Jin Miao, Zuo Xianghao, Blattner Simone M, Frankenreiter Sandra, Metzger Markus, Lu Jingyu, Kikuchi Takuya, Fujimoto Katsuyoshi, Sakurai Atsushi, Wang Gang, Grube Achim, Boeck Georg, Lu Jun
Boehringer Ingelheim (China) Investment Co., Ltd., 257 Li Shizhen Road, Shanghai 201203, China.
Triastek, Inc., 99 Lize Road, Max Science Park, Nanjing, Jiangsu 211100, China.
Mol Pharm. 2025 Sep 1;22(9):5428-5442. doi: 10.1021/acs.molpharmaceut.5c00413. Epub 2025 Aug 11.
Traditional methods for developing modified-release (MR) formulations involve numerous iterations and large quantities of drug substances, which pose considerable challenges in exploration settings. Given the growing necessity for modified-release (MR) formulations in the pharmaceutical industry, particularly during the preclinical research and development phase, modified-release strategies may serve as attractive alternatives to discontinuing clinical development and could mitigate the costs and time associated with identifying new drug candidates. This study specifically explores the application of melt extrusion deposition (MED) 3D printing technology as a rapid prototyping platform for creating extended-release (ER) oral dosage forms tailored for the preclinical phase. Using the model compound BI 894416, the study demonstrated that MED 3D printing enables precise control over drug release profiles through both structural and compositional designs. The physicochemical analysis conducted during the 3D printing process revealed no degradation or compatibility issues. pharmacokinetic (PK) studies in rats and dogs validated the extended-release (ER) performance of BI 894416, with values of 2-4 h in rats and 5 h in dogs. The ER tablets achieved prolonged plasma exposure and reduced peak-to-trough fluctuations compared to those of immediate-release (IR) formulations (ER: 144 versus IR: 929 in dogs). A Level A correlation (IVIVC) was established, demonstrating strong alignment between dissolution and absorption up to 4 h, with a minor lag time observed. These results further confirmed the likely absorption of BI 894416 in the upper gastrointestinal (GI) tract and the potentially ascending colon. These findings highlight the potential of MED 3D printing to streamline the development of MR formulations in preclinical settings, offering a flexible, efficient, and material-sparing alternative to conventional approaches.
传统的缓释（MR）制剂开发方法需要进行大量的反复试验，耗费大量原料药，这在探索阶段带来了巨大挑战。鉴于制药行业对缓释（MR）制剂的需求日益增长，尤其是在临床前研发阶段，缓释策略可能是终止临床开发的有吸引力的替代方案，并且可以降低与确定新候选药物相关的成本和时间。本研究特别探讨了熔融挤出沉积（MED）3D打印技术作为一种快速成型平台的应用，用于创建针对临床前阶段量身定制的缓释（ER）口服剂型。使用模型化合物BI 894416，该研究表明MED 3D打印能够通过结构和成分设计精确控制药物释放曲线。在3D打印过程中进行的物理化学分析表明没有降解或相容性问题。在大鼠和犬身上进行的药代动力学（PK）研究验证了BI 894416的缓释（ER）性能，大鼠的t1/2值为2 - 4小时，犬为5小时。与速释（IR）制剂相比，ER片剂实现了更长的血浆暴露时间并减少了峰谷波动（犬：ER为144，IR为929）。建立了A级体内体外相关性（IVIVC），表明在长达4小时内，体外溶解与体内吸收之间具有很强的一致性，仅观察到轻微的滞后时间。这些结果进一步证实了BI 894416可能在上消化道（GI）和潜在的升结肠中被吸收。这些发现突出了MED 3D打印在临床前环境中简化MR制剂开发的潜力，为传统方法提供了一种灵活、高效且节省材料的替代方案。
