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

ABSTRACT:

Purpose

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.

Methods

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 PEG_40kDa by a self-cleaving ?-eliminative linker with a cleavage half-life of approximately 1 week.

Results

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 PEG_40kDa conjugate would be approximately 2 weeks, and that of the released drug would be approximately 5 days.

Conclusions

We posit that a linker with a cleavage half life of 2 weeks would confer a half life of approximately 7 days to a released small molecule drug in humans, comparable to the half life of approved intravitreal injected macromolecular drugs.

Translational relevance

With this technology, a potent small molecule with an appropriate therapeutic window should be administrable by intravitreal injections in the human at once-monthly intervals.

SUBMITTER: Machinaga N 

PROVIDER: S-EPMC6114027 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature