臺灣博碩士論文加值系統

本實驗利用自由基聚合法製備溫度及酸鹼敏感型高分子，其目的在於應用於藥物釋放。首先先將β-環糊精進行改質，利用與烯丙基甘油醚進行反應，使β-環糊精末端的-OH基變成雙鍵結構，以利接下來步驟的雙鍵聚合。
此實驗合成分為兩種類型，一種為一般的線性高分子；另一種為多添加交聯劑的水凝膠高分子。兩者皆利用已改質過後的β-環糊精與NIPAM和IAM進行共聚反應，共通點為隨著添加的IAM莫耳比例提高，其LCST溫度也會隨之提高。其中線性高分子可藉由TEM觀察到當添加IAM後，其分子具有自組裝的核-殼分明結構的現象產生；而水凝膠可由SEM觀察到隨著添加的IAM莫耳比例提高後，其孔洞會逐漸形成片狀結構，使其吸水效果提升。
在本藥物實驗中，利用在固定的人體溫度37℃下進行兩種不同pH值的緩衝溶液來模擬人體內不同的環境，其中pH2為模擬人體中的胃液之酸鹼值；pH7.4為模擬人體中小腸之腸液酸鹼值。實驗結果發現，在溫度37℃和pH7.4下，其藥物釋放速率最高，證明此高分子具有酸鹼敏感性。

In this study, we use radical polymerization method to synthesize temperature and pH-sensitive polymer for drug release. First, we modify β- cyclodextrin by reacting it with allyl glycidyl ether to change the end of the -OH group into a double bond structure for facilitating the polymerization on the next step.
This synthetic experiment is divided into two types, one is for the general linear polymer; the other is to add cross-linking agent to become hydrogel polymer. Both utilize modified β- cyclodextrin to make copolymerization reaction with NIPAM and IAM.The common point is that as IAM mole ratio increases its LCST temperature will also increase. Wherein the linear polymer can be observed by TEM after adding IAM, whose molecules have the self-assembly distinct core - shell phenomenon distinct structure generation; and hydrogel can be observed by SEM,after IAM molar ratio increases,its holes will gradually form a sheet structure to enhance the absorption effect.
In this drug experiment,we fixed the temperature 37ºC as the body temperature and two different pH values of buffer solution to simulate different environment.The pH2 buffer solution simulates the gastric juice of human body;while pH7.4 simulate the small intestine’s analog of humans.Result shows that at the temperature of 37ºC and pH7.4,it has the highest release rate of the drug release,it also proves that polymer is pH-sensitive.

目錄
審定書 i
摘 要 ii
Abstract iii
致謝 v
目錄 ix
表目錄 xii
圖目錄 xiii
第一章 緒論 1
1-1 前言 1
1-2 實驗動機 2
第二章 文獻回顧 3
2.1 實驗材料介紹 3
2.1.1 環糊精(cyclodextrin)介紹 3
2.1.1.1環糊精之應用 5
2.1.2 N-異丙基丙烯醯胺(N-isopropylacrylamide)介紹 8
2.1.2.1 N-異丙基丙烯醯胺(N-isopropylacrylamide)特性 9
2.1.3 Atorvastatin 10
2.2 智能型材料(intelligent materials) 11
2.2.1 智能型高分子材料(smart polymer) 12
2.2.2 化學物質反應高分子材料(chemical signal-sensitive polymer) 16
2.2.3 酸鹼敏感性高分子材料(pH-sensitive polymers) 17
2.2.4 電場反應高分子材料(electric signal-sensitive polymers) 20
2.2.5 磁場敏感性高分子材料(magnetic signal-sensitive polymers) 21
2.2.6 光敏感性高分子材料(light-sensitive polymers) 23
2.2.7 溫度敏感性高分子材料(Thermo-sensitive polymers) 24
2.2.8 溫度/酸鹼敏感性高分子材料(Thermo&pH-sensitive polymers) 26
2.3 高分子聚合方法(polymer polymerization) 27
2.3.1 高分子共聚排列 30
2.4 藥物釋放 31
2.4.1 藥物釋放體系 32
2.4.2 奈米藥物釋放 34
第三章 實驗 36
3.1 實驗藥品 36
3.2 實驗儀器與測量方法 39
3.2.1 核磁共振儀 (Nuclear Magnetic Resonance spectroscopy，NMR) 41
3.2.2 傅立葉轉換紅外線光譜儀(Fourier Transform Infrared spectroscopy，FTIR) 42
3.2.3 凝膠透析層析儀(Gel Permeation Chromatography；GPC) 43
3.2.4 雷射光穿透度儀(Laser Transmittance Meter) 44
3.2.5 掃描式電子顯微鏡(Scanning Electron Microscope,SEM) 45
3.2.6 高解析穿透式電子顯微鏡(High Resolution Transmission Microscope, HRTEM) 46
3.2.7.熱示差掃描分析儀(Differential Scanning Calorimetry；DSC) 47
3.2.8 紫外光-可見光光譜儀 (Ultraviolet-Visible Spectroscopy；UV-Vis) 48
3.3實驗流程與藥品前處理 49
3.3.1 實驗流程圖 49
3.3.2 藥品前處理 50
3.3.2.1 β-環糊精純化步驟 50
3.3.2.2 NIPAM單體純化步驟 50
3.4 合成步驟 51
3.4.1 合成allyloxy-β-CD 51
3.4.2 以自由基聚合法合成Poly(CD-NIPAM)及Poly(CD-NIPAM-IAM) 52
3.4.3 以自由基聚合法合成Poly(CD-NIPAM) hydrogel及Poly(CD-NIPAM-IAM) hydrogel 54
3.5 實驗檢測步驟 56
3.5.1 最低臨界溶液溫度 56
3.5.2 膨脹率測試 57
3.6 藥物釋放 58
3.6.1 藥物最大吸收峰 58
3.6.2 藥物檢量線之製作 58
3.6.3 藥物載體之製作 58
3.6.4 藥物包埋率測試 58
3.6.5 藥物釋放實驗 59
第四章 結果與討論 60
4.1核磁共振光譜-氫譜(H-NMR) 分析 60
4.1.1 allyloxy-cyclodextrin之官能基鑑定 60
4.1.2 Poly(CD-NIPAM)之官能基鑑定 62
4.1.3 Poly(CD-NIPAM-IAm)之官能基鑑定 64
4.2 傅立葉轉換紅外線光譜分析(FT-IR)分析 68
4.2.1 單體分析 68
4.2.2 allyloxy-CD之官能基分析 69
4.2.3 Poly(CD-NIPAM)及Poly(CD-NIPAM) gel之官能基分析 70
4.2.4 Poly(CD-NIPAM-IAM) 之官能基分析 71
4.3 GPC分析 73
4.4 相變化圖 74
4.4.1 水溶液濃度之相變化溫度 74
4.4.2 水溶液濃度之透光度 75
4.5 TEM型態觀察 82
4.6 SEM型態觀察 87
4.7 膨潤率測試 92
4.8 藥物釋放 96
4.8.1 Atorvastatin檢量線的建立 96
4.8.2 Atorvastatin藥物包埋效果 98
4.8.3 藥物釋放實驗 100
第五章 結論 102
第六章 參考文獻 104
附錄A 108

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