Current treatments for many ocular disorders have been limited due to the difficulty in delivering drugs to the posterior segment of the eye. Common ocular diseases such as age-related macular degeneration occur in the posterior segment, and some drugs fail to reach therapeutic levels in this region after topical and systemic administration. Intraocular injections and implants have been successful in delivering high concentrations of drug to posterior tissues, but the invasive surgical procedure carries a high risk of severe side effects. Drugs can also be administered to the tissues of the eye wall, and solutions can be injected underneath the conjunctiva to form a drug releasing depot. Although subconjunctival injections are well tolerated by patients and are easy to administer, they have not been as effective in treatment when compared to intraocular delivery methods. The elimination kinetics after subconjunctival injections of various drugs are unknown and have not been fully investigated. Understanding the factors that influence drug absorption and clearance after subconjunctival injection will provide the necessary information for improving drug design and for the fabricating of drug delivery systems.

Drug elimination in the eye has typically been studied by sacrificing multiple animals at various time points and extracting drug from tissue. However, this method does not yield accurate results as drug extraction efficiencies are often low and drug levels may change during the time interval that tissues are being harvested. To study drug elimination kinetics after subconjunctival injection in vivo, 3-dimensional dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was employed to acquire real-time drug concentration levels after administering gadolinium-diethylenetriaminopentaacetic acid (Gd-DTPA; 938 Da) and gadolinium-albumin (Gd-albumin; 67.5 kDa) into albino rabbits. Injections of Gd-DTPA were also performed using different volumes (200 and 600 µl) to determine the effect of injection volume on drug elimination rate. Experiments were performed in vivo and post mortem to distinguish the effect of clearance by diffusion and by lymphatic and blood vessels. A control image was first acquired prior to the bolus injection. After injection, scans were acquired every 11 minutes for 2-5 hours. The subconjunctival tissue compartment was defined by establishing a region-of-interest (ROI) in the image acquired immediately after injection. Average signal intensity values in the ROI were monitored over time and elimination rates were calculated assuming first order clearance.

Preliminary results indicated that injection volume does not have a significant effect on clearance rate both in vivo and post mortem for Gd-DTPA. The elimination rate of Gd-DTPA was 0.0222 ± 0.0013 min^-1 in vivo and 0.0058 ± 0.0003 min^-1 post mortem. The elimination rate of Gd-albumin was 0.0004 ± 0.0003 min^-1 in vivo and 0.0009 ± 0.0005 min^-1 post mortem. While the elimination of Gd-DTPA was significantly faster in vivo than post mortem, the elimination of Gd-albumin was similar both in vivo and post mortem. This suggests that larger molecules are eliminated mostly by diffusion out of the subconjunctival tissue compartment while elimination through blood and lymphatic vessels may play a more dominant role in clearing smaller molecules. Future studies include testing the effect of lipophilicity on elimination rate and utilizing various sustained-release formulations to decrease clearance rates from subconjunctival tissue.