以毛細電泳分離具對掌異構物之藥物的方法開發與應用

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李佳恬(Chia-Tien Li) 查詢紙本館藏

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化學學系

論文名稱

以毛細電泳分離具對掌異構物之藥物的方法開發與應用
(Application of Caplillary Electrophoresis to Separate Enantiomeric Pharmaceutical Drugs)

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摘要(中)

近年來環境檢測之發展對藥物殘留物(pharmaceutical residues)開始產生注目，大量的藥物持續地製造、消耗並排泄到環境之中，但其後環境中會發生的狀況、即將面對的命運與這些殘留物會造成的影響仍是大家未知的問題。特別是對於具對掌特性的藥物，由於不同的對掌異構物(enantiomer)對生物體的生理活性與毒性皆有所不同，目前仍無法完全了解其對環境所遭成的影響，所以此類藥物的研究已引起大眾的關心。
　　本研究將針對凱妥普洛芬(ketoprofen)與異布洛芬(ibuprofen)兩種屬於非類固醇類消炎藥(nonsteroidal anti-inflammatory drugs，簡稱NSAIDs)的對掌異構物進行分析與研究。目前這兩種藥物殘留物都被歸類為「新興污染物」(emerging contaminants)，其副作用可能對人與動物造成衝擊。
　　為檢測台灣市售的成藥與環境水樣品中是否含有凱妥普洛芬與異布洛芬對掌異構物，本研究以毛細管電泳儀(capillary electrophoresis，簡稱CE)搭配紫外光燈源進行實驗。先將成藥直接溶於甲醇(methanol)，並過濾注入毛線管電泳儀做檢測；另外再以固相萃取法(solid phase extraction，簡稱SPE) 萃取出環境水樣品中的待測物。緩衝溶液為20 mM的醋酸鈉，內含10 mM羧酸根-β-環糊精與30 mM三甲基-β-環糊精為對掌選擇劑，同時將pH調整為5.0，在此條件下可於基線完全分離兩組對掌待測物並進行定量工作。檢測結果顯示所測成藥是以消旋混合物的模式存在，並將檢測之結果與包裝上之含量進行比較後，得到之誤差率皆在15 %以下，顯示本方法具有良好的準確度。在200 mL的環境水樣品中，四個對掌待測物之定量極限(limit of quantitation，簡稱LOQ)為1.0 µg/L，水樣品中的添加標準品回收率皆在70 %以上，相對標準偏差(relative standard deviation，簡稱RSD)皆在7.5 %以下，然而，在五個所選擇的水樣品中皆未偵測到四個對掌待測物的存在。
　　此外，為增進選擇性與靈敏度，本研究另行發展一套螢光衍生化為的方法，並搭配雷射誘導螢光儀為偵檢器(laser-induced fluorescence，簡稱LIF)。不過由於螢光衍生化方法的產率不穩定與對基質效應的低容許度，故此螢光衍生化的方法並不適用於本研究。

摘要(英)

Recently, pharmaceutical residues are an emerging concern in environ- mental research. Large quantities of pharmaceuticals are continuously produced, consumed, and excreted into the environment, but the subsequent environmental occurrence, fate, and effects of these residues are not well understood, especially the work on understanding the chiral pharmaceutical residues in our environ- ment. Chirality should be concerned due to their possible different biological and/or toxicological effects from one another and from the racemate.
　Ibuprofen and ketoprofen were used as the model chiral compounds in our study, which are the widely used nonsteroidal anti-inflammatory drugs (NSAIDs) in Taiwan. These two residues have been demonstrated as emerging contami-nants which can cause side effects in organisms and has raised increasing concern about their impact on wildlife and human health.
　A method of capillary electrophoresis (CE) with UV detector was developed to determine the ibuprofen and ketoprofen enantiomers in over-the-counter (OTC) drugs sold in Taiwan and environmental water samples. For OTC drugs, the samples were directly dissolved in methanol and filtered before CE analysis. For environmental water samples, they were extracted by solid-phase extraction (SPE). The analytes were then separated and quantitated by CE with 20 mM sodium acetate buffer, consisting of 10 mM CM-β-CD and 30 mM TM-β-CD used as chiral selectors in dual cyclodextrin system, at pH 5.0. Baseline separation of two pair of chiral compounds confirmed the specificity of the method. Less than 18% of quantitation errors comparison with the contents displaying on the drug-packings and our results for selected OTC-drugs proved the accuracy of the method. The limit of quantitation (LOQ) was less than 1.0 µg/L for each enantiomer in 200 mL of environmental water sample. The spiked recoveries of four enantiomers were above 70 % while RSD was below 7.5 %. However, four enantiomers were not detected in five selected environmental water samples.
　Furthermore, a fluorescent derivatization procedure and CE-laser-induced fluorescence (LIF) detection methods were developed to enhance the sensitivity and selectivity. However, due to the unstability of the derivatives and the low tolerance to matrix effects, the preliminary results show that CE-LIF was not suitable for this kind of studies.

關鍵字(中)

★ 環糊精
★ 非類固醇類消炎藥
★ 對掌異構物
★ 毛細管電泳

關鍵字(英)

★ cyclodextrin
★ enantiomers
★ NSAIDs
★ capillary electrophoresis

論文目次

中文摘要　　　　　　　　　　　　　　　　　　　I
英文摘要　　　　　　　　　　　　　　　　　　　III
謝誌　　　　　　　　　　　　　　　　　　　　　V
目錄　　　　　　　　　　　　　　　　　　　　　VI
圖目錄　　　　　　　　　　　　　　　　　　　　IX
表目錄　　　　　　　　　　　　　　　　　　　　XI
第一章　前言　　　　　　　　　　　　　　　　 1
1-1　研究緣起　　　　　　　　　　　　　　　　1
1-2　研究目標　　　　　　　　　　　　　　　　4
第二章　文獻回顧　　　　　　　　　　　　　　6
2-1　藥物殘留物　　　　　　　　　　　　　　　6
2-1-1　藥物殘留物的來源與影響　　　　　　　　　6
2-1-2　非類固醇類消炎藥　　　　　　　　　　　　8
2-1-3　相關研究文獻　　　　　　　　　　　　　　10
2-2　毛細管電泳法　　　　　　　　　　　　　　16
2-2-1　基本原理　　　　　　　　　　　　　　　　16
2-2-2　電滲透流與帶電荷粒子的遷移行為　　　　　17
2-3　主客錯合現象　　　　　　　　　　　　　　20
2-3-1　基本概念　　　　　　　　　　　　　　　　20
2-3-2　環糊精　　　　　　　　　　　　　　　　　20
2-3-3　內包錯合物　　　　　　　　　　　　　　　23
2-4　對掌異構物的分離　　　　　　　　　　　　26
2-4-1　對掌異構物之簡介　　　　　　　　　　　　26
2-4-2　對掌異構物分離之重要性　　　　　　　　　28
2-4-3　毛細管電泳法於對掌異構物之分離與環糊精　29
2-4-4　雙環糊精系統　　　　　　　　　　　　　　31
2-5　螢光偵測法　　　　　　　　　　　　　　　34
2-5-1　雷射誘導螢光儀　　　　　　　　　　　　　34
2-5-2　螢光衍生化　　　　　　　　　　　　　　　37
2-6　固相萃取法　　　　　　　　　　　　　　　40
第三章　實驗步驟與樣品分析　　　　　　　　　 44
3-1　實驗藥品與設備　　　　　　　　　　　　　44
3-1-1　實驗藥品　　　　　　　　　　　　　　　　44
3-1-2　儀器設備　　　　　　　　　　　　　　　　46
3-2　實驗步驟　　　　　　　　　　　　　　　　48
3-2-1　標準品的配製　　　　　　　　　　　　　　48
3-2-2　緩衝溶液的製備　　　　　　　　　　　　　49
3-2-3　毛細管的處理　　　　　　　　　　　　　　49
3-2-4　毛細管電泳儀參數設定　　　　　　　　　　51
3-2-5　螢光衍生化步驟　　　　　　　　　　　　　52
3-2-6　市售成藥前處理步驟與保存　　　　　　　　53
3-2-7　固相萃取步驟　　　　　　　　　　　　　　54
3-3　水樣採集　　　　　　　　　　　　　　　　56
第四章　結果與討論　　　　　　　　　　　　　 57
4-1　紫外光燈源系統中對掌異構物之分離　　　　57
4-1-1　波長選擇　　　　　　　　　　　　　　　　57
4-1-2　對掌異構物之分離　　　　　　　　　　　　57
4-2　螢光衍生化之探討　　　　　　　　　　　　61
4-2-1　螢光衍生化反應步驟　　　　　　　　　　　61
4-2-2　反應時間對衍生化反應之影響　　　　　　　63
4-2-3　搖晃效果對衍生化反應之影響　　　　　　　65
4-2-4　螢光衍生法的穩定度與再現性　　　　　　　66
4-2-5　雷射誘導螢光系統中對掌異構物之分離　　　67
4-3　檢量線　　　　　　　　　　　　　　　　　71
4-3-1　紫外光燈源系統之檢量線　　　　　　　　　71
4-3-2　雷射誘導螢光儀系統之檢量線　　　　　　　71
4-4　市售成藥之對掌異構物成分確認　　　　　　73
4-4-1　紫外光燈源系統之成分確認　　　　　　　　73
4-4-2　雷射誘導螢光系統之成分確認　　　　　　　75
4-5　固相萃取　　　　　　　　　　　　　　　　79
4-6　真實水樣之分析結果　　　　　　　　　　　　81
第五章　結論與建議　　　　　　　　　　　　　 88
5-1　結論　　　　　　　　　　　　　　　　　　88
5-2　建議　　　　　　　　　　　　　　　　　　89
第六章　參考文獻　　　　　　　　　　　　　　 90

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指導教授

丁望賢(Wang-Hsien Ding)

審核日期

2008-6-30

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