Abstract
Purpose: :
Controlled release of therapeutics in the eye increases patient compliance and should decrease side effects and treatment cost. The most common vehicles for controlled release are micro- and nano-particles. However, these usually require the presence of organic solvents that can denature protein drugs. Another class of common vehicles is hydrogels, the most attractive of which are thermal gels that are liquid at ambient temperature and gel in situ in the eye. However, current gels are typically non-biodegradable. We designed a biodegradable polymer (PureSet) specifically for ocular delivery. This report will discussthe gelling, biocompatibility, and bevacizumab release properties of PureSet.
Methods: :
We determined the gelling response of the polymer with temperature, confirmed the biodegradability in vitro, examined the force needed to inject PureSet solution through 31G needles at ambient temperature, characterized the release of bevacizumab in vitro, performed biocompatibility test in vitro using retina pigmented epithelial cells and cornea endothelial cells, and tested in vivo performance in rabbit eyes.
Results: :
PureSet solution (8-15%) gelling begins at around 27°C and completes at around 36°C. The solution gels within seconds upon injection into artificial vitreous fluid at 37°C. The polymer degrades 22% within 45 days in vitro. The injection force increases with solution concentration and injection speed. 8% solution requires an easily manageable 6 N at 3 mm/s. Thus we were able to easily inject the PureSet through a 31 gauge needle on a TB syringe, which is a typical syringe-needle combination used for intravitreal injections. In vitro test following ISO standard reveals no toxicity of the polymer extract and preliminary in vivo test shows high biocompatibility. The polymer solution releases bevacizumab over 3 months in artificial vitreous fluid at 37°C. 8% solutions injected via 31G needle gelled into transparent spheres in rabbit eyes and preliminary examinations showed no adverse host responses.
Conclusions: :
These data demonstrate the feasibility of in situ gelling of solutions loaded with bevacizumab, the controlled release of bevacizumab, and the biocompatibility of PureSet. A larger scale in vivo experiment is warranted to examine this controlled release platform and to project possibility of clinical translation for intraocular delivery of bevacizumab and other protein drugs.
Keywords: age-related macular degeneration • injection • retinal neovascularization