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研究生:邱顯智
研究生(外文):Hsien-Chih Chiu
論文名稱:以一系列體外及體內評估方法研究經皮吸收促進劑的有效性及安全性:以Flurbiprofen及Curcumin為模式藥物
論文名稱(外文):Evaluation of Efficacy and Safety on Skin Permeation Enhancers: Flurbiprofen and Curcumin as Model drugs
指導教授:方嘉佑
指導教授(外文):Jia-You Fang Ph. D.
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:2003
畢業學年度:91
語文別:中文
論文頁數:151
中文關鍵詞:經皮吸收flurbiprofen非侵入性生物評估方法刺激性促進劑curcumin細胞培養Botryococcus braunii
外文關鍵詞:Percutaneous absorptionbioengineering methodirritationenhancercurcuminflurbiprofencell cultureBotryococcus braunii
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中文摘要
此研究以體內及體外的方法評估常被使用的經皮吸收促進劑的有效性及安全性。本實驗有設計有三部分: (一)以flurbiprofen作為模式藥物,檢視其在添加經皮吸收促進劑後,flurbiprofen穿透量的變化。處方中添加經皮吸收促進劑後,在體外穿透試驗以Franz cell裝置進行有效性評估,在體內實驗方面則檢視投與後皮內Flurbiprofen含量變化。藉由體外皮膚細胞培養方式,體內非侵入性生物評估方法以及皮膚組織型態的改變,來評估經皮吸收促進劑對皮膚所造成的刺激性。(二)以curcumin作為模式藥物,檢視其經以經皮吸收促進劑預處理後,curcumin穿透量的變化。在體外穿透試驗以Franz cell裝置進行有效性評估,在體內實驗方面則檢視投與後皮內curcumin含量變化。以terpenes, flavonoids和 cholestanol為作經皮吸收促進劑。以體內非侵入性生物評估方法以及皮膚組織型態的改變,來評估經皮吸收促進劑對皮膚所造成的刺激性。(三) 以flurbiprofen作為模式藥物,皮膚經以經皮吸收促進劑預處理後,檢視flurbiprofen穿透量的變化,所使用的經皮吸收促進劑萃取自Botryococcus braunii中的脂肪酸和與其同比例化合物混合的脂肪酸或單一成份進行比較。且以表皮水分散失 (TEWL)、電子顯微鏡 (SEM) 的改變、組織切片的病理現像和經細胞培養所產生PGE2的量,來評估經皮吸收促進劑對皮膚所造成的刺激性。
而d-limonene的促進效果則略低於脂肪酸。Azone和l--lecithin甚至會對flurbiprofen投與後產生抑制作用。由研究結果得知,經皮吸收促進劑對皮膚的破壞及所造成的發炎反應和其促進結果並無絕對的相關性。雖然以不同的方法所觀察到的刺激性並不完全一樣,但以單一不飽和脂肪酸有較大的刺激性,其次是混合的脂肪酸,Azone、d-limonene又次之,l--lecithin有最小的刺激性。
以cyclic monoterpenes當作經皮吸收促進劑,其對curcumin有最好的促進效果。而在投與經皮吸收促進劑以terpineol有最高的TEWL值,而ketocholestaol的TEWL值和控制組比較幾乎無差異;組織學的變化以carveol最大,而ketocholestanol與控制組相似。
以一系列的單一成份不飽和脂肪酸當作經皮吸收促進劑,其對flurbiprofen有最好的促進效果;而萃取自Botryococcus braunii中的脂肪酸,其促進效能與同比例化合物混合的脂肪酸,有相似的促進效能,但較單一成份脂肪酸促進效果和緩,且其TEWL、SEM的改變、組織切片的病理現像和經細胞培養所產生PGE2的量,皆比同比例化合物混合的脂肪酸或單一成分的刺激性低,這說明Botryococcus braunii中的脂肪酸為一種有效且毒性較低的經皮吸促進劑,值得進一步開發及研究。
研究結果得知,經皮吸收促進劑對皮膚的破壞及所造成的發炎反應和其促進結果並無絕對的相關性。由此研究實驗的設計可建立對一些常用的經皮吸收促進劑的完整評估模式。
關鍵字:經皮吸收、 flurbiprofen、curcumin、促進劑、刺激性、非侵入性生物評估方法、細胞培養、Botryococcus braunii
Abstract
The efficacy and safety of commonly used enhancers were evaluated by in vitro and in vivo methods in this study. In this study, three sections were investigated: (1) Flurbiprofen was used as the model drug to examine the enhancing capacity of these enhancers. Both in vitro permeation by Franz cells and in vivo kinetics of skin disposition were performed to determine the flurbiprofen permeation by enhancers. In vitro prostaglandin E2 (PGE2) release by cell culture, in vivo bioengineering methods, and skin morphology change were evaluated to examine the irritation of enhancers on skin. (2) Curcumin was used as the model drug to examine the enhancing capacity of these enhancers. The in vitro and in vivo skin absorption of curcumin was investigated after application of enhancers using Wistar rat as an animal model. The enhancers were selected in this study including terpenes, flavonoids, and cholestanol. The irritant profiles of these enhancers were also established by transepidermal water loss (TEWL) and histological observations. (3) Flurbiprofen was used as the model drug to examine the enhancing capacity of these enhancers. The in vitro and in vivo skin absorption of flurbiprofen was investigated after application of enhancers using Wistar rat as an animal model. The enhancers were selected in this study including fatty acids extraction from Botryococcus braunii、oleic acid、linolenic acid and mixed fatty acid. The irritant profiles of these enhancers were also established by transepidermal water loss (TEWL) 、SEM、cell culture and histological observations.
A series of unsaturated fatty acids showed the greatest enhancement for flurbiprofen permeation. The pure fatty acid generally showed the most irritant properties, followed by mixed fatty acids and fatty acids extraction from Botryococcus braunii. Fatty acids extraction from Botryococcus braunii and mixed fatty acids showed the same enhancement on flurbiprofen permeation. The enhancing effect of d-limonene was slightly lower than that of fatty acids. Azone and l--lecithin even reduced skin depot after flurbiprofen application. The fatty acids generally showed the most irritant properties, followed by Azone, d-limonene and l--lecithin.
Cyclic monoterpenes generally showed the stronger enhancement on curcumin permeation than the other enhancers. The modulation of concentration and pretreatment duration of enhancers may indicate the enhancers varied in their abilities and mechanisms to enhance curcumin permeation. Terpineol produced the highest TEWL values among the enhancers tested, whereas ketocholestanol showed no or negligible increase in TEWL as compared to control. The results showed that skin disruption and inflammation did not necessary correspond to the enhancing efficiency of the enhancers.
The results showed that the skin disruption and inflammation did not necessary correspond to the enhancing efficiency of enhancers. Moreover, some discrepancies were observed in these irritant profiles by using various methods.
A complete portrait about efficacy and safety of commonly used enhancers was therefore established in this study.
Keywords: Percutaneous absorption、 flurbiprofen、 curcumin、 enhancer、 irritation、bioengineering method、 cell culture、Botryococcus braunii
目 錄 頁 數
指導教授推薦書
口試委員會審定書
授權書
簽署人須知
中文摘要
英文摘要
誌謝
壹、緒論 1
(一) 皮膚及皮膚用藥 1
(二) 模式藥物 13
(三) 研究目的 18
貳、材料與方法 20
(一)、試劑、醫材與儀器設備 20
(二)、方法 25
(三)、統計分析方法 42
參、結果與討論 43
(一)、Flurbiprofen 43
(二)、Curcumin 81
(三)、Botryococcus braunii 108
肆、結論 144
(一)、Flurbiprofen 144
(二)、Curcumin 144
(三)、Botryococcus braunii 145
伍、參考文獻References 146
伍、參考文獻
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