多成分环境对中药口服吸收影响的评价方法研究
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摘要
中药的作用特点往往是多种成分同时发挥药效,对于单一成分来说,其处于受其他成分影响的多成分环境中。因此,中药成分的吸收必定会受到多成分环境的影响。但无论是美国FDA、欧盟EMA乃至中国CFDA,对多成分环境中单一成分的吸收评价方法皆无规定。基础研究中,多成分环境对单一成分吸收影响的评价方法也是空白。因此,采用对比研究的科研设计,在目标单一成分的吸收特征研究基础上,将其置于多成分环境中进行实验,通过多成分环境中目标化合物的定性锁定、定量测试和数学分析,以建立多成分环境对中药吸收影响的评价方法流程。
国际公认药物吸收的三个核心要素为溶解度、溶出度和肠渗透性,这也是生物药剂学分类的核心指标,本文主要是基于测定多成分环境对药物上述三个因素的变化情况,研究多成分环境对药物吸收的影响。科研设计的具体实施过程是以葛根素为目标单一成分,将其置于葛根芩连方中其他药味高含量成分模拟的多成分环境中,对多成分环境作用于葛根素溶解度、溶出度和渗透性的影响趋势、影响程度进行实验,对实验结果采用最小二乘法、人工神经网络等算法进行建模分析,进而构建了影响评价研究的方法流程,并制定了详尽的标准操作规程。具体研究内容包括以下几方面进行：
1.多成分环境对葛根素溶解度及溶出度影响的研究。
(1)首次研究多成分环境(黄芩苷、小檗碱和甘草酸)对葛根素溶解度的影响：采用递进式的实验设计方法,分别研究了单一成分(分别为黄芩苷、小檗碱和甘草酸)环境、两成分环境(分别为黄芩苷+甘草酸、黄芩苷+小檗碱和甘草酸+小檗碱)和三成分环境(黄芩苷+甘草酸+小檗碱)对葛根素溶解度影响的变化趋势,从而建立了多成分环境对葛根素溶解度影响的数学回归模型方程。在此研究基础上总结了多成分环境对葛根素水溶解度的影响规律：①影响趋势：黄芩苷对葛根素溶解度影响为增加溶解度；小檗碱在单独存在背景下,对葛根素溶解度的影响为先增加后降低的变化趋势,在多成分环境下,小檗碱表现为降低葛根素的溶解度；三成分环境下甘草酸对葛根素溶解度的影响为先增加后降低的变化规律,其他情况下甘草酸主要表现为增加葛根素的溶解度。②影响程度程度：多成分环境中各个成分对葛根素溶解度的影响效应：效应大小为黄芩苷>小檗碱>甘草酸。最后,我们将多成分环境对解葛根素溶解度的影响进行单元组合建模,并采用此模型方程预测了葛根芩连复方环境对葛根素溶解度的影响,预测结果与实测结果对应较好。(2)首次提出了多成分环境对中药单一成分溶出度影响的研究方法。建立了葛根素溶解度和特性溶出速率的关联模型方程,模型方程：特性溶出速率=0.1694x溶解度-0.1877,在此范围之内的决定系数：R2=0.9984,RMSE=0.0137。首次建立了葛根芩连复方片剂中葛根素于五种不同生理介质中(pH1.0,pH4.0,pH6.8,pH7.4和水)的溶出曲线,并采用Weibull、Higuchi和Ritger-Peppas等数学模型进行方程拟合,结果为：葛根芩连复方片剂中葛根素的溶出行为采用Weibull模型方程拟合效果最好,可采用此模型作为葛根素在制剂中的溶出行为描述。并采用f因子法和聚类分析法评价了在五种不同生理溶出介质下,复方中多成分对葛根素溶出行为的影响。结果表明,多成分环境(葛根芩连复方片)对葛根素的溶出行为的影响主要体现其在pHl.0溶出介质中溶出速度和程度均较慢,结果表明多成环境对葛根素在机体内的胃液中溶出是限制其吸收的主要环节。
2.多成分环境对葛根素渗透性影响的研究。
(1)葛根素肠渗透性研究：分别应用离体翻转肠囊模型、在体单向肠灌流模型和单向肠灌流并行肠静脉采血模型,测定葛根素单一成分和两成分环境下的渗透系数。通过比较三种模型的肠渗透系数定量分析结果,确定在体单向肠灌流模型适合于多成分环境对中药成分渗透性影响研究。多成分环境对葛根素渗透性的影响结果为：①影响趋势：小檗碱降低葛根素的渗透性,黄芩苷促进葛根素的渗透性,甘草酸也表现为降低葛根素的渗透性。②影响程度程度：首次提出了多成分环境下渗透性影响系数P影响概念,Pm肠=Ps肠(P影响+1),从多成分环境下多种组合对葛根素渗透系数的影响分析,其中有6种组合的P影响小于0,所以这6组加入成分均降低葛根素的肠渗透性；另外7种组合的P影响均大于0。表明上述7组加入成分提高了葛根素的肠渗透性。综合分析,加入甘草酸组P影响几乎全部为负值,甘草酸能显著降低葛根素肠渗透性。(2)建立了肠渗透性研究方法标准操作规程,重点解决单向肠灌流模型水分校正误差,单向肠灌流方法质控关键点。(3)探索构建一套多成分环境影响中药成分肠渗透性研究方法,根据本论文研究结果,离体翻转肠囊模型、在体单向肠灌流模型组合运用的策略是可行的,首先通过翻转肠囊法定性锁定可吸收成分,然后运用在体单向肠灌流法定量测定肠渗透系数,分别研究在不同的模拟多成分体系下中药成分的吸收情况,通过多成分环境下吸收影响系数P影响参数刻画多成分环境对中药成分吸收的影响。
3.建立了多成分环境对中药成分口服吸收影响的评价方法流程。
构建了多成分环境影响中药吸收的评价方法流程。具体分成三步,第一步是研究中药单一成分的吸收情况,以明确药物吸收的影响因素。第二步是根据多成分环境对药物吸收的影响结果,建立具有预测功能的数学模型,以分析多成分环境对药物吸收的影响趋势和强度。第三步是制订多成分配伍方案,创造适合吸收的多成分环境。
上述三个方面的内容,将药物吸收三因素相结合,体外和在体评价相结合,已有模型方程和自建数学模型方程相结合,提出多成分环境对药物吸收影响的评价的方法及药物吸收改进的方向。
The characteristic of traditional Chinese medicine is a variety of ingredients produce efficacy. When a single component in a complex environment, it will be affected by other components of the environment. But whether the FDA, EMA or CFDA, single ingredient adsorption in a complex environment evaluation method are not specified. In basic research, evaluation method of single component absorption in complex environments is also blank. Therefore, using the comparison method, a single target component was put into a complex environment to study absorption characteristics after individual environment research, through qualitative analysis, quantitative test and mathematics to lock the target compounds in the complex environment. Our aim is to establish an evaluation method of the complex environmental impact on the traditional Chinese medicine absorption.
Three key elements of drug absorption are solubility, dissolution and intestinal permeability, which is the main index of biopharmaceutics classification. This paper based on the determination of complex environmental changing drug on these three factors, in order to study the complex environmental impact on drug absorption. The method and procedure validation experiments, peurarin is the target drug, to research on its aqueous solubility, dissolution and intestinal permeability trends and strength in the Gegenqinlian prescription complex environment. With through mathematic modeling, least square method and artificial neural network algorithm, therefore establish standard operating procedures. The research work mainly focuses on the following aspects:
1. Investigation on the solubility and dissolution of puerarin in multicomponent environment.
(1) Investigated the influence of the multicomponent environment (baicalin, berberine and glycyrrhizic acid) to the solubility of puerarin:The experiments were carried out with progressive levels, single component (baicalin, berberine and glycyrrhizic acid), two components (baicalin+glycyrrhizic acid, baicalin+berberine and glycyrrhizic acid+berberine) and three component's environment were used to describe the variation trend of their influence on the solubility of puerarin, respectively. And then, the mathematical regression equation model was established to characterize the solubility of puerarin under multicomponent environment. On this basis, we summarized the influence rule of multicomponent environment to the solubility of puerarin:①influence trend:the influence of baicalin was to increase the solubility of puerarin; When it came to berberine, the influence to puerarin was first increased and then decreased, but once in multicomponent environment, berberine would decrease the solubility of puerarin. Under the environment of three components, the influence to puerarin of glycyrrhizic acid was first increased and then decreased, and in other conditions, glycyrrhizic acid would increase the solubility of puerarin.②influence intension:The influential effect of single component within multicomponent environment:relative effectiveness of the three components was:baicalin>berberine>glycyrrhizic acid. At last, we built a model of the unity constitution of influence to the solubility of puerarin under multicomponent environment and it was used to predict the influence to the solubility of puerarin in the environment of the Gegen Qinlian Compound Tablets. The prediction results represented good correlation with the actual results.(2) First proposed methods that multi-component environment impact solubility of single component. The mathematic model equations of puerarin intrinsic dissolution rate and solubility s established, ntrinsic dissolution rate=0.1694×solubility-0.1877,In this range the coefficient of determination is0.9984and the RMSE is0.0137. We established the dissolution curves of puerarin in five different physiological medium (pH1.0, pH4.0, pH6.8, pH7.4and water) of Gegenqinlian Compound Tablets. This paper fitted Weibull、Higuchi、Ritger-Peppas and others mathematical models. The result indicated Weibull model was the best method to describe the dissolution behavior of puerarin in Gegenqinlian Compound Tablets and it could be used to describe the dissolution behavior of puerarin in preparation. F factor method and clustering methodology were used to evaluate the influence of multicomponent in preparation to the dissolution of puerarin in five different physiological medium. The result was that the influence of dissolution behavior under multicomponent (Gegenqinlian Compound Tablets) mainly embodied in that the dissolution rate and level were slow when in pH1, this suggested us the main rate-limiting step in the absorption of puerarin under multicomponent environment was the dissolution in gastric juice.
2. The influence of the permeability of puerarin in multi-component environments.
(1) Study of puerarin intestinal permeability:the permeability coefficient of puerarin in single component and two component environment was evaluated by applying in vitro reverted gut sac model, in vivo single pass perfusion model and double pass perfusion model. Comparing the results of three models of quantitative analysis, we determine the way in vivo intestinal permeability perfusion model is suitable for study the influence of the permeability of Chinese medicine ingredients in multi-component environments. The study of the influence of the permeability of puerarin in multi-component environments shows:①Trend of impact: Berberine reduced the permeability of puerarin, baicalin promote permeability of puerarin, and glycyrrhizin also performed to reduce the permeability of puerarin.②Degree of impact: Proposed the concept of Pimpact (permeability coefficient of ingredient under the impact of multi-component environmental), pmint estine=Psint estine.[Pimpact+1] for the first time.Analyzing from effects of various combinations of puerarin permeability coefficient in multi-component environment, we found that Pimpact<0under six kinds of combinations, so these added ingredient six combinations reduce the intestinal permeability of puerarin; Pimpact>0under the other seven kinds of combinations, therefore, these added groups increased intestinal permeability of puerarin.Comprehensive analysis of glycyrrhizin group shows that the Pimpact is almost entirely negative,so glycyrrhizin can significantly reduce intestinal permeability of puerarin.(2) Intestinal permeability methods are established, focused on solving the moisture calibration errors of intestinal perfusion method and critical points of quality control applying single pass perfusion model.(3)To establish a methodology system for intestinal permeability of TCM in multicomponent environment. According to the research results of this thesis, Combing the in vitro reverted gut sac model and in vivo single pass perfusion model is feasible. First, locking the absorbable components qualitatively by in vitro revert gut sac method. Then, measuring the intestinal permeability coefficient by in vivo single pass perfusion model. To study respectively the absorption of TCM in different simulated multicomponent system. Through multiple ingredients environment effect on absorption coefficient Pimpact depicting Chinese traditional medicine ingredient absorption in multiple ingredients.
3. To establish a methodologyprocedure for oral absorption of TCM in multicomponent environment.
The methodology of evaluation for drug absorption is established in multicomponent environment It concludes three main steps, the first step is to research the single component absorption and find out the limit factors of absorption, the second step is to establish a mathematical model for predicting compound in complex environment absorption basis on compound absorption in multi component environments, in order to predict drug absorption trend and intensity in complex environments. The third step is to establish a multi component compatibility program and create the suitable multi components for absorption.
The above three aspects of research have combined the three key factors of drug absorption together, combined in vitro and in vivo together, combined model equation and self-construct model together, thus proposed method to study the oral absorption evaluation method of complex environment and can guide the future absorption optimization.
国际公认药物吸收的三个核心要素为溶解度、溶出度和肠渗透性,这也是生物药剂学分类的核心指标,本文主要是基于测定多成分环境对药物上述三个因素的变化情况,研究多成分环境对药物吸收的影响。科研设计的具体实施过程是以葛根素为目标单一成分,将其置于葛根芩连方中其他药味高含量成分模拟的多成分环境中,对多成分环境作用于葛根素溶解度、溶出度和渗透性的影响趋势、影响程度进行实验,对实验结果采用最小二乘法、人工神经网络等算法进行建模分析,进而构建了影响评价研究的方法流程,并制定了详尽的标准操作规程。具体研究内容包括以下几方面进行：
1.多成分环境对葛根素溶解度及溶出度影响的研究。
(1)首次研究多成分环境(黄芩苷、小檗碱和甘草酸)对葛根素溶解度的影响：采用递进式的实验设计方法,分别研究了单一成分(分别为黄芩苷、小檗碱和甘草酸)环境、两成分环境(分别为黄芩苷+甘草酸、黄芩苷+小檗碱和甘草酸+小檗碱)和三成分环境(黄芩苷+甘草酸+小檗碱)对葛根素溶解度影响的变化趋势,从而建立了多成分环境对葛根素溶解度影响的数学回归模型方程。在此研究基础上总结了多成分环境对葛根素水溶解度的影响规律：①影响趋势：黄芩苷对葛根素溶解度影响为增加溶解度；小檗碱在单独存在背景下,对葛根素溶解度的影响为先增加后降低的变化趋势,在多成分环境下,小檗碱表现为降低葛根素的溶解度；三成分环境下甘草酸对葛根素溶解度的影响为先增加后降低的变化规律,其他情况下甘草酸主要表现为增加葛根素的溶解度。②影响程度程度：多成分环境中各个成分对葛根素溶解度的影响效应：效应大小为黄芩苷>小檗碱>甘草酸。最后,我们将多成分环境对解葛根素溶解度的影响进行单元组合建模,并采用此模型方程预测了葛根芩连复方环境对葛根素溶解度的影响,预测结果与实测结果对应较好。(2)首次提出了多成分环境对中药单一成分溶出度影响的研究方法。建立了葛根素溶解度和特性溶出速率的关联模型方程,模型方程：特性溶出速率=0.1694x溶解度-0.1877,在此范围之内的决定系数：R2=0.9984,RMSE=0.0137。首次建立了葛根芩连复方片剂中葛根素于五种不同生理介质中(pH1.0,pH4.0,pH6.8,pH7.4和水)的溶出曲线,并采用Weibull、Higuchi和Ritger-Peppas等数学模型进行方程拟合,结果为：葛根芩连复方片剂中葛根素的溶出行为采用Weibull模型方程拟合效果最好,可采用此模型作为葛根素在制剂中的溶出行为描述。并采用f因子法和聚类分析法评价了在五种不同生理溶出介质下,复方中多成分对葛根素溶出行为的影响。结果表明,多成分环境(葛根芩连复方片)对葛根素的溶出行为的影响主要体现其在pHl.0溶出介质中溶出速度和程度均较慢,结果表明多成环境对葛根素在机体内的胃液中溶出是限制其吸收的主要环节。
2.多成分环境对葛根素渗透性影响的研究。
(1)葛根素肠渗透性研究：分别应用离体翻转肠囊模型、在体单向肠灌流模型和单向肠灌流并行肠静脉采血模型,测定葛根素单一成分和两成分环境下的渗透系数。通过比较三种模型的肠渗透系数定量分析结果,确定在体单向肠灌流模型适合于多成分环境对中药成分渗透性影响研究。多成分环境对葛根素渗透性的影响结果为：①影响趋势：小檗碱降低葛根素的渗透性,黄芩苷促进葛根素的渗透性,甘草酸也表现为降低葛根素的渗透性。②影响程度程度：首次提出了多成分环境下渗透性影响系数P影响概念,Pm肠=Ps肠(P影响+1),从多成分环境下多种组合对葛根素渗透系数的影响分析,其中有6种组合的P影响小于0,所以这6组加入成分均降低葛根素的肠渗透性；另外7种组合的P影响均大于0。表明上述7组加入成分提高了葛根素的肠渗透性。综合分析,加入甘草酸组P影响几乎全部为负值,甘草酸能显著降低葛根素肠渗透性。(2)建立了肠渗透性研究方法标准操作规程,重点解决单向肠灌流模型水分校正误差,单向肠灌流方法质控关键点。(3)探索构建一套多成分环境影响中药成分肠渗透性研究方法,根据本论文研究结果,离体翻转肠囊模型、在体单向肠灌流模型组合运用的策略是可行的,首先通过翻转肠囊法定性锁定可吸收成分,然后运用在体单向肠灌流法定量测定肠渗透系数,分别研究在不同的模拟多成分体系下中药成分的吸收情况,通过多成分环境下吸收影响系数P影响参数刻画多成分环境对中药成分吸收的影响。
3.建立了多成分环境对中药成分口服吸收影响的评价方法流程。
构建了多成分环境影响中药吸收的评价方法流程。具体分成三步,第一步是研究中药单一成分的吸收情况,以明确药物吸收的影响因素。第二步是根据多成分环境对药物吸收的影响结果,建立具有预测功能的数学模型,以分析多成分环境对药物吸收的影响趋势和强度。第三步是制订多成分配伍方案,创造适合吸收的多成分环境。
上述三个方面的内容,将药物吸收三因素相结合,体外和在体评价相结合,已有模型方程和自建数学模型方程相结合,提出多成分环境对药物吸收影响的评价的方法及药物吸收改进的方向。
The characteristic of traditional Chinese medicine is a variety of ingredients produce efficacy. When a single component in a complex environment, it will be affected by other components of the environment. But whether the FDA, EMA or CFDA, single ingredient adsorption in a complex environment evaluation method are not specified. In basic research, evaluation method of single component absorption in complex environments is also blank. Therefore, using the comparison method, a single target component was put into a complex environment to study absorption characteristics after individual environment research, through qualitative analysis, quantitative test and mathematics to lock the target compounds in the complex environment. Our aim is to establish an evaluation method of the complex environmental impact on the traditional Chinese medicine absorption.
Three key elements of drug absorption are solubility, dissolution and intestinal permeability, which is the main index of biopharmaceutics classification. This paper based on the determination of complex environmental changing drug on these three factors, in order to study the complex environmental impact on drug absorption. The method and procedure validation experiments, peurarin is the target drug, to research on its aqueous solubility, dissolution and intestinal permeability trends and strength in the Gegenqinlian prescription complex environment. With through mathematic modeling, least square method and artificial neural network algorithm, therefore establish standard operating procedures. The research work mainly focuses on the following aspects:
1. Investigation on the solubility and dissolution of puerarin in multicomponent environment.
(1) Investigated the influence of the multicomponent environment (baicalin, berberine and glycyrrhizic acid) to the solubility of puerarin:The experiments were carried out with progressive levels, single component (baicalin, berberine and glycyrrhizic acid), two components (baicalin+glycyrrhizic acid, baicalin+berberine and glycyrrhizic acid+berberine) and three component's environment were used to describe the variation trend of their influence on the solubility of puerarin, respectively. And then, the mathematical regression equation model was established to characterize the solubility of puerarin under multicomponent environment. On this basis, we summarized the influence rule of multicomponent environment to the solubility of puerarin:①influence trend:the influence of baicalin was to increase the solubility of puerarin; When it came to berberine, the influence to puerarin was first increased and then decreased, but once in multicomponent environment, berberine would decrease the solubility of puerarin. Under the environment of three components, the influence to puerarin of glycyrrhizic acid was first increased and then decreased, and in other conditions, glycyrrhizic acid would increase the solubility of puerarin.②influence intension:The influential effect of single component within multicomponent environment:relative effectiveness of the three components was:baicalin>berberine>glycyrrhizic acid. At last, we built a model of the unity constitution of influence to the solubility of puerarin under multicomponent environment and it was used to predict the influence to the solubility of puerarin in the environment of the Gegen Qinlian Compound Tablets. The prediction results represented good correlation with the actual results.(2) First proposed methods that multi-component environment impact solubility of single component. The mathematic model equations of puerarin intrinsic dissolution rate and solubility s established, ntrinsic dissolution rate=0.1694×solubility-0.1877,In this range the coefficient of determination is0.9984and the RMSE is0.0137. We established the dissolution curves of puerarin in five different physiological medium (pH1.0, pH4.0, pH6.8, pH7.4and water) of Gegenqinlian Compound Tablets. This paper fitted Weibull、Higuchi、Ritger-Peppas and others mathematical models. The result indicated Weibull model was the best method to describe the dissolution behavior of puerarin in Gegenqinlian Compound Tablets and it could be used to describe the dissolution behavior of puerarin in preparation. F factor method and clustering methodology were used to evaluate the influence of multicomponent in preparation to the dissolution of puerarin in five different physiological medium. The result was that the influence of dissolution behavior under multicomponent (Gegenqinlian Compound Tablets) mainly embodied in that the dissolution rate and level were slow when in pH1, this suggested us the main rate-limiting step in the absorption of puerarin under multicomponent environment was the dissolution in gastric juice.
2. The influence of the permeability of puerarin in multi-component environments.
(1) Study of puerarin intestinal permeability:the permeability coefficient of puerarin in single component and two component environment was evaluated by applying in vitro reverted gut sac model, in vivo single pass perfusion model and double pass perfusion model. Comparing the results of three models of quantitative analysis, we determine the way in vivo intestinal permeability perfusion model is suitable for study the influence of the permeability of Chinese medicine ingredients in multi-component environments. The study of the influence of the permeability of puerarin in multi-component environments shows:①Trend of impact: Berberine reduced the permeability of puerarin, baicalin promote permeability of puerarin, and glycyrrhizin also performed to reduce the permeability of puerarin.②Degree of impact: Proposed the concept of Pimpact (permeability coefficient of ingredient under the impact of multi-component environmental), pmint estine=Psint estine.[Pimpact+1] for the first time.Analyzing from effects of various combinations of puerarin permeability coefficient in multi-component environment, we found that Pimpact<0under six kinds of combinations, so these added ingredient six combinations reduce the intestinal permeability of puerarin; Pimpact>0under the other seven kinds of combinations, therefore, these added groups increased intestinal permeability of puerarin.Comprehensive analysis of glycyrrhizin group shows that the Pimpact is almost entirely negative,so glycyrrhizin can significantly reduce intestinal permeability of puerarin.(2) Intestinal permeability methods are established, focused on solving the moisture calibration errors of intestinal perfusion method and critical points of quality control applying single pass perfusion model.(3)To establish a methodology system for intestinal permeability of TCM in multicomponent environment. According to the research results of this thesis, Combing the in vitro reverted gut sac model and in vivo single pass perfusion model is feasible. First, locking the absorbable components qualitatively by in vitro revert gut sac method. Then, measuring the intestinal permeability coefficient by in vivo single pass perfusion model. To study respectively the absorption of TCM in different simulated multicomponent system. Through multiple ingredients environment effect on absorption coefficient Pimpact depicting Chinese traditional medicine ingredient absorption in multiple ingredients.
3. To establish a methodologyprocedure for oral absorption of TCM in multicomponent environment.
The methodology of evaluation for drug absorption is established in multicomponent environment It concludes three main steps, the first step is to research the single component absorption and find out the limit factors of absorption, the second step is to establish a mathematical model for predicting compound in complex environment absorption basis on compound absorption in multi component environments, in order to predict drug absorption trend and intensity in complex environments. The third step is to establish a multi component compatibility program and create the suitable multi components for absorption.
The above three aspects of research have combined the three key factors of drug absorption together, combined in vitro and in vivo together, combined model equation and self-construct model together, thus proposed method to study the oral absorption evaluation method of complex environment and can guide the future absorption optimization.
引文
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