College of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea.
College of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea.
Int J Pharm. 2024 Aug 15;661:124407. doi: 10.1016/j.ijpharm.2024.124407. Epub 2024 Jun 30.
This study aimed to develop a 3D-printed fixed-dose combination tablet featuring differential release of two drugs using double-melt extrusion (DME). The hot-melt extrusion (HME) process was divided into two steps to manufacture a single filament containing the two drugs. In Step I, a sustained-release matrix of acetaminophen (AAP) was obtained through HME at 190 °C using Eudragit® S100, a pH-dependent polymer with a high glass transition temperature. In Step II, a filament containing both sustained-release AAP from Step I and solubilized ibuprofen (IBF) was fabricated via HME at 110 °C using a mixture of hydroxy propyl cellulose (HPC-LF) and Eudragit® EPO, whose glass transition temperatures make them suitable for use in a 3D printer. A filament manufactured using DME was used to produce a cylindrical 3D-printed fixed-dose combination tablet with a diameter and height of 9 mm. To evaluate the release characteristics of the manufactured filament and 3D-printed tablet, dissolution tests were conducted for 10 h under simulated gastrointestinal tract conditions using the pH jump method with the United States Pharmacopeia apparatus II paddle method at 37 ± 0.5 °C and 50 rpm. Dissolution tests confirmed that both the sustained-release and solubilized forms of AAP and IBF within the filament and 3D-printed tablet exhibited distinct drug-release behaviors. The physicochemical properties of the filament and 3D-printed tablet were confirmed by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy. HME transforms crystalline drugs into amorphous forms, demonstrating their physicochemical stability. Scanning electron microscopy and confocal laser scanning microscopy indicated the presence of sustained AAP granules within the filament, confirming that the drugs were independently separated within the filament and 3D-printed tablets. Finally, sustained-release AAP and solubilized IBF were independently incorporated into the filaments using DME technology. Therefore, a dual-release 3D-printed fixed-dose combination was prepared using the proposed filament.
本研究旨在开发一种使用双熔融挤出（DME）实现两种药物差速释放的 3D 打印固定剂量组合片剂。热熔挤出（HME）过程分为两步，以制造含有两种药物的单根长丝。在第一步中，通过在 190°C 下使用具有高玻璃化转变温度的 pH 依赖性聚合物 Eudragit® S100 进行 HME，获得了乙酰氨基酚（AAP）的缓释基质。在第二步中，通过在 110°C 下使用羟丙基纤维素（HPC-LF）和 Eudragit® EPO 的混合物进行 HME，制造出含有来自第一步的缓释 AAP 和溶解布洛芬（IBF）的长丝，Eudragit® EPO 的玻璃化转变温度使其适合用于 3D 打印机。使用 DME 制造的长丝用于生产直径和高度均为 9mm 的圆柱形 3D 打印固定剂量组合片剂。为了评估所制造的长丝和 3D 打印片剂的释放特性，使用美国药典仪器 II 桨法在 37±0.5°C 和 50rpm 下进行 pH 跳跃法模拟胃肠道条件下进行了 10 小时的溶解试验。溶解试验证实，长丝和 3D 打印片剂内的 AAP 和 IBF 的缓释和溶解形式均表现出明显的药物释放行为。通过热重分析、差示扫描量热法、粉末 X 射线衍射和傅里叶变换红外光谱法确认了长丝和 3D 打印片剂的物理化学性质。热熔挤出将结晶药物转化为无定形形式，证明了它们的物理化学稳定性。扫描电子显微镜和共聚焦激光扫描显微镜表明，长丝内存在缓释 AAP 颗粒，证实药物在长丝和 3D 打印片剂内独立分离。最后，使用 DME 技术将缓释 AAP 和溶解 IBF 分别掺入长丝中。因此，使用提出的长丝制备了一种双释放 3D 打印固定剂量组合。
