经典名方逍遥方新制剂工艺合理性评价方法的研究
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摘要
目的:采用超临界萃取、大孔吸附树脂分离等新技术制备逍遥方新制剂,通过对逍遥方三种制剂(传统汤剂、丸剂、新制剂)的体内外化学成分、疏肝健脾药理效应及谱效相关性对比研究,建立基于整体生物效应与化学成分指纹图谱特征的工艺合理性评价方法,以逍遥方为切入点,为经典名方现代中药制剂工艺合理性评价提供一种新的思路。
方法:本课题采用超临界萃取、大孔吸附树脂纯化等新技术,超临界-CO_2萃取挥发性成分提取工艺,采用正交试验设计方法优选水溶性成分分离纯化条件,确定逍遥方新制剂最佳工艺;通过对逍遥方新制剂、传统汤剂、传统丸剂三种制剂的薄层鉴别、含量测定及指纹图谱,建立质量控制方法;采用肝郁脾虚“证型”动物模型与脾虚“病证”动物模型,通过胃肠功能与神经递质等指标观察,比较逍遥方三种制剂对肝郁脾虚模型神经-内分泌-免疫及胃肠功能的影响;采用指纹图谱技术,获取逍遥方三种制剂体外、体内共有化学成分指纹特征,应用灰关联度分析方法,研究谱效相关性,探讨其药效物质基础,并评价逍遥方现代中药制剂提取分离工艺路线的合理性,建立基于整体生物效应与化学成分指纹图谱特征的工艺合理性评价方法。
结果:逍遥方新制剂优选的工艺参数为:(1)SFE-CO_2萃取:萃取压力约30Mpa,萃取温度约50℃,解析压力约8Mpa,解析温度约40℃;以乙醇作夹带剂,用量为0.1ml/g;循环萃取2h;CO_2流量25～30L/h。(2)大孔吸附树脂纯化:采用D-101型树脂,将药液浓度调整为5～10mg/ml,上柱流速为2～3BV/h。再用各2BV蒸馏水、20%乙醇淋洗,以70%乙醇为洗脱剂,用稀氨水调节pH值为8.0～9.0。以2BV/h流速洗脱,收集4BV洗脱液。(3)低温动态提取:提取二次,第一次加12倍量水提取2h,第二次加10倍量水提取1.5h。采用正交试验对水煎液的醇沉工艺参数进行优选,即水煎液浓缩至相对密度约1.10(60℃测)。(4)絮凝澄清:茯苓、当归、白术水煎液浓缩至生药:水(1:1),加入5%壳聚糖(用量为1 0%),摇匀,于40℃水浴加热15min后,室温放置2h后离心(3000rpm·min-1,15min),取上清液。
建立了逍遥方新制剂的6项TLC鉴别、阿魏酸与芍药苷的含测方法及其HPLC指纹图谱,按国家药典委员会颁布的“中药指纹图谱相似度评价软件”计算相似度结果均在0.9以上。
建立了逍遥方三种制剂的体内外HPLC指纹图谱,其中体外指纹图谱新制剂19个共有峰,丸剂21个峰,汤剂15个峰,其中有12个峰为三种制剂所共有。体内血浆HPLC指纹图谱包括肝郁脾虚模型动物指纹图谱与健康动物指纹图谱,三种制剂模型动物新制剂共有峰11个、丸剂13个、汤剂13个,其中7个峰为三种制剂所共有;健康动物新制剂共有峰8个、丸剂10个、汤剂6个,其中5个峰为三种制剂所共有。体内外指纹图谱共有峰数目与结构分布均表明,逍遥方不同工艺的三种制剂体内外化学成分均发生变化,提示三种制剂药效物质基础发生了变化。肝郁脾虚模型动物与健康动物的体内指纹图谱共有峰数目与结构分布比较,结果提示,逍遥方主要是通过调节机体本身的物质起到免疫双向调节作用。
疏肝健脾药效试验结果表明,逍遥方三种制剂均具有可提高肝郁脾虚大鼠体重,升高血浆单胺类神经递质NE、5-HT的浓度,使胃肠组织细胞中胃肠激素MTL表达升高、SS降低表达;降低脾虚小鼠小肠推进率、提高其胸腺与脾指数等作用。新制剂药效与汤剂相当,并优于等剂量的丸剂。
体外谱效关联度分析结果为大孔吸附树脂所获得的化学成分保留时间t_R=18.111、25.171、27.103共有峰与疏肝健脾作用高度关联;SFE-CO_2萃取所获得的化学成分保留时间t_R=22.191/31.244、35.225共有峰与疏肝健脾作用高度关联,为其工艺优选提供了考察指标。体内、外关联度三种制剂按照体外谱效关联度的大小排列依次为新制剂峰＞汤剂峰＞丸剂峰。结果表明,新制剂工艺稳定、应用技术合理。
结论:选择传统制剂、丸剂作为对照,基于整体生物效应与化学成分指纹图谱特征的工艺合理性评价方法表明,逍遥方新制剂工艺合理,质量可控,药效可靠,为现代中药制剂工艺研究提供了新的思路与方法。
1.Objective:Using SFE-CO_2、separation of macroporous adsorption resin and other new technologies,new preparations were prepared.By comparing the chemical constituents and pharmacological effects and spleen correlation spectral efficiency,three preparation for Xiaoyao preparation traditional decoction,pills,new formulation,we build the chemical constituents and biological effects of the whole process of fingerprint characteristics,with reasonable evaluation method for unfettered,modern Chinese native medicine preparation for classic prescription rationality assessment technique provides a new idea.
2.Methods We use SFE-CO_2,separation of macroporous adsorption resin and other new technologies,by GC-MS determine fat-soluble components extraction technology,use the orthogonal experiment design optimization method of water-soluble ingredients,separation and purification unfettered new preparation conditions;the best Based on new products,the traditional one xiaoyao pill three preparation,traditional thin layer of identification,the content and the fingerprint,establish quality control method,Using stomach "syndrome" animal models and spleen "disease" animal model,through the gastrointestinal function and neurotransmitters indexes,such as observation,compared to unfettered square three preparation stomach model nerve - endocrine - and the effect of gastric bowel function,Using fingerprint technology,three kinds of preparation for unfettered square internal and external mutual chemical composition,the application of grey relational fingerprint characteristics, research spectrum analysis method,this paper discusses the effect of correlation material foundation,and the effects of modern Chinese native medicine preparation unfettered square evaluation of extraction and separation technology, based on the rationality of the route with overall biological effects of chemical composition fingerprint characteristics of rationality assessment method.
3.Results The optimum parameters of unfettered dongfang preparations for (1):the SFE - CO_2 extraction temperature,pressure 30Mpa about 50℃, analytical stress,temperature 8Mpa about 40℃,Entrainment preparation anhydrous alcohol consumption for 0.1 ml/g,Circular extractors 2h,The CO_2 flow 25～30L/h.(2) of macroporous adsorption resin purification:adopt D-101 resin,will adjust for 5～solution concentration 10mg/ml,column 2～3BV velocity/h.2BV distilled water,with the velocity,with 70%alcohol 20%ethanol for elution preparation,adjust pH in dilute aqua ammonia to 8.0～9.0.In 2BV/h, collect 4BV velocity elution eluent.(3) the low temperature dynamic extract: extraction,first and second 12 times the amount of water extraction,the second with 2h 10 times of water extracted 1.5h.By orthogonal experiment on the decoction of alcohol process parameters optimization,namely the decoction to concentrate the relative density of about 60 degrees Celsius(1.10).(4) flocculation clarification,tuckahoe,angelica,limit the decoction to concentrate out:water(1:1),add 5%to 10%of chitosan(amount),shake at 40℃,water heating temperature 15min,after 3000rpm centrifugal(placed 2h,min-1,15 min),take supernatant.
We establish new formulation unfettered 6 kinds of TLC identification,content of measurement methods of ferulic acid and paeoniflorin,and HPLC fingerprint.With the state pharmacopoeia commission issued "medicine fingerprint similarity calculation software",evaluation results are similarity in more than 0.9.Results show that the new preparation quality is stable and controllable.
Establishing three HPLC fingerprint in and outside the body,including new preparation 19 10 characteristic peaks,pills,21 peaks and decoction 15 peaks, 12 peaks for three common preparations in vitro fingerprint.Plasma HPLC fingerprint includes health animal fingerprint and stomach model animals fingerprint,three kinds of new drug of animal model preparation has 11 characteristic peaks,pill has 13 peaks,decoction has 13 peaks,including 7 peaks for three preparation,Healthy animals' new preparation has 8 characteristic peaks,pill has 10,decoction has 13,5 peaks for three preparation. The preparation of three kinds of the chemical constituents were analyzed, including new preparation has 9 characteristic peaks,pills has 9,decoction has 7, including 3 peaks for three preparation.Results show that the new preparation unfettered effective composition content,reveal the three kinds of preparation of material base.
Soothing liver and strengthening spleen test results show that the three kinds of preparation can improve the rat weight and plasma monoamine neural transmitter NE,5-HT concentration,make gastric tissue cells MTL gastrointestinal hormones,SS lower expression expression,Mice intestine motional rate reduced spleen,improve the thymus and spleen index,etc.The efficacy of the new is be equivalent to the decoction,and superior to such dose of pills.
In vitro correlation spectral efficiency analysis,results of macroporous adsorption resin of chemical composition is t_R 27.803、29.726 peaks are highly associated to soothing liver and strengthening spleen function,t_R 46.438 peak of SFE-CO_2 extraction of chemical composition is highly associated to soothing liver and strengthening spleen function,which provides the index selection process.In vivo and in vitro correlation of three preparation in vitro correlation spectral efficiency in accordance with the size of the order is the new preparation peaks＞pills peaks＞decoction peaks.
4.Conclusions The rationality evaluation method of preparation technology based on the chemical constituents and biological effects of the whole process of fingerprint characteristics show that the technics of new preparation is reasonable,the quality is controllable,and the drug effect is reliable,which provides modern TCM preparation technology research a new idea and method.
方法:本课题采用超临界萃取、大孔吸附树脂纯化等新技术,超临界-CO_2萃取挥发性成分提取工艺,采用正交试验设计方法优选水溶性成分分离纯化条件,确定逍遥方新制剂最佳工艺;通过对逍遥方新制剂、传统汤剂、传统丸剂三种制剂的薄层鉴别、含量测定及指纹图谱,建立质量控制方法;采用肝郁脾虚“证型”动物模型与脾虚“病证”动物模型,通过胃肠功能与神经递质等指标观察,比较逍遥方三种制剂对肝郁脾虚模型神经-内分泌-免疫及胃肠功能的影响;采用指纹图谱技术,获取逍遥方三种制剂体外、体内共有化学成分指纹特征,应用灰关联度分析方法,研究谱效相关性,探讨其药效物质基础,并评价逍遥方现代中药制剂提取分离工艺路线的合理性,建立基于整体生物效应与化学成分指纹图谱特征的工艺合理性评价方法。
结果:逍遥方新制剂优选的工艺参数为:(1)SFE-CO_2萃取:萃取压力约30Mpa,萃取温度约50℃,解析压力约8Mpa,解析温度约40℃;以乙醇作夹带剂,用量为0.1ml/g;循环萃取2h;CO_2流量25～30L/h。(2)大孔吸附树脂纯化:采用D-101型树脂,将药液浓度调整为5～10mg/ml,上柱流速为2～3BV/h。再用各2BV蒸馏水、20%乙醇淋洗,以70%乙醇为洗脱剂,用稀氨水调节pH值为8.0～9.0。以2BV/h流速洗脱,收集4BV洗脱液。(3)低温动态提取:提取二次,第一次加12倍量水提取2h,第二次加10倍量水提取1.5h。采用正交试验对水煎液的醇沉工艺参数进行优选,即水煎液浓缩至相对密度约1.10(60℃测)。(4)絮凝澄清:茯苓、当归、白术水煎液浓缩至生药:水(1:1),加入5%壳聚糖(用量为1 0%),摇匀,于40℃水浴加热15min后,室温放置2h后离心(3000rpm·min-1,15min),取上清液。
建立了逍遥方新制剂的6项TLC鉴别、阿魏酸与芍药苷的含测方法及其HPLC指纹图谱,按国家药典委员会颁布的“中药指纹图谱相似度评价软件”计算相似度结果均在0.9以上。
建立了逍遥方三种制剂的体内外HPLC指纹图谱,其中体外指纹图谱新制剂19个共有峰,丸剂21个峰,汤剂15个峰,其中有12个峰为三种制剂所共有。体内血浆HPLC指纹图谱包括肝郁脾虚模型动物指纹图谱与健康动物指纹图谱,三种制剂模型动物新制剂共有峰11个、丸剂13个、汤剂13个,其中7个峰为三种制剂所共有;健康动物新制剂共有峰8个、丸剂10个、汤剂6个,其中5个峰为三种制剂所共有。体内外指纹图谱共有峰数目与结构分布均表明,逍遥方不同工艺的三种制剂体内外化学成分均发生变化,提示三种制剂药效物质基础发生了变化。肝郁脾虚模型动物与健康动物的体内指纹图谱共有峰数目与结构分布比较,结果提示,逍遥方主要是通过调节机体本身的物质起到免疫双向调节作用。
疏肝健脾药效试验结果表明,逍遥方三种制剂均具有可提高肝郁脾虚大鼠体重,升高血浆单胺类神经递质NE、5-HT的浓度,使胃肠组织细胞中胃肠激素MTL表达升高、SS降低表达;降低脾虚小鼠小肠推进率、提高其胸腺与脾指数等作用。新制剂药效与汤剂相当,并优于等剂量的丸剂。
体外谱效关联度分析结果为大孔吸附树脂所获得的化学成分保留时间t_R=18.111、25.171、27.103共有峰与疏肝健脾作用高度关联;SFE-CO_2萃取所获得的化学成分保留时间t_R=22.191/31.244、35.225共有峰与疏肝健脾作用高度关联,为其工艺优选提供了考察指标。体内、外关联度三种制剂按照体外谱效关联度的大小排列依次为新制剂峰＞汤剂峰＞丸剂峰。结果表明,新制剂工艺稳定、应用技术合理。
结论:选择传统制剂、丸剂作为对照,基于整体生物效应与化学成分指纹图谱特征的工艺合理性评价方法表明,逍遥方新制剂工艺合理,质量可控,药效可靠,为现代中药制剂工艺研究提供了新的思路与方法。
1.Objective:Using SFE-CO_2、separation of macroporous adsorption resin and other new technologies,new preparations were prepared.By comparing the chemical constituents and pharmacological effects and spleen correlation spectral efficiency,three preparation for Xiaoyao preparation traditional decoction,pills,new formulation,we build the chemical constituents and biological effects of the whole process of fingerprint characteristics,with reasonable evaluation method for unfettered,modern Chinese native medicine preparation for classic prescription rationality assessment technique provides a new idea.
2.Methods We use SFE-CO_2,separation of macroporous adsorption resin and other new technologies,by GC-MS determine fat-soluble components extraction technology,use the orthogonal experiment design optimization method of water-soluble ingredients,separation and purification unfettered new preparation conditions;the best Based on new products,the traditional one xiaoyao pill three preparation,traditional thin layer of identification,the content and the fingerprint,establish quality control method,Using stomach "syndrome" animal models and spleen "disease" animal model,through the gastrointestinal function and neurotransmitters indexes,such as observation,compared to unfettered square three preparation stomach model nerve - endocrine - and the effect of gastric bowel function,Using fingerprint technology,three kinds of preparation for unfettered square internal and external mutual chemical composition,the application of grey relational fingerprint characteristics, research spectrum analysis method,this paper discusses the effect of correlation material foundation,and the effects of modern Chinese native medicine preparation unfettered square evaluation of extraction and separation technology, based on the rationality of the route with overall biological effects of chemical composition fingerprint characteristics of rationality assessment method.
3.Results The optimum parameters of unfettered dongfang preparations for (1):the SFE - CO_2 extraction temperature,pressure 30Mpa about 50℃, analytical stress,temperature 8Mpa about 40℃,Entrainment preparation anhydrous alcohol consumption for 0.1 ml/g,Circular extractors 2h,The CO_2 flow 25～30L/h.(2) of macroporous adsorption resin purification:adopt D-101 resin,will adjust for 5～solution concentration 10mg/ml,column 2～3BV velocity/h.2BV distilled water,with the velocity,with 70%alcohol 20%ethanol for elution preparation,adjust pH in dilute aqua ammonia to 8.0～9.0.In 2BV/h, collect 4BV velocity elution eluent.(3) the low temperature dynamic extract: extraction,first and second 12 times the amount of water extraction,the second with 2h 10 times of water extracted 1.5h.By orthogonal experiment on the decoction of alcohol process parameters optimization,namely the decoction to concentrate the relative density of about 60 degrees Celsius(1.10).(4) flocculation clarification,tuckahoe,angelica,limit the decoction to concentrate out:water(1:1),add 5%to 10%of chitosan(amount),shake at 40℃,water heating temperature 15min,after 3000rpm centrifugal(placed 2h,min-1,15 min),take supernatant.
We establish new formulation unfettered 6 kinds of TLC identification,content of measurement methods of ferulic acid and paeoniflorin,and HPLC fingerprint.With the state pharmacopoeia commission issued "medicine fingerprint similarity calculation software",evaluation results are similarity in more than 0.9.Results show that the new preparation quality is stable and controllable.
Establishing three HPLC fingerprint in and outside the body,including new preparation 19 10 characteristic peaks,pills,21 peaks and decoction 15 peaks, 12 peaks for three common preparations in vitro fingerprint.Plasma HPLC fingerprint includes health animal fingerprint and stomach model animals fingerprint,three kinds of new drug of animal model preparation has 11 characteristic peaks,pill has 13 peaks,decoction has 13 peaks,including 7 peaks for three preparation,Healthy animals' new preparation has 8 characteristic peaks,pill has 10,decoction has 13,5 peaks for three preparation. The preparation of three kinds of the chemical constituents were analyzed, including new preparation has 9 characteristic peaks,pills has 9,decoction has 7, including 3 peaks for three preparation.Results show that the new preparation unfettered effective composition content,reveal the three kinds of preparation of material base.
Soothing liver and strengthening spleen test results show that the three kinds of preparation can improve the rat weight and plasma monoamine neural transmitter NE,5-HT concentration,make gastric tissue cells MTL gastrointestinal hormones,SS lower expression expression,Mice intestine motional rate reduced spleen,improve the thymus and spleen index,etc.The efficacy of the new is be equivalent to the decoction,and superior to such dose of pills.
In vitro correlation spectral efficiency analysis,results of macroporous adsorption resin of chemical composition is t_R 27.803、29.726 peaks are highly associated to soothing liver and strengthening spleen function,t_R 46.438 peak of SFE-CO_2 extraction of chemical composition is highly associated to soothing liver and strengthening spleen function,which provides the index selection process.In vivo and in vitro correlation of three preparation in vitro correlation spectral efficiency in accordance with the size of the order is the new preparation peaks＞pills peaks＞decoction peaks.
4.Conclusions The rationality evaluation method of preparation technology based on the chemical constituents and biological effects of the whole process of fingerprint characteristics show that the technics of new preparation is reasonable,the quality is controllable,and the drug effect is reliable,which provides modern TCM preparation technology research a new idea and method.
引文
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