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研究生:何怡儂
研究生(外文):Yi-Nung Ho
論文名稱:促進綠茶萃取物生體可利用率之纖維素經皮遞藥系統
論文名稱(外文):Improvement of the Bioavailability of Green Tea Extract in Cellulose-based Transdermal Delivery System
指導教授:謝明發謝明發引用關係
指導教授(外文):Ming-Fa Hsieh
學位類別:碩士
校院名稱:中原大學
系所名稱:醫學工程研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:118
中文關鍵詞:生物利用率兒茶素抗氧化經皮遞藥系統
外文關鍵詞:catechinbioavailabanti-oxidativetransdermal delivery
相關次數:
  • 被引用被引用:3
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  • 收藏至我的研究室書目清單書目收藏:2
本研究製備一種利用聚乙二醇-己內酯改質親水性纖維素作為經皮遞藥系統並搭載綠茶萃取物,比較此系統與口服綠茶萃取物生體可利用率的差異。本研究內容分為四部份: (一)藉由有機溶劑萃取綠茶中的兒茶素,利用高效能液相層析儀定量及定性分析,測試綠茶萃取物在不同濃度與不同反應時間下抗氧化能力,(二)製備不同分子量的聚乙二醇-聚己內酯接枝於纖維素(E50C36-HEC、E50C80-HEC)和純纖維素(HEC)三種貼片,包含材料顯微結構性質分析及接觸角量測,並以體外藥物釋放裝置評估綠茶萃取物滲透豬皮之能力,(三)與巨噬細胞共培養做抗發炎之體外評估,(四)比較貼片與口服兩種不同給藥途徑,綠茶萃取物在大鼠模式下之藥物動力學。本研究以氯仿和乙酸乙酯萃取後可得到純度84 %的綠茶萃取物,同時咖啡因含量為0.09 %,當綠茶萃取物在低濃度0.05 mg/mL與0.01 mg/mL時,自由基清除率達90 %以上,且在3分鐘內自由基清除率達到穩定狀態。在掃描式電子顯微鏡下觀察到,聚乙二醇-己內酯改質後纖維素薄膜表面粗糙度增加,在體外藥物釋放測試結果發現,E50C36-HEC、E50C80-HEC和HEC搭載1.5 mg/cm2綠茶萃取物在48小時後滲透量分別可達到0.8、0.15和0.04 mg/mL。在抗發炎反應中,若先加入4.58 μg/mL之綠茶萃取物與活化後的巨噬細胞共培養24小時,能夠抑制一氧化氮的產生;而先以脂多醣刺激巨噬細胞後再加入綠茶萃取物則沒有抑制效果。第四部份,口服200 mg/kg綠茶萃取物經過24小時後,血漿中EGCG的曲線下面積為34.22 μg.hr/mg;平均血漿中最高濃度為22.7 μg/mg;搭載綠茶萃取物的E50C36-HEC、E50C80-HEC、HEC三種貼片,平均曲線下面積為356.24±3.24、293.45±4.68、245.08±14.65 μg.hr/mg;平均血漿中最高濃度為19.03、16.40、14.66 μg/mg;E50C36-HEC貼片的相對生體可利用率為10.4。未來將探討纖維素之貼片搭載抗氧化及抗炎性之綠茶萃取物,應用於傷口敷料,達到加速傷口癒合的效果。
In this present study, we used mPEG-PCL-graft-2-hydroxycellulose (mPEG-PCL-g-HEC) as a penetration matrix for skin delivery system of anti-oxidative catechins extracted from green tea in order to compare bioavailability of this system and oral administration. The study was divided into four parts: In the first part, different organic solvents were used to extract the catechins from green tea. High-performance liquid chromatography (HPLC) was used to perform qualitative and quantitative analyses of catechins. The anti-oxidant capacity of catechins from green tea extract was evaluated by DPPH radical experiment. In the second part, preparation and characterization of copolymer thin films were performed (E50C36-HEC, E50C80-HEC, HEC). The scanning electron microscopy (SEM) was used to observe the microstructure of patches. Moreover, in-vitro catechin release from prepared patches was obtained through porcine skin. In the third part, the safety evaluations of catechins were confirmed by nitric oxide (NO) and tretrazolium (MTT) assay on macrophages. The cell survival and co-culture were demostrated for anti-inflammatory response. Finally, animal study was examined in rats to measure pharmacokinetics of green tea extract. The HPLC results confirmed that a large amount of caffeine was removed from green tea extract after two steps of chloroform and ethyl acetate extraction. The green tea extract content was high purity with 84 % of EGCG and 0.09 % of caffeine. The radical scavenging activity of the extract was up to 80 % at 0.05 mg/mL and 0.01 mg/mL and the radical scavenging activity able to achieve 98 % within 10 minutes. By adding the PEG-PCL polymer, surface of film was rougher than that of pure cellulose. The drug loading content of E50C36-HEC was 1.5 mg/cm2 and the in-vitro drug release was found to be 0.8 mg/mL for 48 h. In addition, anti-inflammatory response, 4.58 μg/mL of green tea extracts and activated macrophages were co-cultured showed that NO production was generated. Finally, animal experiments were conducted through the oral and transdermal administration. In the oral administration, the green tea extract AUC was 34.22 μg.hr/mg and Cmax was 22.7 μg/mg. In contrast, in the transdermal administration, the green tea extract AUC were 347.21, 293.45 and 245.05 μg hr/mg, and Cmax were 19.03、16.40、14.66 μg/mg for E50C36-HEC, E50C80-HEC and HEC patches, respectively. 10.4 improved relative bioavailability was observed in the transdermal administration of cactechin. We expected that green tea extract in cellulose-base transdermal delivery system will apply to the wound dressing to accelerate the wound healing effect.
中文摘要 I
Abstract III
致謝 V
目錄 VI
圖索引 VIII
表索引 X
縮寫及中英文對照表 XI
第一章 緒論 1
1-1 研究背景 1
1-2 研究動機與目的 3
第二章 文獻回顧 5
2-1 兒茶素簡介 5
2-2 兒茶素生物活性 6
2-3藥物動力學簡介 10
2-3-1 兒茶素之藥物動力學 12
2-4 發炎反應(Inflammation) 14
2-4-1 巨噬細胞(Macrophages)及其功能 14
2-4-2 脂多醣 (Lipopolysaccharide,LPS) 14
2-4-3 發炎與巨噬細胞 15
2-4-4 一氧化氮之特性(Nitric oxide,NO) 16
2-5兒茶素抑制發炎反應 17
2-6 經皮遞藥系統 17
2-6-1 皮膚組織結構 17
2-6-2 藥物經皮途徑 19
2-6-3 促進經皮吸收之方法 21
2-6-4 兒茶素經皮給藥技術 21
第三章 材料與實驗方法 26
3.1 實驗架構 26
3-1-1 實驗儀器 27
3-1-2 實驗藥品 29
3-2 實驗藥品配置 33
3-3萃取兒茶素及分析 35
3-3-1 溶劑法萃取兒茶素 35
3-3-2 HPLC分析綠茶萃取物 35
3-3-3 抗氧化能力測定 36
3-4 纖維素薄膜製備 37
3-4-1 接觸角測定 37
3-4-2 含有綠茶萃取物之貼片製備 37
3-4-3 厚度量測 38
3-4-4 表面型態觀察 38
3-5 巨噬細胞株之培養 38
3-5-1細胞解凍 38
3-5-2 繼代培養 39
3-5-3 細胞計數 39
3-5-4 細胞冷凍保存 40
3-6 細胞評估及生物相容性 40
3-6-1 巨噬細胞分泌 NO 40
3-6-2 MTT分析 41
3-6-3 蛋白質定量分析 42
3-7 體外藥物釋放行為 43
3-7-1 豬皮前處理 43
3-7-2分析綠茶萃取物濃度 43
3-7-3 綠茶萃取物經豬皮穿透實驗 43
3-8貼片之體外藥物釋放實驗 44
3-9 藥物穿透豬皮之擴散速率 45
3-10 動物實驗 46
3-10-1致敏性測試 47
3-10-2藥物動力學 47
3-11 統計分析方法 52
第四章 結果與討論 53
4-1 萃取兒茶素及定量分析 53
4-1-1綠茶萃取物之HPLC分析方法 53
4-1-2 不同濃度之綠茶萃取物清除自由基能力測試 56
4-1-3 綠茶萃取物在不同時間清除自由基能力之測試 57
4-2含有綠茶萃取物之貼片材料性質分析 58
4-2-1接觸角測定 58
4-2-2 利用SEM觀察表面型態 58
4-2-3 厚度量測 58
4-3 抗發炎之體外評估 59
4-3-1 各濃度脂多醣對巨噬細胞之一氧化氮分析 59
4-3-2 各濃度綠茶萃取物對巨噬細胞之一氧化氮分析 60
4-3-3 綠茶萃取物與脂多醣對巨噬細胞共培養之一氧化氮分析 60
4-3-4 綠茶萃取物與脂多醣各濃度對巨噬細胞之細胞存活率分析 62
4-4 體外藥物釋放行為 63
4-4-1 綠茶萃取物溶液經豬皮釋放行為 63
4-4-2 貼片之體外藥物釋放實驗 64
4-4-3 波音波檢測豬皮表面 65
4-5 動物實驗 66
第五章 結論 69
參考文獻 91
圖索引
圖1-1 經皮遞藥控制系統.......................................................................................3
圖2-1 兒茶素結構式...............................................................................................9
圖2-2 綠茶的功效.................................................................................................10
圖2-3 藥物於體內之吸收、分佈、代謝情形.........................................................12
圖2-4 藥物血中濃度-時間曲線變化圖................................................................12
圖2-5 皮膚組織的結構.........................................................................................19
圖2-6 藥物經由皮膚角質層,汗腺與毛囊的穿透路徑.....................................20
圖2-7 藥物經由細胞間或穿透細胞的途徑.........................................................20
圖3-1 綠茶萃取物與PEG-PCL-HEC之混合液..................................................26
圖3-2 MTT原理.....................................................................................................40
圖3-3 Franz擴散裝置.............................................................................................42
圖3-4 固相萃取步驟.............................................................................................44
圖3-5 以餵食管餵食大鼠.....................................................................................46
圖3-6 含有綠茶萃取物貼片貼於大鼠背部.........................................................47
圖3-7 固相萃取步驟.............................................................................................48
圖4-1 萃取兒茶素時各步驟層析圖.....................................................................72
圖4-2綠茶萃取物之UV光譜圖............................................................................73
圖4-3 EGCG、EC、GA、咖啡因四種標準品之層析圖.........................................74
圖4-4 EGCG之校正曲線.......................................................................................75
圖4-5 咖啡因之校正曲線.....................................................................................75
圖4-6 不同濃度綠茶萃取物之DPPH自由基清除能力測試..............................76
圖4-7 兒茶素氧化後結構式.................................................................................76
圖4-8 時間對自由基清除能力之關係.................................................................77
圖4-9 量測背膠改質前後之接觸角.....................................................................78
圖4-10 SEM觀察共聚物薄膜表面微結構型態...................................................79
圖4-11 綠茶萃取物之貼片...................................................................................80
圖4-12 不同濃度脂多醣對巨噬細胞產生亞硝酸之定量分析............................81
圖4-13 不同濃度綠茶萃取物對巨噬細胞產生亞硝酸之定量分析...................81
圖4-14脂多醣與綠茶萃取物對巨噬細胞共培養之一氧化氮含量.....................82
圖4-15 脂多醣與綠茶萃取物共培養刺激巨噬細胞產生的亞硝酸量測............82
圖4-16 不同濃度脂多醣對巨噬細胞之細胞存活率...........................................83
圖4-17 不同濃度的綠茶萃取物對巨噬細胞之細胞存活率...............................83
圖4-18 脂多醣與綠茶萃取物對巨噬細胞共培養之細胞存活率……..…..........84
圖4-19 不同濃度之綠茶萃取物溶液體外藥物釋放測試...................................84
圖4-20 低劑量綠茶萃取物貼片之體外藥物釋放測試........................................85
圖4-20 高劑量綠茶萃取物貼片之體外藥物釋放測試........................................85
圖4-22 波音波觀察豬皮表面結構........................................................................86
圖4-23 敏性測試....................................................................................................87
圖4-24 大鼠血漿中綠茶萃取物濃度與時間曲線................................................87






















表索引
表2-1 四種兒茶素的基本結構...............................................................................9
表2-2 兒茶素於生物體內之濃度.........................................................................11
表4-1 各溶劑萃取步驟EGCG及咖啡因定量分析.............................................88
表4-2 低劑量綠茶萃取物貼片之藥物動力學參數.............................................89
表4-3 高劑量綠茶萃取物貼片之藥物動力學參數..............................................89
表4-4 綠茶萃取物於大鼠體內之藥物動力學參數..............................................90
表4-5 比較不同給藥途徑下藥物動力學參數之比較.........................................90
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