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S.S. Lee, H. Kim, N.S. Wang, M. Tremblay, P.M. Bungay, R.J. Lutz, P. Yuan, K.G. Csaky, M.R. Robinson; The Pharmacokinetics of a Novel Episcleral Cyclosporine Implant for High–Risk Keratoplasties . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2704.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Poor tissue penetration limits the use of topical cyclosporine for prevention of corneal allograft rejection. We developed a cyclosporine episcleral implant to improve drug delivery to the cornea. Methods:A matrix–style cyclosporine implant was developed to deliver an initial higher dose, followed by a tapering maintenance dose, to the cornea for 12 months. In vitro release rates were performed with HPLC. In NZW rabbits, implants were placed on the episclera superotemporally of one eye 5 mm from the limbus. Animals were sacrificed over time and the cyclosporine extracted from different regions of the cornea. Three circular sections of cornea were removed with a 6 mm diameter trephine with the center of the sections 8, 13, and 18 mm away from the center of the implant. In a long–term study, rabbits had a cyclosporine episcleral implant placed and corneal levels were measured over a 6–month period. Results: In vitro, implants with a 30 wt% drug load had a cumulative mean release of 1.57 mg at 6 months. The cyclosporine corneal concentrations at 3 hours were 0.15, 0.07, and 0.05 microgram/milligram of tissue, in corneal sections 8, 13, and 18 mm away from the implant. These concentrations were 1 to 2 log units higher than those reported with a variety of topical cyclosporine formulations and oral dosing. Pharmacokinetic analysis and transport theory, using a diffusion coefficient of 1.0×10–6 cm2/sec for cyclosporine in the corneal stroma, suggested that it was unlikely that diffusion alone could be responsible for the rapidity with which cyclosporine dispersed from the implant to all areas of the cornea. The long–term study showed mean total corneal levels (microgram/ milligram of tissue) of 0.91, 0.42, and 0.10, at 6, 12, and 24 weeks post–implantation, respectively. Conclusions: A single episcleral cyclosporine implant delivered therapeutic drug levels throughout the cornea within 3–hours of implantation, and high tissue levels were maintained for at least 6–months. The episcleral cyclosporine implant has potential for long–term immunosuppressive therapy for high–risk keratoplasties.
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