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Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes

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Abstract

Purpose

The purpose of this study was to evaluate the pharmacokinetics and toxicity of a chitosan (CS) and polylactic acid (PLA) based methotrexate (MTX) intravitreal micro-implant in an animal model using rabbit eyes.

Methods

CS- and PLA-based micro-implants containing 400 μg of MTX were fabricated using lyophilization and dip-coating techniques. The micro-implants were surgically implanted in the vitreous of eight New Zealand rabbits employing minimally invasive technique. The PLA-coated CS-MTX micro-implant was inserted in the right eye and the placebo micro-implant in the left eye of each rabbit. Two rabbits were euthanized at each pre-determined time point post-implantation (days 5, 12, 19, and 33) for pharmacokinetics and histopathology evaluation.

Results

A therapeutic concentration of MTX (0.1–1.0 μM) in the vitreous was detected in the rabbit eyes studied for 33 days. The MTX release from the coated micro-implants followed a first order kinetics (R 2 ~ 0.88), implying that MTX release depends on the concentration of MTX in the micro-implant. Histopathological analysis of the enucleated eyes failed to show any signs of infection or tissue toxicity in any of the specimens.

Conclusion

The PLA-coated CS-MTX micro-implants were able to deliver therapeutic release of MTX for a period of more than 1 month without detectable toxicity in a rabbit model. The micro-implants can be further investigated as a prospective alternative to current treatment protocols of repeated intravitreal MTX injections in intraocular disorders such as primary intraocular lymphoma, and selected cases of non-microbial intraocular inflammation.

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Acknowledgments

This study was supported in part by the combined research assistantship program of the University of Cincinnati’s College of Engineering and Applied Science and an Unrestricted Grant from Research to Prevent Blindness, Inc, New York, NY to the Department of Ophthalmology, University of Cincinnati (James J. Augsburger, M.D., Chairman). The authors would like to acknowledge the support of Anukana Bhattacharjee, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati in sterilizing the micro-implants. The authors would also like to acknowledge the support of Laboratory Animal Medical Services, University of Cincinnati is assisting with the rabbit experiments. Lastly, the authors would like to acknowledge Dr. Julio A. Landero of the Department of Chemistry, University of Cincinnati for facilitating the micro-implant fabrication process and the HPLC study.

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No competing financial interests exist.

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Correspondence to Zelia M. Correa.

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Manna, S., Banerjee, R.K., Augsburger, J.J. et al. Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes. Graefes Arch Clin Exp Ophthalmol 253, 1297–1305 (2015). https://doi.org/10.1007/s00417-015-3007-1

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  • DOI: https://doi.org/10.1007/s00417-015-3007-1

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