臺灣博碩士論文加值系統

白藜蘆醇為天然多酚類化合物，具有諸多生物活性，然而，白藜蘆醇因為本身的低溶解度及於體內被快速代謝等問題，限制了其在臨床上的應用。本研究的目的為製備及評估白藜蘆之自奈米乳化傳遞系統(SNEDS)劑型以增加其口服生體可用率；此外，本實驗亦開發液相層析串聯電化學偵測器(HPLC-EC)之分析方法偵測大鼠血漿中白藜蘆醇的含量。處方經由分散性、穿透度、粒徑大小、安定性及外觀型態進行評估，結果利用溶解度試驗優化之自奈米乳化處方包含Capryol 90，Cremophor EL及Tween 20，其平均粒徑大小為41.3 ± 7.0 nm，分散係數為0.38 ± 0.12，並且在4、25及40C的條件存放30天仍保持良好的安定性。實驗開發之HPLC-EC分析方法成功地運用於分析白藜蘆醇在大鼠血漿中之含量，根據動態系統伏安結果最終選擇+1.0 V作為氧化電位，分析方法的檢量線範圍為10至1500 ng mL-1之間，生物檢體檢測方式的最低定量極限為10 ng mL-1，並具有高度的線性關係（r2>0.9996），同日間及異日間的相對標準偏差小於11.2%，而白藜蘆醇的大鼠血漿萃取回收率高於91%。藥物動力學之結果顯示相較於口服給予未製成劑型之懸浮液，自奈米乳化傳遞系統可以提升白藜蘆醇高達3.1倍之口服生體可用率。

Resveratrol, a naturally occurring polyphenol, has shown various promising bioactivities. Unfortunately, resveratrol is restricted in clinical application due to poor dissolution and absorption. The aims of the current study were to develop and evaluate a self-nanoemulsifying delivery systems (SNEDS) to improve the oral bioavailability of resveratrol. Moreover, a sensitive HPLC-electrochemical detection (HPLC-EC) method for determination of resveratrol in rat plasma was developed. The developed formulations have been characterized by its dispersibility, percentage transmittance, droplet size, stability and morphology. The results indicated that the optimized self-nanoemulsifying formulation consisted of Capryol 90, Cremophor EL and Tween 20 based on the solubility test and it possessed an average particle size 41.3 ± 7.0 nm and the poly dispersity index of 0.38 ± 0.12. The resveratrol in self-nanoemulsifying formulation was stable at 4, 25 and 40C for 30 days. The developed bioanalytical method was successfully applied on the analysis of resveratrol in rat plasma by hydrodynamic voltammogram at +1.0V oxidative mode. The regression equation was linear (r2>0.9996) over the range of 10 ng mL-1 to 1500 ng mL-1 and possessed a limit of quantification of 10 ng mL-1. The RSD of inter- and intra-day assay were less than 11.2%. The recoveries for resveratrol was found to be greater than 91%. Pharmacokinetics study showed resveratrol SNEDS displayed an approximately 3.1-fold increase in oral bioavailability compared to the unformulated resveratrol suspension.

目錄 I
表目錄 V
圖目錄 VI
摘要 VII
Abstract VIII
壹、緒論 1
一、白藜蘆醇基本概述 1
(一) 白藜蘆醇介紹 1
(二) 白藜蘆醇物化特性 2
(三) 白藜蘆醇藥理活性 3
(四) 白藜蘆醇藥物動力學回顧 4
二、白藜蘆醇劑型回顧 6
(一) 自奈米乳化傳遞系統(SNEDS)簡介 7
(二) 油相及界面活性劑之選擇 8
(三) 優點及缺點 8
三、高效液相層析-電化學偵測器 12
貳、研究目的 14
參、實驗材料與儀器設備 15
一、材料與試劑 15
(一) 標準品 15
(二) 賦形劑 15
(三) 實驗試劑 16
二、儀器設備 16
(一) 高效液相層析儀 16
(二) 實驗設備 16
三、軟體 17
肆、研究方法 18
一、白藜蘆醇自奈米乳化傳遞系統之製備 18
(一) 紫外/可見光分光光譜儀全波長掃描 18
(二) 紫外/可見光分光光譜吸收校正曲線建立 18
(三) 賦形劑溶解度測試 18
(四) 自奈米乳化傳遞系統製備 19
二、白藜蘆醇自奈米乳化傳遞系統之評估 20
(一) 分散性試驗 (Dispersibility test) 20
(二) 穿透度試驗 (Percentage transmittance) 21
(三) 粒徑大小與分散係數 (Particle size and polydispersity index) 21
(四) 穿透式電子顯微鏡 22
(五) 處方單位含量測定 22
(六) 處方儲存安定性 22
三、白藜蘆醇於大鼠血漿中之分析方法開發 23
(一) 標準溶液之製備 23
(二) 電化學偵測器之工作電位選擇 23
(三) 移動相條件之選擇 23
(四) 血漿蛋白質沉澱劑之選擇 24
四、白藜蘆醇於大鼠血漿中之分析方法 24
(一) HPLC分析條件 24
(二) 電化學參數 25
(三) 血漿樣品前處理 25
(四) 檢量線建立 25
五、白藜蘆醇於大鼠血漿中之分析方法確效 26
(一) 分析方法之選擇性 26
(二) 分析方法之回收率 26
(三) 同日、異日精確度(Accuracy)與準確度(Precision) 27
(四) 分析方法之安定性 27
六、白藜蘆醇之藥物動力學研究 28
(一) 實驗動物 28
(二) 實驗動物分組 28
伍、結果 29
一、白藜蘆醇自奈米乳化傳遞系統之製備 29
(一) 紫外/可見光分光光譜儀全波長掃描 29
(二) 紫外/可見光分光光譜吸收校正曲線建立 30
(三) 賦形劑溶解度測試 30
(四) 自奈米乳化傳遞系統外觀 32
二、白藜蘆醇自奈米乳化傳遞系統之評估 33
(一) 分散性試驗(Dispersibility test) 33
(二) 穿透度試驗(Percentage transmittance) 36
(三) 粒徑分析與液滴型態分析 36
(四) 處方單位含量測定 39
(五) 處方儲存安定性 39
三、白藜蘆醇於大鼠血漿中之分析方法開發 41
(一) 電化學偵測器之工作電位選擇 41
(二) 移動相條件之選擇 42
(三) 血漿蛋白質沉澱劑之選擇 42
四、白藜蘆醇於大鼠血漿中之分析方法 43
(一) 檢量線建立 43
五、白藜蘆醇於大鼠血漿中之分析方法確效 44
(一) 分析方法之回收率 44
(二) 同日、異日精確度(Accuracy)與準確度(Precision) 44
(三) 分析方法之安定性 46
六、白藜蘆醇之藥物動力學研究 49
(一) 分析方法 49
(二) 藥物動力學 50
陸、討論 54
一、HPLC-EC分析方法應用於分析大鼠血漿中白藜蘆醇之優勢 54
二、白藜蘆醇自奈米乳化傳遞系統之藥物動力學探討 54
柒、結論 57
捌、參考文獻 59

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