Oldfield Lee Roy, Mentrup Aaron Felix Christofer, Klinken-Uth Stefan, Auel Tobias, Seidlitz Anne
Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutics and Biopharmaceutics, Universitätsstraße 1, 40225 Düsseldorf, Germany.
INVITE GmbH, Otto-Bayer-Straße 32, 51061 Cologne, Germany.
Int J Pharm X. 2024 Oct 26;8:100299. doi: 10.1016/j.ijpx.2024.100299. eCollection 2024 Dec.
MUPS (multiple unit particle systems) are oral dosage forms consisting of small particles which are filled into capsules or compressed into tablets. Compared to monolithic sustained-release tablets, MUPS tablets rapidly disintegrate inside the stomach releasing the contained small particles, which can be emptied from the stomach independent of housekeeping waves. Control of release can be achieved by adapting the particle composition. Despite the advantages of MUPS, only a limited number of preparations are available on the market. 3D printing could be a new advantageous method to produce MUPS tablets compared to the conventional production via tableting. Due to the increasing research interest in personalised medicine, especially regarding dose adjustments, this flexible production approach could be a promising concept. Therefore, this work proposes a concept for printing MUPS tablets using a dual extrusion fused filament fabrication 3D printer. The general idea is that the two print heads can be used independently to print a water-soluble tablet shell with the first print head and incorporate functional particles into the tablet shell with a second print head using different materials for each step. In this study, a modular four-particle-layered tablet computer model containing 196 cylindrical particles with a diameter of 1.4 mm, a height of 1.0 mm and a total tablet size of 22.6 × 8.5 × 6.0 mm is proposed. A first proof-of-concept study with drug-free commercially available polylactic acid filament for the particles and polyvinyl alcohol filament for the tablet shell revealed critical parameters (such as filament retraction, z-offset and water content of filaments) for the successful printing of the proposed computer model. In addition, the successfully printed model 3D-MUPS tablets and incorporated particles were characterised, revealing a reproducible manufacturing process. The printed model particles had a diameter of 1.27 ± 0.04 mm and a height of 1.05 ± 0.01 mm. One of the challenges of the new approach was to avoid particle agglomeration because of remelting processes during the printing with two print heads. 57.54 ± 18.59 % of the 196 printed particles were present as single particles. Finally, the transferability and suitability with a model API-loaded (paracetamol) hydroxypropyl methylcellulose filament for the particles and a polyvinyl alcohol tablet shell was successfully tested. On average, 80 % of paracetamol was released within 3 h (2-4 h). Overall, this work shows an innovative new manufacturing method for dose-adjustable personalised MUPS tablets but also considers new challenges arising from the different manufacturing processes.
多单元颗粒系统(MUPS)是由填充到胶囊中或压制成片剂的小颗粒组成的口服剂型。与整体缓释片相比,MUPS片在胃内迅速崩解,释放出所含的小颗粒,这些小颗粒可独立于肠胃蠕动波从胃中排空。通过调整颗粒组成可以实现释放控制。尽管MUPS有诸多优点,但市场上仅有有限数量的制剂。与传统的压片生产方式相比,3D打印可能是生产MUPS片的一种新的有利方法。由于对个性化医疗的研究兴趣日益增加,特别是在剂量调整方面,这种灵活的生产方法可能是一个有前景的概念。因此,这项工作提出了一种使用双挤出熔融长丝制造3D打印机打印MUPS片的概念。总体思路是两个打印头可独立使用,第一个打印头用于打印水溶性片剂外壳,第二个打印头使用不同材料在片剂外壳中加入功能性颗粒,每个步骤使用不同材料。在本研究中,提出了一种模块化的四层颗粒片剂计算机模型,包含196个直径为1.4毫米、高度为1.0毫米的圆柱形颗粒,片剂总尺寸为22.6×8.5×6.0毫米。首次概念验证研究使用市售的用于颗粒的聚乳酸长丝和用于片剂外壳的聚乙烯醇长丝,揭示了成功打印所提出的计算机模型的关键参数(如长丝回缩、z轴偏移和长丝含水量)。此外,对成功打印的模型3D-MUPS片和所含颗粒进行了表征,揭示了可重复的制造过程。打印的模型颗粒直径为1.27±0.04毫米,高度为1.05±0.01毫米。新方法面临的挑战之一是避免在使用两个打印头打印过程中因重熔过程导致颗粒团聚。196个打印颗粒中有57.54±18.59%以单个颗粒形式存在。最后,成功测试了使用含模型活性药物成分(对乙酰氨基酚)的羟丙基甲基纤维素长丝作为颗粒和聚乙烯醇片剂外壳的可转移性和适用性。平均而言,80%的对乙酰氨基酚在3小时内(2 - 4小时)释放。总体而言,这项工作展示了一种用于剂量可调的个性化MUPS片的创新制造新方法,但也考虑了不同制造过程带来的新挑战。