结肠靶向泡沫气雾剂的研究
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摘要
溃疡性结肠炎是一种原因不明的炎症性疾病,多发于结肠部位。较理想的给药方式是直肠给药,结合泡沫气雾剂喷出的泡沫能在结肠部位均匀涂布,可直接与病变部位接触的特点,本课题拟设计一种治疗结肠炎的新剂型-结肠靶向泡沫气雾剂。
本文对自拟处方药材进行处理,筛选剂型的配方,制备出泡沫气雾剂,进而对其结肠定位给药的靶向性、毒理学及药效学进行了研究。得出结论如下:
(1)药物处方的拟定及药材处理
按涩肠止泻、祛腐生肌、清热解毒的原则拟定处方:五味子、乌梅、白及、连翘和地榆。通过正交试验,得到处方药材的最优提取工艺。白及:加水量为药材的12倍,提取1.5 h,提取3次,乙醇浓度80%;五味子及其它药材:加水量为药材的10倍,提取2 h,提取3次。
(2)配方筛选
通过泡沫性能考察和体外透粘膜试验得到泡沫气雾剂最优配方:茶皂苷2.0%,白及胶2.0%,丙二醇4.0%和抛射剂15%。配方中白及胶既是治病的活性成分,又是优良的稳泡剂。
(3)结肠定位给药靶向性评价
利用靶向性评价指标,本文首次通过比较灌胃和直肠给药后血浆与结肠组织液中药物的变化规律,得到评价指标re=4.74,te=4.38,Ce=4.26,表明结肠定位给药泡沫气雾剂具有靶向性。
(4)毒理学及药效学研究
研究发现小鼠LD_(50)为112.8 g/Kg,药液对结肠粘膜无刺激,并具有较强的止血、止泻和抗炎作用。
本文研究的泡沫气雾剂疗效确切,具有靶向性,可作为治疗溃疡性结肠炎的一种新剂型。
Ulcerative colitis(UC) is an unknown inflammatory bowel disease which mostly occurs in colon.The way of retention enem is widely used.Considering aerosol foam bubbles can directly contact with the lesion site of colon,aerosol foam was used as a new form to treat ulcerative colitis.
In this paper,extracted of herbs,screened of prescription,preparated of aerosol foam are studied.Further more,toxicology and pharmacodynamics are discussed.The results are as follows:
(1)Determinating prescription of drug and Extracting herbs
The development of prescription based on the rules of muscle growing and carrion removing,heat clearing and toxicity lifting,Shibuya intestines and diarrhea.The orthogonal test was used to optimize the extraction process of prescription drugs.The optimize extract process of gum bletilla was as follows:adding twenty-six times amount of water,decoting for three times,extracting for half past one hours each time,and alcohol concentration is 70%in the processing of alcohol-precipitation.The optimize extract process of fructus Schisandra chinensiswas as follows:fructus Schisandra chinensiswas were extracted by water cooking for three times with volume ten and cooking for two hours each time.
(2)Selecting of prescriptives
We get the optimal prescriptives of aerosol foam by researching the performance of bubbles and testing permeability of mucosal in vitro:tea saponin 2.0%,gum bletilla 2.0%, propylene glycol 4.0%and 15%of projectile agent.Besides,gum bletilla is the active ingredient of curing disease and also a good foam stabiliter.
(3)Evaluating the targeting effect of Colon-specific drug delivery
The first time,we obtained the changing rule of drug delivery by comparing the concentration in plasma and the fluid of colon tissue.We acquired the evaluation index of targeting effect are as follows:re=4.74,te=4.38,Ce=4.26.
(4)Toxicology and pharmacodynamics
Through the studies we found:the Median lethal dose is 112.8 g/Kg,without stimulation on the colonic mucosa,a strong bleeding,diarrhea and anti-inflammatory effects.
This test shows that the aerosol foam can be used as a new form for the treating of ulcerative colitis.
本文对自拟处方药材进行处理,筛选剂型的配方,制备出泡沫气雾剂,进而对其结肠定位给药的靶向性、毒理学及药效学进行了研究。得出结论如下:
(1)药物处方的拟定及药材处理
按涩肠止泻、祛腐生肌、清热解毒的原则拟定处方:五味子、乌梅、白及、连翘和地榆。通过正交试验,得到处方药材的最优提取工艺。白及:加水量为药材的12倍,提取1.5 h,提取3次,乙醇浓度80%;五味子及其它药材:加水量为药材的10倍,提取2 h,提取3次。
(2)配方筛选
通过泡沫性能考察和体外透粘膜试验得到泡沫气雾剂最优配方:茶皂苷2.0%,白及胶2.0%,丙二醇4.0%和抛射剂15%。配方中白及胶既是治病的活性成分,又是优良的稳泡剂。
(3)结肠定位给药靶向性评价
利用靶向性评价指标,本文首次通过比较灌胃和直肠给药后血浆与结肠组织液中药物的变化规律,得到评价指标re=4.74,te=4.38,Ce=4.26,表明结肠定位给药泡沫气雾剂具有靶向性。
(4)毒理学及药效学研究
研究发现小鼠LD_(50)为112.8 g/Kg,药液对结肠粘膜无刺激,并具有较强的止血、止泻和抗炎作用。
本文研究的泡沫气雾剂疗效确切,具有靶向性,可作为治疗溃疡性结肠炎的一种新剂型。
Ulcerative colitis(UC) is an unknown inflammatory bowel disease which mostly occurs in colon.The way of retention enem is widely used.Considering aerosol foam bubbles can directly contact with the lesion site of colon,aerosol foam was used as a new form to treat ulcerative colitis.
In this paper,extracted of herbs,screened of prescription,preparated of aerosol foam are studied.Further more,toxicology and pharmacodynamics are discussed.The results are as follows:
(1)Determinating prescription of drug and Extracting herbs
The development of prescription based on the rules of muscle growing and carrion removing,heat clearing and toxicity lifting,Shibuya intestines and diarrhea.The orthogonal test was used to optimize the extraction process of prescription drugs.The optimize extract process of gum bletilla was as follows:adding twenty-six times amount of water,decoting for three times,extracting for half past one hours each time,and alcohol concentration is 70%in the processing of alcohol-precipitation.The optimize extract process of fructus Schisandra chinensiswas as follows:fructus Schisandra chinensiswas were extracted by water cooking for three times with volume ten and cooking for two hours each time.
(2)Selecting of prescriptives
We get the optimal prescriptives of aerosol foam by researching the performance of bubbles and testing permeability of mucosal in vitro:tea saponin 2.0%,gum bletilla 2.0%, propylene glycol 4.0%and 15%of projectile agent.Besides,gum bletilla is the active ingredient of curing disease and also a good foam stabiliter.
(3)Evaluating the targeting effect of Colon-specific drug delivery
The first time,we obtained the changing rule of drug delivery by comparing the concentration in plasma and the fluid of colon tissue.We acquired the evaluation index of targeting effect are as follows:re=4.74,te=4.38,Ce=4.26.
(4)Toxicology and pharmacodynamics
Through the studies we found:the Median lethal dose is 112.8 g/Kg,without stimulation on the colonic mucosa,a strong bleeding,diarrhea and anti-inflammatory effects.
This test shows that the aerosol foam can be used as a new form for the treating of ulcerative colitis.
引文
[1]陈敏章.中华内科学[M].北京:人民卫生出版社,2000:19-20
[2]Mitsuyama K,Toyoaga A,Sata M.Intestinal microflora as a therapeutic target in inflammatory bowel disease[J].J Gastro-enterol,2002,37(14):73-77
[3]Rath HC,Schultz M,FreiR,et al.Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice[J].Infect Immun,2001,69:2277-2285
[4]Ogra PL,Mestecky J,Lamm ME,eds.Mucosal immunology[M].Calif:Academic Press,1999:1007-1024
[5]Swidsinski A,Ladhoff A,Pernthaler A,et al.Mucosal flo-ra in inflammatory bowel disease[J].Gastroenterology,2002,122:44-54
[6]Tysk C,Lindberg E,Jarnerot G,et al.Ulcerative colitis and Crohn's disease in an unselected population of monozygotic twins:a study of heritability and the influence of smoking[J].Get,1998,29:990-996
[7]巴德年.当代免疫学技术与应用[M].北京:北京医科大学、中国协和医科大学联合出版社,1998:892
[8]邵传森,朱圣禾.临床疾病与免疫[M].北京:科学出版社,2001:159
[9]张继平.溃疡性结肠炎的免疫学研究进展[J].中国误诊学杂志,2002,2(1):75
[10]BennettJC,Plum F.Cecil Textbook of Medicine[M].Philad el phia:W.B.Saunders Company,1996:707-715
[11]潘国宗,曹世植.现代胃肠病学[M].北京:科学出版社,1994:1245-1259
[12]朱峰,钱家鸣,潘国宗.重症溃疡性结肠炎的药物治疗[J].胃肠病学,1996,1(2):78-80
[13]叶任高.内科学[M].北京:人民卫生出版社,2000:28
[14]Rutigeerts P.Medical therapy of inflammatory bowel disease[J].Digestion,1998,59:453-459
[15]Kirsner JB.inflammatory bowel disease[M].Calif:Academic Press,2001:520-524
[16]Kornbluth A,Sachar DB.Ulcerative colitis practice guidelines in adults-American College of Gastroenterology,Practice Pamameters Committee[J].Am J Gastroenterol,1997,92:204-211
[17]Send BE.Novel therapies for inflammatory bowel disease[J].Gastroenteral Clin N Am.1999,28(2):323-334
[18]Sandbon WJ.Therapy for ulcerative colitis[J].Curr Opin Gastroenteral,1998,14:312-316
[19]赵辉,周建中.益气活血法对慢性非特异性溃疡性结肠炎免疫功能影响初探[J].中医杂志,1990,(6):39
[20]闰洪臣.名医奇方秘术[M].北京:中国医药科技出版社,1991:515-516
[21]王新月,田德禄.溃疡性结肠炎的发病机制与中医辨治思路[R].郑州:中华中医药学会,2003
[22]孙继芳.黄河医话[M].北京:北京科学出版社,1994:244-245
[23]傅南琳,黄俊友.中医药治疗溃疡性结肠炎研究进展[J].中医杂志,1999,40(8):501-502
[24]黄进.慢性溃疡性结肠炎中医药治疗近况[J].现代中西医结合杂志,2001,19:1905-1908
[25]邓长生,夏冰.炎症性肠病[M].北京:人民卫生出版社,1998:314-319
[26]朱忠诚.连理汤加味治疗慢性溃疡性结肠炎临床观察[J].中国社区医师,2003,19(16):31
[27]吴茜,王立军,等.当归芍药散加减治疗溃疡性结肠炎36例临床观察[J].中国中医药科技,2003,10(4):195-196
[28]莫新民,唐利文.三黄丸治疗溃疡性结肠炎临床观察[J].中国中医基础医学杂志,2003,9(7):67-68
[29]陈玉昌.自拟理肠汤治疗溃疡性结肠炎[J].河北中西医结合杂志,1999,8(6):945
[30]林芝韵.自拟祛风胜湿汤治疗溃疡性结肠炎30例[J].上海中医药杂志,1997,(4):21
[31]周发祥,等.“结炎康”治疗慢性非特异性溃疡性结肠炎的临床观察[J].中国中医药信息杂志,1999,6(7):42-43
[32]葛文津,甘毓麟,陈瑜,等.固肠胶囊治疗慢性非特异性溃疡性结肠炎临床与实验研究[J].中医杂志,1994,35(2):92-93
[33]潘洋等.青白灌肠液治疗溃疡性结肠炎60例临床观察[J].中国中医药科技,2002,9(4):220
[34]李忠卓,等.通灌汤治疗非特异性溃疡性结肠炎临床观察[J].辽宁中医杂志,2002,29(12):725-726
[35]史志东,李清,等.用生肌愈溃汤直肠点滴治疗溃疡性结肠炎48例[J].中国中西医结合消化杂志,2005,5:145
[36]马贵同.中药栓剂防治溃疡性结肠炎的临床实验研究[J].上海中医药杂志,1996,(12):2-5
[37]贺晓娟,等.中药内镜下喷洒治疗溃疡性结肠炎30例[J].四川中医,2005,10(5):546-548
[38]李莉群,许晴晴.内镜下药物喷洒治疗溃疡性结肠炎38例疗效观察[J].贵州医药,2005.8:56
[39]丁立,洪醒华.中药气雾剂产品的现状与前景[J].中国中西医结合杂志,2007,27(10):957-959
[40]刘华钢.中药气雾剂的研究概况[J].广西中医学院学报,2003,2(1):58-60
[41]熊爱珍,李锦燕,李玲.复方蛇床子泡沫剂的研制[J].中国中西医结合杂志,2004,17(5):378-381
[42]熊爱珍,李锦燕,李玲.阴复康泡沫气雾剂制备工艺的考察[J].中国医院药学杂志,2007,27(10):1368-1371
[43]杨基森,刘文,等.阴道用中药泡沫气雾剂制备工艺研究[J].中国中药杂志,1997,22(1):26-28
[44]杨放,袁军,付平.五味子的研究概况[J].华西药学杂志,2003,18(6):438
[45]郭冷秋,张鹏,黄莉莉,等.五味子药理作用研究进展[J].中医药学报,2006,34(4):51
[46]曾凡骏,张月天,陈松波.果梅浓缩液的提取工艺研究[J].食品科学技术,2001,5:23
[47]姜贵全.地榆中药用活性成分提取工艺及稳定性研究[D].吉林,东北林业大学,2005
[48]袁振海,孙立立.地榆现代研究进展[J].Chinese Journal of Information on TCM Mar,2007,14(3):399
[49]王军,王春宏,任晓玲,等.白芨胶的临床应用[J].中国医院药学杂志,2004,24(9):1126-1129
[50]邓涛,彭慧珍,赵玛丽.中药地榆研究进展[J].实用中西医结合临床,2006,12(6):6
[51]李晓燕.中药连翘抗菌活性的考察[J].山东医药工业,1997,16(2):46
[52]俞祟灵.连翘抗菌成分的研究[J],药学学报,1960,8(6):241-243
[53]谢崇义,吴杨,李国忠.白芨胶提取工艺的优选[J].安徽医药,2004,8(6):678
[54]张寒,郝保华,徐花荣,杨瑞瑞.白及多糖提取工艺的研究[J].陕西中医,2007,28(2):223
[55]韩丙勇,张学军译.水溶液中的表面活性剂和聚合物[M].北京:化学工业出版社,2005:338-339
[56]孔健,冯敢生,许林蜂,等.白及微球栓塞支气管动脉治疗大咯血[J].临床放射学杂志,2001,20(8):640
[57]游一中.联合国环保署气雾剂会议在毛里求斯召开[J].气雾剂通讯,1998,18(2):616
[58]游一中.为在中国顺利实现药用气雾剂的CFC替代而共同努力[J].气雾剂通讯,1998,18(2):629
[59]朱盛山.药物新剂型[M].北京:化学工业出版社,2003:419-425
[60]陈奇.中药药理研究方法学[M].北京:人民卫生出版社,2006:1139
[2]Mitsuyama K,Toyoaga A,Sata M.Intestinal microflora as a therapeutic target in inflammatory bowel disease[J].J Gastro-enterol,2002,37(14):73-77
[3]Rath HC,Schultz M,FreiR,et al.Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice[J].Infect Immun,2001,69:2277-2285
[4]Ogra PL,Mestecky J,Lamm ME,eds.Mucosal immunology[M].Calif:Academic Press,1999:1007-1024
[5]Swidsinski A,Ladhoff A,Pernthaler A,et al.Mucosal flo-ra in inflammatory bowel disease[J].Gastroenterology,2002,122:44-54
[6]Tysk C,Lindberg E,Jarnerot G,et al.Ulcerative colitis and Crohn's disease in an unselected population of monozygotic twins:a study of heritability and the influence of smoking[J].Get,1998,29:990-996
[7]巴德年.当代免疫学技术与应用[M].北京:北京医科大学、中国协和医科大学联合出版社,1998:892
[8]邵传森,朱圣禾.临床疾病与免疫[M].北京:科学出版社,2001:159
[9]张继平.溃疡性结肠炎的免疫学研究进展[J].中国误诊学杂志,2002,2(1):75
[10]BennettJC,Plum F.Cecil Textbook of Medicine[M].Philad el phia:W.B.Saunders Company,1996:707-715
[11]潘国宗,曹世植.现代胃肠病学[M].北京:科学出版社,1994:1245-1259
[12]朱峰,钱家鸣,潘国宗.重症溃疡性结肠炎的药物治疗[J].胃肠病学,1996,1(2):78-80
[13]叶任高.内科学[M].北京:人民卫生出版社,2000:28
[14]Rutigeerts P.Medical therapy of inflammatory bowel disease[J].Digestion,1998,59:453-459
[15]Kirsner JB.inflammatory bowel disease[M].Calif:Academic Press,2001:520-524
[16]Kornbluth A,Sachar DB.Ulcerative colitis practice guidelines in adults-American College of Gastroenterology,Practice Pamameters Committee[J].Am J Gastroenterol,1997,92:204-211
[17]Send BE.Novel therapies for inflammatory bowel disease[J].Gastroenteral Clin N Am.1999,28(2):323-334
[18]Sandbon WJ.Therapy for ulcerative colitis[J].Curr Opin Gastroenteral,1998,14:312-316
[19]赵辉,周建中.益气活血法对慢性非特异性溃疡性结肠炎免疫功能影响初探[J].中医杂志,1990,(6):39
[20]闰洪臣.名医奇方秘术[M].北京:中国医药科技出版社,1991:515-516
[21]王新月,田德禄.溃疡性结肠炎的发病机制与中医辨治思路[R].郑州:中华中医药学会,2003
[22]孙继芳.黄河医话[M].北京:北京科学出版社,1994:244-245
[23]傅南琳,黄俊友.中医药治疗溃疡性结肠炎研究进展[J].中医杂志,1999,40(8):501-502
[24]黄进.慢性溃疡性结肠炎中医药治疗近况[J].现代中西医结合杂志,2001,19:1905-1908
[25]邓长生,夏冰.炎症性肠病[M].北京:人民卫生出版社,1998:314-319
[26]朱忠诚.连理汤加味治疗慢性溃疡性结肠炎临床观察[J].中国社区医师,2003,19(16):31
[27]吴茜,王立军,等.当归芍药散加减治疗溃疡性结肠炎36例临床观察[J].中国中医药科技,2003,10(4):195-196
[28]莫新民,唐利文.三黄丸治疗溃疡性结肠炎临床观察[J].中国中医基础医学杂志,2003,9(7):67-68
[29]陈玉昌.自拟理肠汤治疗溃疡性结肠炎[J].河北中西医结合杂志,1999,8(6):945
[30]林芝韵.自拟祛风胜湿汤治疗溃疡性结肠炎30例[J].上海中医药杂志,1997,(4):21
[31]周发祥,等.“结炎康”治疗慢性非特异性溃疡性结肠炎的临床观察[J].中国中医药信息杂志,1999,6(7):42-43
[32]葛文津,甘毓麟,陈瑜,等.固肠胶囊治疗慢性非特异性溃疡性结肠炎临床与实验研究[J].中医杂志,1994,35(2):92-93
[33]潘洋等.青白灌肠液治疗溃疡性结肠炎60例临床观察[J].中国中医药科技,2002,9(4):220
[34]李忠卓,等.通灌汤治疗非特异性溃疡性结肠炎临床观察[J].辽宁中医杂志,2002,29(12):725-726
[35]史志东,李清,等.用生肌愈溃汤直肠点滴治疗溃疡性结肠炎48例[J].中国中西医结合消化杂志,2005,5:145
[36]马贵同.中药栓剂防治溃疡性结肠炎的临床实验研究[J].上海中医药杂志,1996,(12):2-5
[37]贺晓娟,等.中药内镜下喷洒治疗溃疡性结肠炎30例[J].四川中医,2005,10(5):546-548
[38]李莉群,许晴晴.内镜下药物喷洒治疗溃疡性结肠炎38例疗效观察[J].贵州医药,2005.8:56
[39]丁立,洪醒华.中药气雾剂产品的现状与前景[J].中国中西医结合杂志,2007,27(10):957-959
[40]刘华钢.中药气雾剂的研究概况[J].广西中医学院学报,2003,2(1):58-60
[41]熊爱珍,李锦燕,李玲.复方蛇床子泡沫剂的研制[J].中国中西医结合杂志,2004,17(5):378-381
[42]熊爱珍,李锦燕,李玲.阴复康泡沫气雾剂制备工艺的考察[J].中国医院药学杂志,2007,27(10):1368-1371
[43]杨基森,刘文,等.阴道用中药泡沫气雾剂制备工艺研究[J].中国中药杂志,1997,22(1):26-28
[44]杨放,袁军,付平.五味子的研究概况[J].华西药学杂志,2003,18(6):438
[45]郭冷秋,张鹏,黄莉莉,等.五味子药理作用研究进展[J].中医药学报,2006,34(4):51
[46]曾凡骏,张月天,陈松波.果梅浓缩液的提取工艺研究[J].食品科学技术,2001,5:23
[47]姜贵全.地榆中药用活性成分提取工艺及稳定性研究[D].吉林,东北林业大学,2005
[48]袁振海,孙立立.地榆现代研究进展[J].Chinese Journal of Information on TCM Mar,2007,14(3):399
[49]王军,王春宏,任晓玲,等.白芨胶的临床应用[J].中国医院药学杂志,2004,24(9):1126-1129
[50]邓涛,彭慧珍,赵玛丽.中药地榆研究进展[J].实用中西医结合临床,2006,12(6):6
[51]李晓燕.中药连翘抗菌活性的考察[J].山东医药工业,1997,16(2):46
[52]俞祟灵.连翘抗菌成分的研究[J],药学学报,1960,8(6):241-243
[53]谢崇义,吴杨,李国忠.白芨胶提取工艺的优选[J].安徽医药,2004,8(6):678
[54]张寒,郝保华,徐花荣,杨瑞瑞.白及多糖提取工艺的研究[J].陕西中医,2007,28(2):223
[55]韩丙勇,张学军译.水溶液中的表面活性剂和聚合物[M].北京:化学工业出版社,2005:338-339
[56]孔健,冯敢生,许林蜂,等.白及微球栓塞支气管动脉治疗大咯血[J].临床放射学杂志,2001,20(8):640
[57]游一中.联合国环保署气雾剂会议在毛里求斯召开[J].气雾剂通讯,1998,18(2):616
[58]游一中.为在中国顺利实现药用气雾剂的CFC替代而共同努力[J].气雾剂通讯,1998,18(2):629
[59]朱盛山.药物新剂型[M].北京:化学工业出版社,2003:419-425
[60]陈奇.中药药理研究方法学[M].北京:人民卫生出版社,2006:1139