Formulation and processability screening for the rational design of ethylene-vinyl acetate based intra-vaginal rings

Koutsamanis, Ioannis; Eder, Simone; Beretta, Michela; Witschnigg, Andreas; Paudel, Amrit; Nickisch, Klaus; Friedrich, M. J.; Eggenreich, Karin; Roblegg, Eva

doi:10.1016/j.ijpharm.2019.04.041

Cited by 20 publications

(20 citation statements)

References 28 publications

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“…It was found that the P4 equilibrium solubility increased with increasing VA content (Figure 2a), corresponding to a decreased crystallinity of the respective EVA, hence, more amorphous regions were accessible facilitating the dissolution of P4. This behavior has also been shown for other small lipophilic molecules including benzocaine [14], estradiol (E2) [18] ethinyl estradiol and etonogestrel (ENG) [23]. By contrast, the diffusivity of P4 reached a maximum in EVA28, decreased in EVA40 and reached values that were even below those found in EVA18 (Figure 2b).…”

Section: Discussionsupporting

confidence: 72%

“…The equilibrium solubility was defined as the concentration of P4 quantified in the EVA film once the partitioning equilibrium of P4 between the aqueous and polymer phase had been reached [20]. The polymer films (250 µm thickness) were produced via vacuum compression molding (VCM, MeltPrep, GmbH, Graz, Austria) following a procedure previously described [18]. The films were cut into squares of 2 × 2 cm and placed into glass vials comprising 15 mL of deionized water and 10 mg of P4 (P4 solubility in water at 37 • C: 11.9 ± 1.0 µg/mL).…”

Section: P4 Solubility In Eva Polymersmentioning

confidence: 99%

“…Since EVA-based systems are manufactured via thermal processing, the effect of thermal treatment on the P4 solubility in potential core polymers (i.e., EVA28 and EVA40) was evaluated. To this end, a method reported by our group was used [18]. Briefly, EVA28 was loaded with 4, 5 and 6 wt.% and EVA40 with 5, 6 and 7 wt.% P4 via impregnation using tetrahydrofuran (THF).…”

Section: P4 Solubility In Eva Polymersmentioning

confidence: 99%

“…For IVRs, the required P4 target release rate is 5 and 10 mg/day [15,16]. In this study, small-scale VCM systems were used, which predict the drug release from the corresponding IVRs [17,18]. The VCM systems consist of a cylindrical core of 10 mm diameter and two EVA membranes attached to the flat circular surfaces of the core [17].…”

Section: Rational Formulation Designmentioning

confidence: 99%

“…Therefore, in our study, we defined both target release rates. In an attempt to save material and time, we applied and further developed small-scale systems that were recently shown to predict the performance of IVRs by our group [17,18]. In a first step, we rationally designed reservoir systems based on the physicochemical properties of the selected drug and the polymers.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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

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Section: Discussionsupporting

confidence: 72%

Section: P4 Solubility In Eva Polymersmentioning

confidence: 99%

Section: P4 Solubility In Eva Polymersmentioning

confidence: 99%

Section: Rational Formulation Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Personalization of Complex Vaginal Inserts of Ethylene Vinyl Acetate via 3D‐Printing

Eder

Küchler

Katschnig

et al. 2023

Adv Materials Technologies

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Ethylene vinyl acetate (EVA) with a vinyl acetate (VA) content of 28 wt.% (EVA28) is frequently used in vaginal inserts and subcutaneous implants due to its biocompatibility and drug‐releasing properties. Traditionally being processed via hot melt extrusion, its processibility via filament‐based 3D‐printing was reported to be impossible. Consequently, no applicable customization concepts for vaginal inserts exist. For the first time, the fabrication of 3D‐printed vaginal inserts (urethra pessaries) of EVA28 is demonstrated by optimizing its viscosity, employing 3D‐printer adaptations, and carefully selecting printing parameters. The infill pattern of fully filled mono‐material pessaries (determining the number and orientation of weld lines) significantly affects the in vitro release of the model drug progesterone (P4), while other critical parameters (the pessary's mechanical properties and appearance) remain unaffected. Weld lines act as diffusion barriers for dissolved P4 molecules. Hence, a high number of weld lines to be crossed reduces the overall P4 diffusivity in EVA28, decreasing the P4 release rate. To further control the P4 release, innovative multi‐material pessary designs (additionally comprising EVA with a VA content of 9 wt.% that is also used in vaginal inserts) allow to tailor the in vitro drug release and the mechanics individually. Thereby, this work highly improves the mechanistic understanding on drug release modifications from 3D‐printed non‐biodegradable devices. The findings build the basis for the first application of customized vaginal inserts, as they are based on polymers used in corresponding marketed products for more than 20 years.

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Free-D Molding: Every Idea Deserves a Prototype

Bramböck,

Treffer

2023

AAPS Advances in the Pharmaceutical Sciences Series

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Formulation and processability screening for the rational design of ethylene-vinyl acetate based intra-vaginal rings

Cited by 20 publications

References 28 publications

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

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

Personalization of Complex Vaginal Inserts of Ethylene Vinyl Acetate via 3D‐Printing

Free-D Molding: Every Idea Deserves a Prototype

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