臺灣博碩士論文加值系統

那普洛辛( Naproxen, NAP )為一非固醇類藥品，在臨床上用於治療風濕性關節炎及痛風性關節炎，此類藥品具有光敏感性，當暴露於汞燈或日光燈下不安定，在儲架期中若經光線照射，甚至有光毒性之顧慮，為了解其光化學反應途徑，本研究進行一系列之光分解相關實驗，評估NAP之光安定性，以作為新劑型開發之參考。研究中將NAP置於極性較高之甲醇溶媒中，當暴露於高壓汞燈下，會進行光解反應，利用質譜儀、熔點測定儀、紫外線光譜儀、紅外線光譜儀、核磁共振光譜儀進行光解產物結構的鑑定。
本研究發現NAP在高壓汞燈下，會進行光解反應，經鑑定確認結構之產物有3個，主產物為2-ethyl-6-methoxy-naphthalene, 1-(6-methoxy-naphthalen-2-yl)-ethanol 和 1-(6-methoxy-naphthalen-2-yl)-ethanone。有關濃度、溶媒、溫度等動力學光分解反應影響之研究方面，濃度效應顯示為ㄧ階動力學模式。在溶媒效應方面發現，極性較大的溶媒對那普洛辛光分解有增加的作用，且有成正相比的關係。在溫度效應方面，依阿瑞尼士方程式可以計算出那普洛辛之活化能為9.5 kcal/mol。

Naproxen (NAP), a well-known anti-inflammatory drug, is widely used for the treament of rheumatoid and osteoarthritis in clinical therapy. However, it is light sensitive when exposed to mercury lamp or sunlight. The drug is mostly unstable or even photoxic when stored on shelves under the exposure of hosehold light. In order to unveil the behavior of its photochemical pathway, a systematic study of the photodegradation of Naproxen was undertaken. Furthermore, the elucidation of the photosability characteristics of propionic acid-derived non-steroidal anti-inflammatory drugs is essential for the development of new dosage forms. In this study, Naproxen was placed in a polar solvent, such as methanol, while it exposed to high pressure mercury lamp, it undergoes photodegradation. The photodecomposition products were separated and identified using UV, IR, MS and NMR spectroscopies.
When Naproxen was exposed to a high pressure mercury lamp, three new photodegradation products of NAP were observed and their structures identified. The main degraded products was 2-ethyl-6-methoxy-naphthalene, 1-(6-methoxy-naphthalen-2-yl)-ethanol and 1-(6-methoxy-naphthalen-2-yl)-ethanone. The influential factor with respect to molar concentration, solvent, temperature and aerobic condition associated with the photodegradation were carefully investigated. The resultsof concentration effect showed that NAP fallows a pseudo first-order kinetic reaction. At aerobic conditions, the photodegradation rate of Naproxen was accelerated. According to the Arrhenius equation, the activation enrgy of NAP is found to be 9.5 kcal/mol.

目 錄
中文摘要........................................................................................................Ⅰ
Abstract ......................................................................................................... Ⅱ
目 錄 ..........................................................................................................Ⅲ
圖 目 錄 ........................................................................................................V
表 目 錄 .......................................................................................................VII
第一章 緒論 ................................................................................................ 1
1.1 那普洛辛的光化學之研究近況 ......................................................2
1.2 研究動機 .............................................................................................6
1.3 研究方法 .............................................................................................7
第二章 結果與討論 .....................................................................................8
2.1 那普洛辛光解產物之分離 ...............................................................8
2.2 那普洛辛光解產物構造式之鑑定 ..................................................8
2.2.1光解主產物NAP-1構造式之鑑定 ..............................................10
2.2.2光解主產物NAP-2構造式之鑑定. .............................................16
2.2.3光解主產物NAP-3構造式之鑑定 ..............................................20
2.2.4那普洛辛光與各光解產物光譜數據比較................................24
2.3 那普洛辛光解動力學研究 ............................................................29
2.3.1 那普洛辛濃度檢量線 .................................................................29
2.3.2 那普洛辛於不同溶媒之降解情形. ..........................................33
2.3.3 那普洛辛於甲醇溶媒之不同濃度的降解情形 .....................36
2.3.4 那普洛辛於甲醇溶媒之不同溫度的降解情形 ......................41
2.4 那普洛辛照光後產生單線態氧之確認實驗. ..............................45
2.5 那普洛辛光解反應途徑的探討. ....................................................51
第三章 實驗材料與方法 .......................................................................... 52
3.1. 材料與儀器 ....................................................................................52
3.1.1 材料 ................................................................................................52
3.1.2 儀器設備 .........................................................................................53
3.2 實驗方法............................................................................................55
3.2.1 樣品處理 ........................................................................................55
3.2.2 光解產物的分離條件 ..................................................................56
3.2.3 分離物之再結晶............................................................................57
3.2.4 結構確認.........................................................................................57
3.2.4.1 紅外線光譜儀(IR) ...................................................................57
3.2.4.2 核磁共振儀(NMR).................................................................. 58
3.2.5 溶媒對那普洛辛光分解速率的影響........................................58
3.2.6 那普洛辛濃度對其光分解速率的影響....................................58
3.2.7 那普洛辛於甲醇溶媒之不同溫度的降解情形.......................59
3.2.6 那普洛辛照光後產生單線態氧之確認實驗...........................59
參考文獻 .......................................................................................................60

參 考 文 獻
1 行政院衛生署, 中華藥典, 第四版: pp. 547-549
2 黃一純; 劉錦泉; 蔡妍菊; 許俊卿; 范育仁. 台灣藥品總覽, 1944. 高華初版社, 第一版: pp. 11777-11778
3 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): pp. 137-141
4 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): pp.11S-15S
5 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 Pconcentrations in rheumatoid arthritis patients: effect of the nonsteroidal anti inflammatory drugs indomethacin, diclofenac and naproxen. Inflammation Research. 44(11): pp. 486-490
6 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): pp.78-82
7 William A.R. ; Jaime N.D. 1991. Textbook of Organic Medicinal and Pharmaceutical Chemistry, ninth edition: p.664
8 Costanzo, L. L.; Guidi, G. D.; Condorelli, G.; Cambria,A.; Fama,M. 1989. Molecular mechanism of drug photosensitization-Ⅱ. Photohemolysis sensitized by Ketoprofen. Photochem. Photobiol., 50(3): pp. 359-365
9 Guidi, G. D.; Chillemi, R.; Costanzo, L. L.; Giuffrida, S.; Condorelli, G. 1993. Molecular mechanism of drug photosensitization-4. Photohemolysis sensitized by Carprofen. J. Photochem. Photobiol., B: Biol. 17: pp. 239-246
10 Guidi, G. D.; Chillemi, R.; Costanzo, L. L.; Giuffrida, S.; Sortino, S.; Condorelli, G. 1994. Molecular mechanism of drug photosensitization-4. Photohemolysis sensitized by Suprofen. J. Photochem. Photobiol., B: Biol. 23: pp. 125-133
11 Giuffrida, S.; Guidi, G. D.; Sortino, S.; Chillemi, R.; Costanzo, L. L.; Condorelli, G. 1995. Molecular mechanism of drug photosensitization part 6. Photohemolysis sensitized by Tolmetin. J. Photochem. Photobiol., B: Biol. 29: pp. 125-133
12 Sik,R. H.; Paschall, C. S.; Chignell, C.F. 1983. The phototoxic effect of Benoxaprofen and its analogs on human erythrocytes and rat peritonal mast cells. Photochem. Photobiol., 38(4): pp. 411-415
13 Valenzeno, D. P. 1987. Photomodification of biological membranes with emphasis on singlet oxygen mechanisms. Photochem. Photobiol., 46(1): pp. 147-160
14 Gastell, J. V.; Gomez-L, M. J.; Miranda, M. A.; Morera, I. M. 1987. Photolytic degradation of Ibuprofen. Toxicity of the isolated photoproducts on fibrobasts and erythrocytes. Photochem. Photobiol., 46(6): pp. 991-996
15 Bosca, F.; Miranda, M. A.; Carganico, G.; Mauleon,D. 1994. Photochemical and photobiological properties of Ketoprofen associated with the benzophenone chromophore. Photochem. Photobiol., 60(2): pp. 96-101
16 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: pp. 337-340
17 Diffey, B. L.; Daymond, T. J.; Fairgreaves, H. 1983. Phototoxic reaction to piroxicam,naproxen and tiaprofenic acid. British Journal of Rheumatology 22: pp. 239-242
18 Costanzo, L. L.; Guidi, G. D.; Condorelli, G. 1989. Molecular mechanism of naproxen photosensitization in red blood cells. J. Photochem. Photobiol., B: Biol. 3: pp. 223-235
19 Ljunggren, B. 1985. Propionic acid-derived non-steroidal anti-inflammatory drugs are phototoxic in vitro. Photodermatology 2: pp.3-9
20 Jekone, B. Z.; Gorgeyne, K.E. Detremination of the end-point of naproxen sodium granules in Glatt VG-WS-CD high-shear granulator fluid bed dryer equipment. 1996. Acta Pharmaceutica Hungarica., 66(6): pp. 247-252
21 Jekone, B. Z.; Gorgeyne, K. E. Determination of the end-point of naproxen sodium granules in Glatt VG-WS-CD high-shear granulator fluid bed dryer equipment. 1996. Nov. Acta Pharmaceutica Hungarica. 66(6): pp. 247-52
22 Velaz, I.; Sanchez, M.; Martin, C.; Martinez-Oharriz, M. C. 1998. Apr-Jun. Effect of PEG 4000 on the dissolution rate of naproxen. European Journal of Drug Metabolism & Pharmacokinetics. 23(2): pp.103-108
23 Martinez, L.J.; Scaiano, J.C. 1998. Nov. Characterization of the transient intermediates generated from the photoexcitation of nabumetone: a comparison with naproxen. J. Photochem. Photobiol., 68(5): 646-51.
24 李浩遠, Naproxen膠囊與Zinc Sulfadiazine之藥效藥劑學研究, 1993, 國立臺灣大學藥學研究所論文.
25 張嘉雄, 抗發炎高分子前驅藥的熱安定性與水解, 1997, 高雄醫學院藥學研究所碩士論文.
26 張春生, 有機溶劑中利用脂肪脢鏡像選擇合成(S)-Naproxen酯類前驅藥及動態動力分割(S)-Naproxen, 1997, 國立成功大學化學工程研究所論文.
27 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): pp. 173-180
28 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: pp. 41-49
29 Odell, G. B.; Brown, R. S.; Kopelman, A. E. 1972. The
photodynamic action of bilirubin on erythrocites. J. Pediatr., 81: pp. 473-482
30 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: pp. 131-134
31 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: pp. 337-340
32 Rodney, F.; Boyer ; Christine, G.; Darby, B.; Mark, H. 1975. Tetrahedron Letters. 47: pp. 4111-4114
33 Takashi, I. 1978. Cellular and Subcelluar mechanism of photodynamic action : the 1O2 hypothesis as a driving force in recent research. Photochem. Photobiol., 28: pp. 493-508