取代位置不同的环糊精硫酸酯对多西紫杉醇的包合作用

 目的制备和鉴定多西紫杉醇-环糊精硫酸酯(6-S-β-CD,2-S-β-CD及随机取代的S-β-CD)包合物,并考察多西紫杉醇与环糊精硫酸酯之间的包合机制、构成摩尔质量比及包合常数。方法应用圆二色谱法研究不同浓度环糊精硫酸酯对DTX圆二色性的影响,并测定了包合常数;采用冷冻干燥法制备DTX-S-β-CD包合物,差示扫描量热法(DSC)和红外光谱法(IR)对包合物进行鉴定;摩尔连续递变法测定包合物的组成比例,相溶解度法测定DTX在25,37,45℃恒温条件下在不同浓度6-S-β-CD,2-S-β-CD,S-β-CD水溶液中的包合稳定常数及相关的热力学常数。结果多西紫杉醇的正性带和负性带强度都随着环糊精硫酸酯浓度的增大而增大,DTX与环糊精硫酸酯形成了稳定的包合物;摩尔包合比均为1∶1,相溶解度曲线为AL型,表观稳定常数K随着温度的升高而下降,包合过程中的吉布斯自由能变化(ΔG)、焓变(ΔH)和熵变(ΔS)均为负值。S-β-CD对DTX的增溶作用强于6-S-β-CD和2-S-β-CD,且DTX-S-β-CD包合物的稳定常数高于DTX-6-S-β-CD,DTX-2-S-β-CD包合物。结论DTX与环糊精硫酸酯可以自发形成可溶性包合物,且低温有利于包合物的形成和稳定。S-β-CD对DTX的增溶作用及与DTX形成包合物的稳定常数均高于6-S-β-CD和2-S-β-CD。

Complexation of Docetaxei with Different Displaced Cyclodextrin Sulfate

OBJECTIVE To prepare and identify the inclusion compounds of docetaxel(DTX) with different kinds of substitued sulfated-β-cyclodextrin(6-S-β-CD,2-S-β-CD and S-β-CD which is randomly substituted),and to investigate the inclusion mechanism,molar ratio and complexation constants of the compounds.METHODS The influence of different concentrations of sulfated-β cyclodextrin on the circular dichroism of DTX was studied.Complexation constants were also determined by using circular dichroism spectra(CD).The inclusion compounds were prepared with lyophilization technique.The measurements of the inclusion molar ratio of the host to guest molecules,apparent complex constants,the thermodynamic parameters and the identification of the inclusion complexes were carried out by several methods such as continuous variation,UV absorption spectroscopy,phase solubility diagram,differential scanning calorimeter(DSC) and infrared spectra(IR) respectively.RESULTS The intensity of negative and positive band of DTX was increased as the increased concentrations of sulfated-β-cyclodextrin.The continuous variation method suggested the formation of soluble complexes with 1∶1 molar ratio.A_L-type phase solubility curves were obtained.The apparent complex constants K was decreased when the temperature was increased.All thermodynamic parameters of ΔG,ΔH and ΔS in the complexes gave negative values.The solubility of docetaxel complexed with S-β-CD was higher than those of docetaxel complexed with 6-S-β-CD and 2-S-β-CD.The apparent complex constant of docetaxel-S-β-CD was higher than those of docetaxel-6-S-β-CD and docetaxel-2-S-β-CD.CONCLUSION The inclusion complexes of DTX-sulfated-β-cyclodextrin could be formed spontaneously,lower temperature is a benefit for the formation and the stability of the inclusion complex.The solubility and the stability constants of docetaxel complexed with S-β-CD is higher than those of docetaxel complexed with 6-S-β-CD and 2-S-β-CD.