湿法研磨结合流化床包衣法制备盐酸度洛西汀肠溶微丸

Duloxetine hydrochloride enteric-coated pellets preparation using wet milling combined fluidized bed coating technology

目的采用湿法研磨技术及流化床包衣法制备盐酸度洛西汀肠溶微丸,并依据体外释放试验对处方进行筛选。方法采用湿法研磨技术将难溶性盐酸度洛西汀与亲水性载体羟丙甲纤维素(HPMC-E5)进行前处理,作为药物混悬包衣液,以羟丙甲纤维素溶液作为隔离层材料,Eudragit L30D-55水分散体作为肠溶层材料,底喷流化床包衣法制成盐酸度洛西汀肠溶微丸。通过考察体外释放度筛选盐酸度洛西汀肠溶微丸工艺处方。结果药物经过湿法研磨后,粒径由2.99×104 nm降低到595 nm。由体外释放试验可知,自制制剂与参比制剂体外释放曲线基本一致,在p H值1.0盐酸溶液中120 min时释放度小于10%,而在p H值6.8磷酸盐缓冲液中60 min时释放度大于75%,符合标准。扫描电镜可见微丸表面光滑、圆整。结论湿法研磨技术可显著降低药物粒径,提高包衣效率及药物体外释放度。盐酸度洛西汀肠溶微丸体外释放符合要求,性状稳定,制备工艺简单易行,有望应用于工业化生产。

Objective Using wet milling technology and fluidized bed coating methods, duloxetine hydrochloride enteric-coated pellets were prepared and the formulation was optimized with respect of in vitro release. Methods The insoluble duloxetine and hydrophilic HPMC-E5 were pretreated by wet milling technology, and drug suspension was coated onto the pellet cores for drug loading process. HPMC-E5 solution and Eudragit L30D-55 aqueous dispersion were used as isolation layer material and enteric layer material by bottom spray fluid bed coating method, respectively. The in vitro release of duloxetine pellets was determined for optimization of formulation and process. Results Particle size of drug was reduced from 29.9 μm to 595.4 nm by wet milling. Similar in vitro release curves were obtained for homemade and reference preparations. The accumulative release was less than 10% at 120 min in p H1.0 hydrochloric acid solution, and higher than 75% at 60 min in p H6.8 phosphate buffer, which meets the quality requirement. Scanning electron microscopy showed that pellets was round in shape with smooth surface. Conclusion Wet milling technology can significantly reduce particle size of drugs, enhance the efficiency of coating and drug release in vitro. The in vitro release of duloxetine enteric-coated pellets could meet the requirement. With this high stability and simple preparation process, it is expected to be applied to industrial production.