Effects of implant microstructure on drug release of ethylene vinyl acetate (EVA) based long-acting implants

The development of long-acting implants with a core-shell reservoir design is challenging because of their complex structure and prolonged testing requirements. While the polymeric shell has been investigated in a previous study, the present study focuses on the implant core, characterizing its microstructural evolution during in vitro drug release in an aqueous medium using in situ micro-computed tomography. Results revealed progressive water uptake into porous depletion layers that developed during drug release. The mechanisms of water transport and drug diffusion were investigated using depletion layer model films fabricated from the implant core and evaluated using diffusion cells experiments. Permeation of a hydrophilic dye, Allura Red, demonstrated interconnected aqueous transport pathways in the water-filled model films. Separately, drug permeability was directly measured using etonogestrel as the permeant. Etonogestrel permeability in water-filled films was approximately 2.7 times that in dried films, primarily attributed to higher drug diffusivity through the interconnected aqueous pore network. Implant microstructure before and after drug depletion was characterized using high-resolution mosaic field-of-view scanning electron microscopy combined with artificial intelligence-based phase identification, supporting a mechanism in which drug particle dissolution generates pores that subsequently undergo structural evolution. The results support two drug transport pathways: (1) diffusion through the polymer phase and (2) diffusion through an interconnected, water-filled pore network. The effects of pore formation, water infiltration, pore connectivity, and pore shrinkage on drug transport were considered in relation to product development, including raw material properties, manufacturing processes, implant microstructure, and dissolution media. This work provides insights into the drug release mechanisms of EVA-based long-acting implants, material and microstructural attributes influencing diffusion kinetics, and analytical approaches that may support the development of generic Nexplanon ® products.