定位—定时多元释药
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摘要
本课题针对溃疡性结肠炎(UC),从现代中药复方释药系统角度出发,以综合疗效发挥为核心,以中医药理论为基础和以新型释药系统理论为手段。根据中西医对UC的病机和治疗原则的分析,以治疗UC有效的结肠康方中黄芪和苦参的提取物为基础,将黄芪中的皂苷、多糖制成胃内吸收,起全身免疫调节作用,苦参中的苦参碱、氧化苦参碱制成结肠定位释药系统,起局部消炎、抗菌作用,体现了中医治疗UC的标本兼治、整体与局部相结合的治疗法则。
口服结肠靶向给药系统(Oral Colon Targeting Drug-delivery System,OCTDS)是通过药物传递技术,使药物口服后,在上消化道不释放,将药物运送到人体回盲部后开始崩解或蚀解并释放出来,从而能够使药物定位于人体结肠后,在结肠部位发挥局部或全身治疗作用。通过对OCTDS释药机理的分析,分别对pH-时滞依赖型和pH-酶依赖型两种联合给药制剂及其评价进行了研究,研制出具有较好结肠定位释药的靶向制剂。
主要研究内容如下:根据药物性质,对半成品进行了性状、TLC鉴别、含量测定等项目的研究,并对相关物质进行了检查,通过对半成品定性、定量方法的考察,建立了半成品的质量标准。
将黄芪和苦参提取物分别制成微丸,通过试验筛选,确定了素丸的制备工艺。对pH-时滞依赖型和pH-酶依赖型两种联合给药系统进行研究,分别筛选出合适的靶向包衣辅料,并确定包衣工艺,将微丸分装胶囊。通过体外释放度试验,研究并建立了制剂体外释放度测定方法,采用硫酸钡造影技术对pH-时滞依赖型和pH-酶依赖型结肠靶向制剂的体内释放性能进行了考察,结果表明,该制剂在正常人体内基本达到结肠定位释放的效果。
对制剂建立了TLC定性鉴别方法,运用高效液相法对制剂进行了含量测定,拟订了制剂中苦参碱、氧化苦参碱的含量要求,建立了制剂的质量标准。
The topic for ulcerative colitis (UC), from the perspective of compound release system of modern Chinese medicine ,the effect of an integrated plays as the core and Chinese medicine based on the theory and the new release system theory as a means of. According to Western medicine in the pathogenesis of UC principles of analysis and treatment, based on the extract of Kushen and Huangqi which effective to UC treation. Astragalus will be the saponin, gastric absorption into polysaccharide, and Systemic immune from regulation. Kushen of matrine, oxymatrine made of colon-release system, from the local anti-inflammatory, antibacterial activity. UC embodies the Chinese medicine treatment of tackling both the symptoms, and overall treatment of a combination of local rules.
The technique of drug transfer is used in Oral Colon-targeting Drug Delivery System (OCDDS), in which drugs does not release in the upper digestive tract with oral administration but begins to collapse or erode when they arrive at ileocecus and act medicinally at colon. Aiming at Ulcerative Colitis (UC),we researched on Jiechangkang, which is an efective cure for UC in clinical use. We design a binary release programme, making it in the stomach and colon, respectively release to going to play the effect. By OCDDS release mechanism analysis,we have got two colonic targeting preparations after research: PH-time lagged relying and pH-enzyme relying delivery systems. The main contents include:
By studying the medical materia character、TLC and assaying ,build up the qualitation and quantitation of half-finished product. The Jiechangkang extraction is prepared into micro-pills,aftert he screen-out experiments on preparing process. The PH-time lagged relying and pH-enzyme relying delivery system shave beens tudied.B oth coating excipients of micro-pills and the coating process have also been decided.
Coating micro-pills are capsuled afterward. By established a method of in vitro dissolution determination for preparations. Reviewed the PH-time lagged relying and pH-enzyme relying colon aration in vivo release by BaSO_4 photographytechnology ,as a result,it could achieve the objective of colon oriented releasem a normal human body.
Build TLC to examine the relative substances and apply the HPLC to assay content, formulated the content limits of matrine and oxymatrine inpreparation ,define the quantitation standard.
口服结肠靶向给药系统(Oral Colon Targeting Drug-delivery System,OCTDS)是通过药物传递技术,使药物口服后,在上消化道不释放,将药物运送到人体回盲部后开始崩解或蚀解并释放出来,从而能够使药物定位于人体结肠后,在结肠部位发挥局部或全身治疗作用。通过对OCTDS释药机理的分析,分别对pH-时滞依赖型和pH-酶依赖型两种联合给药制剂及其评价进行了研究,研制出具有较好结肠定位释药的靶向制剂。
主要研究内容如下:根据药物性质,对半成品进行了性状、TLC鉴别、含量测定等项目的研究,并对相关物质进行了检查,通过对半成品定性、定量方法的考察,建立了半成品的质量标准。
将黄芪和苦参提取物分别制成微丸,通过试验筛选,确定了素丸的制备工艺。对pH-时滞依赖型和pH-酶依赖型两种联合给药系统进行研究,分别筛选出合适的靶向包衣辅料,并确定包衣工艺,将微丸分装胶囊。通过体外释放度试验,研究并建立了制剂体外释放度测定方法,采用硫酸钡造影技术对pH-时滞依赖型和pH-酶依赖型结肠靶向制剂的体内释放性能进行了考察,结果表明,该制剂在正常人体内基本达到结肠定位释放的效果。
对制剂建立了TLC定性鉴别方法,运用高效液相法对制剂进行了含量测定,拟订了制剂中苦参碱、氧化苦参碱的含量要求,建立了制剂的质量标准。
The topic for ulcerative colitis (UC), from the perspective of compound release system of modern Chinese medicine ,the effect of an integrated plays as the core and Chinese medicine based on the theory and the new release system theory as a means of. According to Western medicine in the pathogenesis of UC principles of analysis and treatment, based on the extract of Kushen and Huangqi which effective to UC treation. Astragalus will be the saponin, gastric absorption into polysaccharide, and Systemic immune from regulation. Kushen of matrine, oxymatrine made of colon-release system, from the local anti-inflammatory, antibacterial activity. UC embodies the Chinese medicine treatment of tackling both the symptoms, and overall treatment of a combination of local rules.
The technique of drug transfer is used in Oral Colon-targeting Drug Delivery System (OCDDS), in which drugs does not release in the upper digestive tract with oral administration but begins to collapse or erode when they arrive at ileocecus and act medicinally at colon. Aiming at Ulcerative Colitis (UC),we researched on Jiechangkang, which is an efective cure for UC in clinical use. We design a binary release programme, making it in the stomach and colon, respectively release to going to play the effect. By OCDDS release mechanism analysis,we have got two colonic targeting preparations after research: PH-time lagged relying and pH-enzyme relying delivery systems. The main contents include:
By studying the medical materia character、TLC and assaying ,build up the qualitation and quantitation of half-finished product. The Jiechangkang extraction is prepared into micro-pills,aftert he screen-out experiments on preparing process. The PH-time lagged relying and pH-enzyme relying delivery system shave beens tudied.B oth coating excipients of micro-pills and the coating process have also been decided.
Coating micro-pills are capsuled afterward. By established a method of in vitro dissolution determination for preparations. Reviewed the PH-time lagged relying and pH-enzyme relying colon aration in vivo release by BaSO_4 photographytechnology ,as a result,it could achieve the objective of colon oriented releasem a normal human body.
Build TLC to examine the relative substances and apply the HPLC to assay content, formulated the content limits of matrine and oxymatrine inpreparation ,define the quantitation standard.
引文
[1]郑芝田主编.胃肠学(第二版).北京:人民卫生出版社,2000
[2]邓长生,夏冰.炎症性肠病.北京:人民卫生出版社,1998
[3]候天印编著.溃疡性结肠炎防治120问.北京:金盾出版社,1997
[4]任建平,陈华.溃疡性结肠炎中医辨证论治思想研究述要[J].中国中医药杂志,2004,2(6):334-336
[5]乔成栋,郑昱.溃疡性结肠炎中医药治疗现状及展望[J].兰州医学院学报,2003,29(3):64-65
[6]胡鸿毅.中药防治溃疡性结肠炎的临床和机理研究概况[J].上海中医药杂志,2004,38(3):60-62
[7]王正忠.中药灌肠治疗溃疡性结肠炎近况[J].中医外治杂志,2003,12(2):40-41
[8]杨明,现代中药复方释药系统的构建[J].世界科学技术一中医药现代化,2006,8(5):10-14
[9]陈重.口服结肠靶向给药系统的研究现状[J].中国药业,2002,11(2):76-77
[10]莫韫,张钧寿。结肠靶向给药系统研究进展[J].中国新药杂志,1999,8(6):368-371
[11]傅崇东,徐惠南,张瑜.5-氨基水杨酸与其结肠靶向制剂[J].上海医药,1999,20(4):29-30
[12]邱雪兰.口服靶向给药系统中的辅料[J].中国药业,2005,14(1):21-22
[13]中华人民共和国卫生部药典委员会编.中华人民共和国药典中药薄层色谱彩色图集。科技出版社,1993
[14]郑友兰,张崇嬉,张春红,等,黄芪根、茎叶黄芪皂苷含量的测定[J].吉林农业大学学报,2003,25(5):531-532.535
[15]王莉,刘志勇,鲁建江,等.黄芪多糖的微波提取及含量测定[J].中医药学报,2001,2(6):35-36
[16]国家药品标准(化学药品地方标准上升国家标准)第十六册
[17]国家药品标准(化学药品地方标准上升国家标准)第一册
[18]中华人民共和国卫生部药典委员会编.中华人民共和国药典2005版一部.北京:化学工业出版社,2005
[19]刘红,蔡普生.微丸的制备工艺研究[J].中国药师,2003,6(12):771-773
[20]孙锡维,周芝芳,孙洁胤.结肠靶向给药制剂研究的新进展[J].中国现代应用药学杂志,2002,19(3):196-198
[21]张玉全,陆彬.口服结肠定位给药系统进展[J].中国药学杂志,2000,35(4):221-223
[22]汪芸,姜洪芳.微丸的成型性研究进展[J].江西中医药学院学报,2002,14(1):59-60
[23]Petex JW,Lisbeth L.Colonic delivery[J].Drug Dev Indus Pharm,1997,23(9):893-913
[24]Nagent,Patnplon,Evans,et al.Intestinal luminal pH inflammatory bowel disease:possible determinants and implications for therapy with aminosalicylates and other drugs[J].Gut,2001,48:571-577
[25]HARDY J G,WILSON C G,WOOD E.Drug delivery to the proximal colon[J].J Pharm Pharmacol,1985,37(12):874-877.
[26]M Turkoglu,T Ugurlu.In vitro evaluation of qectin-HPMC compression coated 5-aminosalicylic acid tablets for colonic delivery[J].Eur J Pharm Biopharm,January 1,2002,53(1):65-73
[1]杨明,万琴.从中药复方释药系统研究现状引发的思考[J].世界科学技术-中医药现代化,2007,9(5):12-15
[2]罗晓健,张汝华,毕开顺.复方丹参多层缓释片及其体内外评价方法的研究:[学位论文].沈阳:沈阳药科大学药学院,2003
[3]宋洪涛,张倩,郭鑫金,等.采用多元定时释药技术制备复方中药舒胸缓释胶囊的研制[J].福州总医院学报,2005,12(4):235-238
[4]李青坡,游剑.葛根芩连微丸中指标成分的体外同步释放研究[J].中草药,2006,37(1):40-44
[5]宋洪涛,郭涛,张汝华,等.麝香保心pH依赖型梯度释药微丸的研究[J].药学学报2002,37(10):8 12-817
[6]李莉,李鑫.冠心苏合丸PH依赖型梯度释药微丸的制备工艺[J].黑龙江医药,2003.16(3):208-210
[7]吕竹芬,冯毅凡,黄郁,等.姜桂pH依赖型梯度释药胶囊的研究[J].时珍国医国药,2006,17(8):1421-1422
[8]宋洪涛,郭涛,康鲁平,等.采用多元定位释药技术制备复方中药舒胸缓释剂的研究[J].福州总医院学报2005,12(3):176-180
[9]闰惠俊,龙致贤.肠安康微丸制备工艺及其结肠定位释药评价.北京中医药大学2003年博士研究生毕业论文
[10]杨冬丽,于叶玲,唐星,等.复方丹参pH依赖型延迟释药微丸在家犬体内的药效动力学[J].药学学报,2005,40(12):1075-1079
[11]宋洪涛,郭涛,张汝华,等.pH依赖型梯度释药麝香保心微丸在健康志愿者胃肠道的转运和崩解[J].中国药学杂志,2002,37(12):930-933
[12]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
[13]张正全,陆彬.口服结肠定位给药系统新进展[J].中国药学志,2000,35(4):221-223
[14]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
[15]Katsuma M,Watanabe S,Kawai H,et.Studies o13 lactulose formulations for colon-specific drug delivery[J].lnt J Pharm,2002,249(1-2):33
[16]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
[17]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
[18]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
[19]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]邓长生,夏冰.炎症性肠病.北京:人民卫生出版社,1998
[3]候天印编著.溃疡性结肠炎防治120问.北京:金盾出版社,1997
[4]任建平,陈华.溃疡性结肠炎中医辨证论治思想研究述要[J].中国中医药杂志,2004,2(6):334-336
[5]乔成栋,郑昱.溃疡性结肠炎中医药治疗现状及展望[J].兰州医学院学报,2003,29(3):64-65
[6]胡鸿毅.中药防治溃疡性结肠炎的临床和机理研究概况[J].上海中医药杂志,2004,38(3):60-62
[7]王正忠.中药灌肠治疗溃疡性结肠炎近况[J].中医外治杂志,2003,12(2):40-41
[8]杨明,现代中药复方释药系统的构建[J].世界科学技术一中医药现代化,2006,8(5):10-14
[9]陈重.口服结肠靶向给药系统的研究现状[J].中国药业,2002,11(2):76-77
[10]莫韫,张钧寿。结肠靶向给药系统研究进展[J].中国新药杂志,1999,8(6):368-371
[11]傅崇东,徐惠南,张瑜.5-氨基水杨酸与其结肠靶向制剂[J].上海医药,1999,20(4):29-30
[12]邱雪兰.口服靶向给药系统中的辅料[J].中国药业,2005,14(1):21-22
[13]中华人民共和国卫生部药典委员会编.中华人民共和国药典中药薄层色谱彩色图集。科技出版社,1993
[14]郑友兰,张崇嬉,张春红,等,黄芪根、茎叶黄芪皂苷含量的测定[J].吉林农业大学学报,2003,25(5):531-532.535
[15]王莉,刘志勇,鲁建江,等.黄芪多糖的微波提取及含量测定[J].中医药学报,2001,2(6):35-36
[16]国家药品标准(化学药品地方标准上升国家标准)第十六册
[17]国家药品标准(化学药品地方标准上升国家标准)第一册
[18]中华人民共和国卫生部药典委员会编.中华人民共和国药典2005版一部.北京:化学工业出版社,2005
[19]刘红,蔡普生.微丸的制备工艺研究[J].中国药师,2003,6(12):771-773
[20]孙锡维,周芝芳,孙洁胤.结肠靶向给药制剂研究的新进展[J].中国现代应用药学杂志,2002,19(3):196-198
[21]张玉全,陆彬.口服结肠定位给药系统进展[J].中国药学杂志,2000,35(4):221-223
[22]汪芸,姜洪芳.微丸的成型性研究进展[J].江西中医药学院学报,2002,14(1):59-60
[23]Petex JW,Lisbeth L.Colonic delivery[J].Drug Dev Indus Pharm,1997,23(9):893-913
[24]Nagent,Patnplon,Evans,et al.Intestinal luminal pH inflammatory bowel disease:possible determinants and implications for therapy with aminosalicylates and other drugs[J].Gut,2001,48:571-577
[25]HARDY J G,WILSON C G,WOOD E.Drug delivery to the proximal colon[J].J Pharm Pharmacol,1985,37(12):874-877.
[26]M Turkoglu,T Ugurlu.In vitro evaluation of qectin-HPMC compression coated 5-aminosalicylic acid tablets for colonic delivery[J].Eur J Pharm Biopharm,January 1,2002,53(1):65-73
[1]杨明,万琴.从中药复方释药系统研究现状引发的思考[J].世界科学技术-中医药现代化,2007,9(5):12-15
[2]罗晓健,张汝华,毕开顺.复方丹参多层缓释片及其体内外评价方法的研究:[学位论文].沈阳:沈阳药科大学药学院,2003
[3]宋洪涛,张倩,郭鑫金,等.采用多元定时释药技术制备复方中药舒胸缓释胶囊的研制[J].福州总医院学报,2005,12(4):235-238
[4]李青坡,游剑.葛根芩连微丸中指标成分的体外同步释放研究[J].中草药,2006,37(1):40-44
[5]宋洪涛,郭涛,张汝华,等.麝香保心pH依赖型梯度释药微丸的研究[J].药学学报2002,37(10):8 12-817
[6]李莉,李鑫.冠心苏合丸PH依赖型梯度释药微丸的制备工艺[J].黑龙江医药,2003.16(3):208-210
[7]吕竹芬,冯毅凡,黄郁,等.姜桂pH依赖型梯度释药胶囊的研究[J].时珍国医国药,2006,17(8):1421-1422
[8]宋洪涛,郭涛,康鲁平,等.采用多元定位释药技术制备复方中药舒胸缓释剂的研究[J].福州总医院学报2005,12(3):176-180
[9]闰惠俊,龙致贤.肠安康微丸制备工艺及其结肠定位释药评价.北京中医药大学2003年博士研究生毕业论文
[10]杨冬丽,于叶玲,唐星,等.复方丹参pH依赖型延迟释药微丸在家犬体内的药效动力学[J].药学学报,2005,40(12):1075-1079
[11]宋洪涛,郭涛,张汝华,等.pH依赖型梯度释药麝香保心微丸在健康志愿者胃肠道的转运和崩解[J].中国药学杂志,2002,37(12):930-933
[12]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
[13]张正全,陆彬.口服结肠定位给药系统新进展[J].中国药学志,2000,35(4):221-223
[14]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
[15]Katsuma M,Watanabe S,Kawai H,et.Studies o13 lactulose formulations for colon-specific drug delivery[J].lnt J Pharm,2002,249(1-2):33
[16]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
[17]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
[18]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
[19]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