基于胃内流场模拟的治疗幽门螺旋杆菌感染胃滞留微球的研制及药效研究

发布时间：2018-05-18 02:35

本文选题：胃滞留制剂 + 胃内流场　；参考：《重庆大学》2014年博士论文

【摘要】：胃滞留制剂因可提高胃部疾病治疗效果已经引起了国内外学者越来越多的关注，但当前胃滞留制剂的研究并未结合胃内流场的运动规律，而只关注制剂的特定参数，如密度、膨胀时间等。研究胃内流场以及各参数对制剂胃滞留效果影响是设计新型胃滞留制剂的基础。但由于胃生理结构的特殊性和复杂性，针对胃内流场的相关研究很少。因此通过数学方法仿真胃内流场中流体运动，进而模拟分析制剂性质和胃生理参数对其在胃内滞留效果的影响就显得尤为重要。同时，利用胃滞留制剂清除幽门螺旋杆菌（Helicobacter Pylori, H. pylori）是一个重要的应用方向。经过30多年的临床研究，H. pylori感染的治疗方案不断被改进，但其临床治愈率一直不尽人意。胃滞留制剂由于可使药物长时间滞留在胃内并保持较高的药物浓度，是治疗H. pylori感染的理想选择。但临床中普遍采用三联法进行H.pylori感染治疗，而当前应用胃滞留制剂治疗H. pylori感染的相关研究中常使用单一抗生素进行实验，这使得即使设计的胃滞留制剂具有理想的胃滞留效果也会因治疗方案与临床不一致而无法转化应用。因此，基于胃流场运动规律设计的胃滞留制剂可提高其研发成功率，而利用载三种药物的胃滞留制剂进行H. pylori感染的联合治疗有望提高其临床治愈率。本文基于质量和动量守恒定律，根据胃蠕动真实的瞬时状态固定了计算区域的边界，利用FLUENT软件进行求解。通过模拟胃排空以及密度型胃滞留微球在胃排空过程中的运动，考察了微球密度、粘度和胃液粘度对其胃滞留效果的影响，为设计和开发密度型胃滞留制剂提供理论参考。此外，结合临床处方，首先采用电喷技术制备了载单一药物的低密度多孔微球和肠溶纳米粒，进而使用乳液电喷技术制备了载三种药物的低密度多孔微球和高密度磁性微球，研究了胃滞留微球的理化性质、胃滞留能力、体内外清除H. pylori效果，并且分析了胃滞留实验结果与微球滞留时间模拟预测结果的一致性。本文的主要内容和结果：首先，基于质量和动量守恒定律，提取了一个同时具有3个胃窦收缩波的胃蠕动瞬时状态，固定了计算区域的边界，利用FLUENT软件进行求解，建立了二维的胃内流体运动模型。通过对重力作用下前1100Sec.胃排空过程模拟，发现胃液积分面积在计算时间内减少了42.19%，与真实胃排空过程相近，表明建立的模型可以准确模拟胃内流体的运动过程。此外，利用胃内流体运动模型模拟了常规密度、低密度和高密度微球在胃排空过程中的运动。常规密度微球初始分散于胃液上部；当涡流出现后，微球在胃液内分散，并且随着涡流不断向幽门方向运动，上述过程即为胃内的研磨和混合过程；低密度微球则在胃液表面铺展开并漂浮在其表面；高密度微球接触到胃液后会分散，在不断下沉的同时随着涡流运动，最终在到达幽门之前沉降在胃的底部。模拟结果证实与胃液存在密度差的微球具有胃滞留效果。其次，利用所建立模型考察了不同密度、粘度以及胃液粘度对微球胃滞留效果的影响。微球密度对其胃滞留效果影响显著，当微球密度低于500kg/m3或高于2750kg/m3时，微球在1100Sec.内的剩余积分面积可达到90%以上，而常规密度微球在相同时间内其积分面积下降了32.95%。粘度较低的低密度微球和高密度微球都具有较好的胃滞留效果；滞留在胃内的低密度微球数量随着胃液粘度的增加而增加，而高密度微球的胃滞留能力随着胃液粘度的增加而略微下降。上述结果为设计密度型胃滞留制剂提供一定的理论参考，并为服用密度型胃滞留制剂提供饮食指导。再次，使用电喷法制备了载单一药物的低密度多孔微球和肠溶纳米粒，对其理化性质进行了考察，研究结果为制备载三种药物的胃滞留微球做准备。制备的多孔微球和肠溶纳米粒都具有较高的载药量，低密度多孔微球可以胃内滞留8h以上并保持药物的持续释放，体内实验证明低密度微球与原料药相比表现出了更佳的清除H. pylori效果。最后，根据临床治疗H. pylori感染经验处方，通过乳液电喷技术获得了载三种药物的低密度多孔微球。并提出了设计载多药缓释给药系统中“多种药物的释放量比例应与临床中服用各药的剂量比相等”的原则。在实验中通过调节三种药物的投药量比例，使药物的释放量比与经验处方中药物的剂量比相近，，为载多药扩散依赖型释药系统的发展提供了新的方向。体内实验表明载三种药物低密度微球与原料药相比，在相同剂量时具有更佳的治疗效果。同时，通过引入磁性Fe3O4纳米粒，成功制备了载三种药物的高密度磁性微球，解决了高密度胃滞留制剂难以达到密度要求的难题。制备的高密度磁性微球具有良好的沉降和胃滞留效果，并且在外加磁场作用下，其沉降和胃滞留性能可进一步提高。体内外的H. pylori清除实验证明载三种药物的高密度磁性微球具有抑制H. pylori生长的效果。这预示着制备的载三种药物胃滞留微球具有临床治疗H. pylori感染的潜力。除此之外，微球的胃滞留测试结果表明模拟预测的微球胃滞留效果与实验结果具有一致性。
[Abstract]:Gastric retention preparation has attracted more and more attention from domestic and foreign scholars because it can improve the effect of gastric disease treatment. However, the current research on gastric retention preparation does not combine the movement of gastric flow field, but only concerns the specific parameters of the preparation, such as density, expansion time and so on. Study on the effect of internal flow field and the effect of various parameters on the effect of gastric retention in the preparation of the stomach. It is the basis for the design of a new type of gastric retention preparation. However, because of the particularity and complexity of the physiological structure of the stomach, there are few studies on the intragastric flow field, so it is particularly important to simulate the fluid movement in the intragastric flow field by mathematical method, and then to simulate and analyze the effects of the preparation and the gastric physiological parameters on the effect of the gastric retention. It is an important application direction to remove Helicobacter Pylori (H. pylori) with gastric retention preparation. After more than 30 years of clinical study, the treatment scheme of H. pylori infection has been improved, but its clinical cure rate has been unsatisfactory. The drug concentration is an ideal choice for the treatment of H. pylori infection. However, the triple method is commonly used in the treatment of H.pylori infection, while a single antibiotic is often used in the study of the current application of gastric retention agents in the treatment of H. pylori infection, which makes even the designed gastric retention preparations have an ideal gastric retention effect. Therefore, the gastric retention preparation based on the motion law of the stomach can improve the success rate of the stomach, and the combined treatment of H. pylori infection with three kinds of drugs for gastric retention is expected to improve the clinical cure rate.
Based on the law of conservation of mass and momentum, the boundary of the calculated region was fixed according to the real instantaneous state of gastric peristalsis, and the solution was solved by FLUENT software. The effects of microsphere density, viscosity and gastric juice viscosity on the effect of gastric retention were investigated by simulating the movement of gastric emptying and dense gastric retention microspheres during gastric emptying. In addition, the low density porous microspheres and enteric nanoparticles loaded with single drug were prepared by electrospray technique, and the low density porous microspheres and high density magnetic microspheres carrying three kinds of drugs were prepared by electrospray technique. The physical and chemical properties of the ball, the ability of gastric retention, the effect of H. pylori in vivo and in vitro, and the consistency between the results of gastric retention experiment and the simulation results of the retention time of microspheres were analyzed.
The main contents and results of this paper are as follows:
First, based on the law of mass and momentum conservation, the instantaneous state of gastric peristalsis with 3 gastric antrum contraction waves is extracted and the boundary of the calculated region is fixed. A two-dimensional gastric fluid motion model is established by FLUENT software. The integral area of gastric juice is found through the simulation of the gastric emptying process under the action of gravity under the action of the 1100Sec. stomach. The decrease of 42.19% in the calculation time is similar to that of the real gastric emptying process. It shows that the established model can accurately simulate the movement process of the gastric fluid. In addition, the conventional density, low density and high density microspheres are transported in the gastric emptying process by the model of intragastric fluid motion. When the swirl appears, the microspheres are dispersed in the gastric juice, and as the vortex moves towards the pylorus, the process is the process of grinding and mixing in the stomach, and the low density microspheres spread on the surface of the gastric juice and float on the surface of the stomach. The high density microspheres will disperse after contact with the gastric juice, and then move along with the eddy current at the same time as they continue to sink. The stomach was deposited at the bottom of the stomach before reaching pylorus. The results of the simulation confirmed that the microspheres with poor density in gastric juice had gastric retention effect.
Secondly, the effect of different density, viscosity and viscosity of gastric juice on the effect of gastric retention on microspheres was investigated. Microsphere density had a significant effect on the effect of gastric retention. When the density of microspheres was lower than 500kg/m3 or higher than 2750kg/m3, the remaining integral area of microspheres in 1100Sec. could reach more than 90%, while the conventional density microspheres were the same. The integral area of the intragastric low density microspheres and high density microspheres with lower 32.95%. viscosity had better effect on gastric retention, and the number of low density microspheres retained in the stomach increased with the increase of the viscosity of gastric juice, while the gastric retention ability of high density microspheres decreased slightly with the increase of gastric juice viscosity. The above results were designed. Density gastric retention preparations provide a theoretical reference and provide dietary guidance for the use of density gastric retention preparations.
Thirdly, the low density porous microspheres and enteric nanoparticles loaded with single drug were prepared by electric spray method. The physicochemical properties of the microspheres were prepared. The results were prepared for the preparation of three kinds of drug loaded microspheres. The prepared porous microspheres and enteric nanoparticles both had high drug loading, and the low density porous microspheres could be retained in the stomach for 8h. The sustained release of drugs was maintained and in vivo experiments showed that low density microspheres showed better H. pylori clearance than API.
Finally, according to the clinical treatment of H. pylori infection experience prescription, the low density porous microspheres carrying three kinds of drugs were obtained by emulsion injection technology. The principle of designing "the proportion of the release amount of various drugs should be compared with the dosage of each drug in clinical use" in the design of the drug delivery system. In the experiment, three drugs were adjusted in the experiment. The ratio of the dosage of the drug to the dose ratio of the drug is similar to the dose in the empirical prescription, which provides a new direction for the development of the multidrug diffusion dependent drug release system. In vivo experiments show that three kinds of drug low density microspheres have better therapeutic effects at the same dose compared with the raw materials. At the same time, the magnetic Fe is introduced. 3O4 nanoparticles successfully prepared high density magnetic microspheres carrying three kinds of drugs, which solved the difficult problem of high density gastric retention preparation difficult to achieve density. The prepared high-density magnetic microspheres had good settlement and gastric retention effect, and its settlement and gastric retention performance could be further improved under the effect of applied magnetic field. H. PY in vivo and in vitro Lori scavenging experiments showed that the high density magnetic microspheres carrying three kinds of drugs have the effect of inhibiting the growth of H. pylori. This indicates that the prepared three drug gastric retention microspheres have the potential to treat H. pylori infection. In addition, the results of the microspheres' gastric retention test show that the simulated predicted microsphere retention effect and the experimental results have the results. Uniformity.
【学位授予单位】：重庆大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R573

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