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The safety and effectiveness of cyclodextrins (CD) as nasal absorption promoters of peptide-like macromolecules have been investigated. The relative effectiveness of the cyclodextrins in enhancing insulin nasal absorption was found to be in the descending order of dimethyl-β-cyclodextrin (DMβCD) > α-cyclodextrin (α-CD) > β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HPβCD) > γ-cyclodextrin (γ-CD). A direct relationship linking absorption promotion to nasal membrane protein release is evident, which in turn correlates well with nasal membrane phospholipid release. The magnitude of the membrane damaging effects determined by the membrane protein or phospholipid release may provide an accurate, simple, and useful marker for predicting safety of the absorption enhancers. In order to estimate further the magnitude of damage and specificity of cyclodextrin derivatives in solubilizing nasal membrane components, the enzymatic activities of membrane-bound 5′-nucleotidase (5′-ND) and intracellular lactate dehydrogenase (LDH) in the perfusates were also measured. HPβCD at a 5% concentration was found to result in only minimal removal of epithelial membrane proteins as evidenced by a slight increase in 5′-ND and total absence of LDH activity. On the other hand, 5% DMβCD caused extensive removal of the membrane-bound 5′-ND. Moreover, intracellular LDH activity in the perfusate increased almost linearly with time. The cyclodextrins are also capable of dissociating insulin hexamers into smaller aggregates, and this dissociation depends on cyclodextrin structure and concentration. Enhancement of insulin diffusivity across nasal membrane through dissociation may provide an additional mechanism for cyclodextrin promotion of nasal insulin absorption. [ABSTRACT FROM AUTHOR]