Pharmacokinetic and Safety Evaluation of a Transscleral Sustained Unoprostone Release Device

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: The device could be a useful carrier for intraocular sustained delivery of UNO without producing severe retinal toxicity.