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 exhibiting in vitro ciliogenesis. Enzymatically released human nasal epithelial cells were cultured as sequential monolayer-suspension culture showing in vitro ciliogenesis. Ciliary beat frequency (CBF) was determined by computerized microscope photometry. Among the cyclodextrins investigated (gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, anionic-beta-cyclodextrin polymer, dimethyl-beta-cyclodextrin and alpha-cyclodextrin), it was shown that after 30 min of exposure, gamma-cyclodextrin (10% w/v), hydroxypropyl-beta-cyclodextrin (10.0% w/v) and anionic-beta-CD polymer (8.0% w/v) were not significantly cilio-inhibitory (P0.05). Similarly, CBF remained stable upon cell exposure to alpha-cyclodextrin (2.0% w/v) and dimethyl-beta-cyclodextrin (1.0% w/v). However, higher concentrations of alpha-cyclodextrin and dimethyl-beta-cyclodextrin resulted in mild to severe cilio-inhibition after 45 min 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 observed in this model was lower than reported for chicken trachea model. Given the fact that (1) irreversible cilio-inhibition observed in this study occurred only at concentrations exceeding those used in pharmaceutical formulations and/or at an unusual exposure time (45 min) and that (2) in an in vivo situation, dilution and mucociliary clearance contribute to further decrease in local concentrations of the applied compound, the results of this study confirm the safety of the cyclodextrins investigated as nasal absorption enhancers.
Uchenna Agu
R
R
Laboratorium voor Farmacotechnologie en Biofarmacie, K.U. Leuven, Campus Gasthuisberg O&N, Herestraat 49, B-3000, Leuven, Belgium.
Jorissen
M
M
Willems
T
T
Van den Mooter
G
G
Kinget
R
R
Verbeke
N
N
Augustijns
P
P
D002478:Cells, Cultured; D002923:Cilia / Q000187:drug effects*; D003505:Cyclodextrins / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects; D005079:Excipients / Q000633:toxicity*; D006801:Humans; D008855:Microscopy, Electron, Scanning; D009079:Mucociliary Clearance / Q000187:drug effects; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects; D012996:Solutions; D013997:Time Factors
D003505:Cyclodextrins; D005079:Excipients; D012996:Solutions