Intracochlear PLGA implants for simultaneous controlled release of multiple drugs

Reliable drug delivery to the inner ear is still an unmet clinical need, due to the blood cochlear barrier, which effectively protects this highly sensitive organ. To overcome this hurdle, miniaturized, biodegradable implants were prepared (0.3 mm in diameter), which can be administered into the cochlea via a tiny hole drilled into the round window. They were based on poly(lactic-co-glycolic acid) (PLGA) and prepared by hot melt extrusion. Three drugs were incorporated: (i) 20.0% dexamethasone with anti-inflammatory, anti-fibrotic and protective activity for hair cells (being critical for hearing); (ii) 5.7% lidocaine (free base) as local anesthetic drug and therapeutic potential to treat tinnitus or vertigo; and (iii) 2.1% curcuminoids for their anti-inflammatory and anti-oxidant activities. The implants were thoroughly characterized before and after exposure to artificial perilymph in vitro, by DSC, X-ray diffraction, GPC, optical microscopy, TGA and release measurements. In addition, they were implanted into gerbil cochlea, monitoring the resulting local drug concentrations. Importantly, the implants allowed for the simultaneous controlled release of all drugs. In vitro, lidocaine release was fastest (100% after 10 d), followed by dexamethasone (100% after 10 weeks). The slower release of dexamethasone can be explained by saturation effects within the implant. In vivo, drug release was faster, probably because of accelerated polymer degradation due to local drops in pH and/or the presence of esterases (e.g., 100% dexamethasone release in 2 weeks). Curcuminoids were not detectable in the release medium under the given conditions in vitro, nor in the perilymph in vivo, because of their very limited solubility in aqueous media. Visual observation suggests that they were released within 1-2 weeks in vivo (likely partitioning into lipid phases and/or being metabolized). No noteworthy changes in the animals' behavior or signs for tissue inflammation/damage were detected.