3D-Printed Tablets of Nifurtimox: In Vitro and In Vivo Anti-Trypanosoma cruzi Studies

Introduction

Nifurtimox (NFX) is a nitrofuran antiprotozoal drug prescribed to treat Chagas disease, which is transmitted by the vector Trypanosoma cruzi and affects both animals and humans. According to the Biopharmaceutical Classification System, NFX belongs to class II, exhibiting a low aqueous solubility while presenting satisfactory membrane permeability [1]. Controversially, this drug was also labeled as a class IV drug, indicating that limited permeability could be another concern [2]. This drug’s commercially available dosage form is an immediate-release tablet (Lampit® 120 mg), which presents limited absorption and erratic bioavailability. Clinical use indicates that this dosage should be adjusted, particularly for pediatric patients who require 30 to 60 mg doses, as well as even smaller doses [1,2,3]. Consequently, novel delivery systems are urgently needed to improve their biopharmaceutical properties, providing a suitable treatment for Chagas disease.

Over the last few decades, hot melt extrusion (HME) has emerged as a promising technology in the pharmaceutical field. It involves the mixture of a drug and a polymer at a molecular level, affecting the crystalline state of the drug [4]. This increase in the amorphous phase of drugs and a reduction in particle size have helped improve the aqueous solubility of hydrophobic drugs [4,5,6].

The extrudate filaments obtained by HME are highly versatile and have multiple pharmaceutical applications, such as the preparation of an amorphous solid dispersion for solubility enhancement as granules or pellets, microencapsulation, taste masking, and the preparation of films, implants, semisolid formulations, capsules, and tablets, among others [6,7,8,9]. Recently, the use of HME filaments to feed three-dimensional (3D) printers has been explored, allowing us to obtain tablets with diverse geometries and personalized doses on demand [10,11,12]. In particular, the flexibility to produce customized doses of medications using this approach can be promising for Chagas disease, where patients exhibit a wide range with regard to age and weight, and part of the population may be undernourished [13].

Among the dozens of 3D-printing technologies currently available, the extrusion-based technique, particularly fused deposition modeling (FDM), is one of the most promising and most studied in the pharmaceutical field [14,15,16,17]. Briefly, FDM is based on the deposition of melted filament, where different layers bond with each other as they solidify after cooling, producing the desired dosage form. The small-scale production of personalized medicines can be achieved using industrially produced HME filaments in FDM 3D printers, enabling dose optimization for each patient during follow-up medical appointments. Moreover, FDM 3D printing makes it possible to safely combine various drugs and drug delivery in the same dosage form. Such an approach has been successfully applied with fluconazole, budesonide, hydrochlorothiazide, prednisolone, and acetaminophen, obtaining a wide range of final dosage forms, from controlled release to fast-release drug delivery systems [18,19,20].

During the HME process and the subsequent FDM 3D printing, the drug is exposed to high temperatures. Therefore, drug candidates must demonstrate thermal stability to ensure that no degradation will occur during the processing stages [21,22]. Recent studies have demonstrated that NFX is an excellent candidate for HME/FDM processes, since it is highly prone to remaining amorphous after melting and cooling without thermal degradation [7].

Thus, this work aimed to obtain, for the first time, NFX tablets by FDM 3D printing as an alternative to commercial tablets, allowing for personalized drug dosages and improving their bioavailability. For this purpose, several pharmaceutical polymers used in HME were tested by the film-casting method. Then, the thermal compatibility of NFX with the selected polymers was evaluated. Subsequently, NFX filaments were produced with compatible materials by HME, and the printable filaments were used to produce tablets using FDM 3D printing in two different dosages, 60 and 120 mg. The HME filaments and 3D tablets had their physicochemical properties evaluated, including their thermal and dissolution profiles. Finally, the Anti-T. cruzi activity of these innovative tablets was tested by an in vivo rodent model.

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Materials

NFX (purity 99.9%, lot 160209), benznidazole (N-benzyl-2-nitro-1-imidazolacetamide), and Lampit® (120 mg, lot SVF1381, Bayer S.A., Leverkusen, Germany) were kindly donated by Gador S.A. (Buenos Aires, Argentina) and Secretaria de Salud de la Nación (Buenos Aires, Argentina), respectively. Polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®, BASF, Ludwigshafen, Germany, Lot 84414368EO), polyvinyl alcohol (PVA, Parteck® MXP, Merck, Darmstadt, Germany, Lot: F215B464), 60:40 linear random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (PVP/VA, Plasdone® S-630, Ashland, Mumbai, Maharashtra, India, Lot 0002177615), hydroxypropyl methylcellulose (HPMC, Affinisol®, Colorcon, Harleysville, PA, USA, Lot 1099015561), hydroxypropyl cellulose (HPC, Klucel® ELF, Ashland, Lot 40915), copolymers of ethyl acrylate, and methyl methacrylate with a low content of methacrylic acid ester with quaternary ammonium groups (Eudragit® RLPO, Evonik, Essen, Germany, Lot 6170936626 and Eudragit® RSPO, Evonik, Lot G0310398154) were donated. Triethyl citrate was obtained from Sigma-Aldrich (TEC, St. Louis, MO, USA). All reagents used were analytical grade.

Bedogni, G.R.; Lima, A.L.; Gross, I.P.; Menezes, T.P.; Talvani, A.; Cunha-Filho, M.; Salomon, C.J. 3D-Printed Tablets of Nifurtimox: In Vitro and In Vivo Anti-Trypanosoma cruzi Studies. Pharmaceutics 2025, 17, 80. https://doi.org/10.3390/pharmaceutics17010080

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