A Controlled Release System for Long-Acting Intravitreal Delivery of Small Molecules

Translational Vision Science & Technology
Nobuo MachinagaDaniel V Santi

Abstract

The short half lives of small molecules in the vitreous requires frequent repeated intravitreal injections that are impractical for treatment of chronic eye diseases. We sought to develop a method for increasing the intravitreal half-life of small-molecule drugs. We adapted a technology for controlled release of drugs from macromolecular carriers for use as a long-acting intravitreal delivery system for small molecules. As a prototype, a small molecule complement factor D inhibitor with an intravitreal half-life of 7 hours was covalently attached to a 4-arm PEG40kDa by a self-cleaving β-eliminative linker with a cleavage half-life of approximately 1 week. After intravitreal injection in rabbits, the drug was slowly released in the vitreous, and equilibrated with the retina and choroid. The intravitreal half-life of the intact PEG-drug conjugate in the rabbit was 7 days, and that of the released drug was 3.6 days. We simulated the anticipated pharmacokinetics of the delivery system in human vitreous, and estimated that the half-life of a 4-arm PEG40kDa conjugate would be approximately 2 weeks, and that of the released drug would be approximately 5 days. We posit that a linker with a cleavage half life of 2 weeks would confer a h...Continue Reading

References

Apr 1, 1983·Experimental Eye Research·U B Laurent, J R Fraser
Oct 18, 2011·Investigative Ophthalmology & Visual Science·Chloe M StantonAlan F Wright
Apr 5, 2012·Proceedings of the National Academy of Sciences of the United States of America·Daniel V SantiGary W Ashley
Jun 16, 2012·Nature Reviews. Drug Discovery·Kang ZhangRobert N Weinreb
Jun 4, 2016·Investigative Ophthalmology & Visual Science·Sang Jun ParkSe Joon Woo
Oct 8, 2017·Investigative Ophthalmology & Visual Science·Hao LiHao F Zhang

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Citations

May 24, 2020·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Sahar AwwadSteve Brocchini
Mar 7, 2021·Biomolecules·Dylan E ParsonsVinit B Mahajan

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