BETA-CYCLODEXTRIN DERIVATIVES (2-HP-BETA-CD, SBE4-BETA-CD) DECREASE THE AMPHIPHILICITY AND MEMBRANE PERTURBING EFFECTS OF PILOCARPINE PRODRUGS

The ocular bioavailability of pilocarpine has been improved by bispilo carpic acid diesters but the ocular irritation associated with these p rodrugs is the main limitation of their clinical usefulness. Pilocarpi ne prodrugs show amphiphilic lipid bilayer disrupting properties which partly contribute to the eye irritation. In the present study, the in fluence of complexation with hydrophilic beta-cyclodextrin derivatives , 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutyl ether beta-cyclodextrin with an average degree of substitution of four (SBE4 -beta-CD), on pilocarpine prodrug-induced bilayer perturbation was inv estigated using rabbit erythrocyte hemolysis and calcein release from liposomes as test models. Bispilocarpic acid diesters form 1:1 and 1:2 complexes with HP-beta-CD and 1:1 complexes with SBE4-beta-CD at pH 7 .4. Both beta-CD derivatives decreased the surface activity of the pro drug solutions. The hemolytic activity and liposome disruption of prod rug-CD solutions were 3-10 times and 4-15 times lower than that of par ent prodrug, respectively. The protecting effect of CDs was dependent on the apparent complexation constant of prodrug/CD complex which dete rmines the active free prodrug concentration in CD solution. The prese nt study shows that amphiphilic properties and lipid bilayer perturbin g effects of pilocarpine prodrugs are reduced by complexing them with hydrophilic beta-CD derivatives.