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Ricardo A. De Carvalho, Pamela P. Ko, A. Linn Murphree, Glenwood G. Gum; Kinetics And Safety Of A Topotecan Episcleral Unidirectional Delivery System For The Treatment Of Intraocular Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3247.
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To characterize in vitro and in vivo the drug release kinetics and safety of formulations of PLGA for unidirectional delivery of topotecan hydrochloride from an episcleral exoplant.
Topotecan hydrochloride was formulated in poly(lactic-co-glycolic acid), PLGA, copolymer and incorporated into a silicone unidirectional drug delivery system at different concentrations and doses ranging from 0.1 to 0.6 mg. Dissolution experiments utilized an apparatus 1 (basket, United States Pharmacopoeia) with 150-ml vials containing water and PBS (pH 7.3). Implants were placed in the basket and spun in the dissolution media at 50 RPM rate constantly for the duration of the study. HPLC was utilized for the determination and quantification of topotecan carboxylate, topotecan lactone, and total topotecan. For toxicity evaluation electroretinography (ERG), clinical examination and histopathology were carried out. The ERG parameters (amplitude and implicit time for a and b waves, PhNR and oscillatory potential) under scotopic and photopic conditions were analyzed comparing baseline vs. post-treatment up to 93 days. Two rabbits for each dose group (0.15 mg and 0.6 mg) were evaluated and additional animals were utilzed in pharmacokinetics experiments.
Both forms of topotecan, lactone and carboxylate, were adequately present throughout the drug release period. The selected formulation of topotecan:PLGA (1:9) demonstrated an immediate start of release that lasted for approximately 1000 hours following a triphasic release pattern . There were no detectable differences on the ERG scotopic and photopic responses before and after device placement at any time point in either dose group. The exoplants were well tolerated in the eye and mild conjunctival congestion and slight retraction around the implant site were the only abnormalities reported during the follow-up period. Histopathological evaluation revealed a focal foreign body and granulomatous reaction around the exoplant site. No signs of intraocular toxicity were noticed
Topotecan can be formulated in PLGA polymer for prolonged and sustained delivery over 40 days of both lactone and carboxylate forms. Selective episcleral drug delivery of topotecan is safe to the eye.
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