臺灣博碩士論文加值系統

利用微乳劑發展出sildenafil之鼻腔內迅速傳輸藥物系統。微乳劑主要以油酸 (oleic acid) 為基劑；Cremophor EL或Tween系列為非離子界面活性劑；輔助界面活性劑則以短鏈的單元醇、PEG 600或PG，進行鼻噴劑之發展研究。觀察此微乳劑系統的物化性質和溶解藥物能力，並討論sildenafil微乳劑型在活體兔子內鼻腔吸收的情況。由不同比例的界面活性劑與輔助界面活性劑所發展出的相圖中形成單一均質相的區域稱為微乳劑。隨著界面活性劑比例的增加，相圖中形成微乳劑的區域會越小，但是黏度則會變大。Sildenafil本身雖然屬於難溶性藥物，但是當微乳劑系統組成為40 % 油酸、10 % 水和50 % 的界面活性劑系統，其中界面活性劑系統中Tween 80與ethanol比例為1:4，藥物的溶解度可達到124 mg/ml。鼻腔內投予此sildenafil微乳劑型後，可以快速的被吸收，當給予10 mg的噴鼻劑量後，會立即達到最低有效濃度且作用時間持續超過3個小時。由本研究的結果顯示，oleic acid、Tween 80、ethanol和水組成的微乳劑可快速地將sildenafil經由鼻腔傳輸達到最低有效濃度來治療勃起功能障礙。

An oleic acid-based microemulsion system with Cremophor EL or Tween series as surfactants, and short-chain alcohol, PEG 600 or PG as cosolvents was developed for rapid-onset intranasal delivery of sildenafil. Phase behavior and solubilization capacity of the microemulsion system were characterized and in vivo nasal absorption of sildenafil from microemulsion formulations was investigated in rabbits. A single isotropic region, which is considered as a microemulsion, was found in the pseudo-ternary phase diagrams developed at various surfactants : cosolvents ratios. With the higher weight percentage of surfactant, the region area of microemulsion in the phase diagram decreased whereas the viscosity of microemulsion increased. Sildenafil, a water-insoluble drug, displayed a high solubility of 124 mg/ml in a microemulsion consisting of 40 % oleic acid, 10 % H2O, and 50 % Tween 80:ethanol (at 1:4 weight ratio). Nasal absorption of sildenafil from this microemulsion was found to be fairly rapid. At 10 mg dose, the onset of action was arrived instantly follow administrating the IN formulation and the duration was over 3 hours. These results suggest that the microemulsion system composed of oleic acid, Tween 80, ethanol and water may be a useful approach for the rapid-onset delivery of sildenafil with the erectile dysfunction.

目錄
目錄............................................................................................................. I
附表目錄.................................................................................................. III
附圖目錄.................................................................................................. IV
中文摘要.................................................................................................VII
Abstract ..................................................................................................VIII
第一章緒論.............................................................................................. 1
第一節研究背景介紹...................................................................... 2
一、Sildenafil ............................................................................ 2
(一)基本性質..................................................................... 2
(二)藥物動力學................................................................. 4
(三)劑型之發展................................................................. 6
二、鼻腔內給藥途徑.............................................................. 10
(一)發展背景................................................................... 10
(二)鼻腔生理構造............................................................11
(三)鼻噴劑....................................................................... 12
三、微乳劑系統...................................................................... 22
(一)基本特性................................................................... 22
(二)乳劑與微乳劑的比較............................................... 24
(三)微乳劑鼻腔內藥物傳輸系統................................... 27
第二節研究動機............................................................................ 30
第二章研究材料與實驗方法................................................................ 32
第一節實驗材料與儀器設備........................................................ 32
一、實驗材料.......................................................................... 32
二、儀器設備.......................................................................... 33
第二節Sildenafil 高效液相層析之分析方法............................... 34
一、分析方法之建立.............................................................. 34
二、血漿中Sildenafil 的萃取方法評估............................... 36
三、分析方法之確效.............................................................. 36
第三節溶解度分析........................................................................ 37
第四節相圖建立與物化性質分析............................................... 38
一、相圖建立.......................................................................... 38
二、物化性質分析.................................................................. 40
(一)溶解度測試............................................................... 43
(二)粒徑測定................................................................... 43
(三)黏度測定................................................................... 44
II
(四)安定性測試............................................................... 44
(五)光學顯微鏡之觀察................................................... 44
第五節動物鼻腔內吸收研究........................................................ 45
ㄧ、動物試驗.......................................................................... 45
二、血漿檢品之檢測.............................................................. 46
三、藥物動力學數據分析...................................................... 46
第三章結果與討論................................................................................ 48
第一節Sildenafil 高效液相層析之分析方法............................... 48
一、分析方法之建立.............................................................. 48
二、血漿中Sildenafil 的萃取方法評估................................ 48
三、分析方法之確效.............................................................. 49
第二節溶解度分析........................................................................ 53
第三節相圖建立與物化性質分析............................................... 56
一、相圖建立.......................................................................... 56
二、物化性質分析.................................................................. 85
(一)溶解度....................................................................... 85
(二)液滴粒徑................................................................... 90
(三)黏度........................................................................... 92
(四)安定性....................................................................... 93
(五)光學顯微鏡之觀察................................................... 94
第四節動物鼻腔內吸收研究........................................................ 96
第四章結論.......................................................................................... 106
參考文獻................................................................................................ 107

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