Abstract
Purpose :
There is an unmet need for sustained drug delivery for glaucoma pharmacotherapy. We describe a miniaturized injectable delivery system (MIDS) based on biodegradable polymers engineered for zero-order release of timolol maleate for a minimum of 8 weeks, injected into the intracameral (IC) or intravitreal (IV) space
Methods :
MIDS device is a cylindrical implant (unique thin-film semi-permeable polymeric membrane encapsulating a pharmaceutical core) that provides zero-order drug delivery, and fabricated for use with a 23-gauge needle. In vitro pharmacokinetics studies were performed in temperature- and pH-controlled fluid chambers over 20 weeks. MIDS devices were injected into the IC and IV space of New Zealand rabbits. Eyes were examined weekly, with intraocular pressures (IOP) measurements (Tono-Vet, iCare). At sacrifice at 8 weeks post-injection, eyes were enucleated and dissected, and ocular compartment drug concentrations were determined by lipid chromatography-tandem mass spectrometry. Two tailed student’s t-test was used for statistical analysis.
Results :
In vitro studies of MIDS devices demonstrated approximate zero-order drug release over 1 to 5 months. Ocular safety was acceptable, without significant intraocular inflammation. At 8-week post injection, in vivo studies demonstrated that IOP in experimental eyes was lowered by 11.1±6.5% (N = 5, p = 0.019) for IC devices and 14.6±3.9% (N = 5, p = 0.020) for IV devices. Analysis of ocular tissues revealed different concentration profiles for IC vs. IV at 8 weeks (in ng/g; except for aqueous in ng/mL): aqueous 28.45±5.44 vs 4.50±2.15, iris 36.67±9.73 vs 32.52±25.30, vitreous 0.28±0.26 vs 37.17±19.03, and ciliary body 14.39±3.59 vs 50.93±18.64. Blood concentration of drug was below the quantitation limit (< 0.4ng/ml) at 8 weeks for both groups
Conclusions :
MIDS devices achieved zero-order release of timolol maleate in vitro. Over 8 weeks, implanted eyes' mean IOPs were lowered compared to controls at each weekly timepoint with similar levels of reduction between IC and IV. Target tissue drug concentrations at the ciliary body at 8 weeks exceeded therapeutic levels. Compared to IC, IV injection appeared to result in 4-5 times higher drug levels in the ciliary body. The technology has the potential to be provide continuous IOP-lowering therapy to overcome issues of patient compliance with daily eye drops
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.