Abstract
Adherence to treatment is one of the major challenges in chronic diseases. Inappropriate dosage forms or bad taste are the main factor for non-adherence, especially in paediatric patients. 3D printed medicines could be tailored to specific patients to make medicines more acceptable, however the clinical implementation in hospitals is still limited. This study addresses the challenge of developing pharma-inks (mixtures of drugs and excipients) for semi-solid extrusion (SSE) to produce chewable tablets of Sulfamethoxazole (SMX) and Trimethoprim (TMP) for paediatric oncology patients in a hospital setting. SMX and TMP pharma-inks were stable and printable on demand for more than 3 months. The chewable tablets were also stable, and the drug dissolution profiles were comparable to those of the commercial formulations, indicating potential bioequivalence. Human sensory evaluations confirmed that the formulation improved palatability compared to traditional suspensions. 3D-printed SMX/TMP formulations are an alternative to traditional formulations for paediatric patients in hospital settings, enhancing acceptability and adherence while enabling personalized dosing.
Introduction
The treatment of young patients in hospital settings presents unique challenges, especially with regards to dose personalization and medication acceptability. Paediatric patients, particularly those in oncology, often require medication formulations that are not only appropriately dosed but also palatable to ensure adherence and maximize therapeutic efficacy. For antibiotics like Sulfamethoxazole and Trimethoprim (SMX/TMP), commonly used for prophylaxis and treatment in children (Gillet et al., 2023, Madhi et al., 2023, Mattoo et al., 2021, Nelson et al., 2016, The RIVUR Trial Investigators, 2014, ESPGHAN, 2014), adherence is often compromised due to unappealing formulations (Baguley et al., 2012, Kardas et al., 2021). Current oral dosage forms, such as tablets and suspensions, pose significant challenges: tablets are frequently difficult to swallow for children, and the bitter taste of suspensions often leads to refusal, undermining treatment efficacy (Piana et al., 2017, Romandini et al., 2021, Santer et al., 2014, World Health Organization WHO, 2014). Paediatric patients, who are particularly sensitive to bitterness and generally prefer sweet flavours, are disproportionately affected by these issues, complicating the administration of SMX/TMP and similar medications (Mennella and Bobowski, 2015, Wooding and Ramirez, 2022). Numerous strategies have been explored to improve palatability such as the incorporation of sweeteners, bitter blockers, and cyclodextrins, yet no single approach fully addresses this adherence challenge (Walsh et al., 2014, Flammer et al., 2024, Schwiebert et al., 2021).
Hospital pharmacies have traditionally turned to custom compounding to address these challenges; however, compounding alone has not resolved issues of taste and dosing precision (Heitman et al., 2019); highlighting the need for innovative approaches. Given these limitations, three-dimensional (3D) printing technology offers a transformative, scalable solution, providing precise and personalized dosing capabilities, particularly valuable for paediatric care where adherence is critical (Binson et al., 2021, Juárez-Hernández and Carleton, 2022).
3D printing enables the precise preparation of pharmaceutical forms layer-by-layer, with specific applications in personalized medicine and drug delivery. The adaptability of 3D printing is especially promising in hospitals, where it facilitates the on-demand production of medications tailored to individual needs (Huanbutta et al., 2023, Annereau et al., 2021). This flexibility is crucial for children, who require doses that standard manufacturing methods cannot always provide, thereby enhancing treatment precision and therapeutic outcomes. Semi-solid extrusion (SSE) 3D printing that uses semi-solid pharmaceutical inks (pharma-inks) extruded through a nozzle offers unique advantages.
While SSE-based 3D printing offers significant advantages, such as precise dose personalization, modular drug release, and improved palatability, it also faces several limitations that must be addressed. A key drawback is the longer production time compared to compressed dosage forms, due to the layer-by-layer printing process and the additional drying phase required for water-based chewable tablets. However, gummies can be dried in a conventional oven outside a cleanroom, providing flexibility for hospital-based compounding where controlled environments may be limited. Another challenge is the relatively lower drug loading capacity compared to compressed tablets. Moreover, the extrusion-based nature of SSE can affect printing precision and layer adhesion, potentially resulting in minor variations in tablet dimensions. Lastly, while hydrophilic excipients improve drug solubility, they may increase bitterness, posing a challenge for taste masking—especially in paediatric settings. Despite these limitations, SSE remains a promising approach for personalized medicine in hospital environments (Wang et al., 2023, Seoane-Viaño et al., 2021, Cerveto et al., 2024, Rodríguez-Pombo et al., 2024).
SSE-based 3D printing has gained significant attention for paediatric applications, allowing for the precise fabrication of dosage forms personalized to each child’s age, weight, and metabolic needs (Basit and Gaisford, 2018). Recent studies have demonstrated SSE’s potential for individualizing doses and achieving modified-release profiles, particularly beneficial for children who may struggle with swallowing or frequent dosing requirements (Rodríguez-Pombo et al., 2024, Chatzitaki et al., 2022, Yi et al., 2023, Panraksa et al., 2022, Li et al., 2019). Additionally, SSE technology supports the combination of multiple active ingredients and even the integration of medications with nutritional components, which can address the unique dietary needs of certain patients (Carou-Senra et al., 2023).
This study aims to harness the flexibility of SSE-based 3D printing to develop novel SMX/TMP chewable formulations tailored for paediatric patients to improve adherence, to enhance palatability, and to ensure precise, customizable dosing with suitable stability. Additionally, the clinical implementation of this 3D printed formulations in the Department of Clinical Pharmacy in Gustave Roussy hospital was assessed according to French compounding regulations. The stability and printability of stored pharma-inks was evaluated. 3D printed formulations were benchmarked against the commercial medicine (BACTRIM®). This research aims to improve therapeutic outcomes for paediatric patients, showcasing the transformative potential of 3D printing in personalized medication production.
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Materials
Sulfamethoxazole, Trimethoprim, glacial acetic acid and hydrochloric acid 1 N were purchased from Sigma Aldrich (Sigma-Aldrich chemicals, USA). Maltitol syrup (LYCASIN® 80/55), mannitol (PEARLITOL® 50C), and pregelatinized starch (LYCATAB® PGS) were provided by Roquette (Roquette Frères, Lestrem, France). Gelatine (Emprove® Ph Eur; Bloom degree 110 [90–130]) and sucralose were obtained from Sigma (Sigma-Aldrich chemicals, Saint-Louis, USA), and the water for injection from B.Braun (Aqua B.Braun, Melsungen, Germany), peppermint and cooling aroma were obtained from IFF pharma (International Flavors and Fragrances, New-York, USA). 20-mL Injekt® syringes were supplied by B.Braun (Saint-Cloud, France), food colouring was purchased from Exberry (GNT International B.V, Mierlo, Netherlands). Water, acetonitrile (ACN), triethylamine (TRA) and methanol were HPLC grade and purchased from VWR chemicals (Radnor, Pennsylvania, USA).
Maxime Stoops, Bernard Do, Stéphanie Ramos, Bing Xun Tan, Nicholas Yong Sheng Chua, Roseline Mazet, Nicolas Guiblin, Alexandre Michelet, Stephen Flynn, Samuel Abbou, Alvaro Goyanes, André Rieutord, François-Xavier Legrand, Maxime Annereau, Clinical implementation of a paediatric 3D-printed combination of Sulfamethoxazole and Trimethoprim, International Journal of Pharmaceutics, Volume 676, 2025, 125581, ISSN 0378-5173,
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