Novartis Pharma AG, Basel, Switzerland; Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Novartis Pharma AG, Basel, Switzerland.
Int J Pharm. 2021 Apr 15;599:120417. doi: 10.1016/j.ijpharm.2021.120417. Epub 2021 Feb 27.
3D-printing technologies such as Fused Deposition Modeling (FDM) bring a unique opportunity for personalized and flexible near-patient production of pharmaceuticals, potentially improving safety and efficacy for some medications. However, FDM-printed tablets often exhibit tendency for slow dissolution due to polymer erosion-based dissolution mechanisms. Development of immediate release (IR) 3D-printed dosage with poorly water-soluble compounds is even more challenging but necessary to ensure wide applicability of the technology within pharmaceutical development portfolios. In this work, process and morphology were considered to achieve IR of BCS class IV compound lumefantrine as model active pharmaceutical ingredient (API) using basic butylated methacrylate copolymer (Eudragit EPO) as matrix former, as well as hydrophilic plasticizer xylitol and pore former maltodextrin. Grid-designed tablets with size acceptable for children from 6 years old and varying programmed infill density were successfully 3D-printed with 5% lumefantrine while higher drug load led to increased brittleness which is incompatible with 3D-printing. Lumefantrine assay was 92 to 97.5% of theoretical content depending on drug load and process parameters. 3D-printed tablets with 65% infill density met rapid release criteria, while 80% and 100% showed slower dissolution. Structural characteristics of 3D-printed tablets with non-continuous surface such as accessible porosity and specific surface area by weight and by volume were quantified by a non-destructive automated µCT-based methodology and were found to correlate with dissolution rate. Increase in accessible porosity, total surface area, specific surface area and decrease in relative density were statistically significant critical factors for modification of lumefantrine dissolution rate. Crystallinity in manufactured tablets and filaments was explored by highly sensitive Raman mapping technique. Lumefantrine was present in the fully amorphous state in the tablets exhibiting adequate stability for on-site manufacturing. The study demonstrates feasibility of immediate release FDM-3D-printed tablets with BCS class IV API and illustrates the correlation of FDM design parameters with morphological and dissolution characteristics of manufactured tablets.
3D 打印技术，如熔融沉积成型（FDM），为个性化和灵活的近患者药物生产带来了独特的机会，有可能提高某些药物的安全性和疗效。然而，由于基于聚合物侵蚀的溶解机制，FDM 打印片剂往往表现出溶解缓慢的趋势。开发具有低水溶性化合物的即时释放（IR）3D 打印剂型更加具有挑战性，但对于确保该技术在药物开发组合中的广泛适用性是必要的。在这项工作中，考虑了工艺和形态学，以使用基本的丁基甲基丙烯酸酯共聚物（Eudragit EPO）作为基质形成剂、亲水性增塑剂木糖醇和孔形成剂麦芽糊精，实现 BCS 类 IV 化合物盐酸阿莫地喹作为模型活性药物成分（API）的 IR。成功地使用 5%的盐酸阿莫地喹打印出了大小适合 6 岁以上儿童的网格设计片剂，并且可以改变填充密度，而更高的药物负载会导致脆性增加，这与 3D 打印不兼容。根据药物负载和工艺参数，盐酸阿莫地喹的测定值为理论含量的 92%至 97.5%。填充密度为 65%的 3D 打印片剂符合快速释放标准，而填充密度为 80%和 100%的片剂则显示出较慢的溶解速度。通过非破坏性自动µCT 基于方法学对具有非连续表面的 3D 打印片剂的结构特征（如可及孔隙率和重量比及体积比的比表面积）进行了量化，并发现其与溶解速率相关。可及孔隙率、总表面积、比表面积的增加和相对密度的降低是影响盐酸阿莫地喹溶解速率的重要因素。采用高灵敏度拉曼映射技术研究了制造片剂和长丝中的结晶度。片剂中的盐酸阿莫地喹处于完全非晶态，表现出足够的现场制造稳定性。该研究证明了具有 BCS 类 IV API 的即时释放 FDM 3D 打印片剂的可行性，并说明了 FDM 设计参数与制造片剂的形态学和溶解特性之间的相关性。
