Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium.
Int J Pharm. 2014 Apr 10;464(1-2):65-74. doi: 10.1016/j.ijpharm.2014.01.028. Epub 2014 Jan 28.
In this study, hot-melt co-extrusion was evaluated as a technique for the production of fixed-dose combination products, using ethylcellulose as a core matrix former to control the release of metoprolol tartrate and a polyethylene oxide-based coat formulation to obtain immediate release of hydrochlorothiazide. By lowering the concentration of the hydrophilic additive polyethylene oxide in the plasticized ethylcellulose matrix or by lowering the drug load, the in vitro metoprolol tartrate release from the core was substantially sustained. The in vitro release of hydrochlorothiazide from the polyethylene oxide/polyethylene glycol coat was completed within 45 min for all formulations. Tensile testing of the core/coat mini-matrices revealed an adequate adhesion between the two layers. Raman mapping showed no migration of active substances. Solid state characterization indicated that the crystalline state of metoprolol tartrate was not affected by thermal processing via hot-melt extrusion, while hydrochlorothiazide was amorphous in the coat. These solid state characteristics were confirmed during the stability study. Considering the bioavailability of metoprolol tartrate after oral administration to dogs, the different co-extruded formulations offered a range of sustained release characteristics. Moreover, high metoprolol tartrate plasma concentrations were reached in dogs allowing the administered dose to be halved.
在这项研究中，热熔挤出技术被评估为一种生产固定剂量组合产品的技术，使用乙基纤维素作为核心基质形成剂来控制酒石酸美托洛尔的释放，并使用基于聚环氧乙烷的包衣配方来实现氢氯噻嗪的即刻释放。通过降低增塑乙基纤维素基质中亲水性添加剂聚环氧乙烷的浓度或降低药物载量，可以大大延长核心中美托洛尔酒石酸盐的体外释放。所有配方中，聚环氧乙烷/聚乙二醇包衣从体外释放氢氯噻嗪在 45 分钟内完成。对核心/涂层微型基质的拉伸测试表明两层之间具有足够的附着力。拉曼映射显示没有活性物质的迁移。固态特性表明，热熔挤出过程中热加工不会影响酒石酸美托洛尔的结晶状态，而氢氯噻嗪在包衣中呈无定形状态。这些固态特性在稳定性研究中得到了证实。考虑到狗口服酒石酸美托洛尔后的生物利用度，不同的共挤出配方提供了一系列的缓释特性。此外，狗体内达到了较高的酒石酸美托洛尔血浆浓度，允许将给药剂量减半。
