Studies On Brucine Liposome Modified With Glycyrrhetinic Acid By Targeting Drug Delivery

The hepatic diseases occur frequently in clinical practice.Many drugs used clinically for hepatitis,liver fibrosis,cirrhosis and hepatoma lack organ selectivity,which lead to low drug concentration in liver.The hepatic targeting drug delivery system(HTDDS)selectively distributes drugs to the pathological parts of liver,which not only enhances their bioavailability but also reduces the off target side effects.HTDDS is always the focus of study of pharmaceutics.The aim of this thesis is to design a series of polymers which is simple in synthesis and cheap,we expected the ligand to protrude from liposome and interact without hindrance with the receptor expressed at the surface of the target cells.Choosing the brucine as a model drug,we expected that the new liposome can increase the concentration in liver parenchymal cells and reduce its toxicity.In the first part of this thesis,the novel polymer material was synthesized and characterized with 1H-NMR and FT IR,and they all showed the peaks of glycyrrhetinic acid.And we also investigated the rheology,interfacial tension and haemolyticus of these novel polymers,it still showed the different properties.optimal formulation of Brucine liposome modified with Glycyrrhetinic Acid(CPGL)were determined using central composite design.Response variables selected in the research were entrapment efficiency(%),particle size(nm)and accumulated release.The data were transformed into desirabilities.The observed values agreed well with model predicted values.Central composite design-response surface methodology was successfully used to optimize the formulation of CPGL.Then compared with conventional liposomes(LP)in vitro physical and chemical,the accumulated release and storage stability were better than LP.The CPGL was found that it was round or oval structure and surrounded by a thin layer of material may be due to the long chain of the polymer using transmision electron microsocopy.To evaluate the pharmacokinetics and the parameters of these preparations,we study the pharmacokinetics,tissue distribution and animal imaging in rat in the fourth of this thesis,respectively.The result showed that the CPGL was able to improve the liver targeting of brucine compare with LP,the AUC of CPGL was 2.31 times higher than that of LP,the MRT0-t was 2.11 times than that of LP.The concentration of drugs was significantly increased in the liver,the residence time was prolonged and the concentration of drugs in the brain was discreased greatly.In order to study the uptake of liver cancer cells,the fifth of this thesis was studied the cell uptake profiles.The result shows that the uptake of CPGL is affected by temperature and can be saturated which tell us that the uptake of CPGL mainly by active transport.And the competitive inhibition of glycyrrhetinic acid may suppose that CPGL can be uptake by the glycyrrhetinic acid receptor.In this study,we successed in designing and synthesizing the new polymer materials which used in liposomes and toxic drugs.The research provides a useful reference for such traditional Chiese medicine.