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研究生: 余承曄
Yu, Cheng-Yeh
論文名稱: 膽固醇與溫度效應對類乙醇體陰陽離子液胞的水溶性藥物釋放行為之影響
Effects of Cholesterol and Temperature on Release Behavior of Water-Soluble Drug in Ethosome-Like Catanionic Vesicles
指導教授: 楊毓民
Yang, Yu-Min
學位類別: 碩士
Master
系所名稱: 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年: 2016
畢業學年度: 104
語文別: 中文
論文頁數: 102
中文關鍵詞: 類乙醇體陰陽離子液胞液胞物理特性液胞雙層膜剛性水溶性藥物包覆效率水溶性藥物釋放行為溫度效應膽固醇效應
外文關鍵詞: ethosome-like catanionic vesicles, hydrophilic drug encapsulation efficiency, hydrophilic drug release behaviors, temperature effect, cholesterol effect
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  • 本研究的目的是開發類乙醇體陰陽離子液胞(ethosome-like catanionic vesicle)作為經皮藥物傳輸的載體。首先使用沉澱法製備三種不同碳鏈長度的類脂質離子對雙親分子(ion-pair amphipile, IPA),分別為DeTMA-DS、DeTMA-TS以及DTMA-DS。然後透過半自發製程,在含20%乙醇的緩衝溶液中製備三種類乙醇體陰陽離子液胞,用以包覆水溶性藥物熊果素(Arbutin)。並進一步探討膽固醇的添加對類乙醇體陰陽離子液胞的物理特性和藥物包覆效率之影響。此外,也探討膽固醇濃度及溫度對藥物釋放行為的影響。
    實驗結果顯示,膽固醇的添加對初始粒徑及介面電位之影響並不顯著,但是對管柱分離後液胞粒徑則會有不同的結果。對DeTMA-DS與DeTMA-TS兩個系統,分離後粒徑隨膽固醇濃度增加而增大,而DTMA-DS系統無明顯變化。此結果與膽固醇濃度對包覆效率的影響呈現正相關,但與液胞雙層膜剛性則無一致的關聯,進而推論主導水溶性藥物包覆效率的因素為液胞粒徑,而非雙層膜剛性。溫度上升都會使藥物釋放速率增快;而膽固醇對釋放速率的影響則隨著溫度高低而有不同的結果。在凝膠相(gel phase)添加膽固醇會使其釋放速率加快;在液晶相(liquid-crystalline phase)添加膽固醇會使其釋放速率減緩,推論原因與膽固醇對不同相態的雙層膜剛性有相反作用所致。

    This study aimed at developing ethosome-like catanionic vesicles for transdermal drug delivery. Three ion-pair-amphiphiles, were prepared by precipitation method. They were DeTMA-DS, DeTMA-TS and DTMA-DS, respectively, and were thereafter used as the raw materials for preparing stable ethosome-like catanionic vesicles with the aid of cholesterol and ethanol in aqueous buffer solution whose pH value was 7.4 by the semispontaneous process. The potential applications of the ethosome-like catanionic vesicles as nano-carriers in dermal drug delivery were demonstrated to study cholesterol and temperature effects by release behavior of Arbutin, a water-soluble drug. Furthermore, effects of cholesterol on physical properties and encapsulation efficiency. Experimental results showed that the vesicle size in DeTMA-DS and DeTMA-TS systems were increased, and in DTMA-DS system didn’t change obviously. These results were similar with encapsulation efficiency. Vesicle size was a dominant factor on encapsulation of water-soluble drugs. In the parts of drug release, when the temperature from 20°C to 40°C would make the release rate fast. However, cholesterol caused opposite effects on the release rate for vesicular bilayers at different phases. While release rate was increased with the increase of cholesterol concentration for bilayers at gel phase, release rate was decreased with the increase of cholesterol concentration for bilayers at liquid crystalline phase. The opposite cholesterol effects on release rate were explained by the disordering and condensation effects, respectively, on the rigidity of vesicular bilayers.

    摘要 I Extended Abstract III 致謝 X 總 目 錄 XI 表 目 錄 XV 圖 目 錄 XVI 符號 XXI 第一章 緒論 1 1-1 前言 1 1-2 研究動機與目的 7 第二章 文獻回顧 10 2-1 陰陽離子液胞的形成 10 2-2 乙醇體與類乙醇體陰陽離子液胞 16 2-3 液胞的物理穩定性 18 2-4 液胞的雙層膜特性 20 2-5 液胞的水溶性藥物包覆行為 26 2-5-1 液胞粒徑對水溶性藥物包覆效率的影響 27 2-5-2 液胞雙層膜流動性對水溶性藥物包覆效率的影響 30 2-6液胞的釋放行為 33 第三章 實驗部分 36 3-1實驗藥品 37 3-2 實驗儀器及裝置 40 3-2-1 均質機 (Homogenizier) 40 3-2-2 動態雷射光散射儀/界面電位儀 (Dynamic Light Scattering) 40 3-2-3 螢光光譜儀 (Fluorescence Spectrometer) 42 3-2-4 凝膠層析管(Size Exclusion Chromatography) 43 3-2-5 高效液相層析儀 (High Performance Liquid Chromatography) 44 3-2-6穿透式電子顯微鏡 (Transmission Electron Microscopy) 45 3-3 實驗方法 47 3-3-1離子對雙親分子(Ion Pair Amphiphile)的製備 47 3-3-2類乙醇體陰陽離子液胞的製備 48 3-3-3 粒徑分布、界面電位與液胞存活期的測量 49 3-3-4 液胞包覆水溶性藥物熊果素(Arbutin)與體外釋放實驗 52 第四章 結果與討論 56 4-1 液胞之物理特性分析 56 4-1-1 液胞的初始粒徑 57 4-1-2 液胞的界面電位 58 4-1-3 液胞的穩定性 60 4-1-4 液胞的表面型態 62 4-2 液胞之水溶性藥物包覆特性 64 4-2-1 凝膠層析分離技術的建立 64 4-2-2 初始粒徑與管柱分離後的粒徑分析 66 4-2-3 材料濃度對水溶性藥物包覆效率的影響 67 4-2-4主導水溶性藥物包覆的因素探討 68 4-3液胞之水溶性藥物釋放行為 74 4-3-1膽固醇對水溶性藥物在不同溫度下釋放行為的影響 74 4-3-2溫度對水溶性藥物釋放行為的影響 77 4-3-3水溶性藥物釋放動力學 82 4-3-4液胞雙層膜剛性與釋放速率的關係 88 第五章 結論與建議 91 5-1 結論 91 5-2 建議 93 參考文獻 94

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