評估包覆四環黴素之漂浮顆粒對培養於胃部模擬環境中幽門桿菌之抑制效果

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研究生：	徐語彤 Yu-Tung Hsu
論文名稱：	評估包覆四環黴素之漂浮顆粒對培養於胃部模擬環境中幽門桿菌之抑制效果 Evaluation of the inhibitory effect of Tetracycline- Alginate floating beads on the growth of H. pylori in a simulated gastric environment
指導教授：	高震宇 Chen-Yu Kao
口試委員:	何明樺 Ming-Hua Ho 葉平萍 Peng-Peng Ip
學位類別：	碩士 Master
系所名稱：	應用科技學院 - 醫學工程研究所 Graduate Institute of Biomedical Engineering
論文出版年：	2019
畢業學年度：	107
語文別：	中文
論文頁數：	98
中文關鍵詞：	四環黴素、幽門桿菌、海藻酸漂浮顆粒、胃癌
外文關鍵詞：	Tetracycline, H. pylori, Alginate floating beads, gastric cancer
相關次數：	點閱：285 下載：0
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幽門螺旋桿菌( H. pylori )為一彎曲桿狀的革蘭氏陰性微好氧菌，主要寄居在胃黏膜的上皮細胞，也是目前發現唯一能在人胃中存活的細菌，感染後容易引起胃炎、胃十二指腸潰瘍、胃癌與胃黏膜相關淋巴癌的危險因子，而胃癌是全球第五大常見癌症。目前常見治療幽門螺旋桿菌的方法是利用質子幫浦阻斷劑和服用 clarithromycin 與 amoxicillin 所組成之標準三合一療法與質子幫浦阻斷劑、鉍劑 tetracycline 與 metronidazole 組成的標準四合一療法;然而這兩種療法的滅菌成功率不一，且藥物於胃內滯留時間短，造成藥物並未達到抑制幽門螺旋桿菌的有效濃度就排出體外。因此，本研究第一部分製備了搭載四環素之海藻酸漂浮顆粒以幫助改善藥物在體內快速吸收帶來的副作用，並將藥物以載體包覆，可對藥物的釋放進行控制，達到緩釋作用，並對顆粒進行表面評估和體外測試。第二部分則為幽門螺旋桿菌體外試驗，將幽門螺旋桿菌培養於胃部模擬 3D 模型中，並觀察於不同條件下其體外生長情形。
研究結果顯示，搭載四環素之海藻酸漂浮顆粒表面具有微小孔洞，且顆粒可漂浮於介質上;緩釋效果則顯示出在顆粒中添加 HPMC 者具有較高的累積釋放率;包埋率實驗顯示，添加幾丁聚醣之顆粒其藥物包埋率較高。幽門螺旋桿菌體外試驗結果顯示，幽門螺旋桿菌於 5% 胃黏膜下具有最佳的生長情形;當加入不同 pH 時可觀察到，幽門螺旋桿菌無法在 pH1~2 中存活，若改變胃黏膜之添加量則可使少量的幽門螺旋桿菌可存活於 pH 2 的環境下。
在未來的實驗中我們將會把這兩部份結合，測試搭載四環素之海藻酸漂浮顆粒對培養於胃部模擬 3D 模型之幽門螺旋桿菌抑制的效果，以期能發展出一個符合臨床需求的藥物傳輸系統。

Helicobacter pylori (H. pylori) is a gram-negative microaerophile bacteria that has curved-rod shape. H. pylori is the only kind of bacterium discovered to survive in the human stomach, where they live in the epithelial cell of the gastric mucosa. An H. pylori infection may put people into the higher risk of gastritis, gastric and duodenal ulcers, gastric cancer and gastric mucosa related lymphoma among other conditions. Gastric cancer is currently among the top five most common cancers in the world. At present, the most common treatments of H. pylori infection are the standard triple therapy with proton pump inhibitor, clarithromycin and amoxicillin the other way is the standard quadruple therapy with proton pump inhibitor, bismuth salt, tetracycline, and metronidazole. However, the bactericidal-success-rate of these two standard therapies isn’t consistent. Furthermore, the ephemeral time of residence of the drugs in the stomach cause that is easily eliminated before reaching the concentration level that can effectively inhibit H. pylori. Therefore, the first part of this study was designed to reduce the side effects caused by the fast absorption of the drugs in vivo using the prepared Tetracycline-Alginate floating beads and wrapping the drugs with vectors that control drug release as slowly release. We also carried out the assessment of the beads surface and in vitro tests. In the second part of this study, we performed the in vitro experiments of H. pylori by culturing H. pylori in a simulated 3D model of a gastric environment and then observed and recorded the in vitro growth of the bacteria under different conditions.
As shown by our results, the surface of the Tetracycline-Alginate floating beads
that floated on the medium is full of microspores; the slowly release effects were reflected by the higher accumulated release rate of the beads with the addition of HPMC. Regarding the encapsulation efficiency, the results showed that the beads with chitosan had higher drug encapsulation efficiency. According to the in vitro study results, H. pylori grew best in 5% gastric mucin but cannot survive in the environment of pH value of 1~2. If the quantities of mucin added into the medium that was changed, a trace- amounts of H. pylori may survive even in an environment with a pH value of 2.
In the future experiments, we will further study the inhibitory effect of Tetracycline-Alginate floating beads on the growth of H. pylori in a simulated gastric environment. We anticipate these finding might enhance the clinical success and generate a new therapeutic strategy for treating H. pylori infection.

摘要........................................................................................................................... II
Abstract ....................................................................................................................III
致謝........................................................................................................................... V
目錄.......................................................................................................................... VI
圖目錄........................................................................................................................ X
表目錄...................................................................................................................... XII
縮寫表......................................................................................................................XIII
第一章 緒論..................................................................................................................1
第二章 文獻回顧...........................................................................................................3
1 癌症........................................................................................................................3
1.1 胃癌..................................................................................................................... 3
2 幽門螺旋桿菌( Helicobacter pylori, H. pylori ) ...................................................... 5
3 藥物傳輸系統( Drug Delivery System, DDS ) ........................................................ 8
3.1 藥物胃內滯留型控釋製劑..................................................................................... 9
3.2 聚合物載體..........................................................................................................11
4 海藻酸( Sodium Alginate, SA ) ............................................................................. 13
4.1 海藻酸的單體結構............................................................................................... 15
4.2 海藻酸的高分子結構........................................................................................... 16
4.3 海藻酸交聯反應.................................................................................................. 17
5 幾丁聚醣( Chitosan ) ............................................................................................ 18
6 羥丙基甲基纖維素( HPMC ) .................................................................................. 20
7 四環黴素( Tetracycline, TCs ) ............................................................................... 21
7.1 四環黴素的抑菌作用機轉..................................................................................... 22
第三章 實驗材料與方法.................................................................................................24
1 研究設計.................................................................................................................24
1.1 實驗設計.............................................................................................................. 25
1.2 實驗架構............................................................................................................. 26
2 實驗器材藥品與設備...............................................................................................28
2.1 實驗器材藥品...................................................................................................... 28
2.2 實驗分析儀器設備............................................................................................... 29
3 Tetracycline-Alginate 漂浮顆粒的製備 ................................................................. 30
3.1 海藻酸漂浮顆粒製備參數..................................................................................... 30
3.2 製備 Tetracycline-Alginate 空白漂浮顆粒........................................................... 31
3.3 製備 Tetracycline-Alginate 漂浮顆粒.................................................................. 32
4 Tetracycline-Alginate 漂浮顆粒特性分析 .............................................................. 33
4.1 表面型態觀察...................................................................................................... 33
4.2 Tetracycline-Alginate 漂浮顆粒粒徑大小測量..................................................... 33
4.3 Tetracycline-Alginate 漂浮顆粒膨潤率測量........................................................ 34
4.4 Tetracycline-Alginate 漂浮顆粒漂浮率測試........................................................ 34
4.5 Tetracycline-Alginate 漂浮顆粒體外試驗評估..................................................... 35
5 幽門螺旋桿菌體外試驗............................................................................................37
5.1 幽門螺旋桿菌( H. pylori )的培養........................................................................... 38
5.2 幽門螺旋桿菌原液製作......................................................................................... 38
5.3 不同濃度 Mucin 對 H. pylori 的生長影響.............................................................. 39
5.4 不同添加量 Mucin 對 H. pylori 的生長影響.......................................................... 39
5.5 不同 pH 值對 H. pylori 的生長影響 ...................................................................... 40
5.6 改變 Mucin 添加量與 pH 值後 H. pylori 的生長情形............................................. 40
5.7 添加尿素對 H. pylori 在不同 pH 值下的生長情形 ................................................. 41
5.8 改變 H. pylori 生存環境之 pH 值測試 .................................................................. 42
5.9 以簡易裝置結合漂浮顆粒與培養 H. pylori 兩項實驗 ............................................. 42
第四章 結果...................................................................................................................43
1 海藻酸漂浮顆粒特性評估..........................................................................................43
1.1 顆粒表面型態分析................................................................................................. 43
1.2 顆粒粒徑大小分析................................................................................................ 49
1.3 顆粒膨潤率評估................................................................................................... 49
1.4 顆粒漂浮率評估................................................................................................... 52
1.5 體外釋放及包覆效果評估..................................................................................... 54
2 H. pylori 培養之體外試驗....................................................................................... 58
2.1 不同濃度 Mucin 對 H. pylori 的生長影響評估....................................................... 58
2.2 不同添加量 Mucin 對 H. pylori 的生長影響評估 .................................................. 59
2.3 不同 pH 值對 H. pylori 的生長評估 ..................................................................... 64
2.4 評估改變 Mucin 添加量與不同 pH 值下 H. pylori 的生長情形 .............................. 65
2.5 評估添加尿素對 H. pylori 在不同 pH 值中的生長情形........................................... 66
2.6 改變 H. pylori 生存條件之 pH 值測試結果 ........................................................... 67
2.7 以簡易裝置結合漂浮顆粒與培養 H. pylori 之實驗結果 ......................................... 68
第五章 討論...................................................................................................................71
1 漂浮顆粒之物化性探討.............................................................................................71
2 H. pylori 於不同條件下之生長情形探討 .................................................................. 74
第六章 結論...................................................................................................................76
未來展望.......................................................................................................................77
參考文獻.......................................................................................................................78
                                

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