4D printing of shape-memory polymer-based floating tablets via fused deposition modelling: Transformable helical structure to tablet-like form

The integration of four-dimensional (4D) printing technology into pharmaceutical manufacturing has introduced a transformative approach to drug delivery systems, offering flexible alternatives to improve drug bioavailability. This study advanced the field by developing an innovative 4D-printed floating drug delivery system using Fused Deposition Modelling (FDM) and a temperature-responsive polymer, polylactic acid (PLA). Unlike traditional methods and previous literature that relied on external devices or encapsulation, our approach utilised the shape-memory properties of PLA to create helical structures that transform into tablet-like forms when heated and subjected to an external force.

Highlights

• A novel 4D-printed floating drug delivery system was developed.
• Drug Delivery System utilises PLA-based helical structures for shape transformation.
• Helical constructs transform in response to temperature changes.
• Geometric parameters crucially influence shape-changing performance.

Under gastric conditions, these structures reverted to their original shape, allowing them to float and release drugs over an extended period. In this work, eight helical models (M1 to M8), were designed and fabricated with varying geometric parameters, including helix diameter, number of helical turns, and top/base height, to assess their geometric accuracy, shape-memory performance, drug-loading efficiency, floatability, and release behaviour. Results showed that models with smaller helix diameters and fewer turns exhibited superior shape recovery, with the highest observed at 79.5 % for Model M1 (1.0 mm helix diameter, two helical turns, and 0.5 mm top/base height).

Meanwhile, models with larger diameters showed higher drug-loading capacities. Additionally, the drug-loaded models demonstrated significant shape-recovery and floating performances, suggesting the potential for prolonging drug release for up to 12 h. These findings highlight the potential of 4D printing in developing advanced drug delivery systems, providing new insights into how this technology can improve drug administration and drug delivery through shape-changing tailored systems.

Introduction

Solid oral dosage forms, including powders, granules, capsules, and tablets, are among the most widely used platforms of drug delivery due to their stability, ease of production, cost-effectiveness, and high patient adherence [1,2]. Their convenience makes them a preferred choice for self-administered medications in clinical settings. However, the complex and variable environment of the gastrointestinal (GI) tract poses significant challenges for effective drug delivery [3,4]. Fluctuating pH levels in different GI segments, variable mucus layer thickness, residence time, and the presence of gut bacteria all profoundly impact drug absorbability and bioavailability [[5], [6], [7]]. For example, the stomach’s acidic environment (pH 1–2.5) can degrade many drug molecules, thereby reducing their efficacy. Additionally, first-pass metabolism, where the drug is metabolised in the liver after absorption, leads to a significant loss of the administered dosage. Other challenges include short gastric residence time, inconsistent gastric emptying, and the need for frequent dosing of drugs with short half-lives [8]. These factors, combined with mechanical stresses from peristalsis and osmotic pressure, further reduce drug absorption and therapeutic effectiveness [4]. To address these challenges and improve drug bioavailability, innovative drug delivery systems, such as gastro-retentive drug delivery systems (GRDDS), have been developed. GRDDS are designed to extend the gastric residence time and enable prolonged drug release, especially for drugs with a narrow absorption window in the stomach. These systems help overcome absorption-related challenges within the GI tract, ultimately leading to better therapeutic outcomes. A diverse array of GRDDS have been developed, encompassing high-density [9], expandable [10], magnetic [11], mucoadhesive [12], and floating systems [13,14]. Among these, floating systems have garnered significant attention within pharmaceutical research and industry. By being less dense than gastric fluids, they remain buoyant in the stomach for extended periods, significantly enhancing the bioavailability of drugs absorbed in the stomach or upper small intestine. Traditionally, floating systems have been fabricated from materials such as polypropylene foams and oils, but these offer limited material versatility [15,16].

Three-dimensional (3D) printing is one type of additive manufacturing (AM) that has evolved significantly over the past few decades, with applications spanning industries like automotive, aerospace, biomedical, and pharmaceuticals [17]. Among the various techniques, binder jet 3D printing (BJ-3DP), fused deposition modelling (FDM), semi-solid extrusion (SSE), and stereolithography (SLA) stand out for their potential to develop personalised drug delivery systems [18]. These technologies allow for the creation of complex dosage forms that were once impossible to achieve through traditional methods or would have required costly multi-stage processes. Moreover, 3D printing enables personalised medicine by allowing pharmacists to create formulations tailored to individual patient needs, incorporating precise amounts of active pharmaceutical ingredients (APIs) [19].

Building on the success of 3D printing, the novel concept of four-dimensional (4D) printing introduces time as a critical factor. This approach utilises smart materials–such as shape-memory alloys (SMAs), shape-memory polymers (SMPs), and stimuli-responsive gels–that can change their structure or functionality when exposed to external stimuli like light, temperature, solvents, magnetic fields, enzymes, or pH [20,21]. This dynamic behaviour has significant implications for drug delivery systems, enabling them to adapt to physiological conditions and enhance therapeutic outcomes. Shape-memory polymers (SMPs) are particularly promising for 4D printing applications in biomedical and pharmaceutical fields, as they can be programmed to transition between temporary and permanent shapes in response to specific stimuli [[22], [23], [24], [25]]. For example, temperatures-responsive SMPs, such as polyvinyl alcohol (PVA), polyurethane (PU), crosslinked methacrylate poly (caprolactone), and polylactic acid (PLA), can be deformed into a temporary shape above their glass transition temperature (Tg) and then recover their original shape when triggered by heat [26]. Despite the growing promise of 4D printing, its application in pharmaceutical formulation development is still in its early stages, with limited studies reported. For instance, Uboldi et al. [27] developed expandable bladder-retentive drug delivery systems using PVA-based SMPs, which recovered 70 % of their original shape when exposed to simulated urine at 37 °C for 3 min. Similarly, Melocchi et al. [28] fabricated a PVA-based expandable GRDDS through FDM, programmed into a supercoiled temporary shape for insertion into capsules. Upon immersion in hydrochloric acid (HCl), the capsule disintegrated, allowing the system to expand and recover its original shape. These examples highlight the ability of 4D-printed systems to transform within the body, but they often rely on external devices, such as capsules, for drug delivery.

In this study, we aim to advance the concept of shape-transforming drug delivery by developing a novel 4D-printed floating system that can be administered directly without the need for additional devices, using an FDM printer with a temperature-responsive polymer. Unlike previous approaches that require additional devices such as capsules, our method utilises polylactic acid (PLA) to create helical structures that can transform into a tablet-like form when subjected to heat and external force. Once exposed to gastric conditions, this tablet can revert to its helical shape, enabling it to float in the stomach for prolonged period. This novel approach not only simplifies the drug delivery process by eliminating the need for capsules or additional devices but also has the potential to enhance gastric retention and prolong drug release, particularly for acid-stable drugs, ultimately overcoming common challenges in oral drug delivery.

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Materials

Polylactic acid (PLA) filament with a diameter of 1.75 ± 0.05 mm and a density of 1.24 g/cm3 was purchased from eSun®, Shenzhen Esun Industrial Co., Ltd. (Shenzhen, China). Chlorpheniramine maleate (C20H23ClN2O4, molecular weight 390.9 g/mol), the model drug used in this study, was purchased from S. Tong Chemicals Co., Ltd. (Nonthaburi, Thailand). Ethanol (95.0 %) was purchased from Liquor Distillery Organization Thailand (Chachoengsao, Thailand). 1 N Hydrochloric acid solution (AR grade) was purchased from RCI Labscan Ltd. (Bangkok, Thailand). All other chemicals and reagents used in this study were of analytical grade to ensure consistency and reliability in experimental results.

Pattaraporn Panraksa, Sherif I. Hamdallah, Ozkan Yilmaz, Phennapha Saokham, Pornchai Rachtanapun, Sheng Qi, Pensak Jantrawut, 4D printing of shape-memory polymer-based floating tablets via fused deposition modelling: Transformable helical structure to tablet-like form, Journal of Drug Delivery Science and Technology, Volume 104, 2025, 106534, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106534.

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