Abstract
Purpose: :
The objective was to determine whether a novel sustained release, refillable intraocular drug delivery system can be safely implanted into the rabbit eye. The approach is to have a capsule ring with a drug reservoir that fits within the rabbit lens capsular bag and is inserted through a standard cataract incision while monitoring drug distribution and clearance with both conventional pharmacokinetics and MRI.
Methods: :
The shell for the drug reservoir was made of flexible biocompatible polycarbonate-based polyether urethane (Millipore, CA). Refilling Ports were made of polyimide tubing (Small parts, Inc, FL). The CDR has one face open for a semi permeable membrane (polyethersulfone) to adhere on its surface for sustained drug delivery.New Zealand rabbits were used as the in vivo animal model and Avastin® as the drug of interest. CDR filled with Avastin® formulated in polyvinyl alcohol (PVA) was inserted along with the intraocular lens (IOL) during cataract surgery performed on the rabbits. The PVA is for Avastin® stability and to increase viscosity of drug solution. Avastin® was also linked to a contrast agent for real time pharmacokinetics data using MRI. Control experiments such as blank CDR, intravitreal injection of commercial Avastin® (2.5 mg/0.1 µl) and intravitreal injection of Avastin formulated in PVA were performed on rabbits. The Avastin® samples were collected from different eye tissue sections and assayed by an ELISA protocol.
Results: :
The surgical procedure involved a standard clear phaco-emulsification with intraocular lens implantation followed by CDR lens implantation in 10 rabbit eyes. Eyes were evaluated day 1 after surgery and weekly with no signs of toxicity observed. Amount of Avastin® delivered to the vitreous and retina was in the range of published concentrations after intravitreal injection (16-50 µg/ml). CDR loaded with Avastin® plus PVA showed sustained release as opposed to the intravitreal control injections. MRI scans were done weekly and the images showed that the CDR was well implanted and stable in the lens capsule. MR images also demonstrated real time drug distribution to the areas of interest (posterior tissues).
Conclusions: :
The results demonstrate successful manufacturing and implantation of the CDR in the New Zealand rabbit eye. Pharmacokinetics were superior (closer to near zero-order kinetics) of intravitreal injection. The semipermeable membrane along with the presence of PVA contributed in having sustained release kinetics (currently longer than 2 months).
Keywords: age-related macular degeneration • drug toxicity/drug effects • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)