Quinten Thomas, Gonnissen Yves, Adriaens Els, De Beer Thomas, Cnudde Veerle, Masschaele Bert, Van Hoorebeke Luc, Siepmann Juergen, Remon Jean Paul, Vervaet Chris
Laboratory of Pharmaceutical Technology, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
Eur J Pharm Sci. 2009 Jun 28;37(3-4):207-16. doi: 10.1016/j.ejps.2009.02.006. Epub 2009 Feb 21.
The objective of this study was to produce sustained-release matrix tablets by means of injection moulding and to evaluate the influence of matrix composition, process temperature and viscosity grade of ethylcellulose on processability and drug release by means of a statistical design. The matrix tablets were physico-chemically characterized and the drug release mechanism and kinetics were studied. Formulations containing metoprolol tartrate (30%, model drug), ethylcellulose with dibutylsebacate (matrix former and plasticizer) and L-HPC were extruded and subsequently injection moulded into tablets (375mg, 10mm diameter, convex-shaped) at different temperatures (110, 120 and 130 degrees C). Dissolution tests were performed and tablets were characterized by means of DSC, X-ray powder diffraction studies, X-ray tomography, porosity and hardness. Tablets containing 30% metoprolol and 70% ethylcellulose (EC 4cps) showed an incomplete drug release within 24h (<50%). Formulations containing L-HPC and EC in a ratio of 20/50 and 27.5/42.5 resulted in nearly zero-order drug release, while the drug release rate was not constant when 35% L-HPC was included. Processing of these formulations was possible at all temperatures, but at higher processing temperatures the drug release rate decreased and tablet hardness increased. Higher viscosity grades of EC resulted in a faster drug release and a higher tablet hardness. The statistical design confirmed a significant influence of the EC and L-HPC concentration on drug release, while the processing temperature and EC viscosity grade did not affect drug release. Tablet porosity was low (<5%), independent of the formulation and process conditions. DSC and XRD demonstrated the formation of a solid dispersion. The hydration front in the tablets during dissolution was visualized by dynamic X-ray tomography, this technique also revealed an anisotropic pore structure through the tablet.
本研究的目的是通过注射成型制备缓释骨架片，并通过统计设计评估骨架组成、工艺温度和乙基纤维素的粘度等级对可加工性和药物释放的影响。对骨架片进行了物理化学表征，并研究了药物释放机制和动力学。将含有酒石酸美托洛尔（30%，模型药物）、乙基纤维素与癸二酸二丁酯（骨架形成剂和增塑剂）以及低取代羟丙基纤维素（L-HPC）的制剂进行挤出，随后在不同温度（110、120和130℃）下注射成型为片剂（375mg，直径10mm，凸形）。进行了溶出度试验，并通过差示扫描量热法（DSC）、X射线粉末衍射研究、X射线断层扫描、孔隙率和硬度对片剂进行了表征。含有30%美托洛尔和70%乙基纤维素（4cps的EC）的片剂在24小时内药物释放不完全（<50%）。含有比例为20/50和27.5/42.5的L-HPC和EC的制剂导致药物几乎呈零级释放，而当包含35%的L-HPC时，药物释放速率不稳定。所有温度下都可以对这些制剂进行加工，但在较高的加工温度下，药物释放速率降低，片剂硬度增加。较高粘度等级的EC导致药物释放更快，片剂硬度更高。统计设计证实了EC和L-HPC浓度对药物释放有显著影响，而加工温度和EC粘度等级对药物释放没有影响。片剂孔隙率较低（<5%），与制剂和工艺条件无关。DSC和XRD证明形成了固体分散体。通过动态X射线断层扫描观察了片剂在溶出过程中的水化前沿，该技术还揭示了片剂内部各向异性的孔隙结构。
