Effect of cyclodextrin complexation on the liposome permeability of a model hydrophobic weak Acid

This study examines the effect of a chemically modified beta-cyclodextrin on the liposome bilayer permeability of a liposomally entrapped model hydrophobic weak acid, DB-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin).

Permeability studies were conducted in liposomes prepared by hydration-extrusion in the presence or absence of entrapped hydroxypropyl-beta-cyclodextrin (HPbetaCD). A gradient HPLC method with evaporative light scattering detection was developed for analysis of HPbetaCD. DB-67 was analyzed by HPLC with fluorescence detection.

HPbetaCD entrapped in the aqueous compartment of liposomes was found to be membrane impermeable. Gel phase liposomes were stable in the presence of HPbetaCD. HPbetaCD complexation did not significantly alter the apparent permeability of DB67 lactone, due to its high membrane binding. However, lactone ring-opening and ionization significantly decreased the apparent permeability and improved the liposomal retention of DB-67, an effect that was amplified in the presence of 50 mM HPbetaCD.

In liposomes, cyclodextrin complexation competes with liposomal membrane binding which may temper the potential benefit of complexation in prolonging hydrophobic drug retention. Cyclodextrin complexation combined with drug ionization may nevertheless significantly enhance the retention of ionizable hydrophobic drugs in liposomes as complexation may compete more favorably with membrane binding when the drug is ionized.