Controlled drug release from an ocular implant: An evaluation using dynamic three-dimensional magnetic resonance imaging

PURPOSE. The ability of an episcleral implant at the equator of the eye to deliver drugs to the posterior segment was evaluated, using a sustained-release implant containing gadolinium-DTPA (Gd-DTPA). The movement of this drug surrogate was assessed with magnetic resonance imaging (MRI) in the rabbit eye. The results were compared with a similar implant placed in the vitreous cavity through a scleral incision at the equator. METHODS. Polymer-based implants releasing Gd-DTPA were manufactured and placed in the subconjunctival space on the episclera or in the vitreous cavity in live rabbit eyes ( in vivo) and in freshly enucleated eyes ( ex vivo). Release rates of implants in vitro were also determined. Dynamic three-dimensional MRI was performed using a 4.7-Tesla MRI system for 8 hours. MR images were developed and analyzed on computer. RESULTS. Episcleral implants in vivo delivered a mean total of 2.7 mug Gd-DTPA into the vitreous, representing only 0.12% of the total amount of compound released from the implant in vitro. No Gd-DTPA was detected in the posterior segment of the eye. Ex vivo, the Gd-DTPA concentration in the vitreous was 30 times higher. In vivo eyes with intravitreal implants placed at the equator delivered Gd-DTPA throughout the vitreous cavity and posterior segment. Compartmental analysis of the ocular drug distribution from an episcleral implant showed that the elimination rate constant of Gd-DTPA from the subconjunctival space into the episcleral veins and conjunctival lymphatics was 3-log units higher than the transport rate constant for Gd-DTPA movement into the vitreous. CONCLUSIONS. In vivo, episcleral implants at the equator of the eye did not deliver a significant amount of Gd-DTPA into the vitreous, and no compound was identified in the posterior segment. A 30-fold increase in vitreous Gd-DTPA concentration occurred in the enucleated eyes, suggesting that there are significant barriers to the movement of drugs from the episcleral space into the vitreous in vivo. Dynamic three-dimensional MRI using Gd-DTPA, and possibly other contrast agents, may be useful in understanding the spatial relationships of ocular drug distribution and clearance mechanisms in the eye.