May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Safety and Pharmacokinetics of a Sustained Release Triamcinolone Implant in the Subretinal Space of the Rabbit Eye
Author Affiliations & Notes
  • S. E. Varner
    Ophthalmology, SurModics, Inc., Irvine, California
  • N. R. F. Beeley
    Ophthalmology, SurModics, Inc., Irvine, California
  • J. J. Missling
    Ophthalmology, SurModics, Inc., Irvine, California
  • T. M. Kloke
    Ophthalmology, SurModics, Inc., Irvine, California
  • Footnotes
    Commercial Relationships S.E. Varner, SurModics, Inc., E; SurModics, Inc., P; N.R.F. Beeley, SurModics, Inc., E; SurModics, Inc., P; J.J. Missling, SurModics, Inc., E; SurModics, Inc., P; T.M. Kloke, SurModics, Inc., E; SurModics, Inc., P.
  • Footnotes
    Support None.
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 5797. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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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 
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