臺灣博碩士論文加值系統

　　先前的研究得知，白藜蘆醇 (resveratrol) 及其衍生物如： viniferin、ampelopsin C、vitisin A 和 polydatin 富含 OH 基，較親水性，具有抗癌、抗氧化及抗發炎等作用。而藥物的分子量、官能基及親脂性皆會影響藥物穿透路徑。藥物從皮膚表層直接穿透角質層細胞、穿透角質細胞間隙或經由附屬器官穿透進入到深層皮膚時，這些穿透路徑也會因物化性質而有差異。此研究擬探討 resveratrol 及其衍生物在正常的及不同處理的動物皮的穿透情形，並分析藥物的穿透路徑。進一步，利用人類角質細胞及嗜中性白血球進行抗發炎活性測定。利用裸鼠探討 resveratrol 及其衍生物的藥物安全性、皮膚耐受性以及活體皮內含量；利用生物容積因子預測 resveratrol 及其衍生物的親脂性，由結果發現 vitisin A 為親脂性，polydatin 為親水性。利用體外經皮吸收試驗得知，在 3 mM 的濃度下裸鼠皮、豬皮皮內含量最高的為 resveratrol。穿透能力最佳的為 resveratrol。易被皮膚吸收的分別為 ampelopsin C 和 resveratrol。再經由不同的處理皮後 resveratrol、viniferin 和 ampelopsin C 的皮內含量有增加，而 resveratrol、viniferin、ampelopsin C 及 polydatin 的穿透能力有增加。

　　Previous studies have been reported that resveratrol and its derivatives, such as viniferin, ampelopsin C, vitisin A and polydatin, contain many OH group and are hydrophilic substances with anti-cancer, anti-oxidant and anti-inflammatory effects. The molecular weight, functional group, and lipophilicity of the drug affect the drug penetration pathway. These routes of penetration may be also different due to drug physicochemical properties when the drug penetrates directly from the surface layer of the skin, from the intracellular route, from the intercellular route, or from trans appendage route. Next, our experiment will explore the penetration of resveratrol and its derivatives in normal and differently treated animal skins to analyze drug penetration route. Anti-inflammatory activity assays were performed using HaCaT cells and neutrophils. The nude mice were used to investigate the drug safety test, the cutaneous irritation test, and the living intradermal content of resveratrol and its derivatives. The biological capacity factor was used to predict the lipophilicity of resveratrol and its derivatives. It was found that vitisin A is lipophilic and Polydatin is hydrophilic. Using the in vitro percutaneous absorption test, the highest content of resveratrol in nude mice skin and pig skin at 3 mM concentration was obtained. The best penetration ability is resveratrol. Ampelopsin C and resveratrol are easily absorbed by the skin. After treatment of the skin in different ways, resveratrol, viniferin, and ampelopsin C have increased intradermal content, while resveratrol, viniferin and ampelopsin C have increased the penetration.

目錄
致謝 i
中文摘要 ii
Abstract iii
第一章 緒論 1
第一節 皮膚 1
第二節 表皮層 2
第三節 真皮層 3
第四節 皮下組織 3
第五節 藥物之經皮吸收路徑及影響因素 4
壹、 藥物進入皮膚途徑 4
貳、 藥物穿透皮膚影響因素 6
第六節 發炎現象 7
參、 皮膚與發炎的關係 7
第七節 Resveratrol 及其衍生物藥理活性探討 10
壹、 Resveratrol 10
貳、 Viniferin 11
參、 Ampelopsin C 12
肆、 Vitisin A 12
伍、 Polydatin 14
第二章、 研究動機與實驗設計 15
實驗設計及流程 16
第三章、 材料與方法 17
第一節 實驗試劑、醫療材料與儀器設備 17
壹、 試劑與醫材 17
貳、 儀器設備 19
第二節 實驗方法 21
壹、 藥物之HPLC分析條件建立 21
貳、 藥物之分子特性模擬 22
參、 藥物之容積因子 (log K’) 22
肆、 油水分配係數 (log P) 23
伍、 實驗藥品之配置 23
陸、 體外經皮吸收試驗 24
第四章、 實驗結果 35
第一節 體外經皮試驗 35
壹、 Resveratrol 及其衍生物物化性質測試 35
貳、 Resveratrol 及其衍生物在裸鼠皮與豬皮體外經皮吸收試驗 36
參、 化合物在飽和濃度下體外經皮吸收試驗 49
肆、 化合物穿透皮膚路徑探討 59
伍、 化合物分子模擬 62
陸、 動物實驗 70
第五章、 結論 79
參考資料 82
附錄 94
第一節 化合物之光譜數據及1H NMR光譜 95

 
圖目錄
圖一 皮膚構造示意圖 1
圖二 表皮層意示圖 2
圖三 藥物穿透皮膚示意圖 5
圖 四 resveratrol 及其衍生物 14
圖五 體外經皮吸收裝置 25
圖六 化合物經正常皮吸收施藥端溶液為 10% PG/pH 6 phosphate buffer 之實驗結果圖 40
圖七 化合物經正常皮吸收施藥端溶液為10% PG/pH 6 phosphate buffer 之實驗結果圖 42
圖八 化合物經正常皮吸收施藥端溶液為 10% PEG400/pH 6 phosphate buffer 之實驗結果圖 46
圖九 化合物經正常皮吸收施藥端溶液為 10% PEG400/pH 6 phosphate buffer 之實驗結果圖 48
圖 十 化合物與神經醯胺二 (ceramide II) 之交互作用模擬 64
圖 十一 化合物與神經醯胺三 (ceramide III) 之交互作用模擬 65
圖 十二 化合物與神經醯胺六 (ceramide VI) 之交互作用模擬 66
圖 十三 化合物與棕梠酸 (palmitic acid) 之交互作用模擬 67
圖 十四 化合物與膽固醇硫酸鹽 (cholesteryl sulfate) 之交互作用模擬 68
圖 十五 化合物與膽固醇 (cholesterol) 之交互作用模擬 69
圖十六 3 mM 藥物於生體內皮內含量試驗 70
圖十七 投予 resveratrol 及其衍生物第 0 天至第 5 天皮膚水分散失變化 72
圖十八 投予 resveratrol 及其衍生物第 0 天至第 5 天皮膚色差變化 73
圖十九 投予 resveratrol 及其衍生物第 0 天至第 5 天皮膚酸鹼度變化 74
圖二十 藥物投予 5 天後的組織病理學切片經 H/E stain 染色結果 77
圖二十一 Viniferin 之 1H NMR光譜 96
圖二十二 Ampelopsins C 之 1H NMR光譜 97
圖二十三 Vitisin A 之 1H NMR光譜 98
 
表目錄
表一 五種藥物的 HPLC 分析條件 21
表二 resveratrol 其衍生物物化性質 36
表三 3 mM 藥物懸浮狀態，施藥端溶液為 10% PG/pH 6 phosphate buffer 於 24 小時後裸鼠皮之皮內化合物含量、滲透速率及 S value 50
表四 飽和化合物於 24 小時之後裸鼠皮校正皮內含量、滲透係數及 S value，施藥端溶液為 10% PG/pH 6 phosphate buffer 51
表五 3 mM 藥物懸浮狀態，施藥端溶液為 10% PG/pH 6 phosphate buffer於 24 小時後豬皮之皮內化合物含量、滲透速率及 S value 53
表六 飽和化合物於 24 小時後豬皮校正皮內含量、滲透係數及 S value，施藥端溶液為 10% PG/pH 6 phosphate buffer 53
表七 3 mM 藥物懸浮狀態，施藥端溶液為 10% PEG400/pH 6 phosphate buffer於 24 小時後裸鼠皮之皮內化合物含量、滲透速率及 S value 55
表八 飽和化合物於 24 小時之後裸鼠皮校正皮內含量、滲透係數及 S value，施藥端溶液為 10% PEG400/pH 6 phosphate buffer 56
表九 3 mM 藥物懸浮狀態，施藥端溶液為 10% PEG400/pH 6 phosphate buffer 於 24 小時後豬皮之皮內化合物含量、滲透速率及 S value 58
表十 飽和化合物於 24 小時之後豬皮校正皮內含量、滲透係數及 S value，施藥端溶液為 10% PEG400/pH 6 phosphate buffer 58
表十一 3 mM 化合物質不同處理豬皮之穿透速率 60
表十二 3 mM 化合物質不同處理豬皮之皮內含量 61
表 十三 五種化合物之氫鍵與總極性表面積 63
表 十四 化合物與角質層富含成分交互作用之 negative CDOCKER energy 63

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