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研究生:李岳展
研究生(外文):Yueh-Chan Lee
論文名稱:應用溫感微胞雲點微萃取法偵測抗發炎藥物
論文名稱(外文):Determination of anti-inflammatory drugs using thermosensitive microvesicle-cloud point microextraction
指導教授:陳珮珊陳珮珊引用關係
指導教授(外文):Pai-Shan Chen
口試委員:黃賢達陳惠文
口試委員(外文):Shang-Da HuangHuei-Wen Chen
口試日期:2015-05-29
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:法醫學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:95
中文關鍵詞:雲點萃取法薄層水合法微胞界面活性劑極致效能液相層析儀光電二極體陣列偵測器冷凍穿透式電子顯微鏡
外文關鍵詞:cloud-point extractionthin-film hydrationbinary mixing systemPL121PF68cryo-TEM
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以臨床上藥物或遺傳物質載體設計常常使用的微胞,將其包覆及釋放物質的特性應用在化學萃取上,利用其裝載親水及疏水性物質的特性來增加包覆之萃取物數量。其微小體積增加在水中之懸浮性與溶液之接觸面積,可減少傳統萃取方法所需時間,提高萃取效率。本研究萃取環境中常見的抗發炎藥物,依親水性之差異,選擇七種抗發炎藥物。在環境中,抗發炎類藥物廣為人們所使用,此類藥物儼然成為生活中的一部份。然而,如此廣泛使用的藥物也成為生活中最易暴露的物質之一。當藥物被隨地丟棄,或是因代謝進入排水道系統,甚至醫療院所之廢液處理不全,遂而使原型藥物溶解於水體中,並且排入大自然之河川、溪流、湖泊等等,這些藥物會自然而然的溶入飲用水。因此,要監測水樣中之藥物,樣品前處理方法往往耗時久且工序繁複,需高人力與技術的配合。再者,所用的有機溶劑對環境及人體而言大多有害。本實驗希望開發一種快速、有效、對環境及人體無害的萃取方法。
本研究將兩種界面活性劑組成的雙系統結合雲點萃取法,搭配上製作藥物載體的薄層水合法,來進行抗發炎藥物的萃取,並且使用極致效能液相層析儀-光電二極體陣列偵測器來進行偵測。萃取條件最佳化後,針對PL121及PF68兩種介面活性劑組成的系統在不同溫度下之結構,以冷凍穿透式電子顯微鏡進行分析,確認其結構在攝氏40度時會組成最穩定之球狀複合物,因此可得到最佳萃取效果。
方法最佳化的實驗在去離子水樣中進行,在最佳化的條件之下,萃取物質偵測之線性範圍介於50-8000 μg L-1之間,線性為0.9953-0.9995,偵測極限約為10-100 μg L-1,再現性的標準偏差在14.1%以下。以環境中水樣為真實檢體萃取得到之相對回收率為17.34-133.03%,其中Acetaminophen及Salicylic acid兩種較親水之藥物,其萃取效果濃縮倍率較差,相對回收率也較低。
本方法使用之萃取過程快速且產量高,不使用有機溶劑,是個簡單環保的萃取方法,並特別對疏水性物質有較佳之萃取效果。

A simple cloud-point extraction (CPE) method for the determination of 7 common used anti-inflammatory drugs in the natural water system was developed. The CPE system was built up on a binary mixing system of the non-ionic surfactants of Pluronic series, and the CPE kit, which was coated with PL121 and PF68 surfactants on the bottom of eppendorf, was produced vast amount efficiently by combining the thing-film hydration method which is widely used in manufacturing the clinical drug delivery system. The prepared CPE kit makes the extraction procedure in a much simpler way. Anti-inflammatory drugs (acetaminophen, salicylic acid, ketoprofen, diclofenac, indomethacin, ibuprofen, and mefenamic acid) were extracted from water specimens by adding 2 mL specimen into the CPE kit, then sonication in a water bath was performed for accelerating the thin-film hydration process. After the CPE procedure, anti-inflammatory drugs were present in the surfactant-rich phase, and were analyzed by the Ultra-performance liquid chromatography coupled to photodiode array detection (UPLC-PDA) system directly. For developing an extraction method which is friendly to the environment and non-toxic to the technician, the CPE procedure used only surfactants that were biocompatible and biodegradable, and non of organic solvent has been used.
The optimum analytical conditions for binary mixing and the CPE system were established. Under these conditions, linear calibration curves were obtained over the range of 50 to 8000 μg L-1, and exhibited coefficients of determination (R2) ranging from 0.9953 to 0.9995, with detection limits of 10 to 100 μg L-1 of each analytes. Relative standard deviations (RSDs) were from 3.2 to 12.7% for intraday (n= 5), while for inter-day (n= 15) the values were between 2.5% and 14.1%. The average relative recoveries ranged from 17.34% for acetaminophen to 133.03% for mefenamic acid
Additionally, the self-assembly trend was studied by cryo-TEM, and the optimum aggregation temperature that may produce the maximum stability of the vesicular aggregate of the binary mixing system has been correlated with the CPE experimental results. These results may study forward in CPE techniques and the drug delivery systems in the future.

誌謝 i
中文摘要 iii
ABSTRACT v
CONTENTS vii
LIST OF FIGURES ix
LIST OF TABLES xiii
Chapter 1 Introduction 1
1.1 Microscale pollutants around our environment 1
1.2 Motivation 1
1.3 Cloud-point extraction 3
1.4 Drug delivery techniques 6
1.5 Thin-film hydration 7
Chapter 2 Experimental 9
2.1 Chemicals and reagents 9
2.2 Instrumentation 10
2.3 Sample preparation 11
2.4 CPE kit preparation (thin-film hydration) 11
2.5 Preparation of binary mixing systems 11
2.6 CPE procedures 12
2.7 Size measurements 12
2.8 TEM method 13
2.9 Cryo-TEM method 13
Chapter 3 Results and discussion 14
3.1 PL121 concentration 14
3.2 Binary mixing systems 15
3.3 Optimization of PF68 ratio 17
3.4 Optimization of cloud-point extraction 17
3.4.1 Sonication time 17
3.4.2 Sonication temperature 18
3.4.3 Effect of pH on CPE 20
3.4.4 Effect of sodium chloride concentration 20
3.5 Optimization of CPE 21
3.6 Vesicle size measurments 22
3.7 Regular TEM imaging 22
3.8 Cryo-TEM imaging 23
3.9 Calibration and method validation 26
3.10 Environmental sample analysis 27
3.11 Method comparison 28
Chapter 4 Conclusions 29
Chapter 5 References 88

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