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Nobuhiro Nagai, Yasuko Izumida, Eri Koyanagi, Hirokazu Kaji, Matsuhiko Nishizawa, Takahito Imagawa, Akiko Morikawa, Toru Nakazawa, Yukihiko Mashima, Toshiaki Abe; Pharmacokinetic and Safety Evaluation of a Transscleral Sustained Unoprostone Release Device. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4153.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the ocular tissue distribution of unoprostone isopropyl (UNO) and retinal toxicity after transscleral administration of UNO by a drug delivery device in rabbits.
The device consists of a reservoir, controlled-release cover, and drug formulation, which were made of photopolymeized poly(ethyleneglycol) dimethacrylates. UNO, a prostone and BK channel activator for antiglaucoma eyedrops marketed in Japan, was loaded in the device (length, 10 mm; width, 3.6 mm; height, 0.7 mm) at a content of 2.85 mg UNO. High-performance liquid chromatography was used to evaluate the release amount of UNO in vitro. The UNO metabolite, unoprostone-free acid (M1), concentrations in the retina, choroid, and plasma were determined by liquid chromatography-tandem mass spectrometry at 4, 12, and 24 weeks after implantation in rabbits. Retinal toxicity was evaluated by electroretinogram and optical coherence tomography.
The UNO released from the device in vitro showed zero-ordered kinetics for 12 weeks, then the release gradually decreased to 24 weeks. The area under the M1 concentration curve (AUC) of the retina during 24-week device implantation was higher than the simulated AUC of the retina after topical administration of 0.12% UNO eye-drop (once-a-day for 24-week). No substantial toxic reactions were observed by electroretinogram and optical coherence tomography.
The device could be a useful carrier for intraocular sustained delivery of UNO without producing severe retinal toxicity.
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