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Ricardo De Carvalho, Paulin Wahjudi, Jonathan Moreno, Claudia Mendes, Pamela Ko, Guilherme C Matsutani; Selective and sustained episcleral delivery of brimonidine: In vivo safety, toxiciy and pharmacokinetics. Invest. Ophthalmol. Vis. Sci. 2014;55(13):449.
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To characterize the safety, toxicity and pharamacokinetics of brimonidine delivered via a selective episcleral delivery system
In vitro elution studies were conducted in dissolution chambers. Ex vivo diffusion utilized rabbit sclera mounted in Franz chambers. New Zealand White rabbits were implanted with targeted-transscleral delivery systems (TTDS) containing a formulation of brimonidine in poly(lactic-co-glycolic) acid copolymer 85:15 lactic:glycolic acid ratios. Animals (n=3 per time point) were implanted at day 1 and sacrificed at 2, 3, 8, 15, 20 and 29 days of implantation for drug tissue analysis. Enucleated globes were frozen and bisected in two hemispheres—proximal and distal to the implant location. Choroid, retina and vitreous were dissected from the frozen enucleated globe were analyzed. Plasma samples were also collected and analyzed. Tissue analysis of brimonidine tartrate was carried out by HPLC-MS using a previously developed assay with a limit of detection (LOD) and limit of quantitation (LOQ) are 0.25 ng/mL and 0.50 ng/mL in the ocular samples.
The distribution of brimonidine in the eye prioritized the proximal tissues forming a concentration gradient higher in the choroid followed by the retina and vitreous. The pharmacokinetics results are shown in the graph below. Therapeutic concentrations of brimonidines could be demonstrated throughout the follow period. At 29 days, only 30% of the drug content had been released. ERG and clinical examination up to 3 months disclosed no toxicity and tolerability concerns.
Sustained therapeutic concentrations of brimonidine were detected throughout the study period. Safety and tolerability was demonstrated. Selective episcleral delivery of brimonidine tartrate could provide long-term sustained delivery to the retina.
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