resulted in higher insulin absorption than the same formulation without preservatives (6.31% vs 1.96%).