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研究生:陳鳳玲
研究生(外文):Fung-Lin Chen
論文名稱:二克氯吩鈉之生體可用率研究
論文名稱(外文):Bioavailability studies of Diclofenac sodium
指導教授:劉正雄劉正雄引用關係
指導教授(外文):Cheng-Hsiung Liu
學位類別:碩士
校院名稱:中國醫藥學院
系所名稱:藥物化學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2000
畢業學年度:88
語文別:中文
論文頁數:109
中文關鍵詞:二克氯吩鈉生體可用率
外文關鍵詞:Diclofenac sodiumBioavailability
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二克氯吩鈉(Diclofenac sodium)為一非固醇類抗炎藥,屬於苯基乙酸衍生物,常用於治療風濕性關節炎。目前已廣泛應用於市場上,但因原開發廠的產品較為昂貴,且需仰賴進口,因此有許多國內的藥廠開始研發相同成分、劑量及劑型的產品,本實驗主要是比較兩種二克氯吩鈉持釋劑型配方DSSR及VoltarenR SR在八位健康男性之生體可用率,以及兩種二克氯吩鈉腸衣膠囊WerenR EMC及Diclo-purenR在十二位健康男性之生體可用率,藉由計算出之相關藥物動力學參數以評估其生體可用率及兩組產品的個別生體相等性,以確保用藥者的安全。利用高效液相層析分析法分析個別血漿檢品,使用RP-18層析管,以甲醇:0.1 ﹪磷酸溶液(78/22)作為移動相,以Mefenamic acid作為內部標準品,UV偵測波長280nm來測定之。此一方法具有良好的線性關係,其同日內、異日間精確度,及定量極限之變異係數均在10 ﹪內,相對回收率亦大於90 ﹪。
實驗結果發現持釋劑型DSSR之血漿中diclofenac sodium的最高濃度出現在第3.57 ±0.79小時為0.215 ±0.095 μg/ml,明顯低 VoltarenR SR出現在第5.57 ±2.07小時的0.679 ±0.461 μg/ml;DSSR之曲線下面積為2.93 ±2.57 μg.hr/ml與VoltarenR SR的3.70 ±1.38 μg.hr/ml有明顯差異。而腸衣膠囊WerenR EMC及Diclo-purenR在十二位受試者之平均曲線下面積(2.34 ±0.19 vs.2.34 ±0.22 μg.hr/ml),平均最高濃度(1.16 ±0.20 vs.1.17 ±0.23 μg/ml),及達峰時間(均為1.5 hr)等藥物動力學參數並無統計上之差異。由此可證,持釋劑型DSSR及VoltarenR SR不具有生體相等性。而腸衣膠囊WerenR EMC及Diclo-purenR因藥物動力學參數均無統計上的差異,故可證明兩者具有生體相等性。
Diclofenac sodium is a phenylacetic acid derivatives of the NSAIDs, which is used in in the treatment of rheumatic disorders. In this study, the bioavailability of two sustained-release dosage form of diclofenac sodium: DSSR and VoltarenR SR (Ciba-Geigy) in eight healthy male volunteers, and the bioavailability of two enteric-coated beads dosage form of diclofenac sodium: WerenR EMC (Yu Sheng) and Diclo-purenR (Yung Shin) in twelve healthy male volunteers were evaluated. From calculated pharmacokinetic parameters, the possible bio-equivalency of these two groups formulations were determined.
We used high performance liquid chromatography method to analysis the plasma samples. The HPLC conditions are included RP-18 column, mobile phase is methanol:0.1% ortho-phosphoric acid=78:22, internal standard is Mefenamic acid, and monitoring at UV 280 nm. This method showed good linearity, the intra- and inter-day validation is reasonably with the C.V. less than 10 %. The relative recovery ratio is above 90 %.
We found that two sustained-release dosage form of diclofenac sodium: DSSR and VoltarenR SR were not equal.The two enteric-coated beads dosage form of diclofenac sodium: WerenR EMC and Diclo-purenR, By coparing the pharmacokinetics included AUC, Cmax, Tmax, T1/2, there are no significant statistic difference between each pair of the parameter (P >0.05), This indicated that this two products were equal.
目 錄
目 錄..................................................Ⅰ
附表目錄..................................................Ⅱ
附圖目錄..................................................Ⅳ
中文摘要..................................................Ⅴ
Abstract..................................................Ⅵ
第一章 緒 言...............................................1
第二章 總 論...............................................3
第一節 Diclofenac sodium的來源............................3
第二節Diclofenac sodium的理化特性.........................5
第三節 藥理與臨床作用.....................................7
第四節 定量方法...........................................9
第五節 藥物動力學研究.....................................12
第六節 研究動機及目的.....................................13
第三章 實驗材料與方法.......................................14
第一節 實驗材料...........................................14
第二節 實驗方法...........................................17
第四章 結果與討論...........................................28
第五章 結 論................................................32
附 表....................................................33
附 圖....................................................76
參考文獻....................................................100
附表目錄
表1 有關Diclofenac sodium控釋劑型的文獻研究結果.............11
表2 有關Diclofenac sodium腸衣劑型的文獻研究結果.............11
表3 過去學者所做過的HPLC分析方法............................12
表4 實驗一,人體實驗時服藥及採血情形........................19
表5 實驗二,人體實驗時服藥及採血情形........................21
表6 對照標準血漿檢品之製備..................................24
表7 血漿分析之確效性試驗....................................33
表7-1 Diclofenac sod.之血漿定量分析之同日內精確性試驗.....33
表7-2 Diclofenac sod.之血漿定量分析之異日間精確性試驗.....33
表7-3 Diclofenac sod.之HPLC血漿定量分析之相對回收率試驗...34
表7-4 Diclofenac sod.在血漿中於25℃時的安定性.............35
表7-5 Diclofenac sod.在血漿中於-30℃時的安定性............35
表8 Voltaren SR與DSSR生體相等性預試驗受試者資料.............36
表9 Voltaren SR與DSSR之溶離試驗.............................37
表9-1 water alone.........................................37
表9-2 pH6.8...............................................37
表9-3 pH1.2 for 60 min →pH6.8............................38
表9-4 pH1.2 for 90 min →pH6.8............................38
表10 口服Voltaren SR之血漿中Diclofenac sod.濃度.............39
表11 口服DSSR之血漿中Diclofenac sod.濃度....................40
表12 Voltaren SR與DSSR於個別受試者血漿中Diclofenac sod.
之濃度.................................................41
表13 Voltaren SR與DSSR於血漿中Diclofenac sod.平均濃度.......48
表14 DSSR及Voltaren SR個別及平均之藥物動力學參數............49
表15 Voltaren SR與DSSR個別受試者的藥品動力學參數............50
表16 Voltaren SR與DSSR之平均藥物動力學參數..................53
表17 Diclo-puren與Weren EMC生體可用率比較之受試者資料.......54
表18 Diclo-puren與Weren EMC於pH1.2溶離度試驗................55
表18-1 Weren EMC之溶離度..................................55
表18-2 Diclo-puren之溶離度................................55
表19 Diclo-puren與Weren EMC於pH4.5之溶離試驗................56
表19-1 Weren EMC之溶離度..................................56
表19-2 Diclo-puren之溶離度................................56
表20 Diclo-puren與Weren EMC於pH6.8之溶離試驗................57
表20-1 Weren EMC之溶離度..................................57
表20-2 Diclo-puren之溶離度................................57
表21 Diclo-puren與Weren EMC於H2O之溶離試驗..................58
表21-1 Weren EMC之溶離度..................................58
表21-2 Diclo-puren之溶離度................................58
表22 口服Diclo-puren 50膠囊後血漿中Diclofenac sod.之濃度....59
表23 口服Weren EMC 50膠囊後血漿中Diclofenac sod.之濃度......60
表24 Diclo-puren與Weren EMC個別受試者血漿中之濃度...........61
表25 Diclo-puren與Weren EMC血漿中平均濃度...................67
表26 Weren EMC及Diclo-puren個別及平均之全部藥物動力學參數...68
表27 Diclo-puren與Weren EMC之個別受試者的藥品動力學參數.....69
表28 Diclo-puren與Weren EMC之平均藥物動力學參數.............75
附圖目錄
圖1 Diclofenac sodiun之HPLC層析圖...........................76
圖2 Voltaren SR與DSSR生體相等性預試驗之標準檢量線曲線.......77
圖3 DSSR及Voltaren SR之溶離試驗曲線圖.......................78
圖3-1 Water alone.........................................78
圖3-2 pH 6.8.............................................78
圖3-3 PH1.2 for60min → pH6.8.............................79
圖3-4 PH1.2 for60min → pH6.8.............................79
圖4 DSSR及Voltaren SR之個別血漿中濃度曲線圖.................80
圖5 DSSR及Voltaren SR之平均血中濃度曲線圖...................83
圖6 Diclo-puren與Weren EMC生體可用率比較之標準檢量線曲線....84
圖7 Diclo-puren與Weren EMC生體可用率比較之個別受試者之檢量線85
圖8 Weren EMC及Diclo-puren之溶離試驗曲線圖..................91
圖8-1 pH1.2...............................................91
圖8-2 pH4.5...............................................91
圖8-3 PH6.8...............................................92
圖8-4 H2O.................................................92
圖9 Diclo-puren與Weren EMC個別血漿中濃度曲線圖..............93
圖10 Diclo-puren與Weren EMC之平均血中濃度曲線圖.............99
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