论文总字数：20860字

摘 要

富马酸二甲酯肠溶速释胶囊是2013年以来经美国FDA批准上市的，治疗多发性硬化症（Multiple Sclerosis）的新型口服药物，国内对其的研究仿制还处于初步阶段，因此具有较大的研究价值。目的：本次课题通过对富马酸二甲酯肠溶速释胶囊（TECFIDERA^TM）的研究，从而进行该药物的处方及其工艺的探索与筛选，最终制备出与原研药品外观相似，溶出相似，脆碎度、含水量合适的合格胶囊。方法：运用挤出-滚圆机制备包含药物的丸芯，再通过流化床来进行包衣操作，最终经灌装机灌装制得胶囊。通过单因素筛选法，分别对可能对药物制备有影响的处方因素及工艺因素中的参数进行研究与调整；具体的有如下几方面：（1）药物丸芯处方中的主辅料配比、粘合剂及其溶媒的用量和种类等；包衣层处方中的填充剂和吸收剂、崩解剂等辅料的选择；（2）挤出滚圆机工艺参数考察包括：挤出机孔板孔径及挤出速率、抛丸机的转盘频率、风机频率、干燥时间及温度；流化床工艺参数考察主要包括：风机的频率、雾化的压力、进液速率及进风的温度等。结果：原辅料配比约为12：13，以40% 聚维酮配成的醇溶液为粘合剂，交联羧甲基纤维素钠为崩解剂，MCC301、16%乳糖作为填充剂；挤出机频率为15Hz，孔板孔径选择0.6mm，抛丸机频率50Hz,转盘频率30Hz；流化床风机频率50Hz，进液速度10rpm，进风温度40℃。结论：在上述的处方及工艺条件下所制得的微丸圆整度好，脆碎度、含水量适宜，与原研药具有相似的释放度。

关键词：富马酸二甲酯 肠溶速释胶囊 处方筛选

Study on prescription selection and technology of dimethyl fumarate enteric - coated capsules

Abstract

Dimethyl fumarate delayed-release capsules, which has been approved by the US FDA in recent years, is a new drug for the treatment of multiple sclerosis. It is still in the preliminary stage of its domestic research and might be of great value of its generic drugs. OBJECTIVE: in this paper, the study of Dimethyl fumarate enteric-coated capsules was carried out to screen and develop its prescription and process. As a result, the capsules have appropriate appearance, dissolution, fragility, and water content similar to the original capsules (TECFIDERA™).METHOD: The pellets containing DMF were prepared by extrusion-spheronization method, and then the coating was carried out through the fluidized bed. Finally, the capsules were prepared by filling the filling machine. We test and adjust several factors in its prescription and parameters upon its process, through single factor screening method ,which may affect the drugs ,and the specific contents are as follows:(1)the ratio of the mixed ingredients in the formula; selection of adhesives, lubricants, disintegrants and so on.(2)parameters set during the extrusion-spheronization process: extruder aperture and extrusion rate, shot wheel frequency, fan frequency, drying time and temperature; The parameters of the fluidized bed process include: fan frequency, atomization pressure, feed rate and inlet temperature. RESULTS: The ratio of raw materials is about 12:13, the alcohol solution with 40% PVP is used as binder, CCNa is disintegrant, MCC301, 16% lactose as filler, extruder frequency is 15Hz, pore size selection 0.6mm, shot blasting machine frequency 50Hz, turntable frequency 30Hz; fluidized bed fan frequency 50Hz, feed rate 10rpm, inlet temperature 40℃.CONCLUSION:in the above conditions, the pellets we made have the similiar appearance, breakage and hardness compared with the originals. They also share a similiar degree of release.

Key Words: Dimethyl fumarate; Enteric-coated capsules; Prescription screening

目录

摘要 I

Abstract II

第一章 文献综述 1

1.1多发性硬化症（Multiple Sclerosis，MS） 1

1.1.1病症简介 1

1.1.2流行病学与临床症状 1

1.1.3市场治疗用药 1

1.2富马酸二甲酯（Dimethyl Fumarate，DMF）简介 4

1.3关于富马酸二甲酯药物的研究 4

1.3.1药代动力学研究 4

1.3.2药效学研究 5

1.4课题方向及选题意义 6

1.4.1 立题依据 6

1.4.2 主要研究内容 7

第二章 富马酸二甲酯肠溶速释胶囊处方筛选与工艺研究 8

2.1实验材料与实验仪器 8

2.1.1 实验材料 8

2.1.2实验仪器 8

2.2处方筛选与工艺研究 9

2.2.1评价指标 9

2.2.2初步处方与工艺拟定 9

2.3处方工艺筛选 10

2.3.1丸芯处方工艺筛选 10

2.3.2丸芯工艺筛选 11

2.3.4包衣工艺考察 12

第三章 实验结果与讨论 15

3.1丸芯处方筛选 15

3.1.1粘合剂的选用 15

3.1.2粘合剂的用量 15

3.1.3微晶纤维素MCC的影响 16

3.1.4崩解剂的选择 16

3.1.5粘合剂溶媒的选用 16

3.1.6 乳糖（填充剂）的选用 17

3.2 丸芯工艺参数筛选 17

3.2.1 孔板孔径 17

3.2.2 挤出速率的选择 17

3.2.3 转盘频率 18

3.2.4 风机频率 18

3.2.5 干燥温度 19

3.3 包衣工艺参数筛选 20

3.3.1 内层肠溶包衣层工艺参数筛选 20

3.3.2外层肠溶包衣层工艺参数筛选 21

3.3.3 包衣层增重测算 22

3.4 处方及工艺的确定 23

3.4.1 处方 23

3.4.2 生产工艺确立 24

3.5 工艺路线流程图 25

3.6 本章小结 25

第四章 总结与展望 27

参考文献 28

致谢 30

第一章 文献综述

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