摘要
黄酮类药物分子在结构上有一定的极性,但其在水溶液中却显示很强的疏水性,从而影响了这类药物的溶解度、溶出速率和生物利用度。为改善其药效,在药剂学提出了一系列的方法和技术,如将其与添加辅料制成固体分散体、制成脂质体或凝胶微胶囊、制成环糊精类的包合体等等。在这些制备技术中,辅料与药物的混合性质,直接影响了药剂的物理性质和药效。所以,研究药物+辅料体系的物理化学性质对于提高药效,改进制备技术具有重要的意义。
物质的溶解度、溶解速率以及相平衡状态和其热力学性质直接相关。因此,药物体系的热力学性质也是评价药效的一项基本数据。本文我们研究了黄酮类药物水飞蓟宾、槲皮素与一些辅料如聚乙烯吡咯烷酮(PVP)、聚乙烯醇(PVA)和胆酸钠等构成的二元系的热力学性质,通过测定体系的比热和相变特性,考察体系的状态随组成和温度的变化。具体内容包含如下几个方面:
1.制备槲皮素+PVP K30二元系固体分散体及固态混合物,利用差示扫描量热法(DSC)测定体系的比热,结合傅立叶红外光谱(FT-IR)和X-射线粉末衍射(XRD),分析槲皮素和PVP K30间的相互作用以及样品晶型的变化。结果表明:在槲皮素质量分数w1 < 0.5的组成区间内形成了药物固体分散体,在w1 > 0.5区间内构成了药物晶体与固体分散体的混合物。利用数学模型关联了比热与组成和温度的关系。计算了实验温度区间内的焓变与熵变。此项工作发表在J.Chem.Eng.Data,2010,5856。
2.制备水飞蓟宾+PVP K30二元系的固体分散体和固体混合物,利用DSC测定体系的比热。通过比热的微分曲线dCp/dT-T得到了表征物相状态的方法。结果表明:曲线中的若干极值点可以表征水飞蓟宾在PVP的分散状态,在水飞蓟宾质量分数w1< 0.4的组成区间内形成了固体分散体,在w1> 0.4区间,则是晶态水飞蓟宾与固体分散体的混合状态。利用数学模型方程对实验数据进行了关联。计算了实验温度区间内的焓变和熵变。此项工作发表在Thermochim Acta,2011,99。
3. DSC测定了水飞蓟宾+胆酸钠二元系固体混合物的比热。结合FT-IR和XRD分析了胆酸钠和水飞蓟宾间的相互作用以及样品的晶型变化。结果显示:胆酸钠与水飞蓟宾无化学作用,其状态是微晶混合物。运用Redlich-Kister方程对比热超量与组成的关系进行了关联。计算了实验温度区间内的焓变和熵变。
4.水凝胶是一种引起广泛关注的载药方式。水凝胶的应用性能和生物相容性等与其含水量和持水状态相关。利用反复冷冻-解冻法制备了PVA+PVP复合水凝胶,利用DSC测定了凝胶的失水状况。通过Kissinger法、Flynn-Wall-Ozawa法和速率方程模型法研究了凝胶失水动力学,获得了相关的活化能等动力学参数,考察了PVP的掺入量对PVA凝胶的失水动力学的影响。
Flavonoids, such as silybin and quercetin, are polar in structure, but poorly soluble in water in nature. This hydrophobic property limits their solubility, release rate in water and bioavalibility in medicine application. To improve their medicine efficience, a variety of methods in pharmaceutics have been developed, among them including solid dispersion method, inclusion complex method, and liposome and hydrogel carrier methods. In pharmaceutical technique, the mixing behaviour of drug and their additives directly impact the physical-chemical properties and the medicine efficience. Therefore, it is very important to study the physical-chemical properties of the mixtures of drug + additives.
The solubility, solid release rate in water, and the phase equilibrium state of drugs are mainly determined by their thermochemical properties. Therefore, thermodynamic property is an essential data to evaluate the medicine efficience of drugs. In this article, we focus our attention to some binary systems composed of flavonoids (silybin, quercetin) and their additives (Poly(vinylpyrrolidone) (PVP), Polyvinyl alcohol (PVA) and sodium cholate, etc.). Some basic thermodynamic properties, such as heat capacity and phase transition state, and their changes with temperature and compositions are studied. This work includes four parts.
1. In chapter 2, we report the study on the binary system of (quercetin + PVP K30). Solid dispersions and mixtures of quercetin and PVP K30 are studied by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and heat capacity (Cp) measurements. A solid dispersion is found in the region of w1 < 0.5, and a solid mixture is found in the region of w1 > 0.5, where w1 is the mass fraction of quercetin. The Cp data is correlated to temperature T by a polynomial equation, and changes in enthalpy and entropy were calculated from Cp. The work in this chapter has been published in J.Chem.Eng.Data, 2010, 5856.
2. In chapter 3, we report the study on the binary mixtures of (silybin + PVP K30). The heat capacity Cp of the binary system has been measured by DSC and FT-IR spectroscopy. By analyzing the curves of (dCp/dT) against temperature T, some apparent points, a maxima point and a minima point, to characterize the Cp curve were obtained. The maxima point in the region of w1< 0.4 is a character of amorphous solid state of PVP, where w1 is the mass fraction of silybin. In this region, silybin is dispersed into the amorphous solid of PVP. The minima point in the w1> 0.4 region is a character of crystalline silybin. In this region, a mixture of crystalline silybin with an amorphous solid dispersion is observed. The Cp data is correlated to temperature T by a polynomial equation, and the changes in enthalpy and entropy were calculated from Cp. The work in this chapter has been published in Thermochim Acta, 2011, 99.
3. In chapter 4, we report the work on the binary system of (silybin + sodium cholate). The heat capacity of this binary system has been measured by DSC in the temperature range from 298.15 to 373.15 K. X-ray diffraction and FT-IR spectroscopy were used to determine the solid mixing behaviour. Our result indicates that, the binary system of silybin and sodium cholate is a mixture of two micro-crystaline components. The excess heat capacities of this binary system were correlated by the Redlich-Kister equation. Thermodynamic functions of the entropy and enthalpy were calculated in the experimental temperature range.
4. Hydrogels can be used as a drug carrier. Its application in biology and medicine depends seriously upon its water content. By a repeated freezing and thawing method, the hydrogels of PVA blended with PVP were prepared. The thermal dehydration kinetics of this gel was investigated by DSC measurement, which is significantly dependent on the PVP content. The kinetic parameters of the dehydration process of PVA+PVP gel were obtained by the Kissinger method, by the Flynn-Wall-Ozawa method, and by a method to fit the DSC data with some definite kinetic equations, respectively. The effect of PVP content on the dehydration of PVA hydrogel can be found from the kinetic parameters.
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