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研究生： 温智芳
Wen, Chih-Fang
論文名稱： 經皮藥物傳輸用類乙醇體陰陽離子液胞之研發
Development of Ethosome-like Catanionic Vesicles for Dermal Drug Delivery
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： 2013
畢業學年度： 101
語文別： 中文
論文頁數： 104
中文關鍵詞： 類乙醇體陰陽離子液胞 、包覆和釋放行為 、雙層膜剛性 、流變性質
外文關鍵詞： ethosome-like catanionic vesicles, encapsulation and release behaviors, bilayer membrane rigidity, rheological properties
相關次數： 點閱：94  下載：4 
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    • 以脂質和酒精為主材料而形成的液胞結構即稱為乙醇體（ethosome），研究證實其可促進藥物滲透率。本研究致力於發展類乙醇體陰陽離子液胞（ethosome-like catanionic vesicle）作為藥物經皮傳輸用之載體；首先利用沉澱法形成三種類脂質結構的離子對雙親分子（ion-pair-amphiphile, IPA），分別為DeTMA-DS、DeTMA-TS以及DTMA-DS，藉由乙醇為共溶劑的半自發製程，在pH值為7.4的緩衝溶液環境中製備三種類乙醇體陰陽離子液胞；此外，以液胞包覆維他命E醋酸酯（dl-α-tocopheryl acetate, α-TA），並利用具疏水基團修飾的水溶性高分子作為增稠劑，模擬藥物傳輸的潛力與應用性。
    實驗結果顯示，添加膽固醇可以增加三組液胞系統的穩定性；藉由示差掃描熱卡計（differential scanning calorimetry）可獲得三種IPA系統的雙層膜相轉移溫度，配合螢光偏極化（fluorescence polarization）實驗，發現具相對較低相轉移溫度的DeTMA-DS與DeTMA-TS系統而言，其雙層膜剛性（membrane rigidity）隨膽固醇濃度增加而增加；反之，具有相對較高相轉移溫度DTMA-DS系統，其雙層膜剛性隨膽固醇濃度增加而些微下降。進一步研究發現，維他命E醋酸酯的包覆效率和釋放速率分別與雙層膜剛性呈現正和負相關的趨勢。另外，藉由動態流變儀分析液胞與疏水性高分子膠化後之流變性質，當雙層膜剛性越強時，液胞雙層膜疏水性也越強，進而提升包覆效率。而藥物釋放驅動力可能是藉由雙層膜內外藥物濃度梯度而擴散出去，若雙層膜處於較規則排列狀態時，藥物透過雙層膜擴散至外界的阻力較大，因而抑制釋放效率。

    A carrier for enhancing skin delivery of drugs had been discovered and named ‘‘ethosome,’’ which was phospholipid vesicular system embodying ethanol in relatively high concentrations. This work aimed at developing competent ethosome-like catanionic vesicles for dermal drug delivery. Three kinds of lipid-like ion-pair-amphiphiles, IPAs, were prepared by the precipitation method. They were DeTMA-DS, DeTMA-TS and DTMA-DS, respectively, and were thereafter used as the new raw materials to prepare the ethosome-like catanionic vesicles with the aid of ethanol as the cosolvent in aqueous buffer solution whose pH value was 7.4 by a simple semispontaneous process. In addition, the potential applications of the catanionic vesicles as nano-carriers in dermal drug delivery were demonstrated by the encapsulation of vitamin E acetate (α-tocopherol acetate, α-TA) and used a kind of water-soluble polymer with hydrophobic modification as a thickener to improve the viscosity of vesicular dispersion.
    The experimental results revealed that the vesicle stability could be enhanced by the addition of cholesterol. The bilayer membrane phase transition temperatures of three kinds of IPAs were detected via DSC. Cooperating with the results of fluorescence polarization analysis, we find that the bilayer membrane rigidity for DeTMA-DS and DeTMA-TS systems with relatively lower phase transition temperatures increased with the addition of cholesterol. On the other hand, the bilayer membrane rigidity for DTMA-DS system with relatively higher phase transition temperatures slightly decreased with the addition of cholesterol. Moreover, the encapsulation efficiency and released rate of Vitamin E acetate positively and negatively, respectively, correlated to the bilayer membrane rigidity. Finally, analyze the rheological properties by dynamic rheometer to study the hydrophobic interaction between vesicles and polymers. The more rigid bilayer membrane resulted in the stronger hydrophobic interactions, indicating that the more rigid bilayer membrane possessed the stronger bilayer hydrophobicity as well as the higher encapsulation efficiency. As to the driving force of releasing drug might be the concentration gradient of Vitamin E acetate. The more rigid bilayer membrane could hinder the diffusion of drugs and result in the lower released rate.

    摘要 I Abstract III 致謝 V 總目錄 VI 表目錄 IX 圖目錄 X 符號說明 XIII 第一章、緒論 1 1-1　前言 1 1-2　文獻回顧 7 1-2-1　離子對雙親分子 7 1-2-2　製備陰陽離子液胞 8 1-2-3　乙醇體 11 1-2-4　相轉移行為及測定 13 1-2-5　膽固醇 14 1-2-5-1　膽固醇插排至脂質雙層膜中的影響 15 1-2-5-2　膽固醇影響脂質雙層膜剛性 17 1-2-5-3　膽固醇影響液胞包覆疏水性藥物之行為 18 1-2-5-4　膽固醇影響液胞體外釋放疏水性藥物之行為 19 1-2-6　維他命E簡介 19 1-2-6-1　天然型維他命E 20 1-2-6-2　合成型維他命E醋酸酯 20 1-2-7　液胞與高分子的交聯作用 21 1-3　研究動機與目的 24 第二章、實驗 25 2-1　實驗材料 26 2-1-1　陽離子型界面活性劑 26 2-1-2　陰離子型界面活性劑 26 2-1-3　添加劑 27 2-1-4　油溶性藥物 27 2-1-5　高分子 27 2-1-6　其他 28 2-2　實驗儀器及裝置 28 2-2-1　均質機 28 2-2-2　雷射光散射法粒徑／界面電位分析儀 29 2-2-2-1　粒徑量測原理 29 2-2-2-2　界面電位量測原理 30 2-2-3　穿透式電子顯微鏡 32 2-2-4　示差式掃描式熱卡計 33 2-2-5　螢光偏極化 35 2-2-6　凝膠層析 36 2-2-7　高效能液相層析儀 37 2-2-8　動態流變儀 38 2-3　實驗方法 41 2-3-1　製備離子對雙親分子（IPA） 41 2-3-2　製備類乙醇體陰陽離子液胞 42 2-3-3　量測粒徑、界面電位與液胞存活期 43 2-3-4　穿透式電子顯微鏡觀察液胞型態 44 2-3-5　維他命E醋酸酯之包覆效率 45 2-3-6　體外釋放藥物實驗 47 2-3-7　雙層膜相轉移行為 48 2-3-8　利用螢光偏極化探討雙層膜之流動性 49 2-3-9　量測液胞與高分子混合溶液的流變性質 49 第三章、結果與討論 51 3-1　類乙醇體陰陽離子液胞之物理特性 51 3-1-1　初始粒徑 51 3-1-1-1　DeTMA-DS（C10-C12）系統 52 3-1-1-2　DeTMA-TS（C10-C14）系統 53 3-1-1-3　DTMA-DS（C12-C12）系統 53 3-1-2　界面電位 55 3-1-3　穩定性 58 3-1-4　TEM影像 60 3-2　維他命E醋酸酯之包覆效率 63 3-2-1　凝膠層析之分離技術建立 63 3-2-2　膽固醇對維他命E醋酸酯包覆效率之影響 63 3-3　維他命E醋酸酯之釋放百分比 64 3-3-1　類乙醇陰陽離子液胞作為藥物載體釋放維他命E醋酸酯 64 3-3-2　純維他命E醋酸酯之釋放行為 65 3-4　類乙醇體陰陽離子液胞之雙層膜特性 66 3-4-1　雙層膜相轉移溫度 67 3-4-2　膽固醇對雙層膜剛性之影響 68 3-4-3　雙層膜剛性與類乙醇體陰陽離子液胞包覆藥物行為之關聯 71 3-4-4　雙層膜剛性與類乙醇體陰陽離子液胞釋放藥物行為之關聯 74 3-5　高分子與液胞膠化之流變性質 75 3-5-1　相圖 76 3-5-2　儲存模數（G’） 77 3-5-3　高分子與液胞交聯狀態之鬆弛時間（τ） 81 3-5-4　雙層膜剛性與雙層膜疏水性之關聯 86 3-5-5　雙層膜疏水性與維他命E醋酸酯包覆效率之關聯 88 3-5-6　維他命E醋酸酯之影響 89 第四章、結論與建議 91 4-1　結論 91 4-2　建議 93 參考文獻 94 自述 104

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