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研究生:黃妍菱
研究生(外文):Yen-Ling Huang
論文名稱:微脂粒包覆一系列茶多酚其物理化學性質及體內藥物動力學研究
論文名稱(外文):The physicochemical characteristics and in vivo pharmacokinetics of tea catechins encapsulated with liposomes
指導教授:方嘉佑
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
論文頁數:89
中文關鍵詞:茶多酚微脂粒經皮吸收基底細胞癌酒精
外文關鍵詞:(+)-catechin(−)-epicatechin(−)-epigallocatechin-3-gallate (EGCG)liposomesskintumorethanol
相關次數:
  • 被引用被引用:3
  • 點閱點閱:248
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  • 收藏至我的研究室書目清單書目收藏:1
茶多酚化合物 (catechins) 包括 (+)-catechin, (-)-epicatechin 及 (-)-epigallocatechin-3-gallate (EGCG) 具有預防癌症及抗氧化的效果。口服茶多酚的生體可用率極低,局部投與藥物在標的組織可以減少或排除系統性的副作用且可以避開肝臟的首渡效應。本實驗目的為探討利用微脂粒包覆一系列茶多酚化合物局部投與在腫瘤或皮膚上,在目標組織內的藥物力學。微脂粒的處方內容包含了磷脂質、膽固醇或陰離子界面活性劑,以減壓濃縮的方式再加入水或 15% 酒精水溶液以探針式超音波製備,進行一系列針對微脂粒粒子的粒徑、表面電位和對茶多酚化合物的包埋率等物理化學性質評估。處方中加有 15% 酒精或陰離子界面活性劑如 deoxycholic acid (DA) 或 dicetyl phosphate (DP) 會降低微脂粒脂質雙層膜的堅硬度提高茶多酚自微脂粒釋放速率。微脂粒包覆茶多酚以直接注射的方式注射至腫瘤內比游離藥物能提高藥物在腫瘤內的濃度,減少藥物的代謝延長藥物在目標組織的時間,提高生體可用率。藥物自微脂粒的釋放速率和微脂粒的粒徑對藥物滯留在腫瘤內的時間佔了重要的角色。另一方面含有 15% 酒精 和陰子界面活性劑的微脂粒,對裸鼠皮膚的穿透速率較控制組增加 5~7 倍。提高磷脂質雙層的彈性會促進藥物的經皮傳遞。推測皮膚細胞間空隙是 (+)-catechin 微脂粒經皮吸收的主要途徑。含有沒食子酸酯基團的 (-)-EGCG 的油/水分配係數高,明顯能提高藥物在局部的吸收。皮膚的安全性試驗可用做評估微脂粒實際運用在局部投藥的可行性。
Tea polyphenols, including (+)-catechin, (−)-epicatechin, and (−)-epigallocatechin-3-gallate (EGCG), have been shown to possess potent antioxidant and chemopreventive activities. The aim of this study was to evaluate the possibility of using liposomes encapsulating tea catechins for local delivery, including tumor and skin deposition of these polyphenols. Liposomes containing egg phosphatidylcholine, cholesterol, or anionic species were prepared by the solvent evaporation method and then passed through a probe sonicator. The size, zeta potential, and entrapment efficiency of these liposomal formulations were determined to correlate with the following in vivo study. The release rate study had showed that the inclusion of ethanol and the anionic species such as deoxycholic acid (DA) or dicetyl phosphate (DP) could reduce the rigidity of lipid bilayers, leading to the fast release from these formulations. Liposomes delivered catechins into the solid tumor to a greater amount than the aqueous solution. The drug release rate and vesicle size of liposomes may predominate the drug deposition in tumor tissues. No significant increase of skin deposition of catechins was observed after topical application of liposomes in absence of 15% ethanol. On the other hand, incorporation of anionic surfactants in the liposomes in the presence of 15% ethanol increased the (+)-catechin permeation by 5~7-fold as compared to the control in trandstermal delivery. The flexibility of the bilayers is suggested to be an important factor governing the enhancing effect of liposomes. Intercellular spaces within the stratum corneum but not shunt routes are the major pathways for (+)-catechin delivery from liposomes.. The presence of gallic acid ester in structures (EGCG) significantly increased the tissue uptake of catechins. The skin tolerance test assured the safety of the practical use of liposomes developed in this study local deposition in skin or tumor
目 錄

頁次
中文摘要 1
英文摘要 2
一、研究動機 3
二、大綱 4
1. 微脂粒 4
1-1微脂粒的組成 5
1-2 微脂粒的構造 7
1-3 微脂粒的分類 9
1-4微脂粒的製備 11
1-4-1 多層膜微脂粒的製備方法 ---------------------11
1-4-2大粒單層膜微脂粒的製備方法 ---------------14
1-4-3小粒單層膜微脂粒的製備方法 ---------------14
1-5 微脂粒的安定性 14
1-6 微脂粒的應用 16
2. 皮膚 20
2-1表皮 20
2-2 真皮 21
2-3 皮下組織 22
2-4經皮輸藥系統之簡介 22
2-5藥物穿透皮膚的途徑 23
2-6 藥物穿透皮膚之原理 25
2-7 影響經皮吸收之因素 27
2. 腫瘤內注射 27
3. 模式藥物 catechins------------------------------------------ 27
三、 實驗材料及方法
1. 實驗材料 30
1-1 試劑 30
1-2儀器 31

2. 實驗方法 32
2-1 微脂粒的製備 32
2-2 微脂粒安定性實驗 32
2-2-1粒徑 ------------------------------------------------ 33
2-2-2表面電位 ------------------------------------------ 33
2-3 微脂粒的表面張力 33
2-4 包埋率的測定 33
2-5 體外試驗 34
2-5-1體外藥物釋放試驗 34
2-5-2 體外試驗皮內藥物含量 35
2-5-3 以HPLC分析檢品內藥物含量 35
2-6 體內皮內藥物含量試驗 37
2-7 腫瘤內注射微脂粒 37
2-7-1細胞培養 37
2-7-2皮下植入腫瘤 37
2-7-3 腫瘤內注射一系列包覆茶多酚的微脂粒 38
2-8 統計方法 38

四、實驗結果及討論 39
1. 微脂粒的物理化學性質 39
1-1微脂粒處方 39
1-2微脂粒的粒徑大小及粒子表面電位 41
1-3一系列茶多酚化合物在微脂粒中的包埋率 44
1-4微脂粒安定性的評估 46
2. 一系列茶多酚化合物自微脂粒釋放之評估 49
2-1茶多酚在微脂粒中釋放速率 49
2-2皮膚穿透速率的評估 ---------------------------------- 52
2-3體外穿透試驗 ------------------------------------------- 55
2-4腫瘤內注射茶多酚微脂粒 ---------------------------- 57
五、結論-------------------------------------------------------------- 60
六、未來展望 61
七 、參考文獻 62

圖 目 錄
頁次
圖一 不同結構的兩性分子在水溶液中排列型態 5
圖二 磷脂質的基本結構 6
圖三 脂質雙層結構 7
圖四 藥物在微脂粒中的分布情形 8
圖五 微脂粒結構及分類 10
圖六 薄膜振搖法製備微脂粒 12
圖七 皮膚各層之結構圖 20
圖八 藥物穿透皮膚途徑 24
圖九 藥物以擴散方式穿透膜之簡圖 26
圖十 直立式擴散裝置 35
圖十一 微脂粒安定性試驗,粒子大小的變化 47
圖十二 微脂粒安定性試驗,粒子表面電位的變化 48
圖十三 藥物經時累積濃度變化圖 (人工膜) 為穿透障蔽 50
圖十四 活體模式下 藥物皮內含量分析 54
圖十五 藥物經時累積濃度變化圖 (裸鼠皮) 為穿透障蔽 56
圖十六 腫瘤內注射一系列的茶多酚化合物 59


表 目 錄
頁次
表一 不同取代基的磷脂質 6
表二 微脂粒的應用 16
表三 目前已上市或臨床試驗中之微脂粒藥物 17
表四 catechins 結構圖 29
表五 微脂粒的處方 39
表六 帶電添加物的結構 40
表七 微脂粒處方的粒徑及表面電位結果 43
表八 一系列茶多酚在不同處方的微脂粒的包埋率 -------- 45
表九 一系列茶多酚化合物在微脂粒的釋放速率 51
表十 一系列茶多酚化合物在微脂粒的經皮穿透速率 ----- 55
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