Wet age-related macular degeneration (AMD) is a major causes of vision loss among the elderly. In wet AMD, new abnormal blood vessels grow under the macula, thus displacing the macula from its normal position, and resulting in rapid central vision loss. Overexpression of vascular endothelial growth factor (VEGF) results in the growth of abnormal blood vessels under the retina, and therefore, anti-VEGF therapy has become a potent treatment option for wet AMD. Administration of the anti-VEGF agents is accomplished by intravitreal injections typically every 4 weeks, but this dosing frequency is problematic for patient convenience and compliance, and repeated intravitreal injections may induce infection, inflammation and hemorrhage. Sustained release formulations of the anti-VEGF agents can potentially reduce administration frequency while maintaining the therapeutic concentration in the vitreous. Therefore, we developed injectable poly(lactic-co-glycolic acid) (PLGA) cylindrical implants (0.8 mm diameter), which sustain the release of stable bevacizumab (Avastin®, anti-VEGF antibody). Protein stabilization was accomplished by optimization of the content of both the original excipients from the Avastin® product and bevacizumab in PLGA 50/50 core implants, and release was controlled by a coating the core implants with the same pure PLGA. The optimized implant formulations achieved high bevacizumab loading (7.6 to 8.2 % w/w) and continuous in vitro release kinetics over six weeks with total cumulative release of 82 ± 8 to 89 ± 4 %. Little changes in monomer content, immunoreactivity, and secondary structure of the released antibodies during the 6-week in vitro release period were observed by size-exclusion high performance liquid chromatography, enzyme-linked immunosorbent assay, and circular dichroism spectroscopy, respectively. Anti-VEGF efficacy of the optimized bevacizumab implant was compared to the same dose of free bevacizumab in the rabbit VEGF-induced retinal leakage model (400 µg dose). Six weeks after intravitreal injection of both formulations, only the bevacizumab implant protected retinal blood vessels while significant leakage was observed in the no-treatment control and free bevacizumab groups (4 rabbit eyes/group). The retinal blood vessels of the implant group were still protective over 8 weeks. Hence, this approach may be useful for development of long-acting anti-VEGF therapy.

PLGA-bevacizumab implants for long-acting anti-VEGF efficacy in a rabbit retinal vascular leakage model

255th National Meeting (2018)

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