Controlled-release from high-loaded reservoir- type systems—a case study of ethylene-vinyl acetate and progesterone

Reservoir systems (drug-loaded core surrounded by drug-free membrane) provide long-term controlled drug release. This is especially beneficial for drug delivery to specific body regions including the vagina. In this study, we investigated the potential of reservoir systems to provide high drug release rates over several weeks. The considered model system was an intra-vaginal ring (IVR) delivering progesterone (P4) in the mg/day range using ethylene-vinyl acetate (EVA) as release rate-controlling polymers. To circumvent the high material needs associated with IVR manufacturing, we implemented a small-scale screening procedure that predicts the drug release from IVRs. Formulations were designed based on the solubility and diffusivity of P4 in EVAs with varying vinyl acetate content. High in-vitro P4 release was achieved by i) high P4 solubility in the core polymer; ii) high P4 partition coefficient between the membrane and the core; and/or iii) low membrane thicknesses. It was challenging for systems designed to release comparatively high fractions of P4 at early times to retain a constant drug release over a long time. P4 crystal dissolution in the core could not counterbalance drug diffusion through the membrane and drug crystal dissolution was found to be the rate-limiting step. Overall, high P4 release rates can be achieved from EVA-based reservoir systems.