5-氨基水杨酸结肠靶向片的研制及其药效学药动学初步研究
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摘要
菌群触发型结肠释药系统(bacterially triggered colon specific drug delivery system,BCDDS)系利用大量细菌集中分布在结肠并分泌独特的偶氮还原酶、糖苷酶及糖苷酸酶等多种酶可降解特殊键的特点制备的口服释药系统,使药物在结肠定位释放,可避免药物在上消化道释放引起的副作用和消化酶对药物的破坏,是一种较为理想的靶向释药触发机制。
5-氨基水杨酸(5-aminosalicylic acid, 5-ASA)是治疗溃疡性结肠炎、克隆氏病的有效药物,不良反应较少,主要为胃肠道刺激和肾毒性。临床上多数炎性肠病的病变主要发生在回肠末段和结肠,所以治疗中要求5-ASA在回肠末段和结肠腔内有较高的药物浓度。5-ASA仅以原形在结肠病变部位发挥作用,由于其易在胃肠道上部吸收,因此一般的口服制剂给药后极少有原形5-ASA到达结肠部位,使得5-ASA的治疗效果不理想。尽管国内外已经有几种5-ASA口服制剂上市,但都是缓释制剂或肠溶包衣制剂,都有结肠定位差的缺点,而国内尚无国产5-ASA制剂上市。因此,研究5-ASA结肠靶向释药系统有重要意义。
本课题利用壳聚糖在小肠溶胀而不溶解、在结肠可被特异酶降解的特点,以壳聚糖和丙烯酸树脂(L100-55)包衣5-ASA片芯,制备口服5-ASA结肠靶向片,并对其体内外释放及药效学进行研究。
将不同的填充剂、崩解剂、粘合剂、润滑剂湿法制粒,压片,以崩解时限作为考察指标进行处方设计和优化。结果显示微晶纤维素做填充剂、交联PVP 5%、10%PVP 50%乙醇/水、滑石粉5%,崩解最快(197秒),溶出完全,故采用此处方制备片芯。
考察不同壳聚糖浓度(1%、2%、3%),包衣增重(1%、2%、3%),增塑剂种类(邻苯二甲酸二乙酯、柠檬酸三乙酯、甘油三醋酸脂)、增塑剂用量(10%、20%、30%)的条件下,片子在pH6.8模拟小肠液和在pH7.0模拟结肠液中的溶出度。结果显示壳聚糖浓度、包衣增重、增塑剂用量对溶出度影响较大。筛选出合适的增塑剂邻苯二甲酸二乙酯,用量20%,确定壳聚糖浓度2%,包衣增重2%。
Colon, as a site offers distinct advantages on account of a near neutral pH, a much longer transit time, reduced digestive enzymatic activity and a much greater responsiveness to absorption enhancers. This enables the visualization of this distal part of GIT as a site for delivery of various drug molecules including proteins and peptides. Bacterially triggered colon specific drug delivery system (BCDDS) is using the existing of micro flora to preparation oral colon-specific drug delivery system OCDDS. For local pathologies of colon specific drug deliver, not only increase the bioavailability of drug at the target site, reduce the dose to be administered but also would reduce the side effects.5-aminosalicylic acid (5-ASA) is an important drug treating IBD, including Ulcerative Colon and Crohn's Disease. The major side effect is the stimulation to stomach and small intestine. The active form of 5-ASA to treat IBD is its original shape. But the absorption in the upper GIT will bring the side effect and deactivate the 5-ASA. Several OCDDSs have been coming into the market in the overseas, however they all have the disadvantage that a substantial amount of drug may be released in the small intestine before the delivery system arrives in the colon. There have no domestic 5-ASA preparation came into market. So the study on the 5-ASA colon specific delivery system is of great significance.In this article we use the new colon digested material chitosan film as a coat to protect 5-ASA tablet from the releasing in the small intestine and the Eudragit L100-55 as the enteric coat, meanwhile study the pharmacodynamics and the release profiles of 5-ASA in vitro and in vivo.MicroCellulosePH101 ( filling agent ) PVPP(disintegration agent) PVP K30(binding agent)have been mixed, wet-grained and prepared into tablets. The disintegration time was used as the index to evaluate the factors and Rx. The results showed that the best Rx is the pvpp5% 10%pvp50%ethanol/H2O talcum powder 5% and the disintegration time is 197s.
5-氨基水杨酸(5-aminosalicylic acid, 5-ASA)是治疗溃疡性结肠炎、克隆氏病的有效药物,不良反应较少,主要为胃肠道刺激和肾毒性。临床上多数炎性肠病的病变主要发生在回肠末段和结肠,所以治疗中要求5-ASA在回肠末段和结肠腔内有较高的药物浓度。5-ASA仅以原形在结肠病变部位发挥作用,由于其易在胃肠道上部吸收,因此一般的口服制剂给药后极少有原形5-ASA到达结肠部位,使得5-ASA的治疗效果不理想。尽管国内外已经有几种5-ASA口服制剂上市,但都是缓释制剂或肠溶包衣制剂,都有结肠定位差的缺点,而国内尚无国产5-ASA制剂上市。因此,研究5-ASA结肠靶向释药系统有重要意义。
本课题利用壳聚糖在小肠溶胀而不溶解、在结肠可被特异酶降解的特点,以壳聚糖和丙烯酸树脂(L100-55)包衣5-ASA片芯,制备口服5-ASA结肠靶向片,并对其体内外释放及药效学进行研究。
将不同的填充剂、崩解剂、粘合剂、润滑剂湿法制粒,压片,以崩解时限作为考察指标进行处方设计和优化。结果显示微晶纤维素做填充剂、交联PVP 5%、10%PVP 50%乙醇/水、滑石粉5%,崩解最快(197秒),溶出完全,故采用此处方制备片芯。
考察不同壳聚糖浓度(1%、2%、3%),包衣增重(1%、2%、3%),增塑剂种类(邻苯二甲酸二乙酯、柠檬酸三乙酯、甘油三醋酸脂)、增塑剂用量(10%、20%、30%)的条件下,片子在pH6.8模拟小肠液和在pH7.0模拟结肠液中的溶出度。结果显示壳聚糖浓度、包衣增重、增塑剂用量对溶出度影响较大。筛选出合适的增塑剂邻苯二甲酸二乙酯,用量20%,确定壳聚糖浓度2%,包衣增重2%。
Colon, as a site offers distinct advantages on account of a near neutral pH, a much longer transit time, reduced digestive enzymatic activity and a much greater responsiveness to absorption enhancers. This enables the visualization of this distal part of GIT as a site for delivery of various drug molecules including proteins and peptides. Bacterially triggered colon specific drug delivery system (BCDDS) is using the existing of micro flora to preparation oral colon-specific drug delivery system OCDDS. For local pathologies of colon specific drug deliver, not only increase the bioavailability of drug at the target site, reduce the dose to be administered but also would reduce the side effects.5-aminosalicylic acid (5-ASA) is an important drug treating IBD, including Ulcerative Colon and Crohn's Disease. The major side effect is the stimulation to stomach and small intestine. The active form of 5-ASA to treat IBD is its original shape. But the absorption in the upper GIT will bring the side effect and deactivate the 5-ASA. Several OCDDSs have been coming into the market in the overseas, however they all have the disadvantage that a substantial amount of drug may be released in the small intestine before the delivery system arrives in the colon. There have no domestic 5-ASA preparation came into market. So the study on the 5-ASA colon specific delivery system is of great significance.In this article we use the new colon digested material chitosan film as a coat to protect 5-ASA tablet from the releasing in the small intestine and the Eudragit L100-55 as the enteric coat, meanwhile study the pharmacodynamics and the release profiles of 5-ASA in vitro and in vivo.MicroCellulosePH101 ( filling agent ) PVPP(disintegration agent) PVP K30(binding agent)have been mixed, wet-grained and prepared into tablets. The disintegration time was used as the index to evaluate the factors and Rx. The results showed that the best Rx is the pvpp5% 10%pvp50%ethanol/H2O talcum powder 5% and the disintegration time is 197s.
引文
[1] Merger Metal. Semin Immunol, 1998;10(1):69
[2] Papadakis KA. Gastroenterol Clin North Am. 1999,28(2):283
[3] 周婷,林平,潘慧等.溃疡性结肠炎发病机制及其研究进展[J].世界华人消化杂志,2003,11(11):1782
[4] Crohn's disease[J],The Lancet,2002,3 59(9300):62
[5] 傅崇东,徐惠南,翁伟宇等.HPLC法测定口服5-氨基水杨酸制剂后血浆和尿中的药物及其代谢物[J].复旦学报,2001,28(5):385
[6] 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
[7] 龙启才,赵香兰,曾桂雄,等.国产美沙拉嗪的Ⅰ期临床试验研究[J].中国临床药理学志,1996,12(4):2153
[8] 傅崇东,徐惠南,张瑜.5-氨基水杨酸结肠定位给药时控微丸的制备与体外释放[J].药学学报,2000,35(5):3894
[9] 傅崇东,徐惠南,张瑜.pH依赖缓释型美沙拉秦结肠靶向小丸的制备与评价[J].中国医药工业杂志,2000,31(2):541
[10] Yang L, Chu JS, Fix JA. Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation [J]. Int J Pharm, 2002, 235(1-2):1
[11] Prasad YV, Krishnaiah YS, Satyanarayana S. In vitro evaluation of guargumasa carrier for colon specific drug delivery [J]. J Control Release, 1998, 51(2-3):281
[12] 蒋雪涛 口服结肠定位给药系统[J].国外医学药学分册,1999,26(4):225
[13] Tozaki H, Nishioka J, Komoike J, et al. Enhanced absorption of insulin and (Asu(1,7)) eel-calcitonin using novel azopolymer coated pellets for colon-specific drug delivery[J]. J Pharm Sci, 2001,90(1):89
[14] 邹梅娟,程刚.口服结肠定位给药系统[J].沈阳药科大学学报,2001,18(5):376
[15] Tozaki, H, Komoike J,Tada C, et al. 1997. Chitosan capsules for colon-specific drug delivery: Improvement of insulin absorption from the rat colon[J]. J Pharm Sci,1997,86(9):1016
[16] 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
[17] Tozaki H, Fujita T, Odoriba T, et al. Colon specific delivery of R 68070, a new thomboxene synthase inhibitor, using chitosan capsules: therapeutic effects against 2,4,6 trinitrobenzene sulfonicalid induced ulcerative colitis in rats[J].Life Sci, 1999;64(b): 1155
[18] Feng-Ling Cui, Jing Fan, Wei Li, et al Fluorescence spectroscopy studies on 5-aminosalicylic acid and zinc 5-aminosalylicylate interaction with human serum albumin[j]. J Pharm and Bio,2004,34:189
[19] Yang L, Chu JS, Fix JA. Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation[J]. Int J Pharm, 2002,235(1-2): 1
[20] 中国药典2000版第二部附录
[21] Chen GZ, Huang XZ, Xu JG, et al. Beijing Science Press,1990, P:2-39
[22] 药用聚合物尤特奇使用手册。P:13
[23] 周怀梧等.医药应用概率统计,上海百家出版社,1990,233-264
[24] Ritger PL, Peppas NA. A simple equation for description of solute release. I. Fickian and non-Fickian release form non-swellable devices in the form of slabs, spheres, cylinders or discs[J]. J Controlled Release, 1987,5(1):23
[25] 王晓洁,梁建光,万军利.建立大鼠脾虚型溃疡性结肠炎病理模型的实验[J].烟台师范学院学报,1999,15(2):151
[26] 郑礼,高振强,王淑仙.大鼠溃疡性结肠炎模型的实验研究[J].中国药理学通报,1998,14(4):370
[2] Papadakis KA. Gastroenterol Clin North Am. 1999,28(2):283
[3] 周婷,林平,潘慧等.溃疡性结肠炎发病机制及其研究进展[J].世界华人消化杂志,2003,11(11):1782
[4] Crohn's disease[J],The Lancet,2002,3 59(9300):62
[5] 傅崇东,徐惠南,翁伟宇等.HPLC法测定口服5-氨基水杨酸制剂后血浆和尿中的药物及其代谢物[J].复旦学报,2001,28(5):385
[6] 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
[7] 龙启才,赵香兰,曾桂雄,等.国产美沙拉嗪的Ⅰ期临床试验研究[J].中国临床药理学志,1996,12(4):2153
[8] 傅崇东,徐惠南,张瑜.5-氨基水杨酸结肠定位给药时控微丸的制备与体外释放[J].药学学报,2000,35(5):3894
[9] 傅崇东,徐惠南,张瑜.pH依赖缓释型美沙拉秦结肠靶向小丸的制备与评价[J].中国医药工业杂志,2000,31(2):541
[10] Yang L, Chu JS, Fix JA. Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation [J]. Int J Pharm, 2002, 235(1-2):1
[11] Prasad YV, Krishnaiah YS, Satyanarayana S. In vitro evaluation of guargumasa carrier for colon specific drug delivery [J]. J Control Release, 1998, 51(2-3):281
[12] 蒋雪涛 口服结肠定位给药系统[J].国外医学药学分册,1999,26(4):225
[13] Tozaki H, Nishioka J, Komoike J, et al. Enhanced absorption of insulin and (Asu(1,7)) eel-calcitonin using novel azopolymer coated pellets for colon-specific drug delivery[J]. J Pharm Sci, 2001,90(1):89
[14] 邹梅娟,程刚.口服结肠定位给药系统[J].沈阳药科大学学报,2001,18(5):376
[15] Tozaki, H, Komoike J,Tada C, et al. 1997. Chitosan capsules for colon-specific drug delivery: Improvement of insulin absorption from the rat colon[J]. J Pharm Sci,1997,86(9):1016
[16] 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
[17] Tozaki H, Fujita T, Odoriba T, et al. Colon specific delivery of R 68070, a new thomboxene synthase inhibitor, using chitosan capsules: therapeutic effects against 2,4,6 trinitrobenzene sulfonicalid induced ulcerative colitis in rats[J].Life Sci, 1999;64(b): 1155
[18] Feng-Ling Cui, Jing Fan, Wei Li, et al Fluorescence spectroscopy studies on 5-aminosalicylic acid and zinc 5-aminosalylicylate interaction with human serum albumin[j]. J Pharm and Bio,2004,34:189
[19] Yang L, Chu JS, Fix JA. Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation[J]. Int J Pharm, 2002,235(1-2): 1
[20] 中国药典2000版第二部附录
[21] Chen GZ, Huang XZ, Xu JG, et al. Beijing Science Press,1990, P:2-39
[22] 药用聚合物尤特奇使用手册。P:13
[23] 周怀梧等.医药应用概率统计,上海百家出版社,1990,233-264
[24] Ritger PL, Peppas NA. A simple equation for description of solute release. I. Fickian and non-Fickian release form non-swellable devices in the form of slabs, spheres, cylinders or discs[J]. J Controlled Release, 1987,5(1):23
[25] 王晓洁,梁建光,万军利.建立大鼠脾虚型溃疡性结肠炎病理模型的实验[J].烟台师范学院学报,1999,15(2):151
[26] 郑礼,高振强,王淑仙.大鼠溃疡性结肠炎模型的实验研究[J].中国药理学通报,1998,14(4):370
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