盐酸坦索罗辛缓释微丸的工艺研究

Preparation of tamsulosin hydrochloride sustained-release pellets

目的丙烯酸树脂包衣制备盐酸坦索罗辛缓释微丸。方法以EUDRAGIT（R）NE 30D作为主要缓释材料,配以EUDRAGIT（R）L 30D-55和羟丙基甲基纤维素（HPMC）Methocel（R）E3作为释放调节剂,用流化床底喷先载药空白糖丸,而后进行该单层缓释包衣,制备盐酸坦索罗辛缓释微丸。采用Box-Behnken三因素三水平试验设计,优化缓释层组方中影响微丸释放的3个非线性影响因素：Methocel（R）E3在聚合物中的百分比、EUDRAGIT（R）L 30D-55干聚物在聚合物中的百分比和聚合物总增重,以小丸在2、3和5h的体外累积释放度作为考察指标,并以2h释放在12%～39%、3h释放在44%～70%和5h释放〉70%为优化范围。结果优化后确定了丙烯酸树脂为主的三种材料协同控制药物释放的单层缓释包衣处方中三因素水平为聚合物总增重为12%,其中EUDRAGIT（R）L 30D-55和Methocel（R）E3分别为总干聚物的7%和2%（均以干聚物计）。通过优化配方制得的盐酸坦索罗辛缓释微丸的体外释放度实际值接近预测值,并通过相似因子f2法比较,与市售制剂（Harnal（R））缓释胶囊微丸体外释放行为具有良好的相似性（3批样品的f2分别为71、73、80）。结论本研究处方工艺简便、重现性和稳定性均良好。

Objective To prepare tamsulosin hydrochloride sustained-release pellet by coating with acrylic copolymers. Methods EUDRAGIT NE 30 D was used as the main sustained-release material, EUDRAGIT L 30 D-55 and Methocel E3 were used as release adjust agent; a one layer sustained-release coating was done for tamsulosin hydrochloride-loaded pellet in bottom spray fluid bed. A three factor, three-level Box-Behnken design was used to optimize the percentages of EUDRAGIT L 30 13-55 and Methocel E3 in the total dry polymers and the weight gain of total dry polymers as the three nonlinear factors, which mainly influenced drug release of the pellets in the formula of sustained-release coating layer. In-vitro cumulative drug release after 2 h, 3 h and 5 h was tested and the following target range： 2 h 12%-39%, 3 h 44%-70% and 5 h〉70% were set for optimization. Results The formulation and process of one layer sustained-release coating, which was synergistically controlled by the three materials based on acrylic copolymers, was determined after optimization： the total dry polymers were applied with a weight gain of 12% on drug pellets, with EUDRAGIT L 30 D-55 dry polymers and Methocel E3 being 7% and 2% of the total dry polymers, respectively. The sustained-release pellets coated with the optimized formulation provided a release profile that was close to the predicted value and similar to that of the commercial product Harnal capsule pellets by f2 similarity factor comparison （f2 values of three batches were 71,73 and 80）. Conclusion The established formulation and process is a simple and reproducible method to prepare tamsulosin hydrochloride sustained-release pellets with good stability.