臺灣博碩士論文加值系統

本研究分為兩部份進行一系列光分解實驗。先將卡普洛芬(CPF)及那普洛辛(NAP)分別置於醇類溶媒中如甲醇或乙醇，以Hanovia 200 W高壓汞燈照射數小時下，進行光解反應。
第一部份以管柱層析法將卡普洛芬光解產物分離，共得到三種主要的光解產物，分別命名為 CPF 10、CPF 28及CPF 48。藉由質譜儀、紅外線光譜儀、核磁共振氫譜及碳譜判斷：CPF 10為2-(2-carbazolyl) propionic acid；CPF 28為2-(2-carbazolyl) propionic acid, methyl ester；而CPF 48為2-(6-chloro-2-carbazolyl) propionic acid, methyl ester。在乙醇溶液中則發現有相當於甲醇溶媒滯留時間的CP 11、CP 28及CP 56光解產物生成。CP 56為乙基酯，為酯化反應之衍生物。以上是以高效液相層析法(HPLC)於醇類溶液中監測卡普洛芬進行光解反應並以各類光譜法決定CPF 10、CPF 28及CPF 48產物構造的方法。
第二部份乃發展一個快速、敏感度高及準確的安定性指標的高壓液相層析法來定量那普洛辛。對那普洛辛的分析方法是用Inertsil ODS-3V管柱，移動相則採乙腈:甲醇:水=40:20:40 (v/v/v) ，UV偵測器則設定為230 nm。就已發展出的分析方法，其相關統計及確效包含有高壓液相層析系統規範、波峰純度完整以及光解產物和原料藥之間的解析度，及日內、日間差異分別在4.56%和3.82%以內。靈敏度可偵測到極低的濃度，偵測極限(Limit of Detection；LOD)可測得之濃度為64 ng/mL，而定量極限(Limit of Quantitation；LOQ)可測得之濃度為0.29μg/mL。由此可知，就建立的分析方法表現出良好的選擇性和特異性，適合用來作為那普洛辛的光安定性的分析。

This thesis is divided into two parts. Carprofen or naproxen was placed in a polar solvent, methanol or ethanol separately, then it was exposed to a Hanovia 200 W high pressure mercury lamp.
Firstly, a series of photolytic study of Carprofen(CPF) was undertaken.The photodegradants were separated and quantified by a HPLC method. Three photolytic products, CPF 10, CPF 28 and CPF 48, were isolated by the column chromatography. By way of analyzing MS, NMR and IR spectra, their structures were characterized. Their structures were identified as CPF 10, 2-(2-carbazolyl) propionic acid；CPF 28, 2-(2-carbazolyl) propionic acid, methyl ester；and CPF 48, 2-(6-chloro-2- carbazolyl) propionic acid, methyl ester. Similar photolytic products including CP 11, CP 28, and CP 56 were found in ethanol. CP 56, an ethyl ester of CPF 48 was found as a derivative in ethanol. High-performance liquid chromatographic assay method was used for monitoring the degradation of CPF and its degradants-CPF 10, CPF 28, and CPF 48.
Secondly, we focused on the quantitation studies of the photochemical decomposition of Naproxen (NAP). A rapid, sensitive, and accurate stability-indicating high performance liquid chromatographic assay method for determination of the degradation of NAP was developed and validated under photoirradiated conditions. The quantitation was monitored with an Inertsil ODS-3V column using a mobile phase of acetonitril : methanol : water = 40:20:40 (v/v/v). The UV detector was set at 230 nm. The related statistics of the developed methods including the system criteria, peak integrity, and resolution among the parent drug and its degradation products were calculated. The CV% of intraday and interday tests were lower than 4.56% and 3.82%, respectively. LOD (Limit of Detection) was 64 ng/mL, and LOQ (Limit of Quantitation) was 0.29μg/mL. Our established HPLC assay method shows good selectivity and specificity which is suitable for the stability measurement of NAP.

中文摘要……………………………………………………………… i
英文摘要……………………………………………………………… ii
目次…………………………………………………………………… iii
表目錄………………………………………………………………… v
圖目錄………………………………………………………………… vi
第一章 緒論………………………………………………………… 1
1.1 導論………………………………………………………… 1
1.2 NSAID類藥物光解的研究近況…………………………… 2
1.3 卡普洛芬簡介……………………………………………… 4
1.4 卡普洛芬的研究近況……………………………………… 4
1.5 研究卡普洛芬的動機與目的……………………………… 6
第二章 材料與方法………………………………………………… 8
2.1 實驗材料與儀器…………………………………………… 8
2.1.1 試藥……………………………………………………… 8
2.1.2 儀器設備………………………………………………… 8
2.2 實驗方法 — 光解產物單離………………………………… 10
2.2.1 卡普洛芬(CPF)的樣品置備…………………………… 10
2.2.2 光解產物分離條件……………………………………… 10
2.2.2.1 管柱色層分析法之分析條件………………………… 10
2.2.3 結構確認………………………………………………… 11
2.2.3.1 質譜儀 (MS)………………………………………… 11
2.2.3.2 紅外線光譜儀 (IR)………………………………… 12
2.2.3.3 紫外線光譜儀 (UV)………………………………… 12
2.2.3.4 核磁共振儀 (NMR)………………………………… 12
2.2.4 探討光解產物之生成順序……………………………… 12
第三章 結果與討論………………………………………………… 13
3.1 以液相層析質譜儀分析卡普洛芬及其光解產物………… 13
3.2 光解產物單離與結構鑑定………………………………… 14
3.2.1 光解主產物CPF 10構造式之鑑定…………………… 16
3.2.2 光解主產物CPF 10構造式之光譜…………………… 16
3.2.3 光解主產物CPF 28構造式之鑑定…………………… 17
3.2.4 光解主產物CPF 28構造式之光譜…………………… 17
3.2.5 光解主產物CPF 48構造式之鑑定……………………… 19
3.2.6 光解主產物CPF 48構造式之光譜……………………… 19
3.2.7 光解主產物CP 48構造式之鑑定……………………… 21
3.2.8 光解主產物CP 48構造式之光譜……………………… 21
3.3 光解反應途徑的探討…………………………………………… 23
3.3.1 卡普洛芬在不同因子影響下其光解產物的生成情形 23
3.3.2 甲醇溶媒中卡普洛芬甲基酯光解產物的生成情形… 24
3.3.3 甲醇溶媒中卡普洛芬去氯甲基酯光解產物的生成情形 28
3.3.4 甲醇溶媒中卡普洛芬去氯光解產物再照光後之變化 31
第四章 那普洛辛於醇類溶媒之光解研究………………………… 35
4.1緒論…………………………………………………………… 35
4.2那普洛辛光化學之研究近況………………………………… 36
4.3研究動機……………………………………………………… 39
4.4材料與方法…………………………………………………… 40
4.4.1實驗材料…………………………………………………… 40
4.4.1.1試藥…………………………………………………… 40
4.4.1.2儀器…………………………………………………… 40
4.4.2 NAP 檢量線之實驗設計………………………………… 41
4.4.3 NAP同日間及異日間試驗………………………………… 41
4.5 結果與討論………………………………………………… 42
4.5.1 HPLC之靈敏度試驗……………………………………… 42
4.5.2那普洛辛(NAP) ………………………………………… 43
4.5.3 HPLC系統適合參數……………………………………… 44
4.5.4那普洛辛光解產物之分析………………………………… 49
第五章 結論………………………………………………………… 52
參考文獻……………………………………………………………… 54
表目錄
表2.1 卡普洛芬(CPF)之分析型HPLC分析條件………………………… 11
表3.1 CPF與其醇性溶媒中光解產物CPF 10的光解數據比較表……… 93
表3.2 CPF與其醇性溶媒中光解產物CPF 28的光解數據比較表……… 94
表3.3 CPF與其醇性溶媒中光解產物CPF 28的NMR數據比較表…… 95
表3.4 CPF與其醇性溶媒中光解產物CPF 48的光解數據比較表……… 96
表3.5 CPF與其醇性溶媒中光解產物CPF 48的NMR數據比較表…… 97
表3.6 CPF與其醇性溶媒中光解產物CP 48的光解數據比較表……… 98
表3.7 CPF與其醇性溶媒中光解產物CP 48的NMR數據比較表……… 99
表3.8 卡普洛芬之HPLC分析條件……………………………………… 25
表3.9 卡普洛芬甲基酯光解產物(CPF 48)之HPLC分析條件…………… 29
表3.10 卡普洛芬去氯光解產物(CPF 10)之HPLC分析條件……………… 32
表4.1 那普洛辛(NAP)之分析型HPLC分析條件………………………… 40
表4.2 那普洛辛之日間與日內確效試驗………………………………… 44
表4.3 那普洛辛(NAP)之HPLC系統適合參數…………………………… 48
表4.4 那普洛辛LC/MS的液相層析分析條件…………………………… 50
表4.5 那普洛辛LC/MS的質譜分析條件………………………………… 50
圖目錄
圖1.1 Diclofenac光解反應圖……………………………………… 3
圖1.2 卡普洛芬(CPF)化學結構式………………………………… 4
圖3.1 非固醇類抗發炎製劑在甲醇溶液中，經過光照射後之反應機轉………………………………………………………… 14
圖3.2 以HPLC分析卡普洛芬(CPF)在甲醇溶液中(100μM)照光5小時，分析條件為移動相--乙腈:水:醋酸= 50 : 49 : 1，層析管柱為Inertsil 5 ODS-3V (4.6 x 250mm) …………… 15
圖3.3 以HPLC分析卡普洛芬(CPF)在乙醇溶液中(100μM)照光5小時，分析條件為移動相--乙腈:水:醋酸= 50 : 49 : 1，層析管柱為Inertsil 5 ODS-3V (4.6 x 250mm) …………… 15
圖3.4 卡普洛芬(CPF)之質譜圖……………………………………… 58
圖3.5 CPF之質譜斷裂圖…………………………………………… 59
圖3.6 卡普洛芬(CPF)之UV-VISIBLE圖譜……………………… 59
圖3.7 卡普洛芬(CPF)之IR圖譜…………………………………… 60
圖3.8 卡普洛芬(CPF)之1H-NMR圖譜一………………………… 61
圖3.9 卡普洛芬(CPF)之1H-NMR圖譜二………………………… 62
圖3.10 卡普洛芬(CPF)之1H-NMR圖譜三………………………… 63
圖3.11 卡普洛芬(CPF)之13C-NMR圖譜一………………………… 64
圖3.12 卡普洛芬(CPF)之13C-NMR圖譜二………………………… 65
圖3.13 生成CPF 10之反應途徑…………………………………… 16
圖3.14 CPF 10之質譜圖……………………………………………… 66
圖3.15 CPF 10之質譜斷裂圖………………………………………… 67
圖3.16 CPF 10之UV-VISIBLE光譜吸收圖………………………… 67
圖3.17 生成CPF 28之反應途徑…………………………………… 18
圖3.18 CPF 28之質譜圖……………………………………………… 68
圖3.19 CPF 28之質譜斷裂圖………………………………………… 69
圖3.20 CPF 28之UV-VISIBLE光譜吸收圖………………………… 69
圖3.21 CPF 28之1H-NMR圖譜一…………………………………… 70
圖3.22 CPF 28之1H-NMR圖譜二…………………………………… 71
圖3.23 CPF 28之1H-NMR圖譜三 ………………………………… 72
圖3.24 CPF 28之13C-NMR圖譜一………………………………… 73
圖3.25 CPF 28之13C-NMR圖譜二………………………………… 74
圖3.26 生成CPF 48之反應途徑……………………………………… 20
圖3.27 CPF 48之質譜圖……………………………………………… 75
圖3.28 CPF 48之質譜斷裂圖………………………………………… 76
圖3.29 CPF 48之UV-VISIBLE吸收光譜圖………………………… 76
圖3.30 CPF 48之IR圖譜…………………………………………… 77
圖3.31 CPF 48之1H-NMR圖譜一…………………………………… 78
圖3.32 CPF 48之1H-NMR圖譜二…………………………………… 79
圖3.33 CPF 48之1H-NMR圖譜三…………………………………… 80
圖3.34 CPF 48之13C-NMR圖譜一………………………………… 81
圖3.35 CPF 48之13C-NMR圖譜二………………………………… 82
圖3.36 生成CPF 56之反應途徑…………………………………… 22
圖3.37 CP 56之質譜圖……………………………………………… 83
圖3.38 CP 56之質譜斷裂圖………………………………………… 84
圖3.39 CP 56之UV-VISIBLE吸收光譜圖………………………… 84
圖3.40 CP 56之IR圖譜……………………………………………… 85
圖3.41 CP 56之1H-NMR圖譜一…………………………………… 86
圖3.42 CP 56之1H-NMR圖譜二…………………………………… 87
圖3.43 CP 56之1H-NMR圖譜三…………………………………… 88
圖3.44 CP 56之1H-NMR圖譜四…………………………………… 89
圖3.45 CP 56之13C-NMR圖譜一…………………………………… 90
圖3.46 CP 56之13C-NMR圖譜二…………………………………… 91
圖3.47 CP 56之13C-NMR圖譜三…………………………………… 92
圖3.48 高濃度CPF在高壓汞燈照射下光解產物的生成情形…… 23
圖3.49 低濃度CPF在高壓汞燈照射下光解產物的生成情形…… 23
圖3.50 低濃度CPF在日光照射下光解產物的生成情形………… 24
圖3.51 卡普洛芬於甲醇溶媒中光敏化反應形成卡普洛芬甲基酯光解產物(CPF 48)之HPLC圖…………………………… 26
圖3.52 卡普洛芬於甲醇溶媒中光敏化反應形成卡普洛芬甲基酯光解產物(CPF 48)之生成情形…………………………… 26
圖3.53 卡普洛芬甲基酯光解產物(CPF 48)於甲醇溶媒中光敏化反應形成卡普洛芬去氯甲基酯光解產物(CPF 28)之HPLC圖 30
圖3.54 卡普洛芬甲基酯光解產物(CPF 48)於甲醇溶媒中光敏化反應形成卡普洛芬去氯甲基酯光解產物(CPF 28)之生成情形 30
圖3.55 甲醇溶媒中卡普洛芬去氯光解產物再照光後之變化……… 33
圖3.56 CPF於醇類溶液下之光解途徑……………………………… 34
圖4.1 Naproxen之結構式…………………………………………… 35
圖4.2 那普洛辛在有氧條件下可能之光解機轉…………………… 37
圖4.3 那普洛辛在無氧條件下可能之光解機轉…………………… 37
圖4.4 那普洛辛(NAP)溶於甲醇溶液之濃度檢量線(n=5) ………… 43
圖4.5 甲醇溶媒中高壓汞燈下NAP 1的生成情形………………… 48
圖4.6 甲醇溶媒中高壓汞燈下NAP 2的生成情形………………… 49
圖4.7 那普洛辛光解產物之HPLC分離圖………………………… 51
圖4.8 那普洛辛於醇類溶液下之光解反應途徑推測圖…………… 51
圖5.1 CPF於醇類溶液中已知及待證實之光解途徑……………… 53
圖5.2 CPF於乙醇溶液中之光解途徑……………………………… 53

參考文獻
1. Quintero, B., and Miranda, M. A., (2000) Mechanisms of photosensitization induced by drugs: A general survey. Ars Pharma. 41:1, 27-46
2. Ljunggren B., and Bjellerup, M. (1986) Systemic drug photosensitivity. [Review] [88 refs] Photo-Dermatol, 3(l): 26-35.
3. 洪本嶽。1998。那普洛辛於有機溶媒中之光解研究。台北醫學院藥學研究所碩士論文。
4. 林建良。2001。NSAID藥物光反應進行Hydroxylactonization之研究，第一部份：吲哚美洒辛。台北醫學院藥學研究所碩士論文。
5. 陳峙瑞。2002。第一部份：發展非固醇類抗炎劑安定性指標能力之高壓液相層析分析法 — 托美丁和佐美酸&第二部份：托美丁的光安定性研究。臺北醫學大學藥學研究所碩士論文
6. Couini-Lalanne N., Defais M., and Paillous N. (1998) Nonsteroidal Antiinflammatory Drug-Photosensitized Formation of Pyrimidine Dimer in DNA. Biochem. Phar. , 55: 441-446.
7. Miranda MA., Castell JV., Hernandez D., Gomez-Lechon MJ., Bosca F., Morera IM., and Sarabia Z. (1998) Drug-Photosensitized Protein Modification: Identification of the Reactive Sites and Elucidation of the Reaction Mechanisms with Tiaprofenic Acid/Albumin as Model System. Chem. Res. Toxicol., 11: 172-177.
8. Castell J.V., Gomez-Lecho M.J., Grassa C., Martinez L.A., Miranda M.A. and Tarrega P. (1993) Involvement of Drug-Derived Peroxides in The Phototoxicity of Naproxen and Tiaprofenic Acid. Photochem. Photobiol., 57: 486-490.
9. Encinas S., Bosca F. and Miranda MA. (1998) Phototoxicity Associated with Diclofenac: a Photophysical, Photochemical, and Photobiological Study on the Drug and its Photoproducts. Chem. Res. Toxicol., 11: 946-952.
10. Ljunggren B., and Lundberg K. (1985) In vivo phototoxicity of non-steroidal anti-inflammatory drugs evaluated by the mouse tail technique. Photo-Dermatology, 2(6): 377-82.
11. De Guidi G., Chillemi R., Costanzo LL., Giuffrida S., Sortino S., and Condorelli G., (1993) Molecular mechanism of drug photosensitization. 4. Photohemolysis sensitized by carprofen. J. Photochem. Photobiol. B - Biol., 17(3): 239-46.
12. Bosca F., Encinas S., Heelis PF., and Miguel MA. (1997) Photophysical and photochemical characterization of a photosensitizing drug: A combined steady state photolysis and laser flash photolysis study on carprofen. Chem. Res. Toxicol., 10: 820-827.
13. Moser J., Bosca F., Lovell WW., Castell JV., Miranda MA., and Hye A. (2000) Photobinding of carprofen to protein. J. Photochem. Photobiol. B - Biol., 58: 13-19.
14. Wu AB., Chen CY., Chu SD., Tsai YC., and Chen FA. (2001) Stability-Indicating High-Performance Liquid Chromatographic Assay Method and Photostability of Carprofen. J. Chrom. Sci., 39: 7-11.
15. 王博譽。2002。以液相層析質譜儀分析NSAID藥物-卡普洛芬及那普洛辛之光解產物和鈣離子阻斷劑-尼卡迪平之光解產物。臺北醫學大學藥學研究所碩士論文。
16. Ming-Thau Sheu, Hsiu-O Ho, Po-Yu Wa n g , Yi-Bo Liou, a n d An-Bang Wu (2003) Photolysis of NSAIDs I: photodegradation products of carprofen determined by LC—ESI—MS. Journal of Chromatographic Science, Vol. 41, April
17. Giufirida S., De Guidi G., Sortino S., Chillemi R., Costanzo LL., and Condorelli G. (1995) Molecular mechanism of drug photosensitization. Part 6. Photohaemolysis sensitized by tolmetin. J. Photochem. Photobiol. B - Biol., 29(2-3): 125-33.
18. Bosca F., and Miranda MA. (1998) Photosensitizing drugs containing the benzophenone chromophore. [Review] [97 refs] J. Photochem. Photobiol. B - Biol., 43(1): 1-26.
19. Bosca F., Mann ML., and Miranda MA. (2001) Photoreactivity of the nonsteroidal anti-inflammatoly 2-arylpropionic acids with photosensitizing side effects. [Review] [104 refs] Photochem. Photobiol., 74(5): 637-55
20. Borsarelli CD., Braslavsky SE., Sortino S., Marconi G., and Monti S. (2000) Photodecarboxylation of ketoprofen in aqueous solution. A time-resolved laser-induced optoacoustic study. Photochem. Photobiol., 72(2): 163-71
21. De Guidi G., Giuffrida S., Condorelli G., Costanzo LL., Miano P., and Sortino S. (1996) Molecular mechanism of drug photosensitization. IX. Effect of inorganic ions on DNA cleavage photosensitized by naproxen. Photochem. Photobiol., 63(4): 455-62
22. De Guidi G., Chillemi R., Costanzo LL., Giuffrida S., Sortino S., and Condorelli G. (1994) Molecular mechanism of drug photosensitization. 5. Photohemolysis sensitized by Suprofen. J. Photochem. Photobiol. B - Biol., 23(2-3): 125-33
23. Encinas S., Bosca F., and Miranda MA. (1998) Phototoxicity associated with diclofenac: a photophysical, photochemical, and photobiological study on the drug and its photoproducts. Chem. Res. Toxicol., II(8): 946-52.
24. Radschuweit A., Ruttinger HH., Nuhn P., Wohlrab W., and Huschka C. (2001) UV-induces formation of hydrogen peroxide based on the photochemistry of ketoprofen. Photochem. Photobiol., 73 (2): II 9-27.
25. Bosca F., Canudas N., Mann ML., and Miranda MA. (2000) A photophysical and photochemical study of 6-methoxy-2- naphthylacetic acid, the major metabolite of the phototoxic nonsteroidal antiinflammatory drug nabumetone. Photochem. Photobiol., 71(2): 173-7.
26. Bosca F., Martinez-Manez R., and Miranda MA. (1992) Primo J. Soto J. Vano L. Oxidative decarboxylation of naproxen. J. Pharm. Sci., 81(5): 479-82.
27. Sortino S., De Guidi G., Marconi G., and Monti S. (1998) Triplet photochemistry of suprofen in aqueous environment and in the beta-cyclodextrin inclusion complex. Photochem. Photobiol., 67(6): 603-ll.
28. De Guidi G., Chillemi R., Costanzo LL., Giuffrida S., and Condorelli G. (1993) Molecular mechanism of drug photosensitization. 4. Photohemolysis sensitized by carprofen. J. Photochem. Photobiol. B - Biol., 17(3): 239-46.
29. 賀孝維； 有機化合物之光譜鑑別法, 1973年. 眾光文化事業有限公司, 第四版: pp 133
30. 黃一純； 劉錦泉；蔡研菊； 許俊卿； 范育仁； 台灣藥品總覽, 1944. 高華出版社, 第一版: PP. 11777-11778
31. Solheim L.F.; Ronningen H.; Langeland N. (1986). Effects of acetylsalicylic acid and naproxen on bone resorption and formation in rats. Source. Archives of Orthopaedic & Traumatic Surgery. 105(3): 137-141
32. Vignon E.; Mathieu P.; Charlet C.; Balblanc J.C.; Richard M. (1991). Apr. Effects of naproxen (naprosyne) on the metabolism of arthrotic cartilage in man in vivo. Revue du Rhumatisme et des Maladies Osteo-Articulaires. 58(3)(Pt 2):11S-15S
33. Sacerdote P.; Carrabba M.; Galante A.; Pisati R.; Manfredi B.; Panerai A.E. (1995). Nov. Plasma and synovial fluid interleukin-1, interleukin-6 and substance P concentrations in rheumatoid arthritis patients: effect of the nonsteroidal anti-inflammatory drugs indomethacin, diclofenac and naproxen. Inflammation Research. 44(11): 486-490
34. Zyglewska T.; Sanduja R.; Ohashi K.; Loose-Mitchell DS.; Sanduja SK.; Wu KK. (1992) May 7. Inhibition of endothelial cell prostaglandin H synthase gene expression by naproxen. Biochimica et Biophysica Acta. 1131(1): 78-82
35. William A.R.; Jaime N.D. (1991) Textbook of Organic Medicinal and Pharmaceutical Chemistry, ninth edition: 664
36. Diffey, B.L.; Daymond, T.J.; Fairgreaves, H. (1983). Phototoxic reaction to piroxicam, naproxen and tiaprofenic acid. Br. J. Rheu. 22:239-242
37. Costanzo, L.L.; Guidi, G.D.; Condorelli, G. (1989). Molecular mechanism of naproxen photosensitization in red blood cells. J. Photochem. Photobiol., B:Biol. 3:223-235
38. Ljunggren, B. (1985). Propionic acid-derived non-steroidal anti-inflammatory drugs are phototoxic in vitro. Photodermatology. 2:3-9
39. Moore, D.E.; Chappuis, P.P. (1988). A comparative study of the photochemistry of the non-steroid anti-inflammatory drugs, naproxen, benoxaprofen and indomethacin. Photochem. Photobiol., 47(2): 173-180
40. Schothorst, A.A.; Vansteveninck, L.N.J.; Went, L.N.; Suurmond, D. (1970). Protoporphyrin-induced photohemolysis in protoporphiria and in normal red blood cells. Clin. Chim. Acta, 28:41-49
41. Odell, G.B.; Brown, R.S.; Kopelman, A.E. (1972). The photodynamic action of bilirubin on erythrocites. J. Pediatr., 81:473-482
42. Bosca, F.; Miranda, M.A.; Vano, L.; Vargas, F. (1990). New photodegradation pathways for naproxen, a phototoxic non-steroidal anti-inflammatory drug. J. Photochem. Photobiol., A: Chem. 54:131-134
43. Becker, L.; B Eberlein-Konig, B.; Przybilla, B. (1996). Phototoxicity of non-steroidal anti-inflammatory drugs:in vitro studies with visible light. Acta Derm Venereol. 76:337-340
44. 行政院衛生署管制藥品檢驗局篩檢認證組網站[http://www.nbcd.gov.tw/exm/exm-4.asp]
45. Braithwaite, A., and Smith, F. J., (1996) High-performance liquid chromatography. Chromatographic Methods 5th Ch 6, 258-365