本文選題：胃滯留制劑 + 胃內(nèi)流場��； 參考：《重慶大學(xué)》2014年博士論文

【摘要】：胃滯留制劑因可提高胃部疾病治療效果已經(jīng)引起了國內(nèi)外學(xué)者越來越多的關(guān)注，但當(dāng)前胃滯留制劑的研究并未結(jié)合胃內(nèi)流場的運動規(guī)律，而只關(guān)注制劑的特定參數(shù)，如密度、膨脹時間等。研究胃內(nèi)流場以及各參數(shù)對制劑胃滯留效果影響是設(shè)計新型胃滯留制劑的基礎(chǔ)。但由于胃生理結(jié)構(gòu)的特殊性和復(fù)雜性，針對胃內(nèi)流場的相關(guān)研究很少。因此通過數(shù)學(xué)方法仿真胃內(nèi)流場中流體運動，進而模擬分析制劑性質(zhì)和胃生理參數(shù)對其在胃內(nèi)滯留效果的影響就顯得尤為重要。同時，利用胃滯留制劑清除幽門螺旋桿菌（Helicobacter Pylori, H. pylori）是一個重要的應(yīng)用方向。經(jīng)過30多年的臨床研究，H. pylori感染的治療方案不斷被改進，但其臨床治愈率一直不盡人意。胃滯留制劑由于可使藥物長時間滯留在胃內(nèi)并保持較高的藥物濃度，是治療H. pylori感染的理想選擇。但臨床中普遍采用三聯(lián)法進行H.pylori感染治療，而當(dāng)前應(yīng)用胃滯留制劑治療H. pylori感染的相關(guān)研究中常使用單一抗生素進行實驗，這使得即使設(shè)計的胃滯留制劑具有理想的胃滯留效果也會因治療方案與臨床不一致而無法轉(zhuǎn)化應(yīng)用。因此，基于胃流場運動規(guī)律設(shè)計的胃滯留制劑可提高其研發(fā)成功率，而利用載三種藥物的胃滯留制劑進行H. pylori感染的聯(lián)合治療有望提高其臨床治愈率。 本文基于質(zhì)量和動量守恒定律，根據(jù)胃蠕動真實的瞬時狀態(tài)固定了計算區(qū)域的邊界，利用FLUENT軟件進行求解。通過模擬胃排空以及密度型胃滯留微球在胃排空過程中的運動，考察了微球密度、粘度和胃液粘度對其胃滯留效果的影響，為設(shè)計和開發(fā)密度型胃滯留制劑提供理論參考。此外，結(jié)合臨床處方，首先采用電噴技術(shù)制備了載單一藥物的低密度多孔微球和腸溶納米粒，進而使用乳液電噴技術(shù)制備了載三種藥物的低密度多孔微球和高密度磁性微球，研究了胃滯留微球的理化性質(zhì)、胃滯留能力、體內(nèi)外清除H. pylori效果，并且分析了胃滯留實驗結(jié)果與微球滯留時間模擬預(yù)測結(jié)果的一致性。 本文的主要內(nèi)容和結(jié)果： 首先，基于質(zhì)量和動量守恒定律，提取了一個同時具有3個胃竇收縮波的胃蠕動瞬時狀態(tài)，固定了計算區(qū)域的邊界，利用FLUENT軟件進行求解，建立了二維的胃內(nèi)流體運動模型。通過對重力作用下前1100Sec.胃排空過程模擬，發(fā)現(xiàn)胃液積分面積在計算時間內(nèi)減少了42.19%，與真實胃排空過程相近，表明建立的模型可以準確模擬胃內(nèi)流體的運動過程。此外，利用胃內(nèi)流體運動模型模擬了常規(guī)密度、低密度和高密度微球在胃排空過程中的運動。常規(guī)密度微球初始分散于胃液上部；當(dāng)渦流出現(xiàn)后，微球在胃液內(nèi)分散，并且隨著渦流不斷向幽門方向運動，上述過程即為胃內(nèi)的研磨和混合過程；低密度微球則在胃液表面鋪展開并漂浮在其表面；高密度微球接觸到胃液后會分散，在不斷下沉的同時隨著渦流運動，最終在到達幽門之前沉降在胃的底部。模擬結(jié)果證實與胃液存在密度差的微球具有胃滯留效果。 其次，利用所建立模型考察了不同密度、粘度以及胃液粘度對微球胃滯留效果的影響。微球密度對其胃滯留效果影響顯著，當(dāng)微球密度低于500kg/m3或高于2750kg/m3時，微球在1100Sec.內(nèi)的剩余積分面積可達到90%以上，而常規(guī)密度微球在相同時間內(nèi)其積分面積下降了32.95%。粘度較低的低密度微球和高密度微球都具有較好的胃滯留效果；滯留在胃內(nèi)的低密度微球數(shù)量隨著胃液粘度的增加而增加，而高密度微球的胃滯留能力隨著胃液粘度的增加而略微下降。上述結(jié)果為設(shè)計密度型胃滯留制劑提供一定的理論參考，并為服用密度型胃滯留制劑提供飲食指導(dǎo)。 再次，使用電噴法制備了載單一藥物的低密度多孔微球和腸溶納米粒，對其理化性質(zhì)進行了考察，研究結(jié)果為制備載三種藥物的胃滯留微球做準備。制備的多孔微球和腸溶納米粒都具有較高的載藥量，低密度多孔微球可以胃內(nèi)滯留8h以上并保持藥物的持續(xù)釋放，體內(nèi)實驗證明低密度微球與原料藥相比表現(xiàn)出了更佳的清除H. pylori效果。 最后，根據(jù)臨床治療H. pylori感染經(jīng)驗處方，通過乳液電噴技術(shù)獲得了載三種藥物的低密度多孔微球。并提出了設(shè)計載多藥緩釋給藥系統(tǒng)中“多種藥物的釋放量比例應(yīng)與臨床中服用各藥的劑量比相等”的原則。在實驗中通過調(diào)節(jié)三種藥物的投藥量比例，使藥物的釋放量比與經(jīng)驗處方中藥物的劑量比相近，，為載多藥擴散依賴型釋藥系統(tǒng)的發(fā)展提供了新的方向。體內(nèi)實驗表明載三種藥物低密度微球與原料藥相比，在相同劑量時具有更佳的治療效果。同時，通過引入磁性Fe3O4納米粒，成功制備了載三種藥物的高密度磁性微球，解決了高密度胃滯留制劑難以達到密度要求的難題。制備的高密度磁性微球具有良好的沉降和胃滯留效果，并且在外加磁場作用下，其沉降和胃滯留性能可進一步提高。體內(nèi)外的H. pylori清除實驗證明載三種藥物的高密度磁性微球具有抑制H. pylori生長的效果。這預(yù)示著制備的載三種藥物胃滯留微球具有臨床治療H. pylori感染的潛力。除此之外，微球的胃滯留測試結(jié)果表明模擬預(yù)測的微球胃滯留效果與實驗結(jié)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.
【學(xué)位授予單位】：重慶大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R573

【參考文獻】

相關(guān)期刊論文 前1條

1 Elvira Garza-González;Guillermo Ignacio Perez-Perez;Héctor Jesús Maldonado-Garza;Francisco Javier Bosques-Padilla;;A review of Helicobacter pylori diagnosis, treatment, and methods to detect eradication[J];World Journal of Gastroenterology;2014年06期

本文編號：1904018