EFFICACY, SAFETY AND MECHANISM OF CYCLODEXTRINS AS ABSORPTION ENHANCERS IN NASAL DELIVERY OF PEPTIDE AND PROTEIN DRUGS

Cyclodextrins are used in nasal drug delivery as absorption enhancing compounds to increase the intranasal bioavailability of peptide and pr otein drugs. The most effective cyclodextrins in animal experiments ar e the methylated derivatives, dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin, which are active at low concentrations r anging between 2% and 5%, However, large species differences between r ats, rabbits and humans exist for the nasal absorption enhancement by cyclodextrins. Based on toxicological studies of the local effects of cyclodextrins on the nasal mucosa dimethyl-beta-cyclodextrin and rando mly methylated beta-cyclodextrin are considered safe nasal absorption enhancers. Their effects were quite similar to controls (physiological saline), but smaller than those of the preservative benzalkonium chlo ride in histological and ciliary beat frequency studies. In these stud ies, and in a study of the release of marker compounds after nasal adm inistration, methylated beta-cyclodextrins were less toxic than sodium glycocholate, sodium taurodihydrofusidate, laureth-9 and L-alpha-phos phatidylcholine. Systemic toxicity after nasal cyclodextrin administra tion is not expected, because very low doses of cyclodextrins are admi nistered and only very small amounts are absorbed. The mechanism of ac tion of cyclodextrins may be explained by their interaction with the n asal epithelial membranes and their ability to transiently open tight junctions.