Controlled drug release from an ocular implant: an evaluation using dynamic three-dimensional magnetic resonance imaging.
OBJECTIVE
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 microg 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.
Kim
Hyuncheol
H
Divison of Bioengineering and Physical Sciences, Office of Research Services, National Institutes of Health, Bethesda, MD 20892, USA.
Robinson
Michael R
MR
Lizak
Martin J
MJ
Tansey
Ginger
G
Lutz
Robert J
RJ
Yuan
Peng
P
Wang
Nam S
NS
Csaky
Karl G
KG
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D004341:Drug Evaluation; D004343:Drug Implants; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000493:pharmacokinetics*; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging / Q000379:methods*; D011817:Rabbits; D012160:Retina / Q000378:metabolism; D012590:Sclera / Q000187:drug effects; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism
D003287:Contrast Media; D004343:Drug Implants; D019786:Gadolinium DTPA