Prodrugs - Current development and applications in ocular drug delivery

Abstract

The clinical therapeutic regimen for disease treatment of the anterior portion of an eye involves the use of eye drops with mediocre success due to rapid eye drainage and poor bioavailability. These conventional delivery mechanisms do not penetrate the posterior portion of the eye and are ineffective in treating posterior segment diseases like, retinitis pigmentosa, age related macular degeneration, diabetic retinopathies, and glaucoma. This has led to augmented research in development of drug delivery alternatives for subconjunctival and periocular administration, drug that targets bloodstream to the retinal pigment epithelium or choroidal vasculature, and prodrugs. Ocular pharmacokinetics is a highly studied area to develop strategies that circumvent the associated barriers in ocular drug delivery and achieve better clinical outcomes. The viable strategies for enhancing ocular bioavailability involves physical methods like formulating drugs as solutions, suspensions, gels and chemical methods like development of prodrugs and soft drugs. The application of prodrug design offers the advantages of higher ocular tissue permeability, superior bioavailability, transporter targeting, site specificity and enhanced aqueous solubility with minimal disruption of the barriers to ocular diffusion. This review focuses mainly on recent progress in prodrug strategies like lipid-based prodrugs, transporter targeted prodrugs, hydrophilic and polymeric prodrugs developed to improve delivery to the otherwise resilient eye. The success of conventional and emerging prodrug design strategies depends on many factors like chemical structure of the drug, ease of prodrug synthesis, capacity of targeted transporters and in vivo metabolic activation attributes. Inspite of the associated challenges, prodrugs have witnessed reasonable market success and the new prodrug design strategies are envisaged to enable delivery of conventional drugs, antibodies, oligonucleotides, genes, and growth factors to the eye offering patient compliant, safer and superior treatment of posterior segment diseases.