Abstract
The ocular bioavailability of pilocarpine has been improved by bispilocarpic acid diesters but the ocular irritation associated with these prodrugs is the main limitation of their clinical usefulness. Pilocarpine prodrugs show amphiphilic lipid bilayer disrupting properties which partly contribute to the eye irritation. In the present study, the influence of complexation with hydrophilic β-cyclodextrin derivatives, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether β-cyclodextrin with an average degree of substitution of four (SBE4-β-CD), on pilocarpine prodrug-induced bilayer perturbation was investigated using rabbit erythrocyte hemolysis and calcein release from liposomes as test models. Bispilocarpic acid diesters form 1:1 and 1:2 complexes with HP-β-CD and 1:1 complexes with SBE4-β-CD at pH 7.4. Both β-CD derivatives decreased the surface activity of the prodrug solutions. The hemolytic activity and liposome disruption of prodrug-CD solutions were 3–10 times and 4–15 times lower than that of parent prodrug, respectively. The protecting effect of CDs was dependent on the apparent complexation constant of prodrug/CD complex which determines the active free prodrug concentration in CD solution. The present study shows that amphiphilic properties and lipid bilayer perturbing effects of pilocarpine prodrugs are reduced by complexing them with hydrophilic β-CD derivatives.
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