Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.Thi...Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.This study modified the generation 4 polyamidoamine dendrimer with polyethylene glycol of different molecular weights(5000,2000,1000)to form a series of polyamidoamine-co-polyethylene glycol(PAMAM-co-PEG)as a novel class of oral absorption enhancers.Evodiamine,the major alkaloid found in the traditional Chinese medicine Wu Zhu Yu(Fructus Evodiae),was used as a model drug to verify the absorption-enhancing effects and the safety of this alkaloid.Methods:This study utilized the solubility determination method documented in the Pharmacopoeia of the People’s Republic of China(2015 edition)and the D0 values recommended in the US FDA guidelines to comprehensively evaluate the solubility of evodiamine.The permeability of evodiamine was assessed using the apparent permeability coefficient in experiments based on in vitro cell models.Multiple aspects of the biological safety of PAMAM-co-PEG were explored using the MTT assay,LDH assay,and total protein release of the rat intestinal tract.Moreover,the absorption-enhancing effects of PAMAM-co-PEG at different molecular weights on evodiamine were verified via the use of in vitro cell models and in vivo intestinal loop circulation experiments with rats.Results:Evodiamine exhibited low solubility and permeability and was classified into class IV compounds using the biopharmaceutical classification system.PAMAM-co-PEG 2000 demonstrated improvement in the biosafety and absorption-enhancement effect of evodiamine at a specific concentration.This study showed that 0.05%(w/v)of PAMAM-co-PEG 2000 increased the cumulative penetration of evodiamine via cell transport by 1.32 times,and 0.10%(w/v)of PAMAM-co-PEG 2000 increased the area under curve value of evodiamine by 1.31 times.Conclusion:Evodiamine possesses low solubility and permeability and leads to poor oral bioavailability and a certain degree of cytotoxicity.PAMAM-co-PEG 2000 was found to be a potentially safe and efficient oral absorption enhancer.The results of this study might create a foundation for the development of novel excipients suitable for the complex active ingredients of traditional Chinese medicine.展开更多
基金This research was funded by National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2015ZX09501005)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2016-I2M-1-012).
文摘Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.This study modified the generation 4 polyamidoamine dendrimer with polyethylene glycol of different molecular weights(5000,2000,1000)to form a series of polyamidoamine-co-polyethylene glycol(PAMAM-co-PEG)as a novel class of oral absorption enhancers.Evodiamine,the major alkaloid found in the traditional Chinese medicine Wu Zhu Yu(Fructus Evodiae),was used as a model drug to verify the absorption-enhancing effects and the safety of this alkaloid.Methods:This study utilized the solubility determination method documented in the Pharmacopoeia of the People’s Republic of China(2015 edition)and the D0 values recommended in the US FDA guidelines to comprehensively evaluate the solubility of evodiamine.The permeability of evodiamine was assessed using the apparent permeability coefficient in experiments based on in vitro cell models.Multiple aspects of the biological safety of PAMAM-co-PEG were explored using the MTT assay,LDH assay,and total protein release of the rat intestinal tract.Moreover,the absorption-enhancing effects of PAMAM-co-PEG at different molecular weights on evodiamine were verified via the use of in vitro cell models and in vivo intestinal loop circulation experiments with rats.Results:Evodiamine exhibited low solubility and permeability and was classified into class IV compounds using the biopharmaceutical classification system.PAMAM-co-PEG 2000 demonstrated improvement in the biosafety and absorption-enhancement effect of evodiamine at a specific concentration.This study showed that 0.05%(w/v)of PAMAM-co-PEG 2000 increased the cumulative penetration of evodiamine via cell transport by 1.32 times,and 0.10%(w/v)of PAMAM-co-PEG 2000 increased the area under curve value of evodiamine by 1.31 times.Conclusion:Evodiamine possesses low solubility and permeability and leads to poor oral bioavailability and a certain degree of cytotoxicity.PAMAM-co-PEG 2000 was found to be a potentially safe and efficient oral absorption enhancer.The results of this study might create a foundation for the development of novel excipients suitable for the complex active ingredients of traditional Chinese medicine.
