The Research On Solubilization And Stabilization Effect Of Glycyrrhizic Acid Self-Assembly System To TCM Active Ingredients And Molecular Mechanism For Compatibility

The theory of compatibility is an important part of traditional Chinese medicine?TCM?theory.Interpreting the theory of compatibility with modern scientific means is one of the core contents of modernization of TCM,ingredients in TCM are varied and the compatibility of two or more medicinal herbs makes the prescriptions have comprehensive advantages such as multi-component and multi-target,which also leads to the complex and difficult research on its substance basis and compatibility mechanism.The TCM compatibility not only manifests in the change of chemical composition and synergistic effect on pharmacological effect,it is also possible to change the physical and chemical state,as well as solubility,stability,permeability and other biopharmaceutical properties through the interaction between the ingredients,thereby affecting the in vivo process of active ingredients.Compatibility of component was taken as the guiding ideology and Glycyrrhizic acid?GA?was selected as the research object to systematically studied the influence of GA compatibility on the biopharmaceutical properties of monomer components in this article.Simultaneously,the role and mechanism of GA in compatibility were revealed from the perspective of microscopic substances between molecules based on molecular pharmacy theory,which aims to provide new research ideas for explaining the compatibility mechanism of TCM.Firstly,high-performance liquid chromatography was used to systematically study the effects of GA compatibility on the biopharmaceutical properties of flavonoids,alkaloids,anthraquinones,organic acids totally 26 traditional Chinese medicine monomer components,which mainly includes the effect on the solubility of the monomer components and the stability of 10 flavonoid components under accelerated degradation conditions?80?/p H 9buffer solution?,principal component analysis was used to visualize solubilizing effects and the regularity of the solubilization and stabilization was further analyzed.It has showed that GA has significant solubilizing effects on the 23 Chinese herbal monomer components?P<0.01?with solubilization effect improved by 1711.28,1607.66,1750.83-fold for baicalein,luteolin and aloe-emodin respectively except for matrine,ferulic acid and chlorogenic acid.Besides,GA has a different degree of stabilization effect on the 10 flavonoids with half-life t_0.5increased by 21.62%or above under accelerated degradation conditions,of which the half-life t_0.5of hesperidin and daidzein increased by155.56%?200%respectively.It was also found that the solubilizing and stabilizing effects of GA on flavonoids negatively correlated with the aqueous solubility and intrinsic stabilities of the flavonoids.Based on the results of the solubilization and stabilization effects,baicalein?BA?was taken as a model drug to evaluate the formation and pharmacological characteristics of"potential preparations"during the compatibility of GA from the perspective of molecular pharmaceutics.The single factor experiments of prescription and technology were carried out in terms of encapsulation efficiency?EE?,drug loading?DL?,particle size,polydispersity?PDI?,and Zeta potential in the second part.Then,the optimized prescription was obtained by Box-Behnken effect surface design based on the single factor experiments'results,and the existence state and in vitro release behavior of GA in nanomicelles were explored.The results show that the encapsulation efficiency of BA-GA micelles was?80.95±1.11?%,the rate of drug-loading was?9.15±0.04?%,the average diameter was?196.2±22.5?nm,the polydispersity indices was?0.254±0.012?,while zeta potential was?-55.0±2.6?m V.The formation of GA nanomicelles can significantly improve the solubility of baicalein from 0.15to 690.90?g·m L^-1.BA was wrapped in GA nanomicelles in an amorphous state,and the in vitro release results indicate that release behavior of BA in micelles exhibit certain sustained release characteristics and p H responsiveness.The research results indicate that the improvement of GA on the biopharmaceutical properties of other components may be related to the formation of potential nanomicelles.Glycyrrhizic acid monoammonium salt?GAAS?was selected as supramolecular hydrogel material to further clarify the formation of"potential preparations"of GA in compatibility,the formation conditions of GA supramolecular hydrogel was explored using single factor experiments.A supramolecular gel drug loading system was constructed based on the study of the properties of the gel,which to further reveal the molecular mechanism of GA compatibility from the perspective of the formation of supramolecular complexes.Results have showed that the formation process of the supramolecular hydrogel was sol to gel,in which the concentration and temperature are the main two factors affecting the hydrogel formation,the gel structure could form after cooled at room temperature with 5mg·m L^-1GAAS dissolved in a 60?water bath in the experiment range.GAAS supramolecular hydrogel is a kind of stable acidic gel with the properties of thermal reversibility and"shear thinning"and good"thixotropic recovery".The ingredient BA could be stably wrapped in the hydrogel structure in both crystal and amorphous non-crystalline forms,the total amount of BA in the hydrogel was 82.29?g·m L^-1,of which the amorphous forms was 11.99?g·m L^-1under the experimental conditions.The results of in vitro drug release indicate that the release process of BA in the gel includes burst and sustained stages,the final cumulative release rate could reach at more than 96%at different p H release media.In summary,this article systematically studied the effects of GA on the in vitro biopharmaceutical properties?solubility and stability?of TCM monomer components guided by compatibility theory.The formation of two self-assembling systems of GA?nanomicelles and supramolecular hydrogels?and their effects on TCM ingredients were studied taking BA as a representative model ingredient.The triterpene component GA of Licorice could form different"potential preparations"which play an important role in solubilizing,promoting stability,and changing the release characteristics of other active ingredients of TCM,revealing the molecular mechanism of GA's solubilization and stabilization effects during the compatibility process from the molecular pharmacy level.Meanwhile,our study provides a new research ideas and methods for the mechanism“assistant and guide”effects of Licorice in compatibility.