臺灣博碩士論文加值系統

本研究致力於發展類乙醇體陰陽離子液胞（ethosome-like catanionic vesicle）作為新型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，再進行以乙醇為共溶劑、pH值為7.4的緩衝溶液環境中的半自發製程，製備三種類乙醇體陰陽離子液胞，並包覆一水溶性藥物熊果素(Arbutin)。主要探討膽固醇效應對於類乙醇體陰陽離子液胞物理特性、水溶性藥物包覆及釋放行為的影響。再進一步延伸藥物釋放行為到藥物釋放動力學的探討。
在物理特性的結果顯示，添加膽固醇可以增加液胞的穩定性、改變液胞粒徑的大小，也能改變液胞雙層膜剛性（membrane rigidity），但對於界面電位的影響較不顯著。此外，從螢光偏極化（fluorescence polarization）實驗發現膽固醇對於不同液胞雙層膜剛性呈現相反效應。在水溶性藥物包覆行為上，實驗結果顯示液胞粒徑與包覆效率呈一正相關，液胞雙層膜剛性與包覆效率則無一致的關聯，進而發現主導水溶性藥物包覆效率的主導因素為液胞粒徑。再進一步探討膽固醇對藥物釋放行為的影響，並且與雙層膜剛性作一關聯，結果顯示在DeTMA-DS與DeTMA-TS系統中，藥物釋放速率會隨著膽固醇增加而減緩；在DTMA-DS系統中，藥物釋放速率則會隨著膽固醇增加而加快，推測造成此現象的原因跟膽固醇對雙層膜剛性的相反效應有極大的關聯。另外針對釋放行為的延伸，本研究以ㄧ階釋放動力學(first-order release kinetic)為模型方程式，描述熊果素在液胞內可能的釋放動力學，並依其得到的一階釋放速率常數( First order release constant, k1)與螢光偏極化值作連結，探討因膽固醇添加而改變的雙層膜剛性與速率常數之間的關係。

This work aimed at developing competent ethosome-like catanionic vesicles for dermal drug delivery. Three kinds of ion-pair-amphiphiles, IPAs, were prepared by precipitation method. They were DeTMA-DS, DeTMA-TS and DTMA-DS, respectively, and were thereafter used as the new raw materials to prepare ethosome-like catanionic vesicles with the aid of cholesterol and ethanol as the stabilizer and cosolvent in aqueous buffer solution whose pH value was 7.4 by a simple semispontaneous process. On top of that, potential applications of the catanionic vesicles as nano-carriers in dermal drug delivery were demonstrated to study cholesterol effect by encapsulation and release behavior of Arbutin, a water-soluble drug. Experimental results showed that both vesicle size and encapsulation efficiency increased with cholesterol addition in three systems. Opposite cholesterol effects on membrane rigidity were found, which increased in DeTMA-DS and DeTMA-TS systems and decreased in DTMA-DS system with cholesterol addition. Results showed that vesicle size, comparing to membrane rigidity, was a dominant factor on encapsulation of water-soluble drugs, which meant the larger vesicle size, the higher encapsulation efficiency. On the other hand, membrane rigidity controlled the release of water-soluble drugs. In other words, the higher membrane rigidity, the slower release rate. This work also combined drug release and drug release kinetics and built a correlation between them. It was suggested that first order equation was an appropriate kinetic model to describe drug release in vesicles. Furthermore, relation between membrane rigidity and first order release constant revealed that the higher membrane rigidity, the slower release rate.

摘要 I
Extended Abstract III
致謝 IX
總 目 錄 X
表 目 錄 XIII
圖 目 錄 XV
符號說明 XIX
第一章 緒論 1
1-1 前言 1
1-2 研究動機與目的 6
第二章 文獻回顧 8
2-1 陰陽離子液胞的形成 8
2-2 乙醇體與類乙醇體陰陽離子液胞 13
2-3 液胞的物理穩定性 14
2-4 液胞的雙層膜特性 16
2-5 液胞的包覆行為 20
2-5-1 液胞粒徑對水溶性藥物包覆效率的影響 20
2-5-2 液胞雙層膜流動性對水溶性藥物包覆效率的影響 22
2-6 液胞的釋放行為及釋放動力學 25
第三章 實驗部份 31
3-1 實驗藥品 32
3-2 實驗儀器及裝置 34
3-2-1 均質機 (Homogenizier) 34
3-2-2 動態雷射光散射儀/界面電位儀 (Dynamic Light Scattering, DLS) 34
3-2-3 凝膠層析管（gel chromatography column） 36
3-2-4 高效液相層析儀 (High Performance Liquid Chromatography) 36
3-2-5穿透式電子顯微鏡 (Transmission electron microscopy, TEM) 37
3-3 實驗方法 38
3-3-1離子對雙親分子(ion pair amphiphile)的製備 38
3-3-2類乙醇體陰陽離子液胞的製備 39
3-3-3 粒徑分布、界面電位與液胞存活期的測量 40
3-3-4 液胞包覆水溶性藥物熊果素(Arbutin)與體外釋放實驗 42
3-3-5穿透式電子顯微鏡的分析 45
第四章 結果與討論 46
4-1 液胞之物理特性分析 46
4-1-1液胞的初始粒徑 47
4-1-2液胞的界面電位 51
4-1-3液胞的穩定性 54
4-1-4液胞的表面型態 55
4-2 液胞之水溶性藥物包覆特性 57
4-2-1 凝膠層析分離技術的建立 57
4-2-2管柱分離前後的粒徑分析 57
4-2-3 液胞粒徑對水溶性藥物包覆效率的影響 59
4-2-4 類乙醇體陰陽離子液胞包覆水溶性或油溶性藥物的比較 62
4-2-5 內含/外加膽固醇在類乙醇體陰陽離子液胞包覆水溶性藥物的比較 63
4-3 液胞之水溶性藥物釋放行為及釋放動力學探討 66
4-3-1 水溶性藥物釋放行為 66
4-3-2 水溶性藥物釋放動力學 72
4-3-3 模擬水溶性藥物在液胞中的釋放動力學 76
4-3-4 釋放速率常數與膽固醇濃度及螢光偏極化值的關係 83
第五章 結論與建議 85
5-1 結論 85
5-2 建議 86
參考文獻 87
自述 96

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