酶触型结肠靶向吲哚美辛微丸的研制
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摘要
目的:口服结肠定位释药系统(OCDDS)可用于结肠局部病变的治疗,近年来受到广泛重视。天然多糖类化合物作为制剂辅料应用广泛,因其可被结肠菌群释放的酶特异性降解,成为结肠定位给药系统的新型载体材料。海藻酸钠是从海带或海藻中提取的天然多糖类化合物,易溶于水,无毒,有良好的生物降解性和相容性,现已被大量用作药物的缓释和控释材料,广泛应用于片剂、微丸、微囊、脂质体、纳米粒等缓释制剂中。
本实验以海藻酸钠为辅料,吲哚美辛为模型药物,制备酶触型海藻酸钠/氯化钙结肠靶向传递系统(enzyme triggered colon specific drug delivery System, ECDDS),可将药物定位于结肠局部释药,提高局部治疗浓度的同时,避免胃、小肠吸收引起刺激的副作用。
方法:以海藻酸钠作为辅料,利用海藻酸钠与氯化钙发生胶凝反应,形成疏水性的海藻酸钙骨架结构,药物嵌入骨架结构中形成含药的骨架微丸,结肠部位的特有的酶使海藻酸钙骨架降解,释放药物,实现药物的结肠靶向作用。
配制一定浓度的含药海藻酸钠溶液,通过滴头将海藻酸钠溶液滴入一定浓度的氯化钙溶液中,形成含药海藻酸钙微丸。通过单因素试验选择最佳的微丸制备工艺,分别对滴头口径、滴距、滴速、干燥温度和干燥时间等因素进行考察,从而确定最佳制备工艺。在单因素考察基础上,通过正交试验设计筛选优化处方,选择氯化钙溶液浓度、海藻酸钠溶液浓度、氯化钙溶液pH作为三种影响因素,每种影响因素选取两个不同水平,按L4 (23)正交试验处方,综合评价微丸形态和释放度,通过级差分析和方差分析,确定微丸的最佳处方。
在文献报道和预试验基础上,建立紫外分光光度法(UV)和高效液相分析方法(HPLC),测定吲哚美辛微丸的释放度。对制成的微丸进行释放度考察,在参考USP23和参考文献的基础上,结合本实验确定释放方法。
考察高温、高湿和强光照射等因素对微丸稳定性的影响,分别于试验期间第5天和第10天取样一次,观察其性状和测定释放度。
以大鼠为实验动物,随即分为两组,在乙醚轻度麻醉下通过聚乙烯管为大鼠灌下含药海藻酸钠/氯化钙微丸(实验组)或自制吲哚美辛混悬液(对照组)。用高效液相色谱法测定给药后不同时间的血药浓度,以及胃、小肠、盲肠和结肠等部位内容物中药物的分布情况。
结果:通过对微丸制备工艺的考察,确定滴头口径0.9mm,滴距3cm,滴速2ml/min,干燥温度45℃,干燥时间24h是制备微丸的最佳工艺。处方单因素试验显示,氯化钙溶液浓度、海藻酸钠溶液浓度和氯化钙溶液pH对微丸的释放有较大影响,对正交试验结果进行极差分析,确定制备微丸的最优处方为:1%氯化钙溶液浓度,2%海藻酸钠溶液浓度和pH4氯化钙溶液。
吲哚美辛微丸HPLC释放度测定方法的系统适用性试验结果:吲哚美辛的保留时间为9.995min;方法回收率在:93.80%～101.28%,方法精密度RSD小于3%,符合中国药典规定。此方法能够准确测定吲哚美辛微丸的释放度。
在高温条件下,微丸的性状及释放度均无显著性变化,表明吲哚美辛微丸对热稳定。在高湿条件下,微丸吸湿严重,表明吲哚美辛微丸对湿不稳定,应在干燥环境下保存。在光照条件下,微丸的性状无显著性变化,释放度稍有降低,表明吲哚美辛微丸对光不稳定,应避光保存。
吲哚美辛微丸(实验组)大鼠口服给药后盲肠和结肠中吲哚美辛的浓度明显高于对照组,平均峰浓度分别为1.24±0.15μg/g和1.97±0.26μg/g,血药浓度相对较低而平稳,达峰时间为13 h,峰浓度6.26±1.08μg/g;吲哚美辛混悬液(对照组)平均峰浓度为0.22±0.05μg/g和0.58±0.09μg/g,血药浓度相对较高,达峰时间为3h,峰浓度为10.14±1.89μg/g。微丸中吲哚美辛主要分布于盲肠和结肠中,而在上消化道中检测到很少的药物。混悬液中的吲哚美辛主要分布于上消化道,盲肠和结肠中的药物浓度却很低。实验组和对照组的AUC值分别是71.35±2.56μg·h/mL和88.67±8.34μg·h/mL,统计分析表明两者之间有显著性差异(p<0.05)。和对照组相比,实验组的相对生物利用度为80.47%。
结论:以海藻酸钠/氯化钙为辅料制备的吲哚美辛微丸具有良好的体外释药特征,重现性好;微丸和混悬液中的吲哚美辛在体内的分布是不同的,混悬液中的吲哚美辛主要分布于上消化道;而微丸中的吲哚美辛,主要分布于盲肠和结肠。药物在消化道的吸收部位不同,其药代动力学特征和参数也不同。总之,本实验制备的海藻酸钠/氯化钙结肠靶向微丸在大鼠体内有良好的结肠靶向性,在大肠部位,呈现相对较高的局部药物浓度和较长时间暴露于靶部位,对结肠疾病有较好的治疗作用,也降低了其副作用。
Objectives: In the recent years, oral colon-specific drug delivery system (OCDDS) has been broadly used, because it can be used to the treatment of pathological changes of site in colon. Natural polysaccharide polymer is widely used as excipient, which is to become new carrier excipient of colon-specific drug delivery system, because it can be specifically degradated by enzyme released from colon flora. Alginate is water-soluble, nontoxicity and biocompatible. Alginate is a natural polysaccharide polymer isolated from seaweeds oralgae, which is widely used as a sustained- release and controlled-release excipient of tablets, pellets, microspheres, liposome and nanoparti-cle.
ALG/CaCl_2 microbially triggered colon drug delivery system could release the drug in the colon, which use alginate as excipient and IN as drug. The drug delivery system could increase the drug concentration of the colon and reduce the side effect.
Methods: Pellet containing alginate were prepared by the process of gelatinating reaction of alginate and CaCl2, which form the hydrophobicity backbone frame. The drug fit-into the backbone fram. The special enzyme in colon could degradate the backbone frame and release the drug, that achieved colon-specific delivery of drug after oral.
Pectin aqueous solution including IN at a concentration was prepared. This dispersion was added drop-wise, using a nozzle, into CaCl2 solution of the cross-linking agent, forming the IN ALG/CaCl2 pellets. The single factor experiment was designed to screen technique in the dropper diameter, speed of dropping, temperature of drying and time of drying. The orthogonal experiment was designed to screen prescription in which CaCl2 solution concentration, alginate solution concentration and CaCl2 solution pH were taken as three influential factors and two different levels were selected to part, each conformation of prescription was selected according to the L4(23)orthogonal design table. By analysis of range, the optimization of technique was definite with the colligation evaluation of formation and percent of release.
The UV and HPLC analytical method was found upon reference and preliminary experiment. Drug release studies in the presence of caecal content were carried out according to USP 23 and reference.
The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature and strong light. In the fifth day and the tenth day of the study period, the formulation was observed for change in physical appearance, color and drug release characteristics.
The animals were divide into two groups. Each group administered orally IN pellets or IN suspension via a polyethylene cannula (diameter: 3 mm) with 1ml water under light ether anesthesia. The IN concentrations in plasma, stomach, small intestine, cecum and colon were determined by high performance liquid chromatography after administered.
Results: The pellet were prepared with optimization artwork: dropper diameter 0.9 mm; speed of dropping 2 ml/min, temperature of drying 45℃, time of drying 24 h. The results of the study show that CaCl2 solution concentration, alginate solution concentration and CaCl2 solution pH is the major effect of the release of pellets in vitro. The decibel analysis of orthogonal experiment show the optimization prescription: CaCl2 solution concentration 1%, alginate solution concentration 2%, CaCl2 solution pH 4.
The results of the system serve experiment of the HPLC method to determine the content of IN: the reserve time of IN were about 9.995 min, the recoveries were between 93.80%～101.8%, the precision was below 3%. The method could determine the content of IN accurately and precisely.
There was no change in the physical appearance and percent of release of the IN pellets at the end of the high temperature study. The pellets get heavy moisture absorption at the end of the high moisture study. That means the pellets should be reserved aridity. There was no change in the physical appearance of the IN pellets at the end of the strong light study, while there is a light of decrease in the percent of release. That means the pellets should be reserved away from light.
The mean peak IN concentrations in cecum and colon, respectively, were 1.24±0.15μg/g and 1.97±0.26μg/g for IN released from the pellets, and 0.22±0.05μg/g and 0.58±0.09μg/g for the administration of the suspension. In plasma, the high and sharp drug concentration profile from suspension was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the pellets. In contrast, the observed mean CBmax B from the pellets group (6.26±1.08μg/mL) was lower than that of the uncoated pellets group (10.14±1.89μg/mL). There was a statistically significant difference (p<0.05) in the AUC values between the suspension (88.67±8.34μg·h/mL) and pellets (71.35±2.56μg·h/mL). The relative bioavailability of the pellets is 80.47% by comparing the AUC under the assumption that the BA of IN released from the suspension is 100%.
Conclusions: Combination of alginate and CaCl2 as adjuvant may provide the necessary protection to a drug in the upper GI tract while allowing enzymatic breakdown and drug release in the colon. The distribution of IN pellets was markedly different from that of IN suspension after oral administration. In contrast to suspension dispersal along the whole upper GI tract, IN was predominantly released from the pellets in cecum and colon. The absorption of drug from different regions of the GI tract was found to influence the pharmacokinetic profile and parameters.
In conclusion, colon-specific delivery of IN was achieved after oral administration of the ALG/CaCl2 pellets to the rats. The relatively high local drug concentration with prolonged exposure time provides a potential to enhance colon disease efficacy with low side effect for the treatment.
本实验以海藻酸钠为辅料,吲哚美辛为模型药物,制备酶触型海藻酸钠/氯化钙结肠靶向传递系统(enzyme triggered colon specific drug delivery System, ECDDS),可将药物定位于结肠局部释药,提高局部治疗浓度的同时,避免胃、小肠吸收引起刺激的副作用。
方法:以海藻酸钠作为辅料,利用海藻酸钠与氯化钙发生胶凝反应,形成疏水性的海藻酸钙骨架结构,药物嵌入骨架结构中形成含药的骨架微丸,结肠部位的特有的酶使海藻酸钙骨架降解,释放药物,实现药物的结肠靶向作用。
配制一定浓度的含药海藻酸钠溶液,通过滴头将海藻酸钠溶液滴入一定浓度的氯化钙溶液中,形成含药海藻酸钙微丸。通过单因素试验选择最佳的微丸制备工艺,分别对滴头口径、滴距、滴速、干燥温度和干燥时间等因素进行考察,从而确定最佳制备工艺。在单因素考察基础上,通过正交试验设计筛选优化处方,选择氯化钙溶液浓度、海藻酸钠溶液浓度、氯化钙溶液pH作为三种影响因素,每种影响因素选取两个不同水平,按L4 (23)正交试验处方,综合评价微丸形态和释放度,通过级差分析和方差分析,确定微丸的最佳处方。
在文献报道和预试验基础上,建立紫外分光光度法(UV)和高效液相分析方法(HPLC),测定吲哚美辛微丸的释放度。对制成的微丸进行释放度考察,在参考USP23和参考文献的基础上,结合本实验确定释放方法。
考察高温、高湿和强光照射等因素对微丸稳定性的影响,分别于试验期间第5天和第10天取样一次,观察其性状和测定释放度。
以大鼠为实验动物,随即分为两组,在乙醚轻度麻醉下通过聚乙烯管为大鼠灌下含药海藻酸钠/氯化钙微丸(实验组)或自制吲哚美辛混悬液(对照组)。用高效液相色谱法测定给药后不同时间的血药浓度,以及胃、小肠、盲肠和结肠等部位内容物中药物的分布情况。
结果:通过对微丸制备工艺的考察,确定滴头口径0.9mm,滴距3cm,滴速2ml/min,干燥温度45℃,干燥时间24h是制备微丸的最佳工艺。处方单因素试验显示,氯化钙溶液浓度、海藻酸钠溶液浓度和氯化钙溶液pH对微丸的释放有较大影响,对正交试验结果进行极差分析,确定制备微丸的最优处方为:1%氯化钙溶液浓度,2%海藻酸钠溶液浓度和pH4氯化钙溶液。
吲哚美辛微丸HPLC释放度测定方法的系统适用性试验结果:吲哚美辛的保留时间为9.995min;方法回收率在:93.80%～101.28%,方法精密度RSD小于3%,符合中国药典规定。此方法能够准确测定吲哚美辛微丸的释放度。
在高温条件下,微丸的性状及释放度均无显著性变化,表明吲哚美辛微丸对热稳定。在高湿条件下,微丸吸湿严重,表明吲哚美辛微丸对湿不稳定,应在干燥环境下保存。在光照条件下,微丸的性状无显著性变化,释放度稍有降低,表明吲哚美辛微丸对光不稳定,应避光保存。
吲哚美辛微丸(实验组)大鼠口服给药后盲肠和结肠中吲哚美辛的浓度明显高于对照组,平均峰浓度分别为1.24±0.15μg/g和1.97±0.26μg/g,血药浓度相对较低而平稳,达峰时间为13 h,峰浓度6.26±1.08μg/g;吲哚美辛混悬液(对照组)平均峰浓度为0.22±0.05μg/g和0.58±0.09μg/g,血药浓度相对较高,达峰时间为3h,峰浓度为10.14±1.89μg/g。微丸中吲哚美辛主要分布于盲肠和结肠中,而在上消化道中检测到很少的药物。混悬液中的吲哚美辛主要分布于上消化道,盲肠和结肠中的药物浓度却很低。实验组和对照组的AUC值分别是71.35±2.56μg·h/mL和88.67±8.34μg·h/mL,统计分析表明两者之间有显著性差异(p<0.05)。和对照组相比,实验组的相对生物利用度为80.47%。
结论:以海藻酸钠/氯化钙为辅料制备的吲哚美辛微丸具有良好的体外释药特征,重现性好;微丸和混悬液中的吲哚美辛在体内的分布是不同的,混悬液中的吲哚美辛主要分布于上消化道;而微丸中的吲哚美辛,主要分布于盲肠和结肠。药物在消化道的吸收部位不同,其药代动力学特征和参数也不同。总之,本实验制备的海藻酸钠/氯化钙结肠靶向微丸在大鼠体内有良好的结肠靶向性,在大肠部位,呈现相对较高的局部药物浓度和较长时间暴露于靶部位,对结肠疾病有较好的治疗作用,也降低了其副作用。
Objectives: In the recent years, oral colon-specific drug delivery system (OCDDS) has been broadly used, because it can be used to the treatment of pathological changes of site in colon. Natural polysaccharide polymer is widely used as excipient, which is to become new carrier excipient of colon-specific drug delivery system, because it can be specifically degradated by enzyme released from colon flora. Alginate is water-soluble, nontoxicity and biocompatible. Alginate is a natural polysaccharide polymer isolated from seaweeds oralgae, which is widely used as a sustained- release and controlled-release excipient of tablets, pellets, microspheres, liposome and nanoparti-cle.
ALG/CaCl_2 microbially triggered colon drug delivery system could release the drug in the colon, which use alginate as excipient and IN as drug. The drug delivery system could increase the drug concentration of the colon and reduce the side effect.
Methods: Pellet containing alginate were prepared by the process of gelatinating reaction of alginate and CaCl2, which form the hydrophobicity backbone frame. The drug fit-into the backbone fram. The special enzyme in colon could degradate the backbone frame and release the drug, that achieved colon-specific delivery of drug after oral.
Pectin aqueous solution including IN at a concentration was prepared. This dispersion was added drop-wise, using a nozzle, into CaCl2 solution of the cross-linking agent, forming the IN ALG/CaCl2 pellets. The single factor experiment was designed to screen technique in the dropper diameter, speed of dropping, temperature of drying and time of drying. The orthogonal experiment was designed to screen prescription in which CaCl2 solution concentration, alginate solution concentration and CaCl2 solution pH were taken as three influential factors and two different levels were selected to part, each conformation of prescription was selected according to the L4(23)orthogonal design table. By analysis of range, the optimization of technique was definite with the colligation evaluation of formation and percent of release.
The UV and HPLC analytical method was found upon reference and preliminary experiment. Drug release studies in the presence of caecal content were carried out according to USP 23 and reference.
The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature and strong light. In the fifth day and the tenth day of the study period, the formulation was observed for change in physical appearance, color and drug release characteristics.
The animals were divide into two groups. Each group administered orally IN pellets or IN suspension via a polyethylene cannula (diameter: 3 mm) with 1ml water under light ether anesthesia. The IN concentrations in plasma, stomach, small intestine, cecum and colon were determined by high performance liquid chromatography after administered.
Results: The pellet were prepared with optimization artwork: dropper diameter 0.9 mm; speed of dropping 2 ml/min, temperature of drying 45℃, time of drying 24 h. The results of the study show that CaCl2 solution concentration, alginate solution concentration and CaCl2 solution pH is the major effect of the release of pellets in vitro. The decibel analysis of orthogonal experiment show the optimization prescription: CaCl2 solution concentration 1%, alginate solution concentration 2%, CaCl2 solution pH 4.
The results of the system serve experiment of the HPLC method to determine the content of IN: the reserve time of IN were about 9.995 min, the recoveries were between 93.80%～101.8%, the precision was below 3%. The method could determine the content of IN accurately and precisely.
There was no change in the physical appearance and percent of release of the IN pellets at the end of the high temperature study. The pellets get heavy moisture absorption at the end of the high moisture study. That means the pellets should be reserved aridity. There was no change in the physical appearance of the IN pellets at the end of the strong light study, while there is a light of decrease in the percent of release. That means the pellets should be reserved away from light.
The mean peak IN concentrations in cecum and colon, respectively, were 1.24±0.15μg/g and 1.97±0.26μg/g for IN released from the pellets, and 0.22±0.05μg/g and 0.58±0.09μg/g for the administration of the suspension. In plasma, the high and sharp drug concentration profile from suspension was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the pellets. In contrast, the observed mean CBmax B from the pellets group (6.26±1.08μg/mL) was lower than that of the uncoated pellets group (10.14±1.89μg/mL). There was a statistically significant difference (p<0.05) in the AUC values between the suspension (88.67±8.34μg·h/mL) and pellets (71.35±2.56μg·h/mL). The relative bioavailability of the pellets is 80.47% by comparing the AUC under the assumption that the BA of IN released from the suspension is 100%.
Conclusions: Combination of alginate and CaCl2 as adjuvant may provide the necessary protection to a drug in the upper GI tract while allowing enzymatic breakdown and drug release in the colon. The distribution of IN pellets was markedly different from that of IN suspension after oral administration. In contrast to suspension dispersal along the whole upper GI tract, IN was predominantly released from the pellets in cecum and colon. The absorption of drug from different regions of the GI tract was found to influence the pharmacokinetic profile and parameters.
In conclusion, colon-specific delivery of IN was achieved after oral administration of the ALG/CaCl2 pellets to the rats. The relatively high local drug concentration with prolonged exposure time provides a potential to enhance colon disease efficacy with low side effect for the treatment.
引文
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7徐美华,张桂英。吲哚美辛对结肠癌细胞中细胞周期蛋白的影响,肿瘤,2005,25(3):217-220
8 Semde R, Amighi K, Devleeschouwer MJ, et al. Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate, International Journal of Pharmaceutics, 2000, 197(1-2): 169-179
9 Liu H, Yang XG, Nie SF, et al. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: Screening of formulation variables and in vitro investigation, International Journal of Pharmaceutics, 2007, 332(1-2): 115-124
10 Milojevic S, Newton JM, Cummings JH, et al. Amylose as a coating for drug delivery to the colon: preparation and in vitro evaluation using 5-aminosalicylic acids pellets, Journal of Control Release, 1996, 38(1): 75-84
11 Sinha VR, Mittal BR, Bhutani KK, et al. Colonic drug delivery of 5-fluorouracil: an in vitro evaluation, International Journal of Pharmaceutics, 2004, 269(1): 101-108
1中国药典委员会编,中华人民共和国药典。2005年版,二部
2高青,张吉吉,周立春。高效液相色谱法测定吲哚美辛栓的含量及有关物质,中国药学杂志,2005,40(15):1176-1177
1 He W, Du Q, Cao DY, et al. Study on colon-specific pectin/ethylcellulo film-coated 5-fluorouracil pellets in rats, International Journal of Pharmaceutics, 2008, 348(1-2): 34-35
2 Wu B, Chen ZK, Wei XL, et al. Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: Characterization and methanistic, European Journal of Pharmaceutics and Biopharmaceutics, 2007, 67(3): 707-714
3 Finegold SM, Sutter VL, Mathisen GE. Normal indigenous intestinal flora, Chap. I In: Hentges DJ, ed. Human Intestinal Microflora in Health and Disease, Editor: D. J. Hentges, Academic Press, New York, 1983: 3-13
4 Abu Shamat M. The role of the gastrointestinal microflora in the metabolism of drugs, International journal of pharmaceutics, 1993, 97(1-3): 1-13
1 Prasad YV. Krishnarah YS. Sstyanaryana S. In vitro evaluation of guar gum as a carrier for colon specific drug delivery, Journal of Controlled Release, 1998, 51(2-3): 281-287
2杜文华,焦艳,高春生等。细菌触发型结肠靶向释药系统的研究进展,国外医学药学分册,2003,30(4):245-248
3 Yang L. Biorelevant dissolution testing of colonspecific delivery systems activated by colonic microflora, Journal of Controlled Release, 2008, 125(2): 77-86
4 Masataka K, Shunsuke W, Hitoshi K, et al. Effects of absorption promoters on insulin absorption through colon-targeted delivery, International Journal of Pharmaceutics, 2006, 307(2): 156-162
5 Mladenovska K, Raicki RS, Janevik EI, et al. Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles, International Journal of Pharmaceutics, 2007, 342(1-2): 124-136
6江丽,杭太俊,邱娟等。甲硝唑结肠定位肠溶片在健康人体的药代动力学和生物等效性,中国临床药理学杂志,2006,22(5):340-344
7魏秀莉,孙宁云,吴宝剑等。氯化钙对吲哚美辛果胶骨架片体外释放的影响,中国药学杂志,2006,41(23):1804-1808
8程刚,肖云彩,吴寿荣等。新型茶碱口服结肠靶向给药系统的体内动力学,沈阳药可大学学报,2003,20(1):32-35
9 Wiwattanapatapee R, Lomlim L, Saramunee K. Den- drimers conjugates for colonic delivery of 5-aminosalicylic acid, Journal of Controlled Release, 2003, 88(1): 1-9
10 He W, Du Q, Cao DY, et al. Study on colon-specific pectin/ethylcellulose film-coated 5-fluorouracil pellets in rats, International Journal of Pharmaceutics, 2008, 348(1-2): 35-45
11 Liu H, Yang XG, Nie SF, et al. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: Screening of formulation variables and in vitro investigation, International Journal of Pharmaceutics, 2007, 332(1-2): 115-124
12 Chambin O, Dupuis Q, Champion D, et al. Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance, International Journal of Pharmaceutics, 2006, 321(1-2): 86-93
13 Basan H, Gumusderelioglu M, Orbey T, et al. Release characteristics of salmon calcitonin from dextran hydrogels for colon-specific delivery, European Journal of Pharmaceutics and Biopharmaceutics, 2007, 65(1): 39-46
14 Semde R, Amighi K, Devleeschouwer MJ, et al. Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate, International Journal ofPharmaceutics, 2000, 197(1-2): 169-179
15 Stephen AM, Cummings JH. The microbial contribution to human faecal mass, J. Med. Microbiol, 1980, 13(1): 45-56
16 Stephen AM, Cummings JH. Mechanism of action of dietary fibre in the human colon, Nature, 1980, 284: 283-284
17 Moore WE, Cato EP, Holdeman LV. Some current concepts in intestinal bacteriology, American Journal of Clinical Nutrition, 1978, 31: S33-S42
18 Milojevic S, Newton JM, Cummings JH, et al. Amylose as a coating for drug delivery to the colon: preparation and in vitro evaluation using 5-aminosalicylic acids pellets, Journal of Controlled Release, 1996, 38(1): 84-94
19 Gibson GR, Cummings JH, Macfarlane GT. Use of a three-stage continuous culture system to study the effect of mucin on dissimilatory sulfate reduction and methanogenesis by mixed populations of human gut bacteria, Appl Environ Microbiol, 1988, 54(1): 2750-2755
20 Macfarlane GT, Macfarlane S, Gibson GR. Validation of a three-stage compound continuous culture system for investigating the effect of retention time on the ecology and metabolism of bacteria in the human colon, Microbial Ecology, 1998, 35(2): 180-187
21 Molly K, Vande Woestyne M, Verstraete W. Developm- ent of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem, Appl Microbiol Biotechnol, 1993, 39(2): 254-258
22 Schacht E, Gevaert A, Kenawy ER, et al. Polymers for colon specific drug delivery, Journal of Controlled Release, 1996, 39(2): 327-338
23 Wu B, Chen ZK, Wei XL, et al. Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: Characterization and methanistic, European Journal of Pharmaceutics and Biopharmaceutics, 2007, 67(3): 707-714
2林英,彭惠璇。吲哚美辛的临床新应用,现代医药卫生,2006,22(10):1481
3于恩媛。吲哚美辛临床新用途,中国社区医师,2008,24(364):22
4周丽坤。吲哚美辛抗肿瘤研究进展,牡丹江医学院学报,2003,24(6):34-37
5张桂英,王郁杰等。吲哚美辛对结肠癌细胞成瘤裸鼠作用的蛋白质组学研究,中华消化杂志,2006,26(3):183-186
6王红梅,张桂英。吲哚美辛对人结肠癌HCT116和SW480细胞的影响,中南大学学报(医学版),2004,29(1):28-31
7徐美华,张桂英。吲哚美辛对结肠癌细胞中细胞周期蛋白的影响,肿瘤,2005,25(3):217-220
8 Semde R, Amighi K, Devleeschouwer MJ, et al. Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate, International Journal of Pharmaceutics, 2000, 197(1-2): 169-179
9 Liu H, Yang XG, Nie SF, et al. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: Screening of formulation variables and in vitro investigation, International Journal of Pharmaceutics, 2007, 332(1-2): 115-124
10 Milojevic S, Newton JM, Cummings JH, et al. Amylose as a coating for drug delivery to the colon: preparation and in vitro evaluation using 5-aminosalicylic acids pellets, Journal of Control Release, 1996, 38(1): 75-84
11 Sinha VR, Mittal BR, Bhutani KK, et al. Colonic drug delivery of 5-fluorouracil: an in vitro evaluation, International Journal of Pharmaceutics, 2004, 269(1): 101-108
1中国药典委员会编,中华人民共和国药典。2005年版,二部
2高青,张吉吉,周立春。高效液相色谱法测定吲哚美辛栓的含量及有关物质,中国药学杂志,2005,40(15):1176-1177
1 He W, Du Q, Cao DY, et al. Study on colon-specific pectin/ethylcellulo film-coated 5-fluorouracil pellets in rats, International Journal of Pharmaceutics, 2008, 348(1-2): 34-35
2 Wu B, Chen ZK, Wei XL, et al. Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: Characterization and methanistic, European Journal of Pharmaceutics and Biopharmaceutics, 2007, 67(3): 707-714
3 Finegold SM, Sutter VL, Mathisen GE. Normal indigenous intestinal flora, Chap. I In: Hentges DJ, ed. Human Intestinal Microflora in Health and Disease, Editor: D. J. Hentges, Academic Press, New York, 1983: 3-13
4 Abu Shamat M. The role of the gastrointestinal microflora in the metabolism of drugs, International journal of pharmaceutics, 1993, 97(1-3): 1-13
1 Prasad YV. Krishnarah YS. Sstyanaryana S. In vitro evaluation of guar gum as a carrier for colon specific drug delivery, Journal of Controlled Release, 1998, 51(2-3): 281-287
2杜文华,焦艳,高春生等。细菌触发型结肠靶向释药系统的研究进展,国外医学药学分册,2003,30(4):245-248
3 Yang L. Biorelevant dissolution testing of colonspecific delivery systems activated by colonic microflora, Journal of Controlled Release, 2008, 125(2): 77-86
4 Masataka K, Shunsuke W, Hitoshi K, et al. Effects of absorption promoters on insulin absorption through colon-targeted delivery, International Journal of Pharmaceutics, 2006, 307(2): 156-162
5 Mladenovska K, Raicki RS, Janevik EI, et al. Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles, International Journal of Pharmaceutics, 2007, 342(1-2): 124-136
6江丽,杭太俊,邱娟等。甲硝唑结肠定位肠溶片在健康人体的药代动力学和生物等效性,中国临床药理学杂志,2006,22(5):340-344
7魏秀莉,孙宁云,吴宝剑等。氯化钙对吲哚美辛果胶骨架片体外释放的影响,中国药学杂志,2006,41(23):1804-1808
8程刚,肖云彩,吴寿荣等。新型茶碱口服结肠靶向给药系统的体内动力学,沈阳药可大学学报,2003,20(1):32-35
9 Wiwattanapatapee R, Lomlim L, Saramunee K. Den- drimers conjugates for colonic delivery of 5-aminosalicylic acid, Journal of Controlled Release, 2003, 88(1): 1-9
10 He W, Du Q, Cao DY, et al. Study on colon-specific pectin/ethylcellulose film-coated 5-fluorouracil pellets in rats, International Journal of Pharmaceutics, 2008, 348(1-2): 35-45
11 Liu H, Yang XG, Nie SF, et al. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: Screening of formulation variables and in vitro investigation, International Journal of Pharmaceutics, 2007, 332(1-2): 115-124
12 Chambin O, Dupuis Q, Champion D, et al. Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance, International Journal of Pharmaceutics, 2006, 321(1-2): 86-93
13 Basan H, Gumusderelioglu M, Orbey T, et al. Release characteristics of salmon calcitonin from dextran hydrogels for colon-specific delivery, European Journal of Pharmaceutics and Biopharmaceutics, 2007, 65(1): 39-46
14 Semde R, Amighi K, Devleeschouwer MJ, et al. Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate, International Journal ofPharmaceutics, 2000, 197(1-2): 169-179
15 Stephen AM, Cummings JH. The microbial contribution to human faecal mass, J. Med. Microbiol, 1980, 13(1): 45-56
16 Stephen AM, Cummings JH. Mechanism of action of dietary fibre in the human colon, Nature, 1980, 284: 283-284
17 Moore WE, Cato EP, Holdeman LV. Some current concepts in intestinal bacteriology, American Journal of Clinical Nutrition, 1978, 31: S33-S42
18 Milojevic S, Newton JM, Cummings JH, et al. Amylose as a coating for drug delivery to the colon: preparation and in vitro evaluation using 5-aminosalicylic acids pellets, Journal of Controlled Release, 1996, 38(1): 84-94
19 Gibson GR, Cummings JH, Macfarlane GT. Use of a three-stage continuous culture system to study the effect of mucin on dissimilatory sulfate reduction and methanogenesis by mixed populations of human gut bacteria, Appl Environ Microbiol, 1988, 54(1): 2750-2755
20 Macfarlane GT, Macfarlane S, Gibson GR. Validation of a three-stage compound continuous culture system for investigating the effect of retention time on the ecology and metabolism of bacteria in the human colon, Microbial Ecology, 1998, 35(2): 180-187
21 Molly K, Vande Woestyne M, Verstraete W. Developm- ent of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem, Appl Microbiol Biotechnol, 1993, 39(2): 254-258
22 Schacht E, Gevaert A, Kenawy ER, et al. Polymers for colon specific drug delivery, Journal of Controlled Release, 1996, 39(2): 327-338
23 Wu B, Chen ZK, Wei XL, et al. Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: Characterization and methanistic, European Journal of Pharmaceutics and Biopharmaceutics, 2007, 67(3): 707-714
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