Pharmaceutical Engineering and 3D Printing (PharmE3D) Labs, Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.
Pharmaceutical Engineering and 3D Printing (PharmE3D) Labs, Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.
Int J Pharm. 2020 Nov 30;590:119945. doi: 10.1016/j.ijpharm.2020.119945. Epub 2020 Oct 4.
The current investigation aimed to manufacture and evaluate the structure-function relationship of various 3D printed tablets by conjugating hot-melt extrusion (HME) and fused deposition modeling (FDM) based additive manufacturing (AM) technique. Design of experiments (DoE) and formulation optimization studies were performed by using the Box-Behnken design based on the effect of the design parameters and responses which included drug loading, mechanical properties, and in vitro drug release performance. Key parameters such as shell thickness, infill density, and layer height were selected as independent variables. The tablet's weights (as a function of drug loading), hardness tested at 0° and 45° set-up, the amount of drug released by 180 min, and the average drug release rate were measured as responses. The reproducibility of the printing process was also studied by repeating the mid-point of the DoE data set multiple times (n = 3). A series of evaluation and characterization studies, including DSC, XRD, PLM revealed the amorphous solid-state conversion of the crystalline drug, whereas texture analysis showed robust mechanical properties of developed filaments. All FDM compatible filaments with IBU in amorphous states were successfully utilized to manufacture and evaluate 15 batches of tablets. The shell thickness and infill densities were significant (p-value < 0.05) to the tablet's weights and mechanical properties, and the DoE studies on in vitro drug release showed that the selected individual variables had a significant effect on the amount of drug released at a certain time point as well as drug release rate. In summary, conjugating HME with FDM offers a flexible platform for the on-demand personalized drug product development, and the DoE studies provide robust guidance for the optimization and fabrication of patient-focused drug products while adhering to the regulatory expectations.
本研究旨在通过热熔挤出（HME）和熔融沉积建模（FDM）相结合的增材制造（AM）技术制造和评估各种 3D 打印片剂的结构-功能关系。通过使用基于设计参数和响应的 Box-Behnken 设计（包括载药量、机械性能和体外药物释放性能）进行实验设计（DoE）和配方优化研究。选择壳层厚度、填充密度和层厚等关键参数作为自变量。片剂的重量（作为载药量的函数）、在 0°和 45°设置下测试的硬度、180 分钟内释放的药物量和平均药物释放率作为响应进行测量。还通过多次重复（n = 3）DoE 数据集的中点来研究打印过程的可重复性。一系列评估和表征研究，包括 DSC、XRD 和 PLM，揭示了结晶药物的无定形固态转化，而纹理分析则显示了开发的纤维的稳健机械性能。所有具有 IBU 无定形态的 FDM 兼容纤维都成功用于制造和评估 15 批片剂。壳层厚度和填充密度对片剂的重量和机械性能有显著影响（p 值<0.05），DoE 研究表明，所选的单个变量对特定时间点的药物释放量和药物释放速率有显著影响。总之，将 HME 与 FDM 结合使用为按需个性化药物产品的开发提供了一个灵活的平台，而 DoE 研究为满足监管期望的患者为中心药物产品的优化和制造提供了有力的指导。
