Polyketal-conjugated tafluprost microparticles enable long-acting glaucoma therapy.

Abstract

Long-acting formulations are increasingly sought after for the management of chronic diseases. Drug-conjugated microparticles with degradation-controlled release present a promising modular extended-release platform that can be delivered through minimally invasive approaches. However, many conventional drug-conjugated microparticles have relatively short durations of release and substantial release of pharmacologically inactive drug-conjugated oligomers. Here, we present surface-erodible, drug-conjugated polyketal microparticles for extended release of unmodified pharmacologically active drug. Microparticles made of a polyketal conjugated to the anti-glaucoma agent tafluprost initially release unmodified tafluprost, then about two weeks later predominantly release the biologically active tafluprost acid due to the mildly base-catalyzed hydrolysis of tafluprost, with a cumulative total drug release of ~78% over 540 days in vitro. Notably, no detectable drug-conjugated oligomers are found in release medium. Tafluprost-polyketal conjugate microparticles that further encapsulate unconjugated tafluprost reduce intraocular pressure for approximately 3 months after subconjunctival injection in ocular normotensive female rats, exhibiting a low grade of tissue reaction, no retinal abnormalities or systemic side effects, and enhanced intraocular pressure-lowering efficacy compared with a long-acting bimatoprost-loaded biodegradable implant in an ocular hypertensive rat model. Our findings have broad implications in advancing extended drug delivery systems.