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研究生: 莊明蓁
Chuang, Ming-Chen
論文名稱: 可準確預測水溶性藥物包覆效率的穩定經皮傳輸類乙醇體陰陽離子液胞
Stable Ethosome-Like Catanionic Vesicles for Transdermal Hydrophilic Drug Delivery with Precisely Predictable Encapsulation Efficiency
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: 2021
畢業學年度: 109
語文別: 中文
論文頁數: 111
中文關鍵詞: 陰陽離子界面活性劑類乙醇體陰陽離子液胞經皮藥物傳輸半自發製程乙醇效應膽固醇效應液胞穩定性水溶性藥物包覆效率單一雙層膜液胞模型雙層膜堅硬度螢光非等向性方法
外文關鍵詞: Catanionic surfactant, Ethosome-like catanionic vesicle, Transdermal drug delivery, Semi-spontaneous process, Hydrophilic drug encapsulation efficiency, Unilamellar vesicle (ULV) model, Bilayer rigidity, Fluorescence anisotropy
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  • 本研究利用陰離子與陽離子界面活性劑經沉澱法得到結構類似於脂質的離子對雙親分子decyltrimethylammonium-dodecylsulfate (DeTMA-DS, C10-C12)、decyltrimethylammonium-tetradecylsulfate (DeTMA-TS, C10-C14)作為主材料製備液胞,並經由半自發的製程,透過添加不同比例的乙醇(10-30 vol%)和膽固醇(XCHOL=0-0.5),及pH值為7.4的緩衝溶液(Tris-HCl buffer)得到類乙醇體陰陽離子液胞分散液。接著以液胞作為藥物載體,包覆水溶性藥物(熊果素),探討乙醇及膽固醇對其物理特性、藥物包覆行為之影響並與單一雙層膜液胞模型計算出的包覆效率理論值做比較,進一步探討液胞穩定性及水溶性藥物的包覆行為成功預測之關係。另外,並利用螢光非等向性(FA)方法來測定液胞雙層膜的堅硬度,以判別其作為經皮藥物傳輸載體之適用性。經實驗發現添加適當的乙醇濃度,則可以利於液胞形成,提升液胞穩定性,而添加膽固醇可以使液胞的穩定性更提升。並發現當添加適量的乙醇及膽固醇能使液胞穩定,其多分散指數(粒徑分布指數, Polydisperse Index, PDI)值小於0.3,則可使用單一雙層液胞模型成功準確預期水溶性藥物的包覆效率。此標準的建立可以使獲得包覆效率的數值更快速、便利,只需使用商業化的儀器動態雷射光散射儀 (Dynamic Light Scattering, DLS)確認所製備完成的液胞PDI值小於0.3,再將所測得的粒徑數值代入模型計算,即可獲得液胞的水溶性藥物包覆效率。同時利用螢光非等向性方法來測定液胞雙層膜的堅硬度,找出最適合作為經皮藥物傳輸載體的配方,而大部分適合作為經皮藥物傳輸載體的配方所製備的穩定的類乙醇體陰陽離子液胞,其雙層膜堅硬度相對於乙醇體(dipalmitoylphosphatidylcholine, DPPC)小,但會比乙醇體(Phospholipon 90 , PL-90)來的大,由於兩種乙醇體皆可運用於經皮傳輸上,因此類乙醇體陰陽離子液胞具有足夠軟的液胞雙層膜結構,雖然並非最軟,但也適合作為經皮藥物傳輸的載體。

    Lipid-like catanionic surfactants have emerged as the attractive materials to prepare potential vesicular carriers in drug and gene delivery applications. In particular, the semi-spontaneous process has been developed to fabricate ethosome-like catanionic vesicles for the transdermal drug delivery. In this work, Arbutin (a water-soluble drug) encapsulation efficiency (E.E.) of ethosome-like catanionic vesicles fabricated from decyltrimethylammonium-dodecylsulfate (DeTMA-DS) and decyltrimethylammonium-tetradecylsulfate (DeTMA-TS) with various amounts of ethanol and cholesterol in tris buffer solution was experimentally determined. A simple unilamellar vesicle model, resulting in the theoretical E.E. within ±10% error for most vesicle compositions, was also developed. Stable vesicles with the aid of suitable amounts of ethanol and cholesterol, which led to polydispersity index (PDI) values less than 0.3, can be accurately predicted E.E. Moreover, bilayer rigidity was studied by fluorescence polarization technique. By examining ethanol and cholesterol effects on the fluorescence anisotropy (FA) of bilayers, possible applications for transdermal drug delivery carriers were evaluated. There may have been cholesterol formed cholesterol bilayer domain (CBD) by itself in bilayer which may have made vesicles unstable at high concentration of cholesterol. Therefore, the optimum formulations for transdermal delivery were excluded these compositions. For the optimum formulations, lower bilayer rigidity was exhibited as compared with that of dipalmitoylphosphatidylcholine (DPPC) ethosomes, but it exhibited higher bilayer rigidity than phospholipon 90 (PL-90) ethosomes. In short, ethosome-like catanionic vesicles for transdermal drug delivery was applicable.

    摘要 I Extended Abstract III 致謝 XV 總 目 錄 XVI 表 目 錄 XIX 圖 目 錄 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 8 2-1 陰陽離子界面活性劑(離子對雙親分子) 8 2-2 陰陽離子液胞 10 2-2-1 陰陽離子液胞的製備方式 10 2-2-2 陰陽離子液胞的結構與型態 11 2-3 乙醇體做為經皮藥物傳輸載體的特色 14 2-4 液胞的物理穩定性 16 2-4-1 乙醇效應 18 2-4-2 膽固醇效應 20 2-5 添加劑對液胞雙層膜的特性之影響 21 2-5-1 乙醇效應 21 2-5-2 膽固醇效應 26 2-5-3 雙層膜堅硬度測定之重要性 33 2-6 液胞的水溶性藥物包覆行為 37 2-6-1 液胞粒徑對水溶性藥物包覆效率的影響 37 2-6-2 預測水溶性藥物包覆效率的理論模型 40 第三章 實驗 46 3-1 實驗藥品 47 3-2 實驗儀器及裝置 50 3-2-1 均質機 (Homogenizier) 50 3-2-2 動態雷射光散射儀 (Dynamic Light Scattering, DLS) 50 3-2-3 離心濃縮過濾法(centrifugal filtration concentration)51 3-2-4 高效液相層析儀 (High Performance Liquid Chromatography) 52 3-2-5 螢光分光光譜儀 (Fluorescence spectrometer) 52 3-2-6 電子控溫裝置 55 3-2-7 穿透式電子顯微鏡 (Transmission electron microscopy, TEM) 56 3-3 實驗方法 57 3-3-1 離子對雙親分子(ion pair amphiphile)的製備 57 3-3-2 類乙醇體陰陽離子液胞的製備 58 3-3-3 粒徑分布與液胞存活期的測量 58 3-3-4 液胞水溶性藥物熊果素(Arbutin) 包覆效率測定實驗 60 3-3-5 液胞雙層膜之螢光非等向性的測量 62 3-3-6 穿透式電子顯微鏡的分析 63 第四章 結果與討論 64 4-1 類乙醇體液胞之物理特性分析 65 4-1-1 乙醇效應 65 4-1-2 膽固醇效應 68 4-2 類乙醇體液胞之水溶性藥物包覆效率 74 4-2-1 乙醇及膽固醇效應對水溶性藥物包覆效率的影響 77 4-2-2 理論、實驗水溶性藥物包覆效率比較 80 4-2-3單一雙層液胞模型準確預測包覆效率之標準 81 4-3 類乙醇體液胞之雙層膜堅硬度 83 4-3-1 乙醇及膽固醇效應對雙層膜堅硬度的影響 83 4-3-2適合做為經皮藥物傳輸載體的配方 92 4-4 經皮傳輸應用之適用性--類乙醇體陰陽離子液胞與乙醇體之比較 96 第五章 結論與建議 98 5-1 結論 98 5-2 建議 100 參考文獻 101

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