Guthmann C, Lipp R, Wagner T, Kranz H
Pharmaceutical Development, Bayer Schering Pharma AG, Berlin, Germany.
Eur J Pharm Biopharm. 2008 Jun;69(2):667-74. doi: 10.1016/j.ejpb.2007.12.017. Epub 2007 Dec 28.
The drug substance SAG/ZK has a short biological half-life and because of its weakly basic nature a strong pH-dependent solubility was observed. The aim of this study was to develop a controlled release (cr) multiple unit pellet formulation for SAG/ZK with pH-independent drug release. Pellets with a drug load of 60% were prepared by extrusion/spheronization followed by cr-film coating with an extended release polyvinyl acetate/polyvinyl pyrrolidone dispersion (Kollidon SR 30 D). To overcome the problem of pH-dependent drug release the pellets were then coated with a second layer of an enteric methacrylic acid and ethyl acrylate copolymer (Kollicoat MAE 30 DP). To increase the drug release rates from the double layered cr-pellets different osmotically active ionic (sodium and potassium chloride) and nonionic (sucrose) additives were incorporated into the pellet core. Drug release studies were performed in media of different osmotic pressure to clarify the main release mechanism. Extended release coated pellets of SAG/ZK demonstrated pH-dependent drug release. Applying a second enteric coat on top of the extended release film coat failed in order to achieve pH-independent drug release. Already low enteric polymer levels on top of the extended release coated pellets decreased drug release rates at pH 1 drastically, thus resulting in a reversal of the pH-dependency (faster release at pH 6.8 than in 0.1N HCl). The addition of osmotically active ingredients (sodium and potassium chloride, and sucrose) increased the imbibing of aqueous fluids into the pellet cores thus providing a saturated drug solution inside the beads and increasing drug concentration gradients. In addition, for these pellets increased formation of pores and cracks in the polymer coating was observed. Hence drug release rates from double layered beads increased significantly. Therefore, pH-independent osmotically driven SAG/ZK release was achieved from pellets containing osmotically active ingredients and coated with an extended and enteric polymer. In contrast, with increasing osmotic pressure of the dissolution medium the in vitro drug release rates decreased significantly.
药物活性成分SAG/ZK的生物半衰期较短，且由于其弱碱性，观察到其溶解度强烈依赖于pH值。本研究的目的是开发一种用于SAG/ZK的控释（cr）多单元微丸制剂，使其药物释放不依赖于pH值。通过挤出/滚圆法制备载药量为60%的微丸，然后用缓释聚醋酸乙烯酯/聚乙烯吡咯烷酮分散体（Kollidon SR 30 D）进行cr薄膜包衣。为克服药物释放依赖pH值的问题，随后用肠溶型甲基丙烯酸和丙烯酸乙酯共聚物（Kollicoat MAE 30 DP）对微丸进行第二层包衣。为提高双层cr微丸的药物释放速率，将不同的渗透活性离子（氯化钠和氯化钾）和非离子（蔗糖）添加剂加入微丸芯中。在不同渗透压的介质中进行药物释放研究，以阐明主要释放机制。SAG/ZK的缓释包衣微丸表现出药物释放依赖pH值。在缓释薄膜包衣之上再施加一层肠溶包衣未能实现药物释放不依赖于pH值。在缓释包衣微丸之上即使是低水平的肠溶聚合物也会使pH值为1时的药物释放速率大幅降低，从而导致pH依赖性逆转（在pH 6.8时比在0.1N盐酸中释放更快）。添加渗透活性成分（氯化钠、氯化钾和蔗糖）增加了水性流体进入微丸芯的吸收，从而在微丸内部提供饱和药物溶液并增加药物浓度梯度。此外，观察到这些微丸的聚合物包衣中孔隙和裂缝形成增加。因此，双层微丸的药物释放速率显著提高。所以，通过含有渗透活性成分并包有缓释和肠溶聚合物的微丸实现了不依赖pH值的渗透驱动的SAG/ZK释放。相反，随着溶出介质渗透压的增加，体外药物释放速率显著降低。
