Implantable and insertable drug delivery systems (IDDS) frequently use ethylene vinyl acetate (EVA) co-polymers as carriers due to i) their broad applicability, ii) their potential for long-time controlled drug delivery (i.e., up to several years), and iii) their favorable inflammatory characteristics [1]. Intra-vaginal IDDS use EVA with a comparatively high vinyl acetate (VA) content of 28 % not only to control the drug release but also to provide suitable mechanical characteristics [2], which is of utmost importance for intra-vaginal IDDS [3]. These IDDS are manufactured via extrusion technologies, which limit the IDDS structure to rather simple designs and lacks the potential of customization. The authors recently showed that filament-based 3D-printing serves the purpose of manufacturing customized vaginal inserts of complex geometry – so called vaginal pessaries used to treat stress urinary incontinence via mechanical stabilization – based on a thermoplastic co-polyester [4,5] and different grades of thermoplastic polyurethanes [6]. Similarly, EVA was reported to be processable via 3D-printing, which was however limited to i) EVAs with a VA content lower than 18 % and ii) rather simple designs that do not account for any customization potential [7]. The present study aims at tackling these shortcomings by the establishment of an advanced 3D-printing process together with a custom-tailored hardware to enable the fabrication of complex, customized structures made from EVA with a high VA content. In a first set or experiments, EVA 28 was processed into filaments via hot melt extrusion that were subsequently 3D-printed into urethra pessaries using a 3-axis, gantry-based 3D-printer equipped with a dual-printhead tailored for highly elastic materials and able to print two materials in one print job (Hage3D GmbH, Graz, Austria). More precisely, the printhead uses profiled drives (form fit) for fast and reliable filament conveying. Additionally, a low-loss and partly spring-mounted transmission system increases the efficiency of conveyance between the stepper motor and filament drive. Extremely short and friction-free filament paths ensure a kink-free filament feed, even when the filaments are very soft (i.e. Shore A hardness below 80). Finally, the specialized hot-end provides a counterpressure-minimized nozzle zone. During the 3D-printing process set up, the i) nozzle size, ii) printing speed, iii) infill pattern, iv) build platform temperature, and v) cooling cycles were thoroughly evaluated, while keeping the nozzle temperature well below the degradation temperature of EVA (i.e., 230 °C). EVA 28-based urethra pessaries without any surface defects and enclosed air bubbles were manufactured applying i) a minimum nozzle size of 0.6 mm to avoid nozzle clogging, ii) a comparatively low printing speed to avoid plunging of the individual layers, iii) a perimetric infill pattern, and iv) a low build platform temperature (i.e., non-heated printer bed). In a second set of experiments, the combination potential of EVA 28 and EVA 9 (i.e., an EVA with a VA content of 9%) – a stiffer EVA grade that is used in commercial products as thin membrane to control drug release – in one urethra pessary was assessed. In other words, the pessary was partly made from EVA 28 and partly made from EVA 9. Thereby, the pessary mechanics could be tailored predominantly via the EVA 9 part; more specifically, via i) its fraction, ii) its location in the pessary and iii) its infill design. In a third set of experiments, the part made of EVA 28 was replaced by EVA 28 loaded with a model drug. Thereby, the drug release properties could not only be modified via the EVA 28/drug part, including its fraction and location in the pessary but also via the spatial arrangement of the EVA28/drug and the EVA 9 part. Summarizing, our results demonstrate that 3D-printing is a promising technology to develop customized, complex IDDS using the well-established pharmaceutical polymer EVA. Customized hardware design together with proper process design and innovative multi-material concepts facilitated individualization of both, the mechanical properties and the release patterns of complex pessary structures, which builds the basis for personalized vaginal IDDS products.
References
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