Polyester-based microdisc systems for sustained release of neuroprotective phosphine-borane complexes

Abstract

Phosphine-borane complexes are recently developed redox-active drugs that are neuroprotective in models of optic nerve injury and radioprotective in endothelial cells. However, a single dose of these compounds is short-lived, necessitating the development of sustained-release formulations of these novel molecules. We screened a library of biodegradable co- and non-block polyester polymer systems for release of incorporated phosphine-borane complexes to evaluate them as drug delivery systems for use in chronic disease. Bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1) was combined with biodegradable polymers based on poly(D,L-lactide) (PDLLA), poly(L-lactide) (PLLA), poly(caprolactone) (PCL), poly(lactide-co-glycide) (PLGA), or poly(dioxanone-co-caprolactone) (PDOCL) to make polymer microdiscs, and release over time quantified. Of 22 polymer-PB1 formulations tested, 17 formed rigid polymers. Rates of release differed significantly based on the chemical structure of the polymer. PB1 released from PLGA microdiscs released most slowly, with the most linear release in polymers of 60:40 LA:GA, acid endcap, Mn 15 000–25 000 and 75:25 LA:GA, acid endcap, Mn 45 000–55 000. Biodegradable polymer systems can, therefore, be used to produce sustained-release formulations for redox-active phosphine-borane complexes, with PLGA-based systems most suitable for very slow release. The sustained release could enable translation to a clinical neuroprotective strategy for chronic diseases such as glaucoma.

Keywords:

• Phosphine-borane
• sustained release
• polymer
• polyester
• neuroprotection

Acknowledgements

This work was supported by the Glaucoma Research Foundation; National Institutes of Health under grant numbers R21 EY017970, R21 EY025074, and P30EY016665; and an unrestricted departmental grant from Research to Prevent Blindness, Inc. LAL is Canada Research Chair in Translational Visual Science.

Disclosure statement

The following are declared as possible conflicts of interest: LAL is a consultant on neuroprotection to Aerie, Inotek, Quark, and Regenera. He is an inventor on patents for phosphine-borane complexes that have been assigned to the Wisconsin Alumni Research Foundation. DAJ, CJL, and MEC declare no conflicts of interest.

Additional information

Funding

This work was supported by the Glaucoma Research Foundation; National Institutes of Health under grant numbers R21 EY017970, R21 EY025074, and P30EY016665; and an unrestricted departmental grant from Research to Prevent Blindness, Inc. LAL is Canada Research Chair in Translational Visual Science.