The influence of absorption enhancers on intranasal insulin absorption in normal and diabetic subjects

Abstract

The bioavailability of intranasally administered insulin in humans is very low, because insulin is a high molecular weight and hydrophilic substance. In healthy volunteers and diabetes patients some absorption enhancers proved to be very effective, including the bile salts sodium deoxycholate and glycocholate, sodium taurodihydrofusidate (STDHF), laureth-9 and didecanoyl- l-α-phosphatidylcholine (DDPC). Several studies reported an insulin bioavailability in the order of 5–10%. However, some of these absorption enhancers may be harmful for nasal epithelial membranes, because in vitro studies showed morphological damage and severe inhibition of nasal ciliary movement. In vivo, laureth-9 and sodium deoxycholate are associated with nasal irritation, and STDHF leads to painful stinging and lacrimation. Cyclodextrins, especially dimethylated β-cyclodextrin (DMβCD), improve the nasal absorption of insulin in rats. This compound is relatively non-toxic, as has been shown in various studies concerning its effect on nasal epithelial tissue. Nasal administration of liquid insulin-DMβCD solution in rats results in an almost complete insulin absorption. In contrast, experiments in rabbits and man with the same formulation show no nasal insulin absorption. However, the nasal administration of a lyophilized insulin-DMβCD powder formulation results in a rapid nasal insulin absorption with a peak level reached after about 10 min. In diabetic patients the mean absolute bioavailability of insulin with this formulation was 5.1%. Only a slight initial itch was reported. Rapid absorption of intranasally administered insulin provides a pharmacokinetic profile similar to intravenous insulin and the postprandial endogenous insulin secretion by the pancreas. Therefore, its potential may be considered as an adjunct to subcutaneous treatment. Although the results so far with a few absorption enhancers are encouraging, the nasal insulin bioavailability is very low and the long-term safety of nasal insulin therapy has to be proven. Therefore, an intranasal insulin formulation is still far away from reaching the market.