Controlled-Release from High-Loaded Reservoir-Type Systems—A Case Study of Ethylene-Vinyl Acetate and Progesterone

Abstract

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

Development of Porous Polyurethane Implants Manufactured via Hot-Melt Extrusion

“…Diverse formulation possibilities can be considered based on mainly two factors. Firstly, the physicochemical properties of the API in question, which will affect the polymer/API interactions and consequently the drug release [ 32 , 40 , 47 ]. Secondly, the type of TPU matrix in terms of hydrophobicity.…”

“…One example is poly(ethylene-vinyl acetate) (EVA), a non-biodegradable copolymer of ethylene and vinyl acetate. Compared to pure polyethylene, EVA is preferred for drug delivery applications due to its higher drug permeability, which in turn is a function of the varying (up to 40 wt%) vinyl acetate content in the copolymer [ 18 , 38 , 39 , 40 ]. Therefore, besides commercialized IDDS (e.g., Probuphine ® , Nexplanon ® , Iluvien ® and Retisert ® ), EVA has been implemented for oral applications [ 41 , 42 ], drug-releasing stents [ 43 ] and vaginal rings (Nuvaring ® , generics thereof and rings in development [ 18 , 19 , 44 , 45 , 46 ]).…”

Solubility Improvement of Progesterone from Solid Dispersions Prepared by Solvent Evaporation and Co-milling

“…T g (glass transition temperature) was computed: for progesterone from Koutsamanis et al, 2020 [5]; for HPMC from Shin-Etsu Technical information manual; for HPMCAS and PVP from Lehmkemper et al 2018 [32] and for MCC from Szczesniak et al 2008 [33]. Figure 2 presents FTIR spectra of PG and PG solid dispersions prepared by solvent evaporation (SE) and co-milling (BM).…”

“…While enhancement in solubility could be attributed to transformation of the drug to amorphous state, the nature of carrier was also shown to have a major impact on dissolution [1,4]. Although nowadays state of the art mechnanochemical methods such as hot-melt extrusion are exploited for their ability to enhance drug release in conjunction with polymers, there are only a few reports for their application to progesterone, e.g., reservoir systems of progesterone loaded into polymeric matrix for controlled release [5]. Mechano-chemical activation is often applied by dry or wet milling and is used to enhance the solubility and dissolution rate of poorly soluble drugs [3,6].…”

Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion

“…To confirm the solid state of the hormones in EVA at the processing temperature of 120 • C, thin cryo-cuts of the extrudates (manual microtome MT.5503, Euromex, Arnheim, The Netherlands) were investigated by means of polarised optical microscopy (Olympus BX51M, Olympus K.K., Tokyo, Japan) with a temperature-controlled stage (THMS 600/720, LINKAM Scientific Instruments, Tadworth, UK) as described in [35,46].…”