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研究生: 王俊為
Wang, Chun-Wei
論文名稱: 單一雙層陰陽離子液胞的水溶性藥物包覆效率之理論與實驗比較研究-乙醇及膽固醇效應
Comparative Theoretical and Experimental Studies of Ethanol and Cholesterol Effects on the Hydrophilic Drug Encapsulation Efficiency of Unilamellar 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: 2018
畢業學年度: 106
語文別: 中文
論文頁數: 94
中文關鍵詞: 陰陽離子界面活性劑半自發製程類乙醇體陰陽離子液胞水溶性藥物包覆效率單一雙層陰陽離子液胞模型
外文關鍵詞: catanionic surfactant, semi-spontaneous process, ethosome-like catanionic vesicle, hydrophilic drug, encapsulation efficiency, unilamellar vesicle (ULV) model
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  • 本研究利用沉澱法得到結構類似於脂質的離子對雙親分子(DeTMA-TS, CH3(CH2)9N(CH3)3-CH3(CH2)13SO4)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和膽固醇,及pH值為7.4的緩衝溶液得到穩定的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。最後透過理論模型預測藥物包覆效率並與實驗結果比較、討論。
    物理特性上顯示,添加乙醇會使液胞粒徑減小。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。另一方面,添加膽固醇可以增加液胞的穩定性,並增加液胞粒徑、液胞數量。而透過螢光非均向性的研究發現,膽固醇藉由改變液胞雙層膜的堅硬度,影響液胞粒徑的大小。
    在水溶性藥物包覆行為上,增加乙醇濃度會使液胞粒徑減小,因此導致水溶性藥物的包覆效率跟著降低。而隨著膽固醇濃度增加,包覆效率也呈現提升的趨勢,這是因為液胞粒徑增加以及液胞數量增加的緣故。
    乙醇和膽固醇的添加對液胞粒徑有相反的影響,但液胞粒徑和包覆效率還是呈現正相關,因此推測水溶性藥物包覆的主導因素為液胞粒徑。
    從理論、實驗包覆效率的比較可以發現,低膽固醇濃度時,實驗跟理論包覆效率具有偏差,其原因可能是液胞穩定性不佳,而形成其他結構型態,因此無法包覆藥物。添加足夠的膽固醇後,液胞具良好的穩定性,所以理論跟實驗值也趨近相同。含有20 %乙醇的組成具有最佳的穩定性,僅需添加少量膽固醇即可達到穩定,也就是理論預測值與實驗質相同。其他乙醇組成,則需要添加更多的膽固醇來穩定液胞。此理論與實驗的比較分析結果與物理穩定性之結論具有一致的結果。
    膽固醇的添加使類乙醇體陰陽離子液胞具備高穩定性和高包覆效率,因此添加膽固醇具有其必要性。

    Lipid-like catanionic surfactants (also known as ion-pair amphiphiles, IPAs) have emerged as the attractive materials for preparing vesicular carriers of potential drug and gene delivery systems. A simple semi-spontaneous process has been developed for fabricating ethosome-like catanionic vesicles for the transdermal delivery of drugs by using catanionic surfactant, a relatively high concentration of ethanol, and cholesterol (CHOL) in buffer solution. In this work, water-soluble drug (Arbutin) encapsulation efficiency of ethosome-like catanionic vesicles was estimated theoretically by employing a unilamellar vesicle (ULV) model and determined experimentally for 10 mM decyltrimethylammonium-tetradecylsulfate (DeTMA-TS, CH3(CH2)9N(CH3)3-CH3(CH2)13SO4) with various amounts of ethanol and CHOL in 15 mM tris buffer solution. The results showed that the experimental encapsulation efficiencies were well predicted within ±20% by the ULV model for most compositions with ethanol in the range of 10-30 vol% and extra addition of CHOL up to 10 mM. Less agreement, however, resulted from compositions at lower or higher ethanol concentrations without higher enough amounts of CHOL, which endow insufficient stability to the as-fabricated catanionic vesicles.

    摘要 I Extended Abstract III 致謝 XIII 總 目 錄 XIV 表 目 錄 XVI 圖 目 錄 XVII 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 陰陽離子液胞的結構型態 11 2-3 乙醇體與類乙醇體陰陽離子液胞 14 2-4 液胞的物理穩定性 17 2-5 添加劑對液胞雙層膜的特性之影響 18 2-6 非均向性測量原理(Fluorescence Anisotropy) 24 2-7 液胞的水溶性藥物包覆行為 29 2-7-1 液胞粒徑對水溶性藥物包覆效率的影響 29 2-7-2 液胞雙層膜流動性對水溶性藥物包覆效率的影響 31 第三章 實驗部份 34 3-1 實驗藥品 35 3-2 實驗儀器及裝置 37 3-2-1 均質機 (Homogenizier) 37 3-2-2 動態雷射光散射儀 (Dynamic Light Scattering, DLS) 37 3-2-3 離心濃縮過濾法(centrifugal filtration concentration) 38 3-2-4 高效液相層析儀 (High Performance Liquid Chromatography) 39 3-2-5 穿透式電子顯微鏡 (Transmission electron microscopy, TEM) 39 3-3 實驗方法 41 3-3-1 離子對雙親分子(ion pair amphiphile)的製備 41 3-3-2 類乙醇體陰陽離子液胞的製備 42 3-3-3 粒徑分布與液胞存活期的測量 43 3-3-4 液胞包覆水溶性藥物熊果素(Arbutin)實驗 45 3-3-5 穿透式電子顯微鏡的分析 47 第四章 結果與討論 48 4-1 液胞之物理特性分析 48 4-1-1 乙醇效應 48 4-1-2 膽固醇效應 51 4-2 液胞之水溶性藥物包覆特性 59 4-2-1 離心過濾濃縮分離技術的建立 59 4-2-2 熊果素質量平衡 63 4-2-3 膽固醇和乙醇對水溶性藥物包覆效率的影響 65 4-3 水溶性藥物包覆效率理論模型 68 4-3-1 單一雙層陰陽離子液胞模型 68 4-3-2 理論、實驗水溶性藥物包覆效率比較 72 第五章 結論與建議 76 5-1 結論 76 5-2 建議 78 參考文獻 79

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