(T1230-03-17) FDM 3D Printing Tablets Containing Iron Oxide Nanoparticles to Treat Iron Deficiency

Purpose: The oral treatment of iron deficiency commonly shows a low bioavailability and is related to a high frequency of adverse effects, mainly gastrointestinal events. Recent studies have demonstrated that iron oxide nanoparticles (IONP) are effectively absorbed by enteric cells after oral administration. Furthermore, the controlled release of iron by nanoparticles increases the bioavailability of this metal and significantly reduces the incidence of adverse effects. In this context, the purpose of this study was to assess for the first time the feasibility of producing tablets containing IONP using FDM 3D printing in order to personalize the treatments, especially required in the case of pregnant women and children.

Methods: The IONP where prepared by the co-precipitation method using FeSO₄· 7H₂O (Fe²⁺) and the FeCl₃·6H2O (Fe³⁺) in a 1:2 molar ratio. Then, filaments of IONP (15%, w/w), glycerin (20%, w/w), and polyvinyl alcohol (65%, w/w) were produced by hot-melt extrusion (180 °C, 60 rpm, 1.8 mm die, HAAKE MiniCTW ThermoScientific^®). Next, cylinder shape tablets with a mean volume of 0.569 cm³ were obtained using these filaments by means of a Zmorph FAB printer^®. The printing temperature and bed were set at 210° and 80 °C, respectively. The layer height was 0.2 mm, and the infill pattern was rectilinear with a density of 50%. Samples were dissolved and evaluated regarding particle diameter, polydispersity index (pdI), and zeta potential. Moreover, the printed tablets' thermal, mechanical, morphological, and spectroscopies characteristics were also analyzed. Finally, the dissolution profiles of samples were determined using 900 mL of HCl 0.1 mol L^-1 medium. The temperature was maintained at 37 °C, and apparatus 2 (paddle) was used, operating at 100 rpm for 6h. Iron determination was performed by atomic absorption spectrometry.

Results: IONP were synthesized, leading to the formation of stable magnetite with high magnetic properties. The particles had an iron content of about 67.2 ± 0.6 %. Dynamic light scattering measurements showed a diameter of around 200 nm of controlled agglomerate state. TEM analysis confirmed the agglomeration of individualized IONP of approximately 10 nm (Figure 1). The HME filament had a brown color, similar to the IONP powder, a homogeneous aspect, and a mean diameter of 1.52 ± 0.08 mm (Table 1). The printability of the filament was confirmed by the fracture force assay. In fact, the filament underwent a rapid elastic deformation passing to a stable phase of plastic deformation until its fracture at 24.3±1.5 N. The predominant plastic deformation and the fracture force higher than 5 N indicate that the filament is ductile and presents suitable mechanical features for FDM 3D printing process. The obtained tablets had a mean weight of 0.595 ± 0.047 g, with a coefficient of variation of less than 10%. A thermal and spectroscopy characterization showed the maintenance of stability and original characteristics of the components. A dramatic difference in dissolution profiles between free IONP and its 3D printed tablet can be observed (Figure 2). In fact, after 6h, the dissolution of iron from the 3D tablets was 63%, against only 31% from its free form. Over time, the iron nanoparticles agglomerate and precipitate more intensely with free IONP samples. The formation of polymeric nanoparticles was observed in 3D tablet samples, reducing iron agglomeration and precipitation (Figure 2). In summary, 3D printing matrices can keep IONP dispersed and nanostructured, which will probably favor their gastrointestinal absorption.

Conclusion: The oral treatment of iron deficiency can benefit from inserting IONP in 3D printing platforms. In addition to the versatility and industrial scale-up advantages of 3D printing, therapeutic advantages are suggested arising from stabilizing the colloidal state of nanoparticles. In fact, this study proved that FDM 3D printing could enhance the interaction between the polymeric matrix and the IONP, favoring the coating of nanoparticles that ultimately increases its stability and dispersion on an aqueous medium. Thereby, FDM 3D printing demonstrates excellent potential to be applied to an oral administration of iron supplements.

Acknowledgements: The authors declare that they have no conflict of interest. The authors acknowledge the Federal District Research Support Foundation (FAP-DF, Brazil, grants n. 00193-00000817/2021-64, and n. 00193-00000735/2021-10).

Table 1. Filaments and 3D tablets manufacturing specifications and characterization data.

Figure 1. Hydrodynamic diameter (nm) and transmission electron microscopy image of the iron oxide nanoparticles in powder.

Figure 2. Dissolution profile of the iron oxide nanoparticles (IONP) free and in FDM 3D tablets after 6h, together with transmission electron microscopy images of tablets dissolution medium.