Amphiphilic properties of pilocarpine prodrugs

Abstract

Corneal permeability of pilocarpine has been increased by prodrug derivatization, but ocular irritation is associated with the in vivo use of the prodrugs. To determine possible amphiphilic nature of the prodrugs, we determined the critical micelle concentrations and lipid bilayer disrupting properties of bispilocarpic acid diester prodrugs. Surface activity of prodrugs in water was determined using interfacial tensiometer. Lipid bilayer disruption was tested by calcein release from liposomes and hemolysis of rabbit erythrocytes in vitro. Molar phospholipid and cholesterol contents of the liposomes (EPC:DOPE:DPPG:Ch 8:6:1.5:1.5) were designed on the basis of the lipid content of the corneal epithelium. Surface activities of the pilocarpine prodrugs increased with the increasing lipophilicity of the derivative and increasing pH. The critical micelle concentrations of the prodrugs were 0.1-1 mM at pH 5.0. The concentrations of the prodrugs to induce 50% leakage of calcein were 0.5 mM (V), 1.2 mM (III), 2.2 mM (IV) and 0.25 mM (V), 0.8 mM (III), 3.5 mM (IV) to cause 50% hemolysis. Also, eye irritation of these prodrugs increased with their increasing lipophilicity, pH and concentration. Lipophilic pilocarpine prodrugs show amphiphilic properties which may contribute to the eye irritation. The harmful effects of pilocarpine prodrugs on cell membranes on ocular surface may limit their usefulness. Possible amphiphilicity of lipophilic prodrugs may be a limitation of the prodrug technique in ocular drug delivery.