多单元口崩脉冲控释片的研制.Ⅰ.盐酸地尔硫脉冲控释小丸的制备

Preparation of Multiple-unit, Pulsatile Controlled-release Orally Disintegrating Tablets .Ⅰ. Preparation of Diltiazem Hydrochloride Pulsatile Controlled-release Pellets

采用流化床侧喷技术将盐酸地尔硫(1)细粉(≤0.075 mm)制成芯粒(约0.15 mm),继而增大成微丸(0.25 mm),再以聚丙烯酸树脂为包衣材料采用底喷技术制备了1脉冲控释小丸。通过单因素试验确定芯粒的处方,采用正交设计优化了脉冲控释小丸的处方。结果表明,以胶态二氧化硅为润滑剂、6%共聚维酮(Kollidon VA64)为黏合剂,采用流化床侧喷技术将药物细粉制成芯粒,再喷入含有药物细粉、胶态二氧化硅和VA 64的50%乙醇溶液,继续增大制成微丸。然后采用底喷工艺将此微丸用聚丙烯酸树脂[Eudragit RS100与Eudragit L100/S100(1∶1)的重量比为3∶1,增塑剂枸橼酸三乙酯用量为20%]包衣,增重为70%。所制1脉冲小丸经约4 h时滞后形成一波脉冲式释放,5 h时累积释放率约为20%,随后以近恒定速率释药,24 h时药物基本释放完全。稳定性试验结果表明,制品在(40±2)℃、相对湿度(75±5)%条件放置6个月和(30±2)℃、相对湿度(65±5)%条件放置24个月,体外释放行为无明显变化。

The diltiazem hydrochloride microspheres with mean diameter of about 0.25 mm were prepared by fluidized-bed tangential-spraying technology with drug-loaded particles （about 0.15 mm） which were prepared with bulk powder （≤0.075 mm） by the same technique. Then the pulsatile controlled-release pellets were prepared with the above microspheres by bottom-spraying technology. The formulations of the drug-loaded particles and pellets were optimized by single-factor test and orthogonal test, respectively. The optimal preparation was as follows： the particles were prepared by tangential-spraying technology with colloidal silica as lubricant and Kollidon VA64 as adhesive, then sprayed 50 % ethanol （containing bulk powder, colloidal silica and Kollidon VA64） to obtain microspheres. The microspheres were coated with the mixture of Eudragit RS100 and Eudragit L100/S100 （1 ： 1） of the weight ratio of 3 ： 1 （containing 20% triethyl citrate as plasticizer） at coating level of 70% to obtain the pellets. The pulsatile release was observed after a lag time of about 4 h. The cumulative amount at 5 h was about 20 %, then the drug was released at a nearly constant rate. Finally, the drug was completely released at 24 h. The results of stability test showed that in vitro release behavior of the product stored at （40±2） ℃ [relative humidity of （75±5） %] for 6 months and （30±2） ℃ [relative humidity of （65±5） %] for 24 months was not significantly changed.