甘油单油酸酯/水立方液晶体系作为药物载体体系的研究

【作者】 王志宁；

【导师】 郑利强；

【作者基本信息】 山东大学 ， 物理化学， 2005， 硕士

【摘要】 一定浓度的两亲性脂质在水中会自发形成热力学稳定的脂质双层,然后再重组形成具有各种形状和结构的立方液晶体系。这种立方液晶具有独特的内部双水道结构,它能够缓慢的释放出包封的药物,并且具有靶向性、生物亲和性和可生物降解等优点,因此脂质立方液晶能够成作为一种优良的药物载体。该类立方液晶的内部结构是三维延伸的,属于双连续的网络结构,在充分溶胀情况下,水道的直径约5nm,双层膜的厚度大约是3.5nm,粘度和膜强度都很大,这些都有利于脂质立方液晶包结药物,提高药物的稳定性,并最终达到在体内缓慢释放药物的目的。 在脂质立方液晶中添加蔗糖可以改变体系的相态,降低体系的粘度,这样就能够改进脂质立方液晶作为药物载体粘度过大的缺点,为其实现多途径给药创造了条件。蔗糖间接作用在脂质与水的界面（Hofmeister效应）,减少界面水的含量,从而使脂质分子的平均截面积变小,有利于体系向反相六角状液晶转变。含1%蔗糖的立方液晶体系模量值最大,在频率较小时损耗模量大于储能模量,粘性较为突出,随频率的增加储能模量超过了损耗模量,这时体系的弹性性质更突出。当体系中蔗糖含量为10%时,模量值最低,并且其粘性性质始终强于弹性性质,说明体系处于中间态,其内部结构尚未形成完美的六角状液晶。其它体系的储能模量在整个振荡频率范围内都大于损耗模量。根据体系流变性质的变化和偏光显微镜照片,得出随着蔗糖含量的增加,MO/水体系发生了由反相立方液晶到反相六角状液晶的相转变。蔗糖与MO分子通过氢键相互作用,减弱了两亲分子间的静电斥力。当蔗糖含量增加到一临界值时,体系的立方结构被破坏,继续增加蔗糖的含量,体系就会形成新的反相六角状液晶。 利用小角X光散射进一步研究了蔗糖对MO和水质量比为7:3时的立方液晶体系内部结构的影响,发现20℃时,30wt%水含量的MO/水体系形成了Ia3d的晶型（C_G）,而蔗糖/MO/水体系的内部结构随蔗糖含量的上升而发生了转变,蔗糖含量5wt%时体系发生了立方液晶内部的相转变,由Ia3d晶型转变为Pn3m,而当蔗糖含量上升到10wt%后,体系由Pn3m的立方液晶转变为反相六角状液晶H₁₁。另外,通过体系的晶格常数的变化计算得出Ia3d晶格的临界堆积参数大约为1.2左右,而Pn3m晶格的临界堆积参数约为1.3,反相六角状液晶的临界堆积更多还原

【Abstract】 Monoglyceride （MO） is degradable and innoxious to human body and it can form various liquid crystalline phases spontaneously in the presence of various amount of water at room temperature. The appropriate compositions from binary phase diagram of MO/H₂O were selected to form cubic phases. The cubic liquid crystal has a transparent, stiff, and gel-like appearance and is built up of a three-dimensional network of curved lipid bilayers which were separated by a network of congruent water channels. There are two kinds of water channels in the bicontinuous cubic phase: one is open to the outer continuous phase, and the other is closed and isolated from outer environment. Drugs can be encapsulated in the bicontinuous cubic phases and sustainedly released for the particular structure of the cubic phase. It is prone to esterase activity and can be easily cleared from the body. These degradable delivery systems erode or dissolve in the gingival crevice, avoiding removal after treatment.The effects of sucrose on the phase behavior of the cubic phases formed from MO/H₂O mixture were studied by the rheological method. The results revealed that the phase transition of reversed Cubic phase to reversed hexagonal phase occurred when the amount of sucrose in mixture was increased. The hydrogen bonds formed between the molecules of MO and sucrose may decrease the electrostatic repulsive force between the lipid molecules, and induce the phase transition.The effect of sucrose on the structure of molecular assemblies formed in MO/H₂O mixture has been studied by using a small angle X-ray scattering method. It was found that the phase transition of Ia3d → Pn3m → H_II occurs with the increase in the sucrose concentration in the mixture with the composition of 70 wt% MO at 20°C. This structural change induced by the sucrose addition would be ascribed to a cosmotropic property of sucrose, which leads to the dehydration of MO head group, and hence, causes the decrease in the effective area occupied by MO molecule at the polar/apolar interface, which facilitates the formation of molecular assembly with high curvature for reversed liquid-crystal mesophase. These sucrose-induced phasetransitions may be interpreted qualitatively in terms of the change in the critical packing parameter of MO molecules resulting from the sucrose effect on the hydration of MO head group.When sucrose is dissolved in an aqueous medium, the free water in a bulk aqueous phase would be reduced due to a strong hydration power of sucrose （i.e., a cosmotropic property of sucrose）. This would shift the hydration equilibrium of MO head group toward the promotion of the dehydration of the head group. This results in the decrease in the effective volume of the MO head group, and also, in the effective area occupied by MO molecule at the polar/apolar interface of a molecular assembly formed in the MO/H2O mixture. That is, sucrose would act to increase the critical packing parameter, which facilitates the formation of molecular assemblies with high curvature in the case of reversed mesophases.It is well known that the dispersions of cubic lipid-water phases can be used for development of controlled release formulations of biologically active agents in the field of drug delivery and for the encapsulation of enzymes in food technology. Dispersions with moderate kinetic stability have been obtained. In order to differentiate from liposomes, these particles have been termed "cubosomes". The morphology and the microstructure of the dispersed particles, which are formed from monoolein/monopalmitin/water mixture, have been studied. The freeze-fracture TEM shows clearly that the aqueous dispersed particles have irregular cubic shapes. X-ray diffraction technique has been utilized to.study the microstructure of the particles and it is found that these particles still retain the cubic character.In order to understand the physical properties of lipids and lipid mixtures, the study of phase science of the constituent fatty acid mixtures must be useful, since it would provide basic information regarding the interaction between different acyl chains, which is an important factor to determine the physical properties and phase behavior of lipid mixtures. From this point of view, we have been carrying out the systematic study on the phase behavior of binary fatty acid mixtures, particularly stressing the systems containing oleic acid as one of the two components in the mixture. Solid-liquid phase behavior of binary mixtures of oleic acid （OA）/capric acid（ClOA） was investigated by means of differential scanning calorimetry （DSC） and X-ray diffraction. The phase diagram of OA/CIOA mixture constructed from the DSC results suggested that a molecular compound with the composition of OA:C10A = 3:2 is formed in a solid phase , and OA and the molecular compound are miscible, while ClOA and the molecular compound are completely immiscible. The formation of the molecular compound was confirmed by the X-ray diffraction measurements, and a possible model of the structure was proposed on the basis of X-ray diffraction spectrum in small angle region. No such compound formation has been observed in mixtures of OA with saturated fatty acids so far examined. This characteristic behavior of OA/CIOA mixture may be attributed to the fact that the acyl chain length of ClOA is close to a half length of OA molecule, or the length of two segments divided by a cis-double bond existing at the center of acyl chain of OA. Dissipative particle dynamics （DPD） simulation is used to study the structure of the OA/CIOA mixture. It can be found that the structure of the molecular compound of OA/CIOA is consilient to the imaginary model.更多还原