In Vivo Comparison of Intracameral and Intravitreal Implantation of a Timolol Maleate Miniaturized Injectable Delivery System Device.

PURPOSE: Miniaturized injectable delivery system (MIDS) devices engineered for zero-order release of timolol maleate are evaluated for intracameral (IC) or intravitreal (IVT) injection for ocular safety, effects on intraocular pressure (IOP) reduction, and target tissue drug concentrations.

DESIGN

Preclinical study with in vitro testing of MIDS drug delivery devices together with intraocular injection of the devices in normotensive rabbit eyes.

SUBJECTS: Twenty-four New Zealand rabbits received intraocular injections of MIDS devices.

METHODS

Timolol maleate MIDS devices were injected IC or IVT into normotensive New Zealand rabbit eyes (n = 24), with weekly ophthalmic examinations and IOP measurements for 8 or 16 weeks. Eight weeks postimplantation, eyes were enucleated for quantification of tissue drug concentrations by liquid chromatography with tandem mass spectrometry and histology on whole globes.

MAIN OUTCOME MEASURES: Drug release pharmacokinetics; ocular safety and biocompatibility; IOP; and blood and target tissue drug concentrations.

RESULTS

At 8 weeks, IOP in experimental eyes was lowered by 11.1 ± 2.9% (n = 5, P = 0.019) and 18.1 ± 2.6% (n = 6, P < 0.001), for IC and IVT devices, respectively. In extended studies of IVT devices, IOP was numerically lower at 16 weeks by 8.5 ± 5.1% (n = 3, P = 0.24). Intracameral versus IVT injections achieved different tissue distributions (in ng/g; except for aqueous in ng/mL): aqueous 28.5 ± 2.7 vs. 4.5 ± 1.2 (P < 0.001), vitreous 0.3 ± 0.1 vs. 37.2 ± 11.0 (P = 0.010), and ciliary body 14.4 ± 1.8 vs. 50.9 ± 10.8 (P = 0.011). Intraocular inflammation and drug- or device-related adverse effects were absent on examinations and histopathology. Blood drug concentration was below the quantitation limit (<0.4 ng/ml).

CONCLUSIONS

Intravitreal and IC devices showed similar IOP reductions; IVT injection led to a higher drug concentration in the target ciliary body tissue, and in normotensive rabbit eyes showed general reduction of IOP over 8 weeks, indicating the potential of MIDS technology to address issues of patient adherence with glaucoma eye drops.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.