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Morgan V. Fedorchak, Jeremy Wingard, Carlos Medina, Sam N. Rothstein, Joel S. Schuman, Steven R. Little; Rationally Designed, Controlled-release Glaucoma Treatments Achieve One Month Of Iop Reduction With A Single Dose. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1750.
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IOP reduction in patients with glaucoma is typically accomplished through the administration of eye drops, the difficult and frequent nature of which contributes to patient compliance rates as low as 50%. Medications such as brimonidine tartrate (BT) require 2-3 times daily dosing and have yet to be adapted into controlled-release formulations that could drastically improve compliance. The purpose of this study was to develop and test an optimal controlled release BT formulation both in vitro and in vivo.
Poly(lactic-co-glycolic) acid (PLGA) microparticles were fabricated using a standard double emulsion procedure and characterized with SEM. In vitro release of BT was quantified by incubating a known mass of microparticles in buffer and measuring the absorption. For our in vivo studies, healthy Dutch belted rabbits were randomized to receive blank microparticles (no drug), BT-loaded microparticles, or BT drops (Alphagan®, Allergan, Irvine, CA). Rabbits in both microparticle groups received subconjunctival injection of microparticles suspended in sterile saline on Day 0 in one eye. Rabbits in the positive control group received a single drop of Alphagan® solution in one eye twice a day each day of the study. Intraocular pressure was monitored over 28 days in both eyes. Following sacrifice on Day 28, both eyes were enucleated for histological analysis. All slides were masked prior to performing histopathological analysis for evidence of irritation or foreign body response.
Microparticles were confirmed to have a diameter of 7.5±2.9 μm with a primarily poreless morphology. They released an average of 0.62±0.34 μg BT/mg particles/day in our in vitro setup. Our in vivo study of the BT-loaded microparticles demonstrated that the decrease in IOP was significantly lower (p<0.05) in the treated eye for BT drops versus BT microparticles for all time points. There was no significant difference in ΔIOP for the untreated eye between BT drops and BT microparticles. In contrast, IOP steadily increased in rabbits injected with the blank microparticles. The microparticle bleb was visible using light microscopy and no evidence of microparticle migration was seen. Histological analysis showed no signs of foreign body response due to the microparticles.
Our BT-loaded PLGA microparticles delivered over 28 days of therapeutic levels of BT with a single dose. These microparticles demonstrated effectiveness at reducing IOP with no evidence of irritation or infection. We are currently adapting the microparticle formulation into a clinically relevant dosage form that patients can easily apply and we will be testing this new device in a rabbit model.
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