異丙基烯醯胺與磺基甜菜鹼共聚水凝膠之製備與性質研究及其於藥物控制釋放之行為

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研究生：	王駿傑 Jun-Jie Wang
論文名稱：	異丙基烯醯胺與磺基甜菜鹼共聚水凝膠之製備與性質研究及其於藥物控制釋放之行為 Preparation and Properties of Poly(N-isopropylacrylamide-co- sulfobetaine methacrylate) Hydrogels for Swelling-Controlled Drug Delivery Applications
指導教授：	陳文逸 Wen-Yih Chen
口試委員:
學位類別：	碩士 Master
系所名稱：	工學院 - 化學工程與材料工程學系 Department of Chemical & Materials Engineering
畢業學年度：	100
語文別：	中文
論文頁數：	122
中文關鍵詞：	水凝膠、膨潤行為、硫代甜菜鹼、異丙基烯醯胺、膨潤機制、蛋白質釋放
外文關鍵詞：	protein release, N-isopropylacrylamide, swelling mechanism, hydrogel, sulfobetaine methacrylate, swelling behavior
相關次數：	點閱：9 下載：0
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本實驗的水膠製備是利用自由基聚合法之方式合成，選用具溫度敏感性之單體-異丙基烯醯胺(N-isopropylacrylamide，NIPAAm)與雙離子性之單體-硫代甜菜鹼 (sulfobetaine methacrylate，SBMA)，交聯劑為N,N''-methylene-bis-acrylamide，製備了三種NIPAAm/SBMA之共聚水膠並控制總單體濃度為10 wt %，其中單體之莫耳比分別為95:5，90:10與 80:20 mol %。此外，我們也製備了未含SBMA組成的非離子性水膠poly(NIPAAm)來當作一對照組。藉此探討水膠內NIPAAm與SBMA之單體組成在不同溫度下的膨潤機制與溶脹時蛋白質之釋放行為。
由作用力參數χ計算的結果顯示：隨著溫度的增加，會造成水膠與水分子間的交互作用力變弱，然而當SBMA組成的添加能提高水膠與溶劑間的交互作用力。藉由焓貢獻χH與熵貢獻χS之作用力參數可進一步得到水膠的混合焓(?H)與混合熵(?S)。我們發現溫度從25℃升至45℃時，poly(NIPAAm)具有相較於poly(NIPAAm-co-SBMA)水膠較大之亂度減少趨勢。而從χ值與亂度的結果可以得知高分子鏈之疏水性變強，使得鏈周圍形成許多有序排列的水分子，因而造成水膠在高溫之膨潤程度變小。
動態膨潤實驗的結果發現，poly(NIPAAm)水膠是以非費克擴散的方式進行溶脹；當SBMA組成的添加能提升凝膠高分子鏈鬆弛的速率，使得溶脹機制轉變為費克擴散的行為，使得水分子可以較快速進入水膠內而膨潤開來。
最後，進一步的分析水膠膨潤機制對於溶脹時蛋白質lysozyme與BSA在不同溫度下釋放的影響。結果顯示SBMA的添加有助於蛋白質在37℃下於poly(NIPAAm-co-SBMA)水膠的釋放，且釋放機制由溶脹控制轉變為擴散控制的方式進行。

A series of copolymeric hydrogels based on N-isopropylacrylamide (NIPAAm), zwitterionic sulfobetaine methacrylate (SBMA) were prepared by free radical polymerization in this study. N,N''-methylene -bis-acrylamide (NMBA) as a crosslinker, we prepared three types of poly(NIPAAm-co-SBMA) copolymeric hydrogels and controlled the total monomer concentration was 10 wt%, which the monomer molar ratio were 95:5, 90:10 and 80:20 mol%, respectively. In addition, we also prepared a poly(NIPAAm) hydrogel as a control to investigate the swelling mechanism and the release of protein in the swelling from hydrogels in various compositions and temperatures.
The results of the interaction parameter χ calculated showed that the presence of the SBMA composition decreases the interaction parameter because of the increasing interaction between hydrogel networks and water. Enthalpy change (?H) and entropy change (?S) were obtained by
χ H and χ S . They were both negative, and their absolute values increased with the temperature; this meant that the number of ordered water increased with decreasing total water content at elevated temperature. Furthermore, the phenomenon was more obvious for p(NIPAAm) gel than for p(NIPAAm/SBMA) gels because of the greater hydrophobicity of p(NIPAAm).
In the dynamic swelling experiment, we have attempted to investigate the effect of composition and temperature on the swelling mechanism of NIPAAm containing SBMA hydrogels. The results revealed that the content of SBMA in poly(NIPAAm) hydrogels would facilitate the increase of relaxation rate and diffusion coefficient of water entering the hydrogels.
Furthermore, the presented copolymeric hydrogels are investigated for using in protein release. The results were observed that the addition of SBMA in hydrogel could increase the releasing of protein in hydrogels at 37 ℃. And the releasing of protein increase with the amount of SBMA increase in hydrogel.With increasing the content of SBMA in p(NIPAAm) hydrogel, it would facilitate the behavior of protein release. And the mechanism of release would transfer from relaxation-controlled process to diffusion-controlled process.

中文摘要 .................I
Abstruct ............. III
致謝 ................... V
目錄 .................. VI
表目錄 ................. X
圖目錄 ................. XI
第一章 緒論 ........................ 1
第二章 文獻回顧 .................... 3
1水凝膠之定義、分類、結構 .......... 3
2水凝膠之膨潤行為 ................. 7
2.1水凝膠膨潤之熱力學 ............. 8
2.2水凝膠膨潤之動力學 ............. 9
3水凝膠之相互作用力 ............... 10
3.1相互作用力種類 ................ 10
3.2作用力參數 (Interaction parameter)........ 12
4 藥物控制釋放系統 ...................... 14
4.1擴散控制(Diffusion-Controlled)之傳遞系統 .......... 14
4.2溶脹控制(Swelling-Controlled)之傳遞系統 ..........18
4.3化學反應控制(Chemical-Controlled)之傳遞系統 .......... 21
5水凝膠於生醫領域上之應用 .................. 24
6智能型水凝膠於藥物傳遞系統 ................ 26
6.1溫度敏感型水凝膠 ....................... 27
6.1.1溫度敏感水凝膠的特性 .................. 27
6.1.2溫度敏感水凝膠在藥物控制釋放的應用 ............. 28
6.2pH敏感型水凝膠 ............................... 30
6.2.1pH敏感水凝膠的特性 ......................... 30
6.2.2pH敏感水凝膠在藥物控制釋放的應用 ................ 32
6.3 pH和溫度敏感型水凝膠 ........................... 33
6.3.1 pH和溫度敏感水凝膠的特性 ................... 33
6.3.2 pH和溫度敏感水凝膠在藥物控制釋放的應用 ... 35
7 含SB類雙離子性單體之高分子水凝膠性質 ................ 36
第三章 實驗藥品、儀器及方法 ............................ 38
1實驗藥品 ......................... 38
2儀器設備 ..................... 40
3水膠薄膜的製備 .................... 42
3.1 NIPAAm 單體純化步驟 .............. 42
3.2 NIPAAm/SBMA 水膠之製備 ........... 42
4.3化學反應控制(Chemical-Controlled)之傳遞系統 .......... 21
5水凝膠於生醫領域上之應用 .................. 24
6智能型水凝膠於藥物傳遞系統 ........................... 26
6.1溫度敏感型水凝膠 ................................. 27
6.1.1溫度敏感水凝膠的特性 ........................... 27
6.1.2溫度敏感水凝膠在藥物控制釋放的應用 ............. 28
6.2pH敏感型水凝膠 .................................. 30
6.2.1pH敏感水凝膠的特性 .............................. 30
6.2.2pH敏感水凝膠在藥物控制釋放的應用 ................ 32
6.3 pH和溫度敏感型水凝膠 ............................ 33
6.3.1 pH和溫度敏感水凝膠的特性 ............... 33
6.3.2 pH和溫度敏感水凝膠在藥物控制釋放的應用 ... 35
7 含SB類雙離子性單體之高分子水凝膠性質 ......... 36
第三章 實驗藥品、儀器及方法 ......................... 38
1實驗藥品 .................... 38
2儀器設備 .................... 40
3水膠薄膜的製備 ............... 42
3.1 NIPAAm 單體純化步驟 ............... 42
3.2 NIPAAm/SBMA 水膠之製備 ............ 42
3.3 包覆蛋白質之NIPAAm/SBMA水膠製備 .................... 44
4 實驗設計與步驟 ............................... 45
4.1 水膠平衡膨潤度實驗 .......................... 45
4.2 水膠膨潤動力學實驗 .......................... 46
4.3 水膠之應力/應變實驗 ......................... 47
4.4 水膠之交聯點分子量與網目大小計算 ............... 48
4.5 水膠與水之混合焓(?H)與混合熵(?S)計算 .......... 50
5 NIPAAm/SBMA水凝膠之藥物釋放實驗 ................ 51
5.1 蛋白質釋放實驗 ............................. 51
5.2 蛋白質溶液濃度檢測 ........................... 51
5.3蛋白質釋放之動力學分析 ......................... 52
第四章 結果與討論............... 55
1 NIPAAm/SBMA共聚水膠之平衡膨潤度 ............... 56
1.1單體組成對於平衡膨潤度之影響 .................... 56
1.2溫度對於平衡膨潤度之影響 ........................ 58
2 NIPAAm/SBMA共聚水凝膠之結構參數 .................. 60
1.1單體組成與溫度對於結構參數之影響 .................. 60
3 NIPAAm/SBMA共聚凝膠之作用力參數(χ) ............... 63
3.1單體組成對於作用力參數χ值之影響 ............... 63
3.2溫度對於作用力參數χ值之影響 ...................... 64
3.3 膨潤之熱力學分析 ............................... 66
4 NIPAAm/SBMA共聚水膠之膨潤動力學 ................... 71
4.1溫度對於膨潤機制之影響 ............................ 72
4.2單體組成對於膨潤機制之影響 ........................ 79
5蛋白質於NIPAAm/SBMA共聚水膠之釋放行為................... 80
5.1 Lysozyme與BSA於凝膠薄膜之釋放行為 ................... 82
5.2溫度對於lysozyme與BSA釋放機制之影響 ............... 87
5.3 Poly(NIPAAm-co-SBMA)水膠於控制釋放之應用 ........ 94
結論 ........................................ 95
參考文獻 ............................... 97
附錄 ..................................... 104

                                

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