Long-acting delivery of a model monoclonal antibody from ethylene vinyl acetate implants at a high loading: Drug release and protein stability.

Delivering large therapeutic monoclonal antibodies (mAbs) from solid polymer matrices via hot-melt extrusion (HME) is a promising approach to achieving a prolonged release profile. However, this approach presents significant challenges due to protein instability under high temperatures and high shear forces typically involved in the extrusion process and during extended-release duration in physiological conditions. Herein, we discuss the encapsulation of a large therapeutic mAb (MW ∼150 kDa) at a high loading (≥50%) via HME and vacuum compression molding (VCM) with ethylene vinyl acetate (EVA) and its stability analysis upon release from EVA rods. Protein stability of a model mAb (mAb1) with respect to protein aggregation, structural stability, and relative binding activity was evaluated. A solid spray-dried formulation of mAb1 can maintain its protein stability against elevated temperature and repeated heating cycles during the manufacturing process with EVA. In the present work, we show that applying a second thermal step via VCM can enable a homogeneous distribution of solid spray-dried particles of mAb1 embedded within the solid EVA matrix. Additionally, our results demonstrate that implementing a membrane coating on EVA rods can yield a slow release of mAb1 from EVA rods without significantly impacting protein stability, representing a viable approach for long-acting delivery of mAbs using EVA as a non-biodegradable polymer implant.

### Background: Delivering large therapeutic monoclonal antibodies (mAbs) from solid polymer matrices via hot-melt extrusion (HME) is a promising approach to achieving a prolonged release profile. However, this approach presents significant challenges due to protein instability under high temperatures and high shear forces typically involved in the extrusion process and during extended-release duration in physiological conditions.

### Methods: Herein, we discuss the encapsulation of a large therapeutic mAb (MW ∼150 kDa) at a high loading (≥50%) via HME and vacuum compression molding (VCM) with ethylene vinyl acetate (EVA) and its stability analysis upon release from EVA rods. A solid spray-dried formulation of mAb1 can maintain its protein stability against elevated temperature and repeated heating cycles during the manufacturing process with EVA. In the present work, we show that applying a second thermal step via VCM can enable a homogeneous distribution of solid spray-dried particles of mAb1 embedded within the solid EVA matrix. Additionally, our results demonstrate that implementing a membrane coating on EVA rods can yield a slow release of mAb1 from EVA rods.

### Results: Protein stability of a model mAb (mAb1) with respect to protein aggregation, structural stability, and relative binding activity was evaluated. A solid spray-dried formulation of mAb1 can maintain its protein stability against elevated temperature and repeated heating cycles during the manufacturing process with EVA. Applying a second thermal step via VCM enabled a homogeneous distribution of solid spray-dried particles of mAb1 embedded within the solid EVA matrix. Implementing a membrane coating on EVA rods yielded a slow release of mAb1 from EVA rods without significantly impacting protein stability.

### Data Summary: The encapsulation involved a large therapeutic mAb (MW ∼150 kDa) at a high loading (≥50%). The solid spray-dried formulation of mAb1 maintained protein stability against elevated temperature and repeated heating cycles. The membrane coating enabled slow release without significantly impacting protein stability.

### Conclusions: Implementing a membrane coating on EVA rods can yield a slow release of mAb1 from EVA rods without significantly impacting protein stability, representing a viable approach for long-acting delivery of mAbs using EVA as a non-biodegradable polymer implant.

### Practical Significance: This approach represents a viable approach for long-acting delivery of mAbs using EVA as a non-biodegradable polymer implant.