An Effective Absorption Behavior of Insulin for Diabetic Treatment Following Intranasal Delivery Using Porous Spherical Calcium Carbonate in Monkeys and Healthy Human Volunteers

Abstract

Porous spherical calcium carbonate (PS-CaCO₃), in contrast to regular calcium carbonate (CaCO₃), which has a cuboidal particle shape, has a characteristic spherical particle shape with a large number of porous, sliver crystals. The effect of PS-CaCO₃ as a drug carrier on intranasal insulin absorption was investigated in cynomolgus monkeys and healthy human volunteers. Each insulin formulation (powder) containing PS-CaCO₃ or regular CaCO₃ was administered intranasally. Serum insulin and glucose levels after administration were evaluated. The insulin absorption after intranasal administration with each CaCO₃ was found to be much more rapid than that after subcutaneous administration. The serum insulin level after intranasal insulin delivery(16 U per monkey) with PS-CaCO₃ showed a higher C_max (403.5 μU/mL) and shorter T_max (0.167 h) when compared with regular CaCO₃. The serum glucose level reduction rate after intranasal delivery using PS-CaCO₃ was faster than that of regular CaCO₃, reflecting the difference in absorption rates. Following repeated intranasal administrations for 4 weeks in monkeys, no toxicity was observed even with a maximum insulin dose level of 25 U. Furthermore, the intranasal insulin absorption rate with PS-CaCO₃ in healthy humans was also observed to be considerably faster than that with regular CaCO₃. Effects of PS-CaCO₃ on a more effective absorption behavior of insulin were considered to be the result of a greater affinity between the nasal mucosa layer and PS-CaCO₃, which is closely related to its structural characteristics. Thus, intranasal insulin delivery using PS-CaCO₃ is thought to be a safe and highly available system enabling more effective insulin absorption behavior with the appearance of endogenous postprandial insulin secretion in healthy humans. We believe that our intranasal insulin delivery system enabling a rapid and short-acting pharmacological effect against postprandial hyperglycemia will be more beneficial than pulmonary insulin delivery systems in the treatment of diabetes.