臺灣博碩士論文加值系統

在我們的研究中，主要分成兩大部分：第一部份為利用液相層析串聯式質譜儀（LC-MS/MS）發展測定去羥梔子苷（geniposide）及其代謝物梔子平（genipin）且能與微透析取樣技術結合的分析方法。
梔子為Gardenia的果實，被用來當做中草藥或者天然的色素來源，此生藥中的代表性化合物為iridoid glycoside。去羥梔子苷（geniposide）即為其主要成分之一，且其水解產物為梔子平。由於去羥梔子苷為極性化合物且結構上帶有一個六碳醣的官能機，容易藉由在動相中加入少量的揮發性添加劑，而使去羥梔子苷上的羥基與陽離子（如：NH4+）形成錯合物或去羥梔子苷上的羥基與有機酸根（如：CH3COO-）形成氫鍵來產生陰離子加成物。而這些陰陽加成物離子（[M+陽離子]+和[M+陰離子]-），可經由電灑游離過程被質譜儀偵測。因[M+NH4]+相對於其他加成物離子有較好的訊號強度，所以我們以此加成物離子來發展LC-MS/MS方法。至於，梔子平則靠在動相中加入少量的酸來形成分子離子（[M-OH]+）。
我們用C8的逆相層析管柱和動相溶液組成分別為ACN/0.2 mM NH4OAc＝15：85或MeOH/0.2 mM NH4OAc，分別來流析添加於灌流液（進行微透析取樣過程中所用之等張性溶液）中的去羥梔子苷和梔子平，其偵測極限分別約為1 ng/mL和20 ng/mL，所建立之檢量線的線性範圍分別在5～1000 ng/mL及60～5000 ng/mL，且相關係數均大於0.995。另外，在同日與異日內的驗證亦有不錯的再現性，去羥梔子苷和梔子平量測的準確度與精確度分別小於11%與5%，以及7%與13%。此外，當以去羥梔子苷的確效校正曲線來測定添加於老鼠血中透析液的品管樣品時，其量測的準確度與精確度分別小於12%與10%。
第二部份則為利用軟體發展訊號處理之方法，來改善分析物層析峰之訊雜比。訊號處理部份再細分成兩個子題，分別為：
（1）兩個連續的匹配濾波器（matched-filter）之間以雜訊頻譜修正技術來改善LC-MS/MS層析峰訊雜比之研究，此一方法能有效地改善LC/MS/MS層析圖譜中所出現的尖狀雜訊，使處理後低濃度樣品的訊號增進倍率達約16倍。其效果並非由兩個連續的匹配濾波器所造成，因匹配濾波器屬於低通濾波器，因此若直接以兩個均為低通濾波器進行訊號處理，其對訊雜比的改善很有限，所以主要原因還是在於乘積的運算發揮雜訊頻譜修飾的作用所致。另一方面我們也校正了時間軸（即x軸），使訊號處理後的訊號峰均能出現在同一時間點上，而我們也計算其波峰面積及滯留時間在確效上的數據證明其再現性，用此訊號處理方法處理前後波峰面積其相對標準差分別小於35%和27%，且處理後滯留時間相對標準差小於3%。
（2）兩個連續的低通濾波器（low-pass filter）之間以雜訊頻譜修正技術和小波轉換（wavelet transform）來改善LC-MS/MS所測定梔子平的最低偵測極限之應用。雖然我們已成它a發展出匹配濾波器-乘積-匹配濾波器（MF-M-MF）方法來改善訊雜比，但此方法本身的一些條件並未最佳化，所以我們將利用田口法幫助我們找到最佳化趨勢。由於以匹配濾波器做訊號處理後，匹配濾波器會使波峰寬度變寬，為使用此濾波器之缺點。以致於我們需要嘗試利用其他的低通濾波器來取代它，例如：Savitzky-Golay濾波器（Savitzky-Golay filter）和小波轉換，我們整合這些低通濾波器，並於兩連續的低通濾波器之間，同樣進行乘積的運算。我們期望此改變能改善因濾波器造成波峰變寬之影響，並保持乘積運算修飾雜訊頻譜之作用。在此部分共發展了SG-M-MF、WT-M-WT、SG-M-WT和WT-M-SG等方法，以低濃度樣品測試發現SG-M-WT有最好的訊雜比增進倍率。最後我們選擇用MF-M-MF及SG-M-WT等方法，對一組梔子平的檢量線及品管樣品做訊號處理，處理後相關係數均大於0.995，經MF-M-MF方法處理後準確度與精確度分別小於8%與13%，而SG-M-WT方法處理後準確度與精確度分別小於12%與10%。因此證明此二方法良好的線性及在可接受的誤差範圍內，而且也使梔子平的最低定量極限亦成它a延伸至20 ng/mL。
另外，在離散小波轉換（DWT）的過程中，小波收縮對消除雜訊而言是一個很重要的步驟，我們使用多重解析度分析及小波收縮來移除在LC-MS/MS層析圖譜中尖狀雜訊及消除雜訊。在經DWT處理後，將於小波收縮的步驟中藉由設定門檻值，把小波係數中雜訊的成分給排除，所以在小波收縮的方法中，主要的工作就是設定適當的門檻值來選擇小波係數，因為門檻值的設定需要小心地微調，故此步驟將是最花時間的。目前我們已嘗試多種小波濾波器來處理一組梔子平樣品，經此訊號處理後，以波峰面積建立檢量線且其相關係數均大於0.995，最後，所有訊號處理步驟均能將定量極限能均延伸至20 ng/mL且在低濃度樣品的訊雜比增進倍率有約9～12倍的提升。

The first project of this dissertation is using LC-MS/MS to develop the methods of determining geniposide and its metabolite genipin, and also can combine with microdialysis sampling technique.
Zhi-Zi is the fruit of Gardenia. It has been utilized as a Chinese herbal medicine and a source of natural pigment. The representative compounds in this crude drug are iridoid glycosides; geniposide is one of the major constituents. The hydrolytic product of geniposide is genipin. Because geniposide is a polar compound and has a sugar moiety on its structure, hydroxyl groups on the sugar moiety of geniposide are able to form complex with cations (ex: ammonium ion) or to form hydrogen bond with carboxylate anions (ex: formate or acetate ion) when small amount of volatile additives are added into the mobile phase. These positive or negative adduct ion can be detected via electrospray ionization processes. Because the ammonium adduct ion ([M+NH4]+) has stronger signal intensity than the other adduct ions, we use this adduct ion to develop LC-MS/MS methods. As for genipin, it can be formed a molecular ion ([M-OH]+) easily by adding a few acid in the mobile phase.
We use C8 reverse phase column and mobile phase solvents containing acetonitrile and 0.2 mM ammonium acetate aqueous solution at the ratio 15 : 85 or methanol and 0.2 mM ammonium acetate（pH 4）aqueous solution at the ratio 40 : 60 are employed to elute geniposide and genipin samples spiked in the perfusate, respectively. The detection limits of geniposide and genipin are about 1 ng/mL and 20 ng/mL respectively. These methods we established for geniposide and genipin are calibrated range from 5 to 1000 ng/mL and 60 to 5000 ng/mL. These correlation coefficient of calibration curves are greater than 0.995. The measurement accuracy and precision of geniposide are within 11% and 5% respectively whereas the accuracy and precision of genipin are within 7% and 13% respectively. Besides, when the validated calibration curves are used to determine spiked control samples in rat blood dialysates, the geniposide determination errors of accuracy and precision are within 12% and 10% respectively.
The second project is using software techniques to develop signal processing methods to improve the signal-to-noise ratios (SNR) of analyte signal peaks.
(1) We developed a technique to alter the noise spectrum between two consecutive matched filters to improve the peak SNR enhancement. That is to do multiply operation between two consecutive matched filters match-filtered. Noise in low frequency cannot be eliminated by first matched filter. Noise spectrum will shift from low frequency regime toward high frequency regime by doing multiply operation. Then, second matched filter can have better filtering efficiency to eliminate it. Therefore, the method can improve the situation when there are many spike-like noises in the LC-MS/MS chromatogram. The peak SNR using this technique can be enhanced about ~16 folds. In addition, we also calibrated time axis shift due to digital filtering computations to make the signal to appear at the original retention time after signal processing procedures. We have also calculated the validation data of peak area and retention time to prove their reproducibility. Finally we employ Taguchi experimental design methods to optimize filtering parameters.
(2) But using matched filter to do signal processing procedures, it will make signal peak more boarder. That’s a disadvantage in using matched filter. So that we need to try other low-pass filters to replace matched filter. Therefore, we have integrated various types of low-pass filters, and also multiplied the filtered chromatograms with other artificial ones between the two consecutive low-pass filters. Our goal is to improve the filtering effects without peak broadening. We have used two types of low-pass filters (ex: Savitzky-Golay filter (SG) and wavelet transform (WT)) to develop four signal processing methods, including SG-M-MF, WT-M-WT, SG-M-WT, and WT-M-SG. We tested these methods by using low concentration sample, and found SG-M-WT has the best S/N improvement. Consequently, we selected MF-M-MF and SG-M-WT methods to process one set of genipin’s samples. The correlation coefficients of calibration curves using these filtering techniques are greater than 0.995. The signal processing accuracy and precision of MF-M-MF are within 8% and 13% respectively whereas the accuracy and precision of SG-M-MF are within 12% and 10% respectively. We have proved these two methods have good linearity and their error range is acceptable. They also let genipin’s limit of quantification concentration can extent to 20 ng/mL, successfully.
(3) During the discrete wavelet transform (DWT) procedure, wavelet shrinkage method is an important procedure for de-noising. Therefore, we also try to use multi-resolution analysis and wavelet-shrinkage to do spike removal and de-noising in the LC-MS/MS chromatograms. After the DWT procedure, the wavelet coefficient of the noisy signal will be removed by setting threshold in the wavelet shrinkage. In the wavelet shrinkage method, the major work is to set appropriate threshold for coefficients selection. Because threshold setting needs to be fine tune, the procedure will cost a lot of time. In the present, we have tried five wavelet filters to process one set of genipin’s samples. After the signal processing procedures, we used peak area to build calibration curves, and all of the correlation coefficients are greater than 0.995. Finally, all the signal processing procedures can extent the limit of quantification concentration to 20 ng/mL, and the SNR improvement of low concentration samples also have 9~12 folds enhancement.

總目錄………………………………………………………………………………..Ⅰ
圖目錄………………………………………………………………………………..Ⅶ
表目錄………………………………………………………………………………..Ⅹ
中文摘要…………………………………………………………………………..ⅩⅡ
Abstract……………………………………………………………………………ⅩⅤ

第一章 緒論…………………………………………………………………………1

第二章 以液相層析串聯式質譜儀測定梔子中去羥梔子苷（geniposide）與梔子平（genipin）的分析方法開發……………………………………………………...7
1. 前言……………………………………………………………………………….7
1-1. 液相層析質譜術簡介………………………………………………………….9
1-1-1. 電灑游離法原理介紹…………………………………………………....11
1-1-2. 大氣壓力化學游離法原理介紹..................................15
1-1-3. 四極柱質譜儀之原理介紹……………………………………………....16
1-1-4. 液相層析串聯式質譜儀原理…………………………………………....18
1-2. 樣品基質對質譜儀的干擾…………………………………………………..22
1-2-1. 質譜儀偵測之干擾……………………………………………………....22
1-2-2. 樣品的前處理方法……………………………………………………....24
1-3. 梔子簡介………………………………………………………………......28
1-4. 研究目的與動機……………………………………………………………..31
2. 研究方法……………………………………………………………………....33
2-1. 藥品…………………………………………………………………………..33
2-2. 實驗器材與儀器設備………………………………………………………..34
2-3. 藥品與溶液之製備………………………………………………………....35
2-3-1. 儲備溶液之配製………………………………………………………....35
2-3-2. 動相之配製……………………………………………………………....35
2-3-3. 去羥梔子苷及梔子平單一濃度標準品溶液之配製…………………....36
2-3-4. 灌流液之配製................................................38
2-3-5. 直接注入之樣品前處理過程…………………………………………....39
2-4. 儀器設定……………………………………………………………………..40
2-4-1. 液相層析儀之相關條件設定…………………………………………....40
2-4-2. 質譜儀之相關條件設定………………………………………………....40
2-5. 方法之建立與確效………………………………………………………....41
2-5-1. 檢量線建立……………………………………………………………....41
2-5-2. 方法確效....................................................41
3. 實驗結果與討論……………………………………………………………....42
3-1. 去羥梔子苷所形成之分子離子……………………………………………..42
3-2. 去羥梔子苷所形成之加成物陰陽離子…………………………………....42
3-3. 質譜儀相關條件設定之探討………………………………………………..43
3-3-1. 離化源溫度對訊號強度之影響..................................43
3-3-2. 去溶劑溫度對訊號強度之影響………………………………………....44
3-4. 動相組成對分析物之影響…………………………………………………..44
3-4-1. 動相內有機相比例對分離之影響……………………………………....44
3-4-2. 動相內水溶液組成對加成物離子之影響…………………………......45
3-5. 分析物中基質之影響………………………………………………………..45
3-6. 分析物條件初始化…………………………………………………………..45
3-7. 分析方法之可行性評估……………………………………………………..46
3-7-1. 檢量線建立之驗證…………………………........................46
3-7-2. 方法確效之驗證………………………………………………………....47
3-7-3. 以血液透析液進行去羥梔子苷方法確效之驗證………………........47
4. 結論………………………………………………………………………………48

第三章 兩個連續的匹配濾波器之間輔以雜訊頻譜修飾技術來改善LC-MS/MS層析峰訊雜比之研究……………………………………………………………….............50
1. 前言……………………………………………………………………………..50
1-1. 以軟體的方法減少雜訊……………………………………………………..51
1-1-1. 軟體簡介………………………………………………………………51
1-1-2. 數位訊號處理與雜訊的簡介…………………………………………....52
1-2. 交互相關運算與匹配濾波器………………………………………………..57
1-3. 乘積（multiplication）的訊號處理方法…………………………………58
1-3-1. 乘積運算原理說明……………………………………………………....59
1-4. MF-M-MF訊號處理的流程……………………………………………….....59
1-4-1. 經過MF-M-MF訊號處理後分析物訊號強度的校正……………….......60
1-5. 人造高斯參考峰……………………………………………………………..61
2. 實驗部份…………………………………………………………………………62
2-1. 藥品及實驗器材……………………………………………………………62
2-2. 實驗器材、儀器裝置及軟體………………………………………………..62
2-3. 藥品與溶液之製備…………………………………………………………..63
2-3-1. 動相之配製..................................................63
2-3-2. 儲備溶液之配製..............................................63
2-3-3. 單一濃度標準品及內標準品溶液之配製……………………………....64
2-3-4. 含標準品及內標準品之溶液配製……………………………………....64
2-4. 儀器參數之設定………………………………………………………......64
2-4-1. 液相層析儀之相關設定………………………………………………....64
2-4-2. 質譜儀之相關條件設定………………………………………………....65
3. 結果與討論………………………………………………………………………66
3-1. MF-MF與MF-M-MF兩個方法之差異……………………………………......66
3-2. 乘積運算之頻譜分析………………………………………………………..66
3-3. 時間軸之重新設定……………………………………………............66
3-4. 處理前後層析峰性質之比較………………………………………………..67
4. 結論………………………………………………………………………………69

第四章 用兩個連續的低通濾波器（low-pass filter）之間輔以雜訊頻譜修飾技術及離散小波轉換（discrete wavelet transform）兩種訊號處理方法來改善LC-MS/MS所測定梔子平的最低偵測極限……………………………………….....................70
1. 前言………………………………………………………………………………70
1-1. 田口方法簡介………………………………………………………………..72
1-1-1. 田口方法的實施步驟…………..................................72
1-1-2. 實驗計畫方法介紹……………………………………………………....73
1-1-3. 品質損失函數…………………………………………………………....75
1-1-4. 品質特性的訂定………………………………………………………....76
1-1-5. 實驗因子的定義與選擇………………………………………………....77
1-2. 實例說明：MF-M-MF濾波器之最佳化趨勢找尋.......................77
1-3. Savitzky-Golay濾波器………………………………………………………78
1-4. 小波轉換……………………………………………………………………..78
1-4-1. 連續小波轉換................................................79
1-4-2. 離散小波轉換…………………………………………………………....80
1-5. 多重解析度分析……………………………………………………………..81
1-6. 離散小波轉換-小波種類…………………………………………………….82
1-7. 雜訊濾除與門檻值設定……………………………………………………..83
1-8. 本實驗所採行之門檻值估測與小波收縮方法……………………………..85
1-9. 在小波轉換中所採行之門檻值估測與小波收縮方法……………………..86
2. 實驗部份…………………………………………………………………………88
2-1. 藥品…………………………………………………………………………..88
2-2. 實驗器材與儀器設備………………………………………………………..88
2-3. 藥品與溶液之製備…………………………………………………………..89
2-3-1. 儲備溶液之配製………………………………………………………....89
2-3-2. 動相之配製……………………………………………………………....89
2-3-3. 梔子平單一濃度標準品溶液之配製…………………………………....90
2-3-4. 灌流液之配製…………………………………………………………....91
2-3-5. 直接注入之樣品前處理過程…………………………………………....91
2-4. 儀器設定……………………………………………………………………..92
2-4-1. 液相層析儀之相關條件設定…………………………………………....92
2-4-2. 質譜儀之相關條件設定………………………………………………....92
2-5. 方法之建立與確效…………………………………………………………..93
2-5-1. 檢量線建立……………………………………………………………....93
2-5-2. 方法確效………………………………………………………………....93
2-6. 各訊號處理方法之流程……………………………………………………..94
2-6-1. MF-M-MF方法………………………………………………………….....94
2-6-2. SG-M-MF方法………………………………………………………….....94
2-6-3. SG-M-WT方法………………………………………………………….....94
2-6-4. WT-M-SG方法………………………………………………………….....95
2-6-5. WT-M-WT方法………………………………………………………….....95
2-6-6. 單一WT方法…………………………………………………………......96
2-6-7. 訊雜比計算方式……………………………………………............97
3. 結果與討論………………………………………………………………………98
3-1. 田口法之結果與驗證………………………………………………………..98
3-1-1. 田口法之結果…………………………………………………………....98
3-1-2. 田口法所得趨勢之驗證………………………………………………....99
3-2. 搭配不同低通濾波器……………………………………………………….100
3-2-1. SG濾波器參數尋找過程………………………………………………...100
3-2-2. 小波轉換參數尋找過程………………………………………………...100
3-2-3. 處理前後檢量線及品管樣品之比較…………………………………...101
3-3. 以小波轉換進行訊號處理………………………………………………...101
3-3-1. 不同小波濾波器對訊號處理的影響…………………………………...101
3-3-2. 不同小波濾波器對處理前後之影響…………………………………...102
3-3-3. 以不同小波濾波器處理後檢量線之線性……………………………...103
3-3-4. 小波轉換後波寬之變化………………………………………………...103
4. 結論…………………………………………………………………………….104

第五章 未來展望…………………………………………………………………107

參考文獻..........................................................108

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