肠宁滴丸的药学研究
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摘要
本文针对溃疡性结肠炎(UC),根据临床需要和中药治疗特点,选择治疗UC具有显著疗效、成分在胃肠道易被破坏、仅灌肠给药的美洲大蠊提取物作为原料药物,制备肠宁口服结肠定位制剂,进行了半成品质量标准、制剂体内外评价、质量标准等研究。主要研究内容如下:
对半成品进行了药材来源、性状、TLC鉴别、含量测定等项目的研究,建立了半成品定性、定量的质量标准。
选择将含油性成分较多的半成品制备成滴丸,再包上肠溶衣,达到结肠定位释放的目的。在滴丸成型工艺研究中,首先采用单因素考察方法,对基质种类、基质与药物的比例、料液温度、冷凝剂种类、冷凝温度、滴距、滴速等影响因素进行了考察。在单因素考察的基础上,选择基质与药物的比例、料液温度和滴速等对滴制工艺有较大影响的因素作为考察因素,选择其较优参数作为考察水平,安排正交试验,最终确定滴丸的成型工艺。在包衣工艺研究中,针对单层包衣pH依赖制剂在小肠的药物泄漏问题,参考西药CODES~(TM)结肠释药设计,采用pH—酶依赖和多层包衣法,制剂由内到外为:滴丸丸芯、多糖衣、肠溶衣、隔离衣、酸溶衣,选择体外释放度作为评价方法,考察并确定了滴丸的包衣工艺。将多层包衣滴丸置扫描式电子显微镜下观察,研究其释药机理,实验证明多层包衣滴丸的释药行为与原设计相吻合.
对制剂进行体外释放度的研究,结果表明,多层包衣滴丸在胃内药物无释放,在小肠内药物泄漏极少(6.1%),在含酶肠液0.5小时内累积释放48.7%,1小时内累积释放86.5%,有明显的突释过程,在含酶肠液中2小时药物释放完全,释药曲线最为符合结肠定位给药设计。采用X射线Baso_4显影法研究多层包衣滴丸在人体内的释药行为,结果表明,包衣滴丸在和人体内能顺利地通过胃;在小肠运转过程中,多层包衣滴丸外形完整,基本无变化;包衣滴丸崩解部位集中在升结肠和横结肠,多层包衣滴丸具有良好的结肠定位性能。
对制剂建立了TLC鉴别方法,对相关物质进行了检查,运用分光光度法和氨基酸自动测定两种方法对制剂进行了含量测定,建立了定量标准。
To aim at ulcerative colitis(UC),according to the clinic use and character of Chinese medicine,choosing Periplaneta Americana which has significant curative effect in clinic of UC,with its main component(component ~ protein) easily destroyed in protein and to give only by clysters as research object,prepare it as ChangNing colon delivery praeparatum for oral use,and research the quality standard of half-finished product,,exterior and interior evaluation and quality standard etc.The main contents include:
By studying the medical material resource、character、TLC and assaying,build up the qualitation and quantitation of half-finished product.Choose half-finished product with more oil components to prepare dripping pills,then coating colon-dissolving material to achieve the purpose of delivery dispelling in colon.In the artwork research of dripping pills,apply mon-factor investigation to find out the kind of base material、the ratio of base material and medicine、the temperature of dosage liquor、the kind of condensing agent、the temperature of condensing agent、the dripping distance and speed etc.Further more,chose the ratio of base material and medicine、the temperature of dosage liquor and the dripping speed which have larger influence factors,with better indexes as research levels to decide the forming artwork of dripping pills with orthogonal experiment.In the research of coating artwork, referring CODES~(TM) colon dispelling design of western medicine,apply pH-enzyme relying association leechdom mechanism and multi-coating technology,settle the coating artwork as:(from inside to outside)heart of dripping pill,sugarcoating,enteric coating,isolation gown,acid-dissolving coating.With the evaluation of vitro-delivery, decide the coating artwork of dripping pill.Observing the dripping pills under sweep electron microscope,research the dispelling mechanism of medicine,and the experiment shows that the dispelling of the dripping pills is identical with the design.
In the research of vitro-dispelling degrees of praeparatum,the result shows that it won't dispel in stomach and almost won't leak out in small intestine(61%),however, it dispels 48.7%within 0.5 hours in zymo- intestinal juice,and 86.5%in 1 hour with obviously sudden dispelling process,and in 2 hours,totally dispelling.The results also show that the multi-coating dripping pills has excellent locating disposition of colon in body.Using X ray Baso_4 visualization to study the dispelling proceeding of multi-coating dripping pills in human bodies,study found that the coating dripping pills can pass the stomach and keep shape in small intestine;the disaggregation of coat almost happens at AC and colon transversum.So the coating dripping pills have good location effect in colon.
Build TLC to examine the relative substances and apply the absorption spectrometry and amino acids auto-measuring to assay content,and define the quantitation standard.
对半成品进行了药材来源、性状、TLC鉴别、含量测定等项目的研究,建立了半成品定性、定量的质量标准。
选择将含油性成分较多的半成品制备成滴丸,再包上肠溶衣,达到结肠定位释放的目的。在滴丸成型工艺研究中,首先采用单因素考察方法,对基质种类、基质与药物的比例、料液温度、冷凝剂种类、冷凝温度、滴距、滴速等影响因素进行了考察。在单因素考察的基础上,选择基质与药物的比例、料液温度和滴速等对滴制工艺有较大影响的因素作为考察因素,选择其较优参数作为考察水平,安排正交试验,最终确定滴丸的成型工艺。在包衣工艺研究中,针对单层包衣pH依赖制剂在小肠的药物泄漏问题,参考西药CODES~(TM)结肠释药设计,采用pH—酶依赖和多层包衣法,制剂由内到外为:滴丸丸芯、多糖衣、肠溶衣、隔离衣、酸溶衣,选择体外释放度作为评价方法,考察并确定了滴丸的包衣工艺。将多层包衣滴丸置扫描式电子显微镜下观察,研究其释药机理,实验证明多层包衣滴丸的释药行为与原设计相吻合.
对制剂进行体外释放度的研究,结果表明,多层包衣滴丸在胃内药物无释放,在小肠内药物泄漏极少(6.1%),在含酶肠液0.5小时内累积释放48.7%,1小时内累积释放86.5%,有明显的突释过程,在含酶肠液中2小时药物释放完全,释药曲线最为符合结肠定位给药设计。采用X射线Baso_4显影法研究多层包衣滴丸在人体内的释药行为,结果表明,包衣滴丸在和人体内能顺利地通过胃;在小肠运转过程中,多层包衣滴丸外形完整,基本无变化;包衣滴丸崩解部位集中在升结肠和横结肠,多层包衣滴丸具有良好的结肠定位性能。
对制剂建立了TLC鉴别方法,对相关物质进行了检查,运用分光光度法和氨基酸自动测定两种方法对制剂进行了含量测定,建立了定量标准。
To aim at ulcerative colitis(UC),according to the clinic use and character of Chinese medicine,choosing Periplaneta Americana which has significant curative effect in clinic of UC,with its main component(component ~ protein) easily destroyed in protein and to give only by clysters as research object,prepare it as ChangNing colon delivery praeparatum for oral use,and research the quality standard of half-finished product,,exterior and interior evaluation and quality standard etc.The main contents include:
By studying the medical material resource、character、TLC and assaying,build up the qualitation and quantitation of half-finished product.Choose half-finished product with more oil components to prepare dripping pills,then coating colon-dissolving material to achieve the purpose of delivery dispelling in colon.In the artwork research of dripping pills,apply mon-factor investigation to find out the kind of base material、the ratio of base material and medicine、the temperature of dosage liquor、the kind of condensing agent、the temperature of condensing agent、the dripping distance and speed etc.Further more,chose the ratio of base material and medicine、the temperature of dosage liquor and the dripping speed which have larger influence factors,with better indexes as research levels to decide the forming artwork of dripping pills with orthogonal experiment.In the research of coating artwork, referring CODES~(TM) colon dispelling design of western medicine,apply pH-enzyme relying association leechdom mechanism and multi-coating technology,settle the coating artwork as:(from inside to outside)heart of dripping pill,sugarcoating,enteric coating,isolation gown,acid-dissolving coating.With the evaluation of vitro-delivery, decide the coating artwork of dripping pill.Observing the dripping pills under sweep electron microscope,research the dispelling mechanism of medicine,and the experiment shows that the dispelling of the dripping pills is identical with the design.
In the research of vitro-dispelling degrees of praeparatum,the result shows that it won't dispel in stomach and almost won't leak out in small intestine(61%),however, it dispels 48.7%within 0.5 hours in zymo- intestinal juice,and 86.5%in 1 hour with obviously sudden dispelling process,and in 2 hours,totally dispelling.The results also show that the multi-coating dripping pills has excellent locating disposition of colon in body.Using X ray Baso_4 visualization to study the dispelling proceeding of multi-coating dripping pills in human bodies,study found that the coating dripping pills can pass the stomach and keep shape in small intestine;the disaggregation of coat almost happens at AC and colon transversum.So the coating dripping pills have good location effect in colon.
Build TLC to examine the relative substances and apply the absorption spectrometry and amino acids auto-measuring to assay content,and define the quantitation standard.
引文
[1]王吉耀.内科学[M].北京:人民卫生出版社,2002年.
[2]姜杰新.溃疡性结肠炎病因及发病机制的研究进展[J].医师进修杂志(内科版),2004,27(12):51-52.
[3]褚行琦,郑家驹,史肖华.炎症性肠病的治疗进展[J].中华消化杂志,2002,22(10):624-625.
[4]宋玉柱.中医药治疗溃疡性结肠炎研究进展[J].中华医学丛刊,2004,4(7):20-22.
[5]杨仓良,齐英杰主编.动物本草[M].北京:中医古籍出版社,2001年
[6]姚廉.中药蜚蠊化学成分的研究:氨基酸成分的初步分析[J].天津药学,1994,6(3):26-28
[7]赵红缨,李文龙等.康复新低温保留灌肠治疗慢性结肠炎50例[J].云南中医中药杂志,1995,16(3):7-8
[8]钟毅,周红等.康复新液治疗难治性消化性溃疡50例临床观察[J].中西医结合杂志,2004,14(6):333-336
[9]谭琳.口服康复新液治疗消化道溃疡的临床观察[J].成都医药,2002,28(2):89-89
[10]吕文,张筱凤等.康复新液保留灌肠治疗溃疡性结肠炎临床疗效观察[J].中国综合临床,2003,19(10):912-913
[11]高黎黎,魏贺梅,孙雅清.康复新液在消化系统疾病治疗中的应用[J].中国药业,2006,15(20):60-61
[12]姚秀琴,赵海剑.康复新液在放疗后皮肤粘膜损伤护理中的应用[J].南方护理学报,2002,9(6):6
[13]杨新蕾,张新合.康复新液治疗Ⅱ度烧伤疗效观察[J].中华中西医学杂志,2004,2(1):49-50
[14]李玛建,高爱平等.康复新液对宫颈糜烂微波凝固术后康复的疗效观察[J].中国医药学报,2004,19(11):685-686
[15]曹亮,张钧寿,刘玉峰等.果胶钙胶囊结肠定位释放介质的确定[J].中国药科大学学报,2002,33(3):203-207
[16]张兆旺.中药药剂学[M].北京:中国中医药出版社,2003:383
[17]王昌利,张文平,孙静.中药滴丸剂的研究进展[J].中医药学刊,2006,24(1):62-64
[18]朱盛山.药物新剂型[M].北京:化学工业出版社,2003:239
[19]侯惠民,王浩.药用辅料应用技术[M].北京:中国医药科技出版社,2002:156
[20]杨宇杰,李小勇,李汉蕴.甲硝唑结肠定位肠溶片的制备及质量控制.中国新药杂志,2004,13(4):330:332
[21]Marvola M,Nykanen P,Rautio S,et al.Enteric polymers as binders and coating materials in multiple unit site-specific drug delivery systems[J].Eur J Pharm Sci,1999,7(3):259-271
[22]Muraoka M,Kimura G,Zhaopeng H,et al.Ulcerative colitis-colon delivery of 5-aminosalicylic acid[J].Nippon Rinsho,1998,56(3):788-797
[23]Tozaki H,Komoike J,Tada C,et al Chitosan capsules for colon-specific drug delivery:improvement of insulin absorption from the rat colon[J].J Pharm Sci,1997,86(9):1016-1028
[24]邹浪、郭晓秋、严喜鸾.结肠定位给药系统研究概况[J].江西中医学院学报,2005,17(6):79-80
[25]徐彦,齐宪荣.5一氨基水杨酸结肠定位给药pH与时间同时控释小丸的制备与体外释放[J].中国新药杂志,2004,13(2):129-133
[26]李丽平.保留灌肠治疗溃疡性结肠炎4例[J].河南中医,2005,25(5):54-55
[1]Ishibashi T,Pitcarirn GR,Yoshino H,et al.Scintigraphic evakmtion of a new capsule-type colon specific drug delivery system in health volunteers[J].Pharm Sci,1998,87(5):531
[2]张正全,陆彬.口服结肠定位给药系统新进展[J].中国药学杂志.2000,35(4):221-223
[3]Wang CL.An oral preparation for drug delivery to human colon.Abstracts of the 5~(th) Congress of the Asian Federation of Colo-proctology,Korea,Seoul:1995:128
[4]KatsumaM,Watanabe S,Kawai H,et.Studies o13 lactulose formulations for colon-specific drug delivery[J],lnt J Pharm,2002,249(1-2):33
[5]颜大海,王斌.结肠定位给药制剂现状[J].黑龙江医药,2001,14(4):292-293
[6]Yano H,Hirayama F,Arima H,et al.Prednisolone-appended alphacyclodextrin:alleviation of systemic adverse effect of prednisolone after intracolonic administration in 2,4,6-trinitrobenzenesulfonic acid-induced colitis rats[J].J Pharm Sci,2001,90(12):2103
[7]Prasad YUR,Krishnaiah YSR,Satyanarayana S.In vitro evaluation of guar gum as a Carrier for colon-specific drug delivery[J].J Controlled Release,1998,51(2-3):281
[8]Rubinstein A,Radai R,Ezra M,et al.In vitro evaluation of calcium pectinate:a potential colon-specific drug delivery carrier[J].Pharm Res.1993,10(2):258-263
[2]姜杰新.溃疡性结肠炎病因及发病机制的研究进展[J].医师进修杂志(内科版),2004,27(12):51-52.
[3]褚行琦,郑家驹,史肖华.炎症性肠病的治疗进展[J].中华消化杂志,2002,22(10):624-625.
[4]宋玉柱.中医药治疗溃疡性结肠炎研究进展[J].中华医学丛刊,2004,4(7):20-22.
[5]杨仓良,齐英杰主编.动物本草[M].北京:中医古籍出版社,2001年
[6]姚廉.中药蜚蠊化学成分的研究:氨基酸成分的初步分析[J].天津药学,1994,6(3):26-28
[7]赵红缨,李文龙等.康复新低温保留灌肠治疗慢性结肠炎50例[J].云南中医中药杂志,1995,16(3):7-8
[8]钟毅,周红等.康复新液治疗难治性消化性溃疡50例临床观察[J].中西医结合杂志,2004,14(6):333-336
[9]谭琳.口服康复新液治疗消化道溃疡的临床观察[J].成都医药,2002,28(2):89-89
[10]吕文,张筱凤等.康复新液保留灌肠治疗溃疡性结肠炎临床疗效观察[J].中国综合临床,2003,19(10):912-913
[11]高黎黎,魏贺梅,孙雅清.康复新液在消化系统疾病治疗中的应用[J].中国药业,2006,15(20):60-61
[12]姚秀琴,赵海剑.康复新液在放疗后皮肤粘膜损伤护理中的应用[J].南方护理学报,2002,9(6):6
[13]杨新蕾,张新合.康复新液治疗Ⅱ度烧伤疗效观察[J].中华中西医学杂志,2004,2(1):49-50
[14]李玛建,高爱平等.康复新液对宫颈糜烂微波凝固术后康复的疗效观察[J].中国医药学报,2004,19(11):685-686
[15]曹亮,张钧寿,刘玉峰等.果胶钙胶囊结肠定位释放介质的确定[J].中国药科大学学报,2002,33(3):203-207
[16]张兆旺.中药药剂学[M].北京:中国中医药出版社,2003:383
[17]王昌利,张文平,孙静.中药滴丸剂的研究进展[J].中医药学刊,2006,24(1):62-64
[18]朱盛山.药物新剂型[M].北京:化学工业出版社,2003:239
[19]侯惠民,王浩.药用辅料应用技术[M].北京:中国医药科技出版社,2002:156
[20]杨宇杰,李小勇,李汉蕴.甲硝唑结肠定位肠溶片的制备及质量控制.中国新药杂志,2004,13(4):330:332
[21]Marvola M,Nykanen P,Rautio S,et al.Enteric polymers as binders and coating materials in multiple unit site-specific drug delivery systems[J].Eur J Pharm Sci,1999,7(3):259-271
[22]Muraoka M,Kimura G,Zhaopeng H,et al.Ulcerative colitis-colon delivery of 5-aminosalicylic acid[J].Nippon Rinsho,1998,56(3):788-797
[23]Tozaki H,Komoike J,Tada C,et al Chitosan capsules for colon-specific drug delivery:improvement of insulin absorption from the rat colon[J].J Pharm Sci,1997,86(9):1016-1028
[24]邹浪、郭晓秋、严喜鸾.结肠定位给药系统研究概况[J].江西中医学院学报,2005,17(6):79-80
[25]徐彦,齐宪荣.5一氨基水杨酸结肠定位给药pH与时间同时控释小丸的制备与体外释放[J].中国新药杂志,2004,13(2):129-133
[26]李丽平.保留灌肠治疗溃疡性结肠炎4例[J].河南中医,2005,25(5):54-55
[1]Ishibashi T,Pitcarirn GR,Yoshino H,et al.Scintigraphic evakmtion of a new capsule-type colon specific drug delivery system in health volunteers[J].Pharm Sci,1998,87(5):531
[2]张正全,陆彬.口服结肠定位给药系统新进展[J].中国药学杂志.2000,35(4):221-223
[3]Wang CL.An oral preparation for drug delivery to human colon.Abstracts of the 5~(th) Congress of the Asian Federation of Colo-proctology,Korea,Seoul:1995:128
[4]KatsumaM,Watanabe S,Kawai H,et.Studies o13 lactulose formulations for colon-specific drug delivery[J],lnt J Pharm,2002,249(1-2):33
[5]颜大海,王斌.结肠定位给药制剂现状[J].黑龙江医药,2001,14(4):292-293
[6]Yano H,Hirayama F,Arima H,et al.Prednisolone-appended alphacyclodextrin:alleviation of systemic adverse effect of prednisolone after intracolonic administration in 2,4,6-trinitrobenzenesulfonic acid-induced colitis rats[J].J Pharm Sci,2001,90(12):2103
[7]Prasad YUR,Krishnaiah YSR,Satyanarayana S.In vitro evaluation of guar gum as a Carrier for colon-specific drug delivery[J].J Controlled Release,1998,51(2-3):281
[8]Rubinstein A,Radai R,Ezra M,et al.In vitro evaluation of calcium pectinate:a potential colon-specific drug delivery carrier[J].Pharm Res.1993,10(2):258-263