3D printing personalized orally disintegrating tablets with complex structures for the treatment of special populations

Abstract

Individuals with special needs, such as children, the elderly, and the visually impaired, encounter significant hurdles in the field of personalized pharmacotherapy due to their distinctive medication needs. 3D printing technology, a novel approach for preparing drug products with intricate personalized designs, has shown considerable promise in improving the safety and adherence to patient medication regimens. This study chose acetaminophen, a commonly employed antipyretic analgesic, as the model drug and employed binder jetting 3D printing (BJ-3DP) to manufacture oral disintegrating tablets (ODTs) with multiple specifications and complex structures. The study initiated with an assessment of the printable properties of powder and ink formulations, proceeding to craft ODTs with individualized dosages and surfaces embedded in QR codes, cartoon figures, textual information, and raised braille. These tablets are internally designed with spaces that do not eject ink, resulting in a loose powder structure. The results of tests including porosity, surface roughness, Micro CT scanning, mechanical properties, and in vitro drug release of the printed product indicate that the personalized ODTs with complex structures designed in this study can offer treatment solutions for specific populations.

Introduction

Among the commendable trends in contemporary society is the growing focus on the unique medication needs of special populations, coupled with sustained initiatives to enhance their quality of life. In contrast to the broader public, these individuals are at a heightened risk of encountering drug-related complications, predominantly due to an increased likelihood of medication errors (Protopapa et al., 2024). Currently, special populations commonly identified as having unique medication needs include children, the elderly, and the visually impaired.

Concerning pediatric medication, children are sometimes colloquially termed “little adults”. Nevertheless, their psychological and physiological attributes diverge substantially from those of mature individuals. Presently, pediatricians often depend on clinical expertise to modify adult dosages for pediatric use, which frequently results in the inclusion of “half-tablet” dosing instructions in prescriptions (Batchelor and Marriott, 2015). Altering the structure of a medication’s formulation can modify its in vivo pharmacokinetics, potentially resulting in toxicity and diminished efficacy. Moreover, children prefer for medicinal preparations that feature appealing shapes, vivid colors, and pleasant flavors, as opposed to conventional formulations (Wang et al., 2021). Hence, the provision of personalized pediatric medication continues to pose a substantial challenge within the pharmaceutical domain.

For the elderly, adverse drug events (ADEs) represent the most prevalent safety issue, arising from three principal factors: the progression of age, the presence of multiple morbidities, and the use of multiple medications (Cross et al., 2020, Prince et al., 2015). Elderly patients are susceptible to medication errors, which may result from inappropriate dosing or drug interactions, the ingestion of expired pharmaceuticals, or a failure to adhere to pharmacists’ guidance (Cross et al., 2020). The efficacy of accurate diagnoses and prescriptions is compromised without appropriate medication administration. Therefore, it is essential to reinforce reminders to ensure that the elderly take their medications correctly.

The visually impaired encounter difficulties with medication use due to the fact that available formulations are typically designed with sighted individuals in mind, thereby complicating the accurate identification of medications. The costs of assistive technologies on which they often rely heavily, such as voice recognition devices, audio feedback systems, and assistance from caregivers, can hinder adherence to drug therapy (Protopapa et al., 2024). Researchers estimate that by 2050, the global prevalence of blindness will reach 61 million individuals. Currently, approximately 1.1 billion people experience some form of vision impairment (VI), which includes 474 million with moderate to severe VI, 360 million with mild VI, and 866 million with uncorrected presbyopia (Bourne et al., 2021). Therefore, developing strategies to enhance medication adherence among individuals with the visually impaired is of critical importance.

Orally Disintegrating Tablets (ODTs) represent a rapidly disintegrating dosage form that could allow a rapid release of the active ingredient, and contributing to improved patient compliance (Ochoa et al., 2024). Pursuant to the Chinese Pharmacopoeia, ODTs are described as “tablets that swiftly disintegrate or dissolve in the oral cavity without the need for water”. Acetaminophen, as one of the most popular and commonly used antipyretic analgesic in the world, is particularly suitable for special populations such as children because of its remarkable antipyretic and analgesic effects, high safety profile, and less irritation to the gastrointestinal tract, and was therefore chosen as the model drug for this study (Jóźwiak-Bębenista and Nowak, 2013). Moreover, three-dimensional printing technology was integrated into the process to design and refine the formulation of acetaminophen ODTs, with the objective of bolstering patient adherence.

As a technique rooted in additive manufacturing, 3D printing technology fabricates products with unique geometries and intricate internal structures by sequentially layering materials based on digital model design (Tracy et al., 2023). Within the pharmaceutical sector, 3D printing technology has been applied to produce a range of medical products, such as rapidly dissolving tablets, controlled-release tablets, dispersible films, microneedles, and transdermal patches (Mancilla-De-la-Cruz et al., 2022). Compared to traditional manufacturing processes, 3D printing offers greater flexibility, enabling the design of complex product structures, precise dose adjustments, and rapid small-scale production, thereby better facilitating personalized treatments for patients (Norman et al., 2017). In children’s medication, 3D printing technology allows for more precise control of product doses and can enhance patient compliance by modifying the appearance and taste. For example, a variety of child-friendly chewable tablets, color cartoon children’s dispersible tablets, compound dispersible tablets, and mini tablets can be prepared by 3D printing technology to meet children’s physiological and psychological needs (Wang et al., 2021, Herrada-Manchón et al., 2020, Hong et al., 2021, Krause et al., 2021). For the medication of the elderly population, various personalized drug preparations can be prepared using 3D printing technology to improve medication safety and compliance. For example, the preparation of customized doses of oral disintegrating tablets to solve the problem of dysphagia in patients and the preparation of multi-layer tablets can realize the combination of multi-drugs and significantly improve the safety of the medication (Shaoling et al., 2023, Robles-Martinez et al., 2019). Additionally, 3D printing technology can print formulations into special shapes or with unique markings on their surfaces, providing convenience for the visually impaired (Awad et al., 2020). For instance, Awad et al. (Awad et al., 2020) took the lead in using Selective Laser Sintering (SLS) technology to prepare personalized acetaminophen oral disintegrate tablets with braille or moon patterns on the surface. Protopapa et al. (Protopapa et al., 2024) applied 3D printing technology to prepare them for the Sustained release of bupropion hydrochloride tablets bearing Braille imprints for the visually impaired. In addition, 3D printing technology can also be used to print various Braille characters on the oral dissolving films (Eleftheriadis and Fatouros, 2021).

The BJ-3DP technology has a wide range of applications in the pharmaceutical field, as it can be used to prepare various types of drug formulations, including orally rapidly releasing dosage forms, sustained-release preparations, controlled-release preparations, multi-drug composite formulations, preparations for children, and implants (Chen et al., 2022). Especially in the preparation of orally rapidly releasing formulations, the BJ-3DP technology has demonstrated its unique advantages and application potential. BJ-3DP is a 3D additive manufacturing technology based on the powder bed, which has a wide selection of excipients and the ability to produce pharmaceutical formulations with various high-porosity structures that can prepare immediate-release preparations such as ODTs (Tian et al., 2018, Wang et al., 2022). In 2015, Aprecia Pharmaceuticals utilized BJ-3DP technology to produce Spritam®, a medication for treating epilepsy. This tablet features a porous structure that rapidly disintegrates in the mouth, making it highly beneficial for patients with swallowing difficulties. Currently, Spritam® is available in four dosage strengths: 250, 500, 750, and 1000 mg. The patent highlights that it is the only tablet capable of oral dispersion with high-dose active pharmaceutical ingredients up to 1000 mg. In addition, Tian et al. (Tian et al., 2018) successfully developed three different specifications of warfarin ODTs using BJ-3DP technology; these tablets disintegrate quickly and release the drug, which is especially suitable for patients with dysphagia. Wang et al. (Wang et al., 2021) also prepared a color cartoon shape levetiracetam preparation for children through this technology, which not only has excellent mechanical properties but also can achieve rapid drug dispersion and release, which significantly improves children’s medication compliance. Therefore, personalized drug preparations prepared by BJ-3DP technology have the potential to meet the special drug needs of special groups such as children and the elderly.

Compared to other 3D printing technologies for drugs, direct printing with stereolithography poses potential toxicity concerns (Deshmane et al., 2021); selective laser sintering is costly with limited availability of excipients (Alhnan et al., 2016); and material extrusion suffers from low resolution and the risk of degradation of drugs and excipients due to high-temperature printing (Cheng et al., 2020, Thanawuth et al., 2021).

In this study, the BJ-3DP technology was employed to fabricate personalized acetaminophen ODT characterized by customized appearances, dosages, and structures, thereby addressing the medication needs of special populations. However, the printing of QR codes, text information, cartoon patterns, raised Braille, as well as the hollow and loose powder structure within the ODTs, all pose specific requirements for the precision of the printing equipment, the personalized design of the model, and the printability of the ink and powder materials. In this study, we utilized our self-developed 3D printer and successfully implemented high-precision printing of acetaminophen ODTs by integrating formulation exploration and flexible digital model design.

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Materials

Acetaminophen (Hubei Xinmingtai Chemical Co., Ltd., China), Commercially available acetaminophen Orally Disintegrating Tablets (Hainan Puli Pharmaceutical Co., Ltd., China), Microcrystalline cellulose (MCC PH101, Asahi Kasei, Japan), Mannitol ( Pearlitol 100SD, Roquette, France), Sucralose (Jiangxi Alpha High-tech Pharmaceutical Co., Ltd., China), Lactose (Guangzhou Tianrun Pharmaceutical Co., Ltd., China), Polyvinylpyrrolidone (PVP K30, BASF, Germany) (Mw ∼ 3.8 × 104), Colloidal Silicon Dioxide (Evonik).

Zhiqiang Tang, Xuejun Chen, Xiaoxuan Hong, Xiaolu Han, Jia Li, Shuwei Duan, Jie Wu, Zengming Wang, Aiping Zheng, 3D printing personalized orally disintegrating tablets with complex structures for the treatment of special populations, International Journal of Pharmaceutics, 2025, 125371, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125371.

Read also our introduction article on 3D Printing here: