Extended drug delivery for ophthalmologic diseases offers to reduce treatment burden, improve outcomes with available agents, and enable novel therapeutic approaches. The aim is to test the feasibility of engineered thin-film biopolymer devices adapted for delivery of a range of drugs available for retinal diseases and glaucoma, assessed by in vitro pharmacokinetics and in vivo performance in animal models.
Devices in disc and cylinder formats (6 to 10mm) were constructed from polycaprolactone (PCL) films spin-cast on zinc oxide templates to generate nano-porous membranes (20 m thickness), or polyethylene glycol additives for micro-porous membranes (4-70 m thicknesses). Reservoirs of pelleted, lyophilized drugs were encapsulated by heat sealing. In vitro drug elution was quantified in controlled PBS fluid chambers with fluorometry, high-pressure liquid chromatography (HPLC), and UV spectrophotometry. In animal models, devices were implanted in the anterior chamber or vitreous for in vivo studies, with mass spectrometry or size exclusion chromatography used to measure drug concentrations.
Rapamycin, a macrolide under clinical development for non-infectious uveitis (MW 0.9kD) was fabricated in micro-porous devices and showed linear release over 5 weeks in vitro at 1 mg to 0.6 g/day, dependent on film thickness. In rabbit eyes, mean rapamycin concentration at 16 weeks (n=5) was 5.2 ng/ml in the vitreous and 206 ng/ml in retina-choroid. Another small molecule, DE-117, an anti-glaucoma prostaglandin analog under development, showed zero-order in vitro release up to 6 months at 0.5ug/day in multilayer unstructured devices. In rabbit eyes the drug and its active form showed viable aqueous and ocular tissue levels to 8 weeks, and produced a mean 4.6 mmHg reduction intra-ocular pressure over 160 days (vs. +0.3 mmHg in controls, p<0.005). Nano-porous devices for ranibizumab (48kD) showed biphasic release rates in vitro over 4 months (1.8 g/day through week 5; 0.6 g/day week 10 to 16; n=17). In rabbit eyes (n=13), in vivo ranibizumab concentrations in the vitreous averaged 0.96 g/ml over 12 weeks, with 93% stability at 6 weeks. Residual payload extrapolated to 25 weeks for drug depletion. Microporous devices for another biologic drug (Protein X) showed linear release at 25 ug/day over 11 weeks in vitro (extrapolated to 4 months), with ocular tolerance and normal macula on OCT in non-human primate eyes for up to 84 days (n=4).
Intraocular drug release from thin film biopolymer devices was seen at therapeutically sufficient levels for a range of both small molecules and the biologic ophthalmic drugs, with acceptable ocular tolerance. Device parameters could be tailored to attain desired release rates.