CYCLODEXTRINS AS PROTECTION AGENTS AGAINST ENHANCER DAMAGE IN NASAL DELIVERY SYSTEMS .2. EFFECT ON IN-VIVO ABSORPTION OF INSULIN AND HISTOPATHOLOGY OF NASAL MEMBRANE

An in vivo rat model was used to study the nasal absorption of insulin in the presence of selected enhancers (Laureth 9, glycodeoxycholate a nd L-alpha-lysophosphatidylcholine) either alone or in combination wit h 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin. All the enh ancers when administered alone with insulin produced about 50% decreas e in the blood glucose concentrations, an indirect measure of the abso rption of insulin across the rat nasal mucosa. In the presence of cycl odextrins the enhancing effect of L9 was maintained, whereas that of G DC and LPC was considerably reduced, but the duration of action of ins ulin was prolonged. Concomitantly, the histological effect of these ag ents on the rat nasal epithelium was studied using a perfusion fixatio n technique. The absorption of insulin did not consistently correlate with the histological observations and the results obtained in previou s haemolysis studies. However, the histological and haemolysis observa tions complemented each other in that the formulations [L9:HPbetaC (1: 4), GDC:gamma-CD (1:2) and LPC:HPbetaC (1:12)] which caused the least damage to the epithelial membrane had been shown to completely prevent haemolysis. In conclusion, the combination of L9 and possibly LPC wit h cyclodextrins may provide formulations which have almost the require d balance between activity and safety, for nasal delivery of insulin a nd could possibly be used as an adjunct to subcutaneous therapy.