Abstract
Purpose::
To evaluate the safety and pharmacokinetics of a subretinal triamcinolone drug delivery implant in rabbit eyes.
Methods::
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.
Results::
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.
Conclusions::
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.
Keywords: retina • corticosteroids • drug toxicity/drug effects