A microparticle/hydrogel combination drug-delivery system for sustained release of retinoids.

PURPOSE To design and develop a drug-delivery system containing a combination of poly(D,L-lactide-co-glycolide) (PLGA) microparticles and alginate hydrogel for sustained release of retinoids to treat retinal blinding diseases that result from an inadequate supply of retinol and generation of 11-cis-retinal. METHODS To study drug release in vivo, either the drug-loaded microparticle-hydrogel combination was injected subcutaneously or drug-loaded microparticles were injected intravitreally into Lrat(-/-) mice. Orally administered 9-cis-retinoids were used for comparison and drug concentrations in plasma were determined by HPLC. Electroretinography (ERG) and both chemical and histologic analyses were used to evaluate drug effects on visual function and morphology. RESULTS Lrat(-/-) mice demonstrated sustained drug release from the microparticle/hydrogel combination that lasted 4 weeks after subcutaneous injection. Drug concentrations in plasma of the control group treated with the same oral dose rose to higher levels for 6-7 hours but then dropped markedly by 24 hours. Significantly increased ERG responses and a markedly improved retinal pigmented epithelium (RPE)-rod outer segment (ROS) interface were observed after subcutaneous injection of the drug-loaded delivery combination. Intravitreal injection of just 2% of the systemic dose of drug-loaded microparticles provided comparable therapeutic efficacy. CONCLUSIONS Sustained release of therapeutic levels of 9-cis-retinoids was achieved in Lrat(-/-) mice by subcutaneous injection in a microparticle/hydrogel drug-delivery system. Both subcutaneous and intravitreal injections of drug-loaded microparticles into Lrat(-/-) mice improved visual function and retinal structure.