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研究生:翁玟雯
研究生(外文):wen-wen wong
論文名稱:以化學性及物理性方法促進茶鹼及一系列茶多酚經皮膚吸收之研究
論文名稱(外文):Enhancing percutaneous absorption of theophylline and tea catechins by chemical and physical methods
指導教授:方嘉佑
指導教授(外文):jia-you fang
學位類別:碩士
校院名稱:長庚大學
系所名稱:天然藥物研究所
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:2005
畢業學年度:93
語文別:中文
中文關鍵詞:辛夷茶鹼茶多酚電破透入法離子電透入法
外文關鍵詞:theophyllinetea catechinsMagnolia fargesiielectroporationiontophoresis
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中文摘要
為了使親水性藥物包括茶鹼 (theophylline) 和一系列茶多酚,如 (+)-catechin, (-)-epicatechin 和 (-)-epigallocatechin gallate (EGCG) 穿透皮膚,利用化學性和物理性的促進方法,使藥物達到最高的穿透濃度。辛夷精油主要成分是屬於氧化性單萜類 (monoterpenes) 及倍半萜類 (sesquiterpenes),因此對於 theophylline 和 (+)-catechin 在體外穿透試驗具有明顯的促進效果。將辛夷精油作用在活體的穿透試驗中,發現其可增加 (+)-catechin 的皮內含量而 theophylline 則並沒有明顯增加。除此之外,利用生物體內微透析實驗,監測皮下的藥物量,在辛夷精油促進之下,theophylline 相對於控制組則具有高度穿透量。進一步對辛夷所含的各種化合物當促進劑,經過一系列的體外實驗,包括角質層/溶媒分配係數試驗和 微脂粒的融合現象,並探討其結構與活性之間的關係 (Quantitative Structure-Activity Relationship 簡稱QSAR)。在辛夷和萜纇化合物的皮膚耐受性研究上,利用表面水分散失儀和皮膚色差儀確認辛夷對皮膚並不致於造成明顯之刺激性。另外再利用角質層細胞,偵測皮膚細胞存活率和發炎反應,其研究結果顯示辛夷對細胞的毒性作用,與控制組比較並無統計學上的意義,因此顯示經皮促進的作用機制和皮膚的破壞並非絕對相關。利用物理性的促進方式如電破透入法 (electroporation, EP)、離子電透入法 (iontophoresis, ITP) 或合併兩者技術,評估茶多酚在豬皮促進穿透之效果。 (+)-Catechin 和 (-)-epicatechin 屬於同質異構物,當EP合併ITP促進時,則 (+)-catechin 的穿透量具有協同的效果,但 (-)-epicatechin 則無此現象。另一方面,因為 EGCG 結構含有 gallic acid ester 基團,因此於投與後在皮膚內部可明顯增加藥物量。並於此物理促進研究中,以體外表面水分散失測定和角質層脂質微脂粒 (stratum corneum lipid liposomes, SCLLs) 的融合現象,了解茶多酚的經皮傳遞機轉。
To improve the skin permeation of theophylline and tea catechins, including (+)-catechin, (-)-epicatechin and (-)-epigallocatechin-3-gallate (EGCG) enhanced by chemical and physical methods. Oxygenated monoterpenes and sesquiterpenes are the major components of Magnolia fargesii (MF) essential oil. The in vitro permeation of theophylline and (+)-catechin was significantly enhanced after treatment with MF essential oil. The essential oil increased the in vivo skin deposition of (+)-catechin but not theophylline. On the other hand, in vivo microdialysis showed a higher subcutaneous theophylline amount after essential oil treatment. Further, to investigate the mechanism of percutaneous absorption enhancement of (+)-catechin and theophylline across wistar rate epidermis by terpenes. To evaluate the Quantitative Structure Activity Relationship (QSAR) by stratum corneum (SC)/solvent partition experiment and dipalmitoylphousphatidylcholine (DPPC) liposomes fusion phenomenon. The in vivo skin tolerance study determined by transepidermal water loss (TEWL) and colorimetry. It confirmed that no irritation of the skin was detected when using MF essential oil. In vitro cell viability and prostaglandin E2 release by skin keratinocytes indicated that there was low or negligible cytotoxicity by MF essential oil. Further, to assess the effects of electroporation, iontophoresis, and their combination on the transdermal delivery of tea catechins across porcin skin. A synergistic effect was detected for (+)-catechin but not for (-)-epicatechin after application of electroporation followed by iontophoresis. The presence of a gallic acid ester in the structure of EGCG significantly increased the skin uptake of catechins. The mechanisms by these catechins were transported via the skin were elucidated by examining the electric conductivity, TEWL and fusion of stratum corneum lipid liposomes (SCLLs).
目錄 頁數
研究動機與目的 1
一、緒論 2
1. 1 皮膚的組織與結構 2
1. 2 經皮輸藥系統 (Transdermal Drug Delivery System, TDDS) 4
1. 2. 1 藥物穿透皮膚的原理------------------------------------------------------5
1. 2. 2 藥物經皮穿透途徑---------------------------------------------------------6
1. 2. 3 經皮輸藥系統的優點與缺點---------------------------------------------8
1. 2. 4 理想的經皮吸收促進劑---------------------------------------------------8
1. 2. 5 促進經皮吸收的方法------------------------------------------------------9
1. 3 模式藥物 12
1. 3. 1 茶鹼 12
1. 3. 2 茶多酚 13
1. 4 化學促進劑-辛夷 14
二、 材料與方法 17
2. 1 儀器設備與藥品 17
2. 2 辛夷的萃取分析 19
2. 3 化學性促進之處方設計 20
2. 3. 1 經皮穿透試驗 20
2. 3. 2 角質層/溶媒的分配試驗 23
2. 3. 3 DPPC 微脂粒實驗 23
2. 3. 4 微透析------------------------------------------------------------------------23
2. 3. 5 皮膚耐受性試驗 24
2. 3. 6 體外細胞毒性試驗---------------------------------------------------------25
2. 4 物理性促進之處方設計 26
2. 4. 1 經皮穿透試驗 26
2. 4. 2 電位滴定---------------------------------------------------------------------27
2. 4. 3 角質層脂質微脂粒試驗 (SCLLs)---------------------------------------28
2. 4. 4 體外水分散失試驗---------------------------------------------------------28
2. 5 Theophylline 的高效能液相層析分析方法 28
2. 6 (+)-catechin, (-)-epicatechin, (-)-EGCG 的高效能液相層析分析方法 29
2. 7 統計方法 29
三、結果與討論 30
3. 1 辛夷精油的主要成份定量 30
3. 2 體外穿透實驗-化學性促進 (In vitro permeation) 30
3. 2. 1 天然辛夷和人工辛夷的促進效果 40
3. 2. 2 萜類精油的體外穿透試驗 40
3. 2. 3 微透析試驗 43
3. 2. 4 角質層/溶媒的分配係數作用--------------------------------------------45
3. 2. 5 DPPC liposome 的融合現象 49
3. 2. 6 萜類之皮膚耐受性試驗 50
3. 3 活體皮內藥物含量 (In vivo skin deposition) 51
3. 4 細胞發炎反應實驗 (PGE2 determination) 53
3. 5 皮膚耐受性試驗 (In vivo skin tolerance test) 55
3. 6 物理性促進方法之協同作用---------------------------------------------------57
3. 7 從皮內儲存槽釋放 (+)-catechin之試驗 62
3. 8 體外穿透試驗之皮膚結構變化測定------------------------------------------64
四、結論 66
五、參考文獻 68
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