Ocular delivery of the β-blocker, tilisolol, through the prodrug approach

Abstract

Four lipophilic derivatives of tilisolol, which is a β-blocker to decrease intraocular pressure after instillation, were synthesized. Hydrolytic regeneration of the parent compound, tilisolol, from the derivatives in vitro, in vitro ocular membrane penetration and in vivo ocular absorption were examined in order to evaluate their usefulness as prodrugs of tilisolol in rabbits. All derivatives, including O-acetyl, O-propionyl, O-butyryl and O-valeryl esters, showed increased lipophilicity due to the introduction of a lipophilic function. They were gradually hydrolyzed to tilisolol in a pH 7.4 buffer solution. They also showed rapid enzymatic conversion to tilisolol in ocular tissue homogenates. This rapid conversion was reflected in the enhanced penetration of tilisolol in vitro through corneal, conjunctival and scleral membranes. Most of the drug which penetrated through the ocular membranes was detected as tilisolol, not as intact derivative, in the receiver side. Conjunctival membranes showed higher permeability than corneal and scleral membranes. Corneal penetration of lipophilic derivatives was 3–6-fold higher than of tilisolol. The corneal permeability coefficients of drugs demonstrated a linear relationship with their lipophilicities. The lipophilic derivatives did not show significant difference from tilisolol in conjunctival and scleral penetration. The derivatives also increased the concentration of tilisolol in aqueous humor 1 h after instillation to rabbits. The linear relationship between in vivo absorption and in vitro corneal penetration of derivatives suggests that the corneal route, rather than the scleral pathway, contributes to the ocular absorption of drug after instillation. These results indicate the potential utility of lipophilic prodrug as an anti-glaucoma agent.