Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
Eur J Pharm Biopharm. 2012 Aug;81(3):683-9. doi: 10.1016/j.ejpb.2012.03.018. Epub 2012 Apr 4.
The aim of this study was to develop a multilayer (core/coat) dosage form via co-extrusion, the core providing sustained drug release and the coat immediate drug release. In this study polymers were selected which can be combined in a co-extruded dosage form. Several thermoplastic polymers were hot-melt extruded and evaluated for processability and macroscopic properties (surface smoothness, die swell). Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were incorporated as sustained and immediate release model drugs, respectively. Based on the polymer screening experiments a combination of polycaprolactone (core) and polyethylene oxide (coat) was selected for co-extrusion trials, taking into account their drug release profiles and extrusion temperature (70 °C). This combination (containing 10% HCT in the coat and 45% MPT in the core) was successfully co-extruded (diameter core: 3 mm/thickness coat: 0.5 mm). Adhesion between the two polymer layers was good. HCT release from the coat was complete within 30 min, while MPT release was sustained over 24 h (55%, 70%, 85% and 100% after 4, 8, 12 and 2 4h, respectively). DSC, XRD and Raman spectroscopy revealed that MPT remained crystalline during extrusion, whereas HCT was dissolved in the polyethylene oxide matrix. The in vivo study revealed no significant differences between the experimental formulation and the reference formulation (Zok-Zid tablet). Fixed-dose combination mini-tablets with good in vitro and in vivo performance were successfully developed by means of co-extrusion, using a combination of polycaprolactone and polyethylene oxide.
本研究旨在通过共挤出开发一种多层（芯/壳）剂型，其中芯提供持续释放药物，壳提供即刻释放药物。在本研究中，选择了可以组合在共挤出剂型中的聚合物。几种热塑性聚合物被热熔挤出，并评估其加工性能和宏观性能（表面光滑度、模口膨胀）。酒石酸美托洛尔（MPT）和氢氯噻嗪（HCT）分别被用作持续释放和即刻释放模型药物。基于聚合物筛选实验，考虑到药物释放曲线和挤出温度（70°C），选择了聚己内酯（芯）和聚氧化乙烯（壳）的组合进行共挤出试验。该组合（壳中含有 10%HCT，芯中含有 45%MPT）成功地进行了共挤出（芯直径：3 毫米/壳厚度：0.5 毫米）。两层聚合物之间的附着力良好。HCT 从壳层中的释放在 30 分钟内完全完成，而 MPT 的释放则持续 24 小时（4、8、12 和 24 小时后分别释放 55%、70%、85%和 100%）。DSC、XRD 和拉曼光谱表明，MPT 在挤出过程中保持结晶状态，而 HCT 溶解在聚氧化乙烯基质中。体内研究表明，实验制剂与参比制剂（Zok-Zid 片）之间没有显著差异。通过共挤出，使用聚己内酯和聚氧化乙烯的组合，成功开发出具有良好体外和体内性能的固定剂量组合迷你片剂。
