【作者】 孙志鹏；

【导师】 何杰；

【作者基本信息】 安徽理工大学 ， 化学工程， 2020， 硕士

【摘要】 层状双金属氢氧化物(Layered Double Hydroxides)是一种层板带正电的无机层状材料,是水滑石和类水滑石化合物的总称。LDHs的结构多样性使其能够通过多种方法制备而成;利用其良好的层间阴离子可交换性能可以通过离子交换法构建药物-LDHs载药体系。卡托普利(Captopril)是一种抗高血压药物,其热稳定性较差,在较低温度就会氧化分解,且其在体内释放速率较快,药效持续时间不长,因此需要使用适当的药物载体对其药物特性进行改善,增强卡托普利的热稳定性,并控制其释放速率。LDHs作为一种新型的药物载体,具有良好的生物相容性和生物可降解性等独特的优势。根据LDHs独特的结构与性质,将卡托普利负载到LDHs层间,并通过其层板丰富的羟基活性位点和空间位阻来达到对药物的缓释作用。本文以共沉淀法和水热法两种方法制备了Zn-Ti-LDHs原样(共沉淀法制备样品记做Cop-Zn-Ti-LDHs、水热法制备样品记做Hyd-Zn-Ti-LDHs),并通过离子交换法将卡托普利负载到两种LDHs层间(共沉淀法样品记做Cap/Cop-Zn-TiLDHs以及水热样品记做Cap/Hyd-Zn-Ti-LDHs)。通过X-射线衍射(XRD)、扫描电子显微镜(SEM)、热重分析仪(TG-DTG)、傅里叶红外光谱(FT-IR)对样品进行结构的表征,探讨共沉淀法与水热法制备的Zn-Ti-LDHs理化性质的异同,并探究LDHs层板与客体药物分子的相互作用。在不同p H的磷酸缓冲溶液中模拟人体小肠肠道(p H=6.8)和人体体液(p H=7.4)内环境进行药物释放实验,采用紫外-可见吸收光谱(UV-vis)对不同时刻溶液中卡托普利的浓度进行测定,绘制药物的释放曲线。对药物的释放曲线进行动力学分析,来得出两种药物-LDHs复合物的释放机理。具体的研究结果如下:XRD表明用共沉淀法和水热法都成功制备了Zn-Ti-LDHs。Hyd-Zn-Ti-LDHs与Cop-Zn-Ti-LDHs相比有着较小层间距离和更好的结晶度,并且通过(003)晶面峰的位置变化可以计算出两种复合物的层间距离都有明显的增大。TG-DTG结果表明Hyd-Zn-Ti-LDHs结晶水的数量较少,且具有更好的热稳定性。Hyd-Zn-TiLDHs与Cop-Zn-Ti-LDHs在晶型以及稳定性的差异,主要是由于水热法相比较共沉淀法具有更高的反应时间以及温度,导致水热法制备Zn-Ti-LDHs层板生长的更加完好。在FT-IR图谱结果显示了卡托普利成功的插层进入了两种LDHs层间,并且卡托普利上酸性的-COOH基团和S-H基团与Zn-Ti-LDHs层间暴露的金属碱羟基相互作用,通过脱水或脱硫化氢缩合。客体卡托普利分子在插层的进入主体层板后的复合主要依赖于主客体之间的酸碱相互作用。通过紫外-可见光谱(UV-vis)绘制了卡托普利的标准曲线,通过卡托普利标准曲线计算得出了两种药物-LDHs复合物的载药量,并在不同p H的磷酸缓冲溶液下进行释放曲线测定。结果显示Cap/Cop-Zn-Ti-LDHs有着较高的释放率,但是其随着释放环境的变化释放量有着较大的变化;Cap/Hyd-Zn-Ti-LDHs虽然释放量较低但是在不同p H环境下的释放的稳定性更加出色,并且有着更加优异的缓释性能。通过药物释放过程的动力学分析,结果显示Cap/Cop-Zn-Ti-LDHs与Cap/Hyd-Zn-Ti-LDHs两种复合物的药物释放过程都可用准二级动力学方程描绘;释放机理为卡托普利的整个释放过程速率主要由颗粒内部扩散为主导,药物在Zn-Ti-LDHs层板间的向溶液中扩散的过程决定着药物的释放行为。图23表7参70更多还原

【Abstract】 Layered double hydroxides(layered double hydroxides)is a kind of inorganic layered materials.The layered double hydroxides have positive charge and good interlayer anion exchange performance.The structure diversity of LDHs enables them to be prepared by various methods,and the drug LDHs drug loading system can be constructed by ion exchange method due to its good interlayer anion exchangeability.Captopril is a kind of antihypertensive drug.Its thermal stability is poor,and it will be oxidized and decomposed at low temperature.Moreover,its release rate in vivo is fast and the duration of its efficacy is not long.Therefore,it is necessary to use appropriate drug carrier to improve its drug characteristics to enhance the thermal stability of captopril and control its release rate.As a new drug carrier,LDHs has unique advantages such as good biocompatibility and biodegradability.According to the unique structure and properties of LDHs,captopril was loaded into the interlayer of LDHs,and the sustained-release effect of captopril was achieved through the abundant hydroxyl active sites and steric hindrance of LDHs.In this paper,Zn-Ti-LDHs were prepared by coprecipitation method and hydrothermal method(Cop-Zn-Ti-LDHs was prepared by coprecipitation method and hyd Zn-Ti-LDHs by hydrothermal method).Captopril was loaded between the two LDHs by ion exchange method(Cap/Cop-Zn-Ti-LDHs for coprecipitation method and Cap/Hyd-Zn-Ti-LDHs for hydrothermal samples).The samples were characterized by X-ray diffraction(XRD),scanning electron microscopy(SEM),thermogravimetry(TG-DTG)and Fourier transform infrared spectroscopy(FT-IR).The physical and chemical properties of Zn-Ti-LDHs prepared by different methods were obtained,and the host guest interaction between LDHs laminates and guest drug molecules was explored.The release experiments of captopril were carried out in phosphoric acid buffer solution with different p H to simulate the internal environment of human intestinal tract(p H=6.8)and human body fluid(p H=7.4).The concentration of captopril in the solution at different times was determined by UV Vis,and the drug release curve was drawn.The release mechanism of LDHs complex was obtained by kinetic analysis of drug release curve.The results are as follows:XRD showed that Zn-Ti-LDHs were successfully prepared by coprecipitation method and hydrothermal method.Compared with Cop-Zn-Ti-LDHs,Hyd-Zn-TiLDHs has smaller interlayer distance and better crystallinity,and it can be calculated from the change of(003)crystal face peak position that the interlayer distance of the two compounds has increased significantly.TG-DTG results show that the amount of crystal water in Hyd-Zn-Ti-LDHs is less and has better thermal stability.The difference of crystal form and stability between Hyd-Zn-Ti-LDHs and Cop-Zn-Ti-LDHs is mainly due to the higher reaction time and temperature of hydrothermal method compared with coprecipitation method,which leads to the better growth of Zn-Ti-LDHs laminates prepared by hydrothermal method.The FT-IR results showed that captopril was successfully intercalated into the two LDHs layers,and the acidic-COOH and S-H groups of captopril interacted with the metal base hydroxyl groups exposed between Zn-Ti-LDHs layers through dehydration or dehydrogenation condensation.The recombination of guest captopril molecules after intercalation into the host laminate mainly depends on the acid-base interaction between host and guest.The standard curve of captopril was drawn by UV-vis.The drug loading of LDHs complex was calculated by the standard curve of captopril,and the release curve was determined in phosphoric acid buffer solution with different p H.The results showed that Cap/Cop-Zn-Ti-LDHs had a high release rate,but its release amount had a great change with the change of release environment;Although the release amount of Cap/Hyd-Zn-Ti-LDHs is low,the stability of the release under different p H conditions is better,and the release performance of Cap/Hyd-Zn-Ti-LDHs is more excellent.The results showed that the drug release process of Cap/Cop-Zn-Ti-LDHs and Cap/HydZn-Ti-LDHs complexes could be described by quasi second order kinetic equation;the release mechanism was that the whole release rate was mainly dominated by the internal diffusion of the particles,and the diffusion process between the Zn-Ti-LDHs layers into the solution determined the drug release behavior.Figure 23 table 7 reference 20更多还原