Study Of Liposome Containing Docetaxel

The objective of this study was to prepare a kind of docetaxel-liposome and to carry out the evaluation in vivo and in vitro.Docetaxel is an semi-product of neoplastic agent of the taxoid family,which is isolated from the needles of the European yew tree.Because it’s poor solubility in water,presently the only available formulation for clinical use consists of high concentration of Tween-80 as the vehicle(Taxotere^?).Though the Taxotere^?has very perfect anti-rumor effect,it still has many disadvantages as follows:the vehicle toxicity, sensitization,and instability after dilution.To reduce the adverse effect caused by tween-80, increase the solubility and stability of docetaxel,prolonged the residence time of drug in vivo,docetaxel-liposome was prepared.A high performance liquid chromatography（HPLC）method was developed to determine the concentration of docetaxel in liposome formation in vitro.This method is precise,convenient,reliable and good recovery,and the solvent and adjuvant have no effects on determination.The apparent solubility of docetaxel in water at three different tempreture were also determinted,and at 45℃its hightest solubility is 5.72μg·mL^-1. Dialysis method was used to determin the encapsulation efficiency,which was both convenient and precise.The liposomes composed of soybean phospholipid only（DOC-L）and containing HSPC（DOC-HL）were prepared by film dispersion method.On the basis of mono-factor investigation,the formulation and preparation were optimized using orthogonal design, with the estimating index of yield efficiency.Most of DOC-L and DOC-HL were unilamellar ones under transmission electron microscope,which were uniform and well dispersed with a mean diameter within 200 nm.The mean entrapment efficiency of three batchs of prepared docetaxel liposomes was above 96%using dialysis method.Because of the characterization of liposomes,diffenent lyo-protectants were choosen.The optimized composition was the mixture of tehalose and mannitol（1.5:1 w/w）,and the quality ratio of phospholipid and lyo-protectants was 1:2.The hemolytic tests sugguested that the preparations were safe and they could fit the regulations of the infusion.It can also proved that docetaxel liposome formation can improve the hemolytic salty of Taxotere^?.For the sample of rat plasma and tissues,we developed the HPLC method to determine the concentration of docetaxel in vivo.The pharmacokinetics of DOC、DOC-L and DOC-HL were compared.And also,tissue distribution of DOC and DOC-L in vivo were compared.The pharmacokinetics results showed:these three formations at the same dose,the pharmacokinetics fit two-compartment model.For the DOC-HL formation,the plasma concentrations were higher than DOC and DOC-L at any time point during the experiment.Moreover,compared to the DOC,the elimination half-life of DOC-L had been prolonged 1.3 times（p＞0.05）,and for DOC-HL it had been prolonged 2.7 times（p＜0.01）. Compared of DOC-L and DOC,both AUC and elimination half-life of DOC-HL were significantly changed（p＜0.01）.For DOC and DOC-L the tissue distribution results indicated that the concentration of docetaxel in determined tissues showed no significant differences.