Safety assessment of selected cyclodextrins - effect on ciliary activity using a human cell suspension culture model exhibiting in vitro ciliogenesis

The objective of this study was to assess the cilio-inhibitory effect of a series of cyclodextrins using a human cell suspension culture system exhibi ting in vitro ciliogenesis. Enzymatically released human nasal epithelial c ells were cultured as sequential monolayer-suspension culture showing in vi tro ciliogenesis. Ciliary beat frequency (CBF) was determined by computeriz ed microscope photometry. Among the cyclodextrins investigated (gamma-cyclo dextrin, hydroxypropyl-beta-cyclodextrin, anionic-beta-cyclodextrin polymer , dimethyl-beta-cyclodextrin and alpha-cyclodextrin), it was shown that aft er 30 min of exposure, gamma-cyclodextrin (10% w/v), hydroxypropyl-beta-cyc lodextrin (10.0% w/v) and anionic-beta-CD polymer (8.0% w/v) were not signi ficantly cilio-inhibitory (P > 0.05). Similarly, CBF remained stable upon c ell exposure to alpha-cyclodextrin (2.0% w/v) and dimethyl-P-cyclodextrin ( 1.0% w/v). However, higher concentrations of alpha-cyclodextrin and dimethy l-beta-cyclodextrin resulted in mild to severe cilio-inhibition after 45 mi n of exposure. The effect of alpha-cyclodextrin (5.0% w/v; 54 +/- 4% cilio- inhibition) was partially reversible while dimethyl-beta-cyclodextrin (10% w/v; 36 +/- 4% cilio-inhibition) was irreversible. The cilio-inhibition obs erved in this model was lower than reported for chicken trachea model. Give n the fact that (1) irreversible cilio-inhibition observed in this study oc curred only at concentrations exceeding those used in pharmaceutical formul ations and/or at an unusual exposure time (45 min) and that (2) in an in vi vo situation, dilution and mucociliary clearance contribute to further decr ease in local concentrations of the applied compound, the results of this s tudy confirm the safety of the cyclodextrins investigated as nasal absorpti on enhancers. (C) 2000 Published by Elsevier Science B.V. All rights reserv ed.