Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Dr., Amarillo, TX 79106, United States.
Department of Industrial, Manufacturing, and Systems Engineering, Texas Tech University, Lubbock, TX 79409-3061, United States.
Int J Pharm. 2018 Jun 10;544(1):285-296. doi: 10.1016/j.ijpharm.2018.04.010. Epub 2018 Apr 20.
Three-dimensional printing (3DP), though developed for nonmedical applications and once regarded as futuristic only, has recently been deployed for the fabrication of pharmaceutical products. However, the existing feeding materials (inks and filaments) that are used for printing drug products have various shortcomings, including the lack of biocompatibility, inadequate extrudability and printability, poor drug loading, and instability. Here, we have sought to develop a filament using a single pharmaceutical polymer, with no additives, which can be multi-purposed and manipulated by computational design for the preparation of tablets with desired release and absorption patterns. As such, we have used hydroxypropyl-methylcellulose (HPMC) and diltiazem, a model drug, to prepare both drug-free and drug-impregnated filaments, and investigated their thermal and crystalline properties, studied the cytotoxicity of the filaments, designed and printed tablets with various infill densities and patterns. By alternating the drug-free and drug-impregnated filaments, we fabricated various types of tablets, studied the drug release profiles, and assessed oral absorption in rats. Both diltiazem and HPMC were stable at extrusion and printing temperatures, and the drug loading was 10% (w/w). The infill density, as well as infill patterns, influenced the drug release profile, and thus, when the infill density was increased to 100%, the percentage of drug released dramatically declined. Tablets with alternating drug-free and drug-loaded layers showed delayed and intermittent drug release, depending on when the drug-loaded layers encountered the dissolution media. Importantly, the oral absorption patterns accurately reproduced the drug release profiles and showed immediate, extended, delayed and episodic absorption of the drug from the rat gastrointestinal tract (GIT). Overall, we have demonstrated here that filaments for 3D printers can be prepared from a pharmaceutical polymer with no additives, and the novel computational design allows for fabricating tablets with the capability of producing distinct absorption patterns after oral administration.
三维打印（3DP），虽然最初是为非医疗应用而开发的，并且一度被认为是未来主义的产物，但最近已被用于药物产品的制造。然而，现有的用于打印药物产品的进料材料（墨水和长丝）存在各种缺点，包括缺乏生物相容性、挤出性和可打印性不足、载药量低和不稳定性。在这里，我们试图开发一种使用单一药物聚合物的长丝，该长丝没有添加剂，可以通过计算设计进行多功能操作，以制备具有所需释放和吸收模式的片剂。因此，我们使用羟丙基甲基纤维素（HPMC）和地尔硫卓（一种模型药物）来制备无药物和药物浸渍的长丝，并研究了它们的热和结晶性能，研究了长丝的细胞毒性，设计并打印了具有不同填充密度和图案的片剂。通过交替使用无药物和药物浸渍的长丝，我们制造了各种类型的片剂，研究了药物释放曲线，并评估了在大鼠中的口服吸收。地尔硫卓和 HPMC 在挤出和打印温度下均稳定，药物载药量为 10%（w/w）。填充密度以及填充图案影响药物释放曲线，因此，当填充密度增加到 100%时，释放的药物百分比急剧下降。具有交替无药物和药物负载层的片剂显示出延迟和间歇性的药物释放，这取决于药物负载层何时遇到溶解介质。重要的是，口服吸收模式准确地再现了药物释放曲线，并显示出药物从大鼠胃肠道（GIT）中立即、延长、延迟和间歇性吸收。总体而言，我们在这里证明了可以使用无添加剂的药物聚合物来制备 3D 打印机的长丝，并且新型计算设计允许制造具有口服给药后产生独特吸收模式的片剂。
