Correlation between material, structure, and drug release of Nexplanon®: an ethylene vinyl acetate (EVA) based...

Nexplanon® is a subdermal implant that provides contraception protection for up to three years. Despite extensive clinical use, the implant's complex structure and drug release mechanisms are not thoroughly investigated. Moreover, conducting drug release testing over three years is time-consuming and labor-intensive, posing challenges on drug release characterization. In this study, material, structure, and drug release of Nexplanon® were characterized and correlated. Key physical phenomena of drug release including drug supersaturation, depletion zone formation, and unstirred boundary layer effect were elucidated using mathematical modeling. The rod shape implant has a core-shell structure with a drug-loaded EVA core encased in an EVA membrane ("skin"), leaving both ends of the implant uncovered. Drug release from the skin and two ends was studied independently. A bi-phasic release profile was observed: an initial burst release phase (first 20 days), followed by a sustained release phase (post day 20). The burst release was mainly driven by exponential decay of supersaturated drug through the skin (degree of supersaturation = 1.4). During sustained release, the drug release rate from skin was approximately 40 % lower than the rate predicted by the Fick's law, attributed to the unstirred boundary layer effect. Overtime, release from both the skin and ends declined due to formation of depletion zones. Drug release rates from ends were higher than the rate predicted by the homogeneous Higuchi model due to higher drug permeability in the water-filled porous depletion zones caused by higher drug permeability in water than in EVA. These findings support the identification of critical material and structural attributes of controlled drug release and development of predictive drug release models.