肠激安胶囊的工艺、质量标准研究及腹泻型肠易激综合征动物模型比较
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摘要
肠易激综合征(irritable bowel syndrome,简称IBS)以腹痛或腹部不适、大便习惯和(或)大便性状的改变等为主要临床表现,多为慢性、间歇性发作,经检查无特异的生物化学或形态组织学异常。流行病学调查表明IBS是胃肠道最常见的功能性疾病,其全球发病率相当高,各地发病率为10%～15%。本病起病隐匿,反复发作,病程可长达数年至数十年,精神、饮食因素常可诱使症状反复或加重,严重影响病人生活质量,同时有较高的医疗费用。然而现代医学针对IBS的药物大多以对症治疗为主,多因只能阻断一两个病理环节,往往疗效不尽理想,而且毒副作用较多,不宜长期应用。中药在IBS的治疗中发挥很好的疗效,且长期服用毒副作用小,多成分、多靶点、多途径的特点,恰是其对机体神经、内分泌、免疫等多系统的整合作用的基础。IBS发病率有逐年上升的趋势,而至今未见同类中成药上市使用。所以研制一种治疗腹泻型IBS的中药制剂将弥补临床上无针对性治疗腹泻型IBS中药制剂的空白。
1工艺研究
首先按照2005版中国药典的要求,对研究所用饮片进行检验,合格方可使用。以萃取率为指标,采用正交试验,优选出超临界CO2萃取工艺参数,结果表明最佳条件是A3B2C3,即萃取压力25 MPa,萃取温度为55℃,萃取时间为3h。又对超临界CO2萃取所得挥发油与水蒸气蒸馏全方所得挥发油进行了镇痛、止泻、抗炎的药效学比较,结果表明两种提取方法所得挥发性成分均有明显的药效作用,能延长排黑粪潜伏期,减少排黑粪数量,具有一定的止泻作用；具有一定的抗炎作用；对化学因素引起的疼痛有较好的镇痛作用,能减少扭体发生的次数,且SEF-CO2法挥发油能延长扭体发生潜伏期。由于超临界CO2萃取法的成本较高,不利于产业化,而超临界CO2萃取法提取与水蒸气蒸馏法提取的挥发性成分在镇痛、止泻、抗炎药效方面两组差异无统计学意义,所以本项目选择水蒸气蒸馏法提取挥发性成分。接着以芍药苷的转移率及总固形物的量为指标,采用正交试验,优选最佳的水提工艺参数,结果表明加10倍水,提取3次,每次1.5小时的工艺最优,验证实验结果水提工艺稳定、重复可行。在干燥工艺研究中,以芍药苷的转移率为指标,比较常压干燥、真空干燥、喷雾干燥几种干燥方法,选择喷雾干燥并优选出工艺参数,结果表明水提清膏相对密度调成为1.10,可使喷雾干燥顺利进行。粉碎工艺研究确定了延胡索、黄连粉碎工艺的可行性。成型工艺研究中,比较了几种混合粉的休止角,结果表明,不加辅料的粉末流动性最好,可直接进行分装,其临界湿度为57%,对生产时的环境和包装提出了要求。
2质量标准研究
在质量标准研究中,按《中国药典》2005年版一部附录Ⅰ制剂通则IL胶囊剂项的要求,对制剂的水分、崩解时限进行了检查；建立了药材延胡索、黄连、陈皮、枳壳、白芍、石榴皮的传统TLC定性鉴别,建立了延胡索、黄连、防风、甘草的微乳TLC定性鉴别；建立了芍药苷的HPLC的含量测定方法；分析了肠激安方中所含挥发油的化学成分。
3动物模型研究
本实验以母乳分离、肠道刺激、束缚刺激为造模的单因素,将三者结合,制定出三因素模型组,将三因素动物模型与单因素IBS模型进行比较。实验结果表明,三因素组无论在大鼠的精神状况、体重、排便情况、直肠敏感性、肠推进运动还是病理方面的检测,都与空白组健康的大鼠有明显的差异,且符合肠易激综合征的诊断标准,说明三因素大鼠造模成功。但是通过比较三因素和各单因素动物模型,三因素组并没有表现出明显的差异。而三因素组更加贴近肠易激综合征临床上多病因、发病机制复杂的情况,在此方面大大优于单因素动物模型。
IBS (irritable bowel syndrome) is a chronic and repeatedly recurring disease with the main clinical expression of bellyache and the change of defecating habit and defecation character, and without differential biochemistry and morphological and histological study abnormity. As IBS is a common dysfunction disease of digestive system, more and more medical scientists pay attention to it. Epidemiology researches prove that IBS is gastrointestinal dysfunction decease with 10%～15%global incidence of disease. IBS begins unconsciously and repeatedly recurs, and it can last for a few or dozens of years, and it can be worsen under the influence of emotion and food, so it seriously affects the patients'life, and health economics proves that it costs IBS patients a lot. Most of the current IBS medicines can only achieve symptomatic treatment, and only interdict one or two pathology taches, and their therapeutic effects can not come up to expectation with a lot of side effects, so they are not fit for using too much. By contrast, TCM has satisfying therapeutic effects with low side effect. The characters of multicomponent, multiple target point and multiple ways serve as material basis to conformity nerve, incretion and immunity systems. The incidence of IBS grows year by year, but relevant proprietary Chinese medicine has not come out yet. So the development of an IBS proprietary Chinese medicine can fill in this kind of blankness.
1. Techn i cal study
The medicinal materials were tested according to the standard of 2005-edition pharmacopoeia before using. Extraction rate was chosen as indexes, and orthogonal design was used for parameters screening of supercritical C02extraction. The results proved that, the best conditions was 25 MPa extraction pressure added with 55℃extraction temperature and 3-hour extration time. The naphtha from supercritical CO2 extraction and vapor distillation was used for the pharmacodynamics comparison in the aspects of analgecize, diarrhoea cure and anti-inflammatory. The results proved that naphtha extracted by these the two ways had significant therapeutic effect. They extended the latent period of black feces, reducing black feces amount and times of mouse writhing. And the naphtha extracted by supercritical CO2 extraction extended the latent period of mouse writhing. As the cost of supercritical C02 extraction is too high, not fitting for industrialization. In addition, in the comparison of the two extraction ways, therapeutic effect variables in the aspect of analgecize, diarrhoea cure and anti-inflammatory were not significant in statistics. So vapor distillation was chosen to extract naphtha. Then the retention rate of Paeoniflorin and the amount of total solid mater were chosen as indexs, and orthogonal design was used for parameters screening of water-extraction. The results proved that, the best condition was tenfold water amount added with three extraction times and 1.5-hour extration time. According to validation test, the water-extraction technics was stable, reproducible and feasible. In the study of dryness technics, the ways of atmospheric drying, vacuum belt drying and spray drying were compared, and spray drying was used and its parameters screening was carried on. The results proved that spray drying went well when the relative density of concentrated liquid was 1.10. The comminution technics of Chinese goldthread and rhizoma corydalis was feasible. In the molding technics, angle of repose was chosen as index, and the results proved that fluidity of the powder without accessories was the best for direct subpackage. The critical humidity was 57%, so the humidity should be controlled under 57%in the producing process.
2. The study of the quality standard
In the study of quality standard, preparation shape, moisture content and disintegration time limited were determined. Traditional TLC and micro emulsion TLC were used for qualitative researches, Traditional TLC methods were established for the identification of corydalis, coptis, tangerine peel, trifoliata Raf., Radix Paeoniae Alba, pomegranate husk, micro emulsion TLC methods were established for the identification of corydalis, coptis, tangerine peel, radix sileris, liquorice. HPLC methods were established for the assayings of Radix Paeoniae Alba. The chemical constituents of volatile oil was analyzed. Supercritical C02 fingerprint was established.
3. The study of animal model
The factors of neonatal-maternal-separation, acetic-acid-irritation, and stress-irritation were combined to make a three-factor model, and the three-factor model group was compared with the one-factor model groups. The results proved that the three-factor model group had significant difference from the blank control group in the aspect of mental condition, weight, defecation, rectum sensitivity, small Intestine propulsive motility and pathologic indexes, and it meet the IBS diagnosis standard. But the three-factor model group did not have significant difference from the one-factor model groups. However, the three-factor model group has the advantage of the similarity to patient's condition with multiple causes and complicated pathogenesis over the one-factor model groups.
1工艺研究
首先按照2005版中国药典的要求,对研究所用饮片进行检验,合格方可使用。以萃取率为指标,采用正交试验,优选出超临界CO2萃取工艺参数,结果表明最佳条件是A3B2C3,即萃取压力25 MPa,萃取温度为55℃,萃取时间为3h。又对超临界CO2萃取所得挥发油与水蒸气蒸馏全方所得挥发油进行了镇痛、止泻、抗炎的药效学比较,结果表明两种提取方法所得挥发性成分均有明显的药效作用,能延长排黑粪潜伏期,减少排黑粪数量,具有一定的止泻作用；具有一定的抗炎作用；对化学因素引起的疼痛有较好的镇痛作用,能减少扭体发生的次数,且SEF-CO2法挥发油能延长扭体发生潜伏期。由于超临界CO2萃取法的成本较高,不利于产业化,而超临界CO2萃取法提取与水蒸气蒸馏法提取的挥发性成分在镇痛、止泻、抗炎药效方面两组差异无统计学意义,所以本项目选择水蒸气蒸馏法提取挥发性成分。接着以芍药苷的转移率及总固形物的量为指标,采用正交试验,优选最佳的水提工艺参数,结果表明加10倍水,提取3次,每次1.5小时的工艺最优,验证实验结果水提工艺稳定、重复可行。在干燥工艺研究中,以芍药苷的转移率为指标,比较常压干燥、真空干燥、喷雾干燥几种干燥方法,选择喷雾干燥并优选出工艺参数,结果表明水提清膏相对密度调成为1.10,可使喷雾干燥顺利进行。粉碎工艺研究确定了延胡索、黄连粉碎工艺的可行性。成型工艺研究中,比较了几种混合粉的休止角,结果表明,不加辅料的粉末流动性最好,可直接进行分装,其临界湿度为57%,对生产时的环境和包装提出了要求。
2质量标准研究
在质量标准研究中,按《中国药典》2005年版一部附录Ⅰ制剂通则IL胶囊剂项的要求,对制剂的水分、崩解时限进行了检查；建立了药材延胡索、黄连、陈皮、枳壳、白芍、石榴皮的传统TLC定性鉴别,建立了延胡索、黄连、防风、甘草的微乳TLC定性鉴别；建立了芍药苷的HPLC的含量测定方法；分析了肠激安方中所含挥发油的化学成分。
3动物模型研究
本实验以母乳分离、肠道刺激、束缚刺激为造模的单因素,将三者结合,制定出三因素模型组,将三因素动物模型与单因素IBS模型进行比较。实验结果表明,三因素组无论在大鼠的精神状况、体重、排便情况、直肠敏感性、肠推进运动还是病理方面的检测,都与空白组健康的大鼠有明显的差异,且符合肠易激综合征的诊断标准,说明三因素大鼠造模成功。但是通过比较三因素和各单因素动物模型,三因素组并没有表现出明显的差异。而三因素组更加贴近肠易激综合征临床上多病因、发病机制复杂的情况,在此方面大大优于单因素动物模型。
IBS (irritable bowel syndrome) is a chronic and repeatedly recurring disease with the main clinical expression of bellyache and the change of defecating habit and defecation character, and without differential biochemistry and morphological and histological study abnormity. As IBS is a common dysfunction disease of digestive system, more and more medical scientists pay attention to it. Epidemiology researches prove that IBS is gastrointestinal dysfunction decease with 10%～15%global incidence of disease. IBS begins unconsciously and repeatedly recurs, and it can last for a few or dozens of years, and it can be worsen under the influence of emotion and food, so it seriously affects the patients'life, and health economics proves that it costs IBS patients a lot. Most of the current IBS medicines can only achieve symptomatic treatment, and only interdict one or two pathology taches, and their therapeutic effects can not come up to expectation with a lot of side effects, so they are not fit for using too much. By contrast, TCM has satisfying therapeutic effects with low side effect. The characters of multicomponent, multiple target point and multiple ways serve as material basis to conformity nerve, incretion and immunity systems. The incidence of IBS grows year by year, but relevant proprietary Chinese medicine has not come out yet. So the development of an IBS proprietary Chinese medicine can fill in this kind of blankness.
1. Techn i cal study
The medicinal materials were tested according to the standard of 2005-edition pharmacopoeia before using. Extraction rate was chosen as indexes, and orthogonal design was used for parameters screening of supercritical C02extraction. The results proved that, the best conditions was 25 MPa extraction pressure added with 55℃extraction temperature and 3-hour extration time. The naphtha from supercritical CO2 extraction and vapor distillation was used for the pharmacodynamics comparison in the aspects of analgecize, diarrhoea cure and anti-inflammatory. The results proved that naphtha extracted by these the two ways had significant therapeutic effect. They extended the latent period of black feces, reducing black feces amount and times of mouse writhing. And the naphtha extracted by supercritical CO2 extraction extended the latent period of mouse writhing. As the cost of supercritical C02 extraction is too high, not fitting for industrialization. In addition, in the comparison of the two extraction ways, therapeutic effect variables in the aspect of analgecize, diarrhoea cure and anti-inflammatory were not significant in statistics. So vapor distillation was chosen to extract naphtha. Then the retention rate of Paeoniflorin and the amount of total solid mater were chosen as indexs, and orthogonal design was used for parameters screening of water-extraction. The results proved that, the best condition was tenfold water amount added with three extraction times and 1.5-hour extration time. According to validation test, the water-extraction technics was stable, reproducible and feasible. In the study of dryness technics, the ways of atmospheric drying, vacuum belt drying and spray drying were compared, and spray drying was used and its parameters screening was carried on. The results proved that spray drying went well when the relative density of concentrated liquid was 1.10. The comminution technics of Chinese goldthread and rhizoma corydalis was feasible. In the molding technics, angle of repose was chosen as index, and the results proved that fluidity of the powder without accessories was the best for direct subpackage. The critical humidity was 57%, so the humidity should be controlled under 57%in the producing process.
2. The study of the quality standard
In the study of quality standard, preparation shape, moisture content and disintegration time limited were determined. Traditional TLC and micro emulsion TLC were used for qualitative researches, Traditional TLC methods were established for the identification of corydalis, coptis, tangerine peel, trifoliata Raf., Radix Paeoniae Alba, pomegranate husk, micro emulsion TLC methods were established for the identification of corydalis, coptis, tangerine peel, radix sileris, liquorice. HPLC methods were established for the assayings of Radix Paeoniae Alba. The chemical constituents of volatile oil was analyzed. Supercritical C02 fingerprint was established.
3. The study of animal model
The factors of neonatal-maternal-separation, acetic-acid-irritation, and stress-irritation were combined to make a three-factor model, and the three-factor model group was compared with the one-factor model groups. The results proved that the three-factor model group had significant difference from the blank control group in the aspect of mental condition, weight, defecation, rectum sensitivity, small Intestine propulsive motility and pathologic indexes, and it meet the IBS diagnosis standard. But the three-factor model group did not have significant difference from the one-factor model groups. However, the three-factor model group has the advantage of the similarity to patient's condition with multiple causes and complicated pathogenesis over the one-factor model groups.
引文
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