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S. E. Varner, N. R. F. Beeley, J. J. Missling, T. M. Kloke; Safety and Pharmacokinetics of a Sustained Release Triamcinolone Implant in the Subretinal Space of the Rabbit Eye. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5797.
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To evaluate the safety and pharmacokinetics of a subretinal triamcinolone drug delivery implant in rabbit eyes.
Subretinal implants 3.5 mm in length and 350 µm in diameter were developed using a fine 100 µm diameter wire scaffold coated with a non-biodegradable poly(n-butyl methacrylate) and polyethylene vinyl acetate polymer matrix containing triamcinolone acetonide (TA). Two formulations were developed, Dose 1 (100 µg TA) and Dose 2 (175 µg TA). Dose 1, Dose 2, and Control (no drug) test articles were implanted into the subretinal space of Dutch Belted rabbits. The implants were introduced transvitreally through a 20 gauge sclerotomy. A partial vitrectomy was performed adjacent to the implant site. A small volume of BSS was injected beneath the retina through a 39 gauge flexible cannula, creating a limited dome-shaped retinal detachment. Using micro-forceps, the implant was deployed into this fluid space and released. At sacrifice intervals of 1 week, 1 month, and 3 months, 8 test articles each of Dose 1 and Dose 2 were explanted, examined by SEM, and assayed for remaining drug content by HPLC. At 1 month, 4 eyes for each treatment group were additionally prepared for histological evaluation. In parallel, in vitro drug elution was monitored in PBS buffer at 37°C.
In vitro steady state elution rates of triamcinolone were approximately 0.03 µg/day and 0.50 µg/day for Dose 1 and Dose 2, respectively. Of the 30 implanted animals, all remained in good general health throughout the study. Follow-up clinical examinations reflected good biocompatibility. Based upon drug content of the explanted test articles, dose separation was preserved in vivo. The average elution rate in vivo between 1 and 3 months was calculated to be 0.04 µg/day for Dose 1 and 0.5 µg/day for Dose 2. At 3 months, 88% and 39% of the drug payload still remained on the Dose 1 and Dose 2 implants, respectively. Extrapolation of these elution rates to longer timepoints suggests an achievable release duration of approximately 5 years with the 0.04 µg/day device. Examination by SEM revealed the explanted coatings for Dose 1 had a slight bumpy surface texture with occasional holes in the coating that ranged in size from 20 µm to 50 µm. For, Dose 2 the overall appearance of the explanted coatings was relatively smooth with a slightly bumpy surface texture.
An implantable system has been developed which provides local therapeutic delivery to the subretinal space. This system appears well tolerated in the rabbit eye and is capable of long-term sustained delivery.
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