甲硝唑结肠靶向制剂的制备及评价
摘要
[目的] 初步确立离心包衣造粒技术制备甲硝唑结肠靶向制剂的方法。[方法]首先，以对乙酰氨基酚为模型药物，淀粉为丸芯材料，50%蔗糖为粘和剂，利用离心包衣造粒法制备淀粉微丸，并以丙烯酸树脂水分散体为包衣材料制备包衣微丸。通过测定微丸粒径大小分布、休止角、脆碎度、水分含量、微丸得率和不同pH条件下的释药特性等优化包衣微丸的制备工艺。其次，以确定微丸制备方法，甲硝唑为模型药物，L-HPC为崩解剂，丙烯酸树脂和乙基纤维素为外层控释包衣材料，邻苯二甲酸二乙酯为增塑剂，滑石粉为润滑剂，来制备控释微丸，用释放度测定法评价微丸在不同pH介质中的释放特性。[结果] 对乙酰氨基酚微丸大小在210?m—1660?m范围的约占88%以上；微丸的休止角为20.06 o，表明流动性良好；微丸的脆碎度为1.11±0.79%, 水分含量为9.05%，一次性微丸得率为51.11%。对乙酰氨基酚包衣微丸在人工胃液和人工肠液的体外溶出实验结果表明，包衣液输送速度小、主机转速快、包衣温度高、包衣液喷浆速度小和喷浆压力大时均可以形成较为均匀的包衣层，使微丸中药物释放速度降低。随着包衣重量增加、乙基纤维素用量增加和崩解剂用量的减少，甲硝唑在人工胃液和人工肠液中的释放呈明显降低的趋势。在Eudragit S100增重25%、增塑剂用量为15%、L-HPC 用量为3%时具有较好的结肠靶向脉冲释放效果。[结论] 离心包衣造粒法可以制备具有结肠靶向特性的甲硝唑微丸，其工艺稳定，批与批之间的重现性良好。
[Objective] To establish a preparation technique of Metronidazole- loaded colon specific drug delivery systems by centrifuge coating granulation method. [Method] First, Acetaminophen was preliminary selected as a model drug. Cornstarch, 50% sucrose syrup and aqueous polymethacrylate dispersion were used as core pellet excipient, adhesion reagent and coating solution, respectively. The coating pellets were characterized by size distribution, angle of repose, resistance to abrasion, moisture content and dissolution test in different pH solution. The preparation method of metronidazole-loaded colon specific drug delivery systems (CSDDS) were studied based on the previous work. The effect of low submitted hydroxypropylcellulose (L-HPC), Eudragit S 100 and ethyl cellulose on the dissolution of metronidazole -loaded CSDDS were evaluated in the simulated gastric fluid and simulated intestinal fluid. [Results] More than 88% of Acetaminophen pellets are in the range of 210-1660?m and the angle of repose is 20.06 o. Result of resistance to abrasion test of pellets is 1.11±0.79%, moisture content is 9.05%. The drug release of acetaminophen pellets were have a tendency of decrease while the coating weight, rotary speed of coating pan and coating air pressure increase, but coating speed reduced. The dissolution data of indicated that a higher amount of coating weight and EC in reduced metronidazole release.
The metronidazole-loaded pellets showed a kind of dissolution phenomenon similar to pulsed and CSDDS, while formulated with 3% L-HPC as disintegrant and coated by 25% Eudragit S 100 and 15% DEP as Plasticizer. [Conclusion] Metronidazole-loaded CSDDS was successively established by centrifuge coating granulation method with low batch variation and reproducible.
[Objective] To establish a preparation technique of Metronidazole- loaded colon specific drug delivery systems by centrifuge coating granulation method. [Method] First, Acetaminophen was preliminary selected as a model drug. Cornstarch, 50% sucrose syrup and aqueous polymethacrylate dispersion were used as core pellet excipient, adhesion reagent and coating solution, respectively. The coating pellets were characterized by size distribution, angle of repose, resistance to abrasion, moisture content and dissolution test in different pH solution. The preparation method of metronidazole-loaded colon specific drug delivery systems (CSDDS) were studied based on the previous work. The effect of low submitted hydroxypropylcellulose (L-HPC), Eudragit S 100 and ethyl cellulose on the dissolution of metronidazole -loaded CSDDS were evaluated in the simulated gastric fluid and simulated intestinal fluid. [Results] More than 88% of Acetaminophen pellets are in the range of 210-1660?m and the angle of repose is 20.06 o. Result of resistance to abrasion test of pellets is 1.11±0.79%, moisture content is 9.05%. The drug release of acetaminophen pellets were have a tendency of decrease while the coating weight, rotary speed of coating pan and coating air pressure increase, but coating speed reduced. The dissolution data of indicated that a higher amount of coating weight and EC in reduced metronidazole release.
The metronidazole-loaded pellets showed a kind of dissolution phenomenon similar to pulsed and CSDDS, while formulated with 3% L-HPC as disintegrant and coated by 25% Eudragit S 100 and 15% DEP as Plasticizer. [Conclusion] Metronidazole-loaded CSDDS was successively established by centrifuge coating granulation method with low batch variation and reproducible.
引文
[1] 药剂学（第四版）,毕殿洲主编,人民卫生出版社
[2] 傅崇东,徐惠南,张瑜,5-氨基水杨酸与其结肠靶向制剂,上海医药,1999,20（4）:29-30
[3] 陶雅菊,徐惠南,口服结肠靶向释药系统.中国临床药学杂志,1996,5:81
[4] Van den Mooter G, Kinget R Oral colon-specific drug delivery. system: a review [J].Drug Deliver,1995,2:81
[5] 莫韫,张钧寿,结肠靶向给药系统研究进展.中国新药杂志, 1999,8（6）:368-370
[6] 梁桂贤,刘谦民.结肠定位给药系统研究概况,国外医药----合成药 生化药 制剂分册, 1999,20（4）:250-252
[7] 张宁,朱家壁.口服缓控释制剂技术发展的新动向,国外医学药学分册,2000,27（4）:240-243
[8] 于少云,王洪光,刘璐,尔艳,刘力.微丸的进展.中国新药杂志.1999,8（12）:803-805
[9] Rutgeerts P.Aliment Pharmacy Ther,1998;3:183
[10] Friend DR,Advanced Drug Delivery Reviews,1991;7:149
[11] 上海医药工业研究院药物制剂研究室,药物辅料应用技术,北京:中国医药科技出版社,1991,140-141
[12] 黄天文,徐群为,郝钦.双氯芬酸钾缓释微丸的初步研制,广西医学,2000,4（22）:704-706
[13] 郝钦,岗艳云,朱家壁,硝酸异山梨酯脉冲控释微丸的研制,中国医药工业杂志,1999,30（3）:109-112
[14] 奚念朱主编,药剂学.第三版,北京:人民卫生出版社,1994:284
[15] 尤孝庆,卢丹,许美蓉,缓释微丸工艺研究,中国医药工业杂志,1996,27（4）:163-165
[16] 钱方,蒋雪涛,王安,右美沙芬缓释微丸的研究,第二军大学学报,1997,8,18（2）:144-146
[17] 刘善奎,钟延强,孙其荣,盐酸尼卡地平肠溶缓释微丸的研制,中国药学杂志,1999,11,34（11）:750-752
[18] 曾环想,潘卫三,陈济民,庄殿友,吲哚美辛肠溶包衣微丸的制备及其释放度的研究,中国药学杂志,1997,7,32（7）:415-418
[19] 陈庆华,1995全国医药工业技术工作年专题报告选编,北京:中国化学制药工业协会,1995:54
[20] 傅崇东,张瑜,徐惠南,增塑剂及热处理对水性包衣美沙拉秦结肠靶向微丸体外释药的影响,中国医药工业杂志, 2000,31（4）:149-151
[21] 陈挺,陈庆华,乙基纤维素水性包衣技术I水分散体与有机溶液包衣方法的比较,中国医药工业杂志,2000,31（1）: 7-11
[22] 张焱,陈庆华.红霉素肠溶微丸及其特性研究,中国医药工业杂志,1996,27（10）:448
[23] 张玉琥,吴畏,李汉蕴,中国医药工业杂志,1993,24（12）:538-540
[24] 张玉琥,张彤等,中国药学杂志,1994,29（9）:533
[2] 傅崇东,徐惠南,张瑜,5-氨基水杨酸与其结肠靶向制剂,上海医药,1999,20（4）:29-30
[3] 陶雅菊,徐惠南,口服结肠靶向释药系统.中国临床药学杂志,1996,5:81
[4] Van den Mooter G, Kinget R Oral colon-specific drug delivery. system: a review [J].Drug Deliver,1995,2:81
[5] 莫韫,张钧寿,结肠靶向给药系统研究进展.中国新药杂志, 1999,8（6）:368-370
[6] 梁桂贤,刘谦民.结肠定位给药系统研究概况,国外医药----合成药 生化药 制剂分册, 1999,20（4）:250-252
[7] 张宁,朱家壁.口服缓控释制剂技术发展的新动向,国外医学药学分册,2000,27（4）:240-243
[8] 于少云,王洪光,刘璐,尔艳,刘力.微丸的进展.中国新药杂志.1999,8（12）:803-805
[9] Rutgeerts P.Aliment Pharmacy Ther,1998;3:183
[10] Friend DR,Advanced Drug Delivery Reviews,1991;7:149
[11] 上海医药工业研究院药物制剂研究室,药物辅料应用技术,北京:中国医药科技出版社,1991,140-141
[12] 黄天文,徐群为,郝钦.双氯芬酸钾缓释微丸的初步研制,广西医学,2000,4（22）:704-706
[13] 郝钦,岗艳云,朱家壁,硝酸异山梨酯脉冲控释微丸的研制,中国医药工业杂志,1999,30（3）:109-112
[14] 奚念朱主编,药剂学.第三版,北京:人民卫生出版社,1994:284
[15] 尤孝庆,卢丹,许美蓉,缓释微丸工艺研究,中国医药工业杂志,1996,27（4）:163-165
[16] 钱方,蒋雪涛,王安,右美沙芬缓释微丸的研究,第二军大学学报,1997,8,18（2）:144-146
[17] 刘善奎,钟延强,孙其荣,盐酸尼卡地平肠溶缓释微丸的研制,中国药学杂志,1999,11,34（11）:750-752
[18] 曾环想,潘卫三,陈济民,庄殿友,吲哚美辛肠溶包衣微丸的制备及其释放度的研究,中国药学杂志,1997,7,32（7）:415-418
[19] 陈庆华,1995全国医药工业技术工作年专题报告选编,北京:中国化学制药工业协会,1995:54
[20] 傅崇东,张瑜,徐惠南,增塑剂及热处理对水性包衣美沙拉秦结肠靶向微丸体外释药的影响,中国医药工业杂志, 2000,31（4）:149-151
[21] 陈挺,陈庆华,乙基纤维素水性包衣技术I水分散体与有机溶液包衣方法的比较,中国医药工业杂志,2000,31（1）: 7-11
[22] 张焱,陈庆华.红霉素肠溶微丸及其特性研究,中国医药工业杂志,1996,27（10）:448
[23] 张玉琥,吴畏,李汉蕴,中国医药工业杂志,1993,24（12）:538-540
[24] 张玉琥,张彤等,中国药学杂志,1994,29（9）:533
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