| 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. |
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