Drug Dynamics Institute, University of Texas at Austin, Austin, USA.
Eur J Pharm Biopharm. 2010 Feb;74(2):352-61. doi: 10.1016/j.ejpb.2009.09.008. Epub 2009 Sep 24.
The objective of this study was to investigate the properties of enteric matrix pellets that were prepared by hot-melt extrusion in a one-step, continuous process. Five polymers (Eudragit) L100-55, L100 and S100, Aqoat grades LF and HF) were investigated as possible matrix formers, and pellets prepared with Eudragit S100 demonstrated superior gastric protection and acceptable processibility. Extruded pellets containing Eudragit S100 and up to 40% theophylline released less than 10% drug over 2h in acid, however, the processibility and yields were compromised by the high amounts of the non-melting drug material in the formulation. Efficient plasticization of Eudragit S100 was necessary to reduce the polymer's glass transition temperature and melt viscosity. Five compounds including triethyl citrate, methylparaben, polyethylene glycol 8000, citric acid monohydrate and acetyltributyl citrate were investigated in terms of plasticization efficiency and preservation of the delayed drug release properties. The aqueous solubility of the plasticizer and its plasticization efficiency impacted the drug release rate from the matrix pellets. The use of water-soluble plasticizers resulted in a loss of gastric protection, whereas low drug release rates in acid were found for pellets containing insoluble plasticizers or no plasticizer, independent of the extent of Eudragit S100 plasticization. The release rate of theophylline in buffer pH 7.4 was faster for pellets that were prepared with efficient plasticizers. The microstructure and solid-state properties of plasticized pellets were further investigated by scanning electron microscopy and powder X-ray diffraction. Pellets prepared with efficient plasticizers (TEC, methylparaben, PEG 8000) exhibited matrices of low porosity, and the drug was homogeneously dispersed in its original polymorphic form. Pellets containing ATBC or citric acid monohydrate had to be extruded at elevated temperature and showed physical instabilities in the form of recrystallization at room temperature. Enteric matrix pellets with a diameter below 1mm and containing 30% theophylline could be successfully prepared by hot-melt extrusion when Eudragit S100 plasticized with either TEC or methylparaben was employed as the matrix material.
本研究的目的是研究通过热熔挤出一步连续工艺制备的肠溶性基质丸的性质。研究了 5 种聚合物（Eudragit）L100-55、L100 和 S100、Aqoat 等级 LF 和 HF）作为可能的基质形成剂，结果表明，用 Eudragit S100 制备的丸剂具有优异的胃保护作用和可接受的加工性能。含有 Eudragit S100 的挤出丸剂在酸性条件下 2 小时内释放少于 10%的药物，但由于配方中含有大量未熔化的药物，加工性能和收率受到影响。为了降低聚合物的玻璃化转变温度和熔体粘度，需要对 Eudragit S100 进行有效的塑化。研究了包括柠檬酸三乙酯、对羟基苯甲酸甲酯、聚乙二醇 8000、柠檬酸一水合物和乙酰基三丁基柠檬酸酯在内的 5 种化合物，以评估其增塑效率和对延迟药物释放性能的保持能力。增塑剂的水溶性及其增塑效率影响了基质丸中药物的释放速率。水溶性增塑剂的使用会导致胃保护作用丧失，而对于含有不溶性增塑剂或无增塑剂的丸剂，无论 Eudragit S100 的塑化程度如何，在酸性条件下药物释放率都较低。在缓冲液 pH7.4 中，用高效增塑剂制备的丸剂中茶碱的释放速率较快。通过扫描电子显微镜和粉末 X 射线衍射进一步研究了增塑丸的微观结构和固态性质。用高效增塑剂（TEC、对羟基苯甲酸甲酯、PEG8000）制备的丸剂表现出低孔隙率的基质，药物以其原始多晶型均匀分散。含有 ATBC 或柠檬酸一水合物的丸剂必须在较高温度下挤出，并在室温下以重结晶的形式表现出物理不稳定性。当使用 TEC 或对羟基苯甲酸甲酯塑化的 Eudragit S100 作为基质材料时，可以成功制备直径小于 1mm 且含有 30%茶碱的肠溶性基质丸。
