Cyclodextrins as protection agents against enhancer damage in nasal delivery systems II. Effect on in vivo absorption of insulin and histopathology of nasal membrane

Abstract

An in vivo rat model was used to study the nasal absorption of insulin in the presence of selected enhancers (Laureth 9, glycodeoxycholate and L-α-lysophosphatidylcholine) either alone or in combination with 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin. All the enhancers when administered alone with insulin produced about 50% decrease in the blood glucose concentrations, an indirect measure of the absorption of insulin across the rat nasal mucosa. In the presence of cyclodextrins the enhancing effect of L9 was maintained, whereas that of GDC and LPC was considerably reduced, but the duration of action of insulin was prolonged. Concomitantly, the histological effect of these agents on the rat nasal epithelium was studied using a perfusion fixation technique. The absorption of insulin did not consistently correlate with the histological observations and the results obtained in previous haemolysis studies. However, the histological and haemolysis observations complemented each other in that the formulations [L9:HPβC (1:4), GDC:γ-CD (1:2) and LPC:HPβC (1:12)] which caused the least damage to the spithelial membrane had been shown to completely prevent haemolysis. In conclusion, the combination of L9 and possibly LPC with cyclodextrins may provide formulations which have almost the required balance between activity and safety, for nasal delivery of insulin and could possibly be used as an adjunct to subcutaneous therapy.