Photocurable Hydrogel Implants for the Extended Release of Bevacizumab for the Treatment of Age Related Macular Degeneration

Abstract

 

Purpose

 

As a means to improve treatment of RVO, AMD, and DME, one goal of current therapy is to extend the vitreal half-life of anti-VEGF proteins and peptides. Photocurable hydrogel matrices, in particular, are a promising class of materials for extended intravitreal release of proteins. Herein, we demonstrate the ability to produce extended release ocular implants of bevacizumab, an anti-VEGF monoclonal antibody, by embedding solid state protein microparticles into photocurable hydrogel matrices. Release rate was controlled by hydrogel formulation with linear profiles being obtained.

 

Methods

 

1μm x 1μm preformed PRINT cylinders composed of protein and protective excipients were fabricated using the PRINT® process. The PRINT microparticles were then dispersed in a solution of photocurable PEG, water, and photoinitiator. The resulting suspension was photochemically cured to a pre-formed size. The in vitro release rate of protein was monitored in PBS at 37°C using ELISA. The morphology of the implants was characterized with electron microscopy to determine the distribution of protein microparticles within the implants.

 

Results

 

Implant size and shape was controlled using a preformed template. After photochemical curing, the PRINT microparticles were observed to be uniformly distributed in a solid state hydrogel matrix (Fig 1). In vitro release measurements demonstrate near zero-order release of active protein for a period of over 90 days (Fig 1).

 

Conclusions

 

PRINT technology allows for the design of solid state protein microparticles that can be incorporated into hydrogel implants with zero-order release profiles. Protein release can be tuned to be linear and independent of degradation rate. Design and manufacturing of these types of extended-release systems potentially allow reduced-frequency dosing of anti-VEGF therapies for treatment of retinal diseases.

 

 

Figure 1) Bevacizumab PRINT microparticles embedded in a hydrogel implant (left), in-vitro release curve up to day 97 from the hydrogel implants ELISA (right).

 

Keywords: 412 age-related macular degeneration • 748 vascular endothelial growth factor