Design and in vitro assessment of L-lactic acid-based copolymers as prodrug and carrier for intravitreal sustained L-lactate release to reverse retinal arteriolar occlusions

Abstract

Ophthalmic conditions in which the retinal vasculature is obstructed generally lead to vision loss. Administration of the vasodilator L-lactate might offer a treatment strategy by restoring the blood flow, but unfortunately its effect after single intravitreal injection is short-lived. This study describes a concept in which the sustained release of L-lactic acid from a biodegradable copolymer system is investigated. The 50:50 (n/n) copolymer system, composed of L-lactic acid and L,D-2-hydroxyoctanoic acid, is a viscous injectable that will form an intravitreal drug depot. Hydrolysis of the copolymer will automatically lead to the release of L-lactic acid, which will convert to L-lactate at physiological pH, thereby providing a carrier and pro-drug in one. In vitro and ex vivo release studies demonstrate an L-lactic acid release over several weeks. Biocompatibility of the co-polymer and its degradation products is shown on a human retinal pigment epithelial cell line and on ex vivo retinal tissues. A low molecular weight copolymer (1200 g/mol) with low polydispersity has promising properties with a constant release profile, good biocompatibility and injectability.