本研究利用環境敏感型高分子製備溫度/酸鹼雙重應答之幾丁聚醣/聚(氮-異丙基丙烯醯胺-乙烯胺-氮-羥甲基丙烯醯胺)半互穿型水凝膠。研究中分為三部份來探討，第一部分是利用自由基聚合法合成聚乙烯甲醯胺(Poly(N-vinylforamide), PNVF)，探討PNVF在不同的條件下水解成聚乙烯胺(Poly(N-vinylamine), PVAm)之水解率變化。接著，亦是利用自由基聚合法合成P(NP-co-NVF)，探討氮-異丙基丙烯醯胺(N-isopropylacrylamide，NP)與NVF單體的進料比例對整體共聚物組成及性質之影響，測其共聚物之溫度/酸鹼敏感性質(最低臨界溶解溫度Lower critical solution temperature, LCST)及顆粒尺寸，進一步添加可熱交聯單體N-羥甲基丙烯醯胺(N-methylolacrylamide, NMA)，以自由基聚合法合成P(NP-co-NVF-co-NMA)，透過NMA含量不同，測量共聚物LCST之變化。接著利用P(NP-co-NVF-co-NMA)鏈段上NMA的CH2OH基團，加熱使共聚物自交聯，並添加幾丁聚醣(Chitosan, CS)以提高生物相容性，水解熱交聯以形成CS/P(NP-co-VAm-co-NMA)半互穿型水凝膠。利用FTIR對其化學結構進行分析，並探討不同CS與P(NP-co-NVF-co-NMA)之比例對水凝膠之膨潤率、熱性質及表面型態之影響。根據膨潤結果發現，膨潤率隨著NMA含量增加而下降；而在固定NMA含量下，酸性環境(pH=5.5)下的平衡膨潤率大於鹼性環境(pH=7.4)，且溫度升高，膨潤率下降，表示成功地合成出具溫度/酸鹼雙重應答之水凝膠。藉由熱性質分析顯示，隨著NMA相對含量的提升，玻璃轉移溫度從112 oC提升至122 oC，有助於增強水凝膠之熱穩定性，並透過SEM證實水凝膠之孔洞隨交聯度提升而變小。

In this study, environmentally sensitive chitosan/poly(N-isopropylacrylamide-vinylamine-N-hydroxymethylacrylamide) semi-interpenetrating network hydrogels with temperature/pH dual response were prepared. This research is divided into three parts to discuss. The first part is the synthesis of poly(vinylformamide) (PNVF) by free radical polymerization, and the study of hydrolysis rate of PNVF to poly(vinylamine) (PVAm) under different conditions. Subsequently, P(NP-co-NVF) was after synthesized by free radical polymerization. The effects of the feeding ratio of N-isopropylacrylamide (NP) to NVF monomer on the overall copolymer composition and properties were investigated, and the temperature/pH responsiveness of the copolymer was measured. By further adding thermal crosslinking monomer N-methylol acrylamide (NMA) with the mutual reaction of the P(NP-co-NVF-co-NMA) copolymer was thus synthesized. The variation of LCST was measured with different contents of NMA in the feed. CH2OH group in NMA on the P(NP-co-NVF-co-NMA) to make the copolymer self-crosslinking, and the addition of chitosan (CS) to improve biocompatibility, hydrolysis and thermal   crosslinking occurred simultaneously to form CS/P(NP-co-VAm-co-NMA) semi-IPN hydrogel. FTIR wsa utilized to analyze chemical structure, and the effects of different ratios of CS to P(NP-co-NVF-co-NMA) on the swelling ratio, thermal properties and surface morphology were investigated. According to the swelling data, the swelling ratio decreased with the increase of NMA content. By fixing the NMA content, the equilibrium swelling ratio in an acidic environment (pH=5.5) was greater than that in an alkaline environment (pH=7.4), while it decreased when the temperature was raised, indicating that the hydrogels were responsive to temperature and pH. Moreover glass transfer temperature increasef from 112 oC to 122 oC with the higher content of NMA, which was advantageous for enhancing the thermal stability of the hydrogel. SEM showed that the porosity of the hydrogel decreased with the increase of crosslinking degree.

目錄
中文摘要	I
英文摘要	II
目錄	IV
圖目錄	VII
表目錄	XIII
第一章 緒論	1
1.1前言	1
1.2研究動機	2
第二章 文獻回顧	4
2.1幾丁質及幾丁聚醣	4
2.1.1去乙醯度的測定	7
2.1.2幾丁聚醣黏度平均分子量測定	10
2.2環境敏感型高分子	12
2.2.1溫度敏感型高分子	14
2.2.2酸鹼敏感型高分子	18
2.3智慧型水凝膠簡介	21
2.3.1交聯結構水凝膠	23
2.3.2 水凝膠藥物釋放系統	25
第三章 實驗方法與實驗步驟	31
3.1實驗藥品	31
3.2實驗儀器	34
3.3實驗流程圖	37
3.4實驗步驟	39
3.4.1 幾丁聚醣之性質測試	39
3.4.2 PNVF與PVAm之合成與性質測試	42
3.4.3 P(NP-co-NVF)與P(NP-co-VAm)之製備與性質測試	44
3.4.4 P(NP-co-NVF-co-NMA) 之製備與性質測試	46
3.4.5 CS/P(NP-co-VAm-co-NMA)半互穿水凝膠之製備與性質測試	48
3.5結構及性質分析	50
3.5.1官能基結構鑑定(FTIR、NMR)	50
3.5.2粒徑大小及分佈鑑定(DLS)	50
3.5.3最低臨界溶液溫度之(LCST)測定(UV-Vis)	51
3.5.4 膨潤特性	51
3.5.5熱性質分析 (TGA、DSC)	52
3.5.6水凝膠型態分析(SEM)	52
第四章 結果與討論	53
4.1幾丁聚醣之性質測試	53
4.1.1去乙醯度 (Degree of deacetylation，DDA%)	53
4.1.2黏度平均分子量	59
4.1.3幾丁聚醣結構鑑定 (FTIR)	61
4.2 PNVF與PVAm之合成與性質測試	62
4.2.1合成PNVF之結構鑑定(FTIR、NMR)	62
4.2.2由PNVF水解製備PVAm與性質測試	64
4.3 P(NP-co-NVF)與P(NP-co-VAm)之製備與性質測	71
4.3.1自由基聚合法合成P(NP-co-NVF)之結構鑑定(FTIR、NMR)	71
4.3.2 P(NP-co-NVF)之溫感性質(UV-Vis)	75
4.3.3 P(NP-co-NVF)之熱重損失分析 (TGA)	77
4.3.4 P(NP-co-NVF)之玻璃轉移溫度 (DSC)	79
4.3.5 P(NP-co-VAm)之結構鑑定(FTIR、NMR)	80
4.3.6 P(NP-co-VAm)之溫感性質(UV-Vis)	85
4.3.7 P(NP-co-VAm)之粒徑分析(DLS)	88
4.3.8 P(NP-co-VAm)之熱重損失分析 (TGA)	92
4.3.9 P(NP-co-VAm)之玻璃轉移溫度 (DSC)	94
4.4 P(NP-co-NVF-co-NMA) 之製備與性質測試	95
4.4.1 P(NP-co-NVF-co-NMA)之結構鑑定(FTIR、NMR)	95
4.4.2 P(NP-co-NVF-co-NMA)之溫感性質(UV-Vis)	100
4.5 CS/P(NP-co-VAm-co-NMA)半互穿水凝膠之製備與性質測試	103
4.5.1 CS/P(NP-co-VAm-co-NMA)水凝膠之結構鑑定(FTIR)	104
4.5.2 CS/P(NP-co-VAm-co-NMA)水凝膠之膨潤特性	105
4.5.3 CS/P(NP-co-VAm-co-NMA)水凝膠之熱重損失分析 (TGA)	111
4.5.4 CS/P(NP-co-VAm-co-NMA)水凝膠之玻璃轉移溫度 (DSC)	113
4.5.6 CS/P(NP-co-VAm-co-NMA)水凝膠之型態分析(SEM)	114
第五章 結論	134
第六章 建議事項	136
第七章 參考文獻	137

 
圖目錄
圖1-1 不同劑型之血液中藥物濃度曲線圖	1
圖2-1纖維素結構	4
圖2-2幾丁質結構	4
圖2-3不同排列方式的幾丁質	5
圖2-4幾丁聚醣結構	6
圖2-5 環境刺激時的相對應答行為	12
圖2-6 藥物傳送之刺激響應	13
圖2-7溶液溫度與高分子體積分率()之相變化圖	14
圖2-8 溫度敏感型高分子載體製備及藥物釋放機制示意圖	16
圖2-9 幾丁聚醣-聚(丙烯酸-co-氮異丙基丙烯醯胺)奈米載體示意圖	17
圖2-10 PNVF 酸性水解產生之電子排斥力示意圖	19
圖2-11 智慧型水凝膠對環境產生應答能力	22
圖2-12 化學交聯、物理交聯或雙網絡製備的水凝膠之示意圖	23
圖2-13 (a)Semi-IPNs (b)Full-IPNs合成示意圖	24
圖2-14 藥物釋放系統	25
圖2-15 藥物恆定釋放產生的零級動力學	26
圖2-16 擴散控制系統	26
圖2-17 (a)儲存型系統和(b)基體型系統之載體的幾何形狀	27
圖2-18 膨潤控制系統	29
圖2-19侵蝕控制系統	30
圖3-1 幾丁聚醣純化之流程圖	39
圖3-2 水解裝置示意圖	42
圖3-3 PNVF合成流程圖	43
圖3-4 PNVF不同條件下之水解流程圖	43
圖3-5 自由基聚合法合成P(NP-co-NVF)高分子共聚物流程圖	45
圖3-6 P(NP-co-NVF)之水解流程圖	45
圖3-7自由基聚合法合成P(NP-co-NVF-co-NMA)高分子共聚物流程圖	47
圖3-8 CS/P(NP-co-VAm-co-NMA)水凝膠之流程圖	49
圖4-1幾丁聚醣之H-NMR光譜圖	53
圖4-2幾丁聚醣溶液之導電度與pH值隨加入的NaOH體積變化曲線	54
圖4-3幾丁聚醣溶液之pH值變化曲線一次微分	55
圖4-4不同濃度之N-乙醯基-D-葡萄糖胺一次微分吸光圖	56
圖4-5 N-乙醯基-D-葡萄糖胺一次微分吸光值對濃度之檢量線	57
圖4-6幾丁聚醣紅外線吸收光譜圖	58
圖4-7幾丁聚醣溶液在不同濃度下之還原黏度 (ηred)與固定黏度 (ηinh)	60
圖4-8幾丁聚醣紅外線吸收光譜圖	61
圖4-9自由基聚合法合成之PNVF高分子紅外線光譜圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	62
圖4-10 以自由基聚合法合成之PNVF的NMR圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	63
圖4-11 PNVF水解途徑示意圖	64
圖4-12 PNVF以1 N NaOH(aq)進行40 C水解4小時後的產物之NMR圖	67
圖4-13 PNVF以1 N NaOH(aq)進行40 C水解12小時後的產物之NMR圖	67
圖4-14 PNVF以1 N NaOH(aq)進行80 C水解12小時後的產物之NMR圖	68
圖4-15 PNVF以1 N HCl(aq)進行40 C水解4小時後的產物之NMR圖	68
圖4-16 PNVF以1 N HCl(aq)進行40 C水解12小時後的產物之NMR圖	69
圖4-17 PNVF以1 N HCl(aq)進行80 C水解12小時後的產物之NMR圖	69
圖4-18 PNVF在不同溫度與時間下，以1 N NaOH(aq)進行水解後產物之NMR比較圖	70
圖4-19 PNVF在不同溫度與時間下，以1 N HCl(aq)進行水解後產物之NMR比較圖	70
圖4- 20為自由基聚合法合成的 (a) PNVF、(b) P(NP14-co-NVF)、(c) P(NP19-co-NVF)、(d) P(NP29-co-NVF)以及(e) PNP之FTIR圖	72
圖4-21以自由基聚合法合成之P(NP14-co-NVF)之NMR圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	73
圖4-22以自由基聚合法合成之PNP之NMR圖，起始劑為AIBN，	74
圖4-23以自由基聚合法合成之P(NP19-co-NVF)之NMR圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	74
圖4-24以自由基聚合法合成之P(NP29-co-NVF)之NMR圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	75
圖4-25 PNP與不同P(NP-co-NVF)共聚物在pH7.4下穿透率(λ= 450 nm)對溫度的關係圖(a)及溫度一次微分圖(b)，溶液濃度為0.1 % (w/v)	76
圖4-26不同組成之P(NP-co-NVF)的熱重損失圖	78
圖4-27不同組成之P(NP-co-NVF)的熱重損失圖	78
圖4-28不同P(NP-co-NVF)比例之共聚物的DSC二次升溫曲線圖	79
圖4-29 (a)以自由基聚合法合成的P(NP14-co-NVF)；(b)P(NP14-co-NVF)以1 N HCl(aq)進行80 C水解12小時後的產物P(NP14-co-VAm)之FTIR圖	81
圖4-30 (a)以自由基聚合法合成的P(NP19-co-NVF)；(b)P(NP19-co-NVF)以1 N HCl(aq)進行80 C水解12小時後的產物P(NP19-co-VAm)之FTIR圖	81
圖4-31 (a)以自由基聚合法合成的P(NP29-co-NVF)；(b)P(NP29-co-NVF)以1 N HCl(aq)進行80 C水解12小時後的產物P(NP29-co-VAm)之FTIR圖	82
圖4-32 P(NP14-co-NVF)以1 N HCl(aq)進行80 C水解12小時後的產物P(NP14-co-VAm)之NMR圖(水解率=96.1 %)	82
圖4-33 P(NP19-co-NVF)以1 N NaOH(aq)進行80 C水解12小時後的產物P(NP19-co-VAm)之NMR圖(水解率=27.4 %)	83
圖4-34 P(NP19-co-NVF)以1 N HCl(aq)進行80 C水解12小時後的產物P(NP19-co-VAm)之NMR圖(水解率=98.0 %)	83
圖4-35 P(NP29-co-NVF)以1 N HCl(aq)進行80 C水解12小時後的產物P(NP29-co-VAm)之NMR圖(水解率=98.4 %)	84
圖4-36 PNP與不同P(NP-co-VAm)共聚物在pH7.4下穿透率(λ= 450 nm)對溫度的關係圖(a)及溫度一次微分圖(b)，溶液濃度為0.1 % (w/v)	86
圖4-37 P(NP19-co-VAm)共聚物在不同pH值下穿透率(λ = 450 nm)對溫度的關係圖(a)及溫度一次微分圖(b) ，溶液濃度為0.1 % (w/v)	87
圖4-38 P(NP14-co-VAm)在 pH7.4、37 C下之粒徑分佈圖	89
圖4-39 (NP19-co-VAm)在 pH7.4、37 C下之粒徑分佈圖	90
圖4-40 P(NP29-co-VAm)在 pH7.4、37 C下之粒徑分佈圖	91
圖4-41不同組成之P(NP-co-VAm)的熱重損失圖	93
圖4-42不同組成之P(NP-co-VAm)的熱重損失圖	93
圖4-43不同P(NP-co-VAm)比例之共聚物的DSC二次升溫曲線圖	94
圖4-44為以自由基聚合法合成的P(NP19-co-NVF) (a)與添加不同NMA含量的PFA3 (b)、PFA5 (c)和PFA10 (d)之FTIR圖	97
圖4-45以自由基聚合法合成的PFA3之NMR圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	98
圖4-46進料比NP：NVF為19：1以自由基聚合法合成的PFA5之NMR圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	98
圖4-47進料比NP：NVF為19：1以自由基聚合法合成的PFA10之NMR圖，起始劑為AIBN，反應溫度60 C，反應時間24小時	99
圖4-48利用自由基聚合法合成不同PFA共聚物，在pH7.4下的穿透率(λ = 450 nm)對溫度的關係圖(a)及溫度一次微分圖(b) ，溶液濃度為0.1 % (w/v)	101
圖4-49利用自由基聚合法合成不同PFA共聚物，在pH5.5下的穿透率(λ = 450 nm)對溫度的關係圖(a)及溫度一次微分圖(b) ，溶液濃度為0.1 % (w/v)	102
圖4-50熱交聯反應式	103
圖4-51 CS (a)以自由基聚合法合成的PFA10 (b)以及CS2/PVA10水凝膠(c)之FTIR圖	104
圖4-52不同組成的CS/PVA水凝膠之凝膠分率(GF)	107
圖4-53不同組成的CS/PVA水凝膠在去離子水(pH 6.8)中的平衡膨潤率	107
圖4-54不同組成的CS/PVA水凝膠在不同溫度及不同pH值緩衝液中的平衡膨潤率	109
圖4-55不同組成的CS/PVA水凝膠在不同溫度及不同pH值緩衝液中的平衡膨潤率	109
圖4-56 不同組成之CS2/PVA之水凝膠的熱重損失圖	112
圖4-57不同組成之CS2/PVA之水凝膠的熱重損失圖	112
圖4-58不同NMA比例之水凝膠的DSC二次升溫曲線圖	113
圖4-59 CS1/PVA3水凝膠之掃描式電子顯微鏡圖(浸泡於蒸餾水中)	115
圖4-60 CS1/PVA5水凝膠之掃描式電子顯微鏡圖(浸泡於蒸餾水中)	116
圖4-61 CS1/PVA10水凝膠之掃描式電子顯微鏡圖(浸泡於蒸餾水中)	117
圖4-62 CS2/PVA3水凝膠之掃描式電子顯微鏡圖(浸泡於蒸餾水中)	118
圖4-63 CS2/PVA5水凝膠之掃描式電子顯微鏡圖(浸泡於蒸餾水中)	119
圖4-64 CS2/PVA10水凝膠之掃描式電子顯微鏡圖(浸泡於蒸餾水中)	120
圖4-65 CS之掃描式電子顯微鏡圖(浸泡於pH5.5 PBS Buffer中)	121
圖4-66 CS1/PVA3水凝膠之掃描式電子顯微鏡圖(浸泡於pH5.5 PBS Buffer中)	122
圖4-67 CS1/PVA5水凝膠之掃描式電子顯微鏡圖(浸泡於pH5.5 PBS Buffer中)	123
圖4-68 CS1/PVA10水凝膠之掃描式電子顯微鏡圖(浸泡於pH5.5 PBS Buffer中)	124
圖4-69 CS2/PVA3水凝膠之掃描式電子顯微鏡圖(浸泡於pH5.5 PBS Buffer中)	125
圖4-70 CS2/PVA5水凝膠之掃描式電子顯微鏡圖(浸泡於pH5.5 PBS Buffer中)	126
圖4-71 CS2/PVA10水凝膠之掃描式電子顯微鏡圖(浸泡於pH5.5 PBS Buffer中)	127
圖4-72 CS之掃描式電子顯微鏡圖(浸泡於pH7.4 PBS Buffer中)	128
圖4-73 CS1/PVA5水凝膠之掃描式電子顯微鏡圖(浸泡於pH7.4 PBS Buffer中)	129
圖4-74 CS1/PVA10水凝膠之掃描式電子顯微鏡圖(浸泡於pH7.4 PBS Buffer中)	130
圖4-75 CS2/PVA3水凝膠之掃描式電子顯微鏡圖(浸泡於pH7.4 PBS Buffer中)	131
圖4-76 CS2/PVA5水凝膠之掃描式電子顯微鏡圖(浸泡於pH7.4 PBS Buffer中)	132
圖4-77 CS2/PVA10水凝膠之掃描式電子顯微鏡圖(浸泡於pH7.4 PBS Buffer中)	133
 
表目錄
表2-1幾丁聚醣的黏度常數a和K與溶劑、溫度、去乙醯度之關係	11
表2-2 常見LCST型溫度敏感性高分子及其臨界溶液溫度44	15
表2-3 Peppas釋放速率方程式中不同幾何形狀之釋放指數74	28
表3-1自由基聚合合成P(NP-co-NVF)之進料配方	44
表3-2自由基聚合合成P(NP-co-NVF-co-NMA)之進料莫爾比	46
表3-3 CS/PFA之進料比例	48
表4-1不同方法所測定之幾丁聚醣去乙醯度統整表	58
表4-2不同濃度的幾丁聚醣樣品所測得之滯留時間與其黏度參數	59
表4-3 PNVF在12 mL 1 N NaOH(aq) 水解成PVAm的結果整理	66
表4-4 PNVF在12 mL 1 N HCl(aq) 水解成PVAm的結果整理	66
表4-5 不同比例P(NP-co-NVF)之官能基紅外線吸收峰位置整理	73
表4-6不同組成之P(NP-co-NVF)之起始重量損失溫度 (Td, 5%)、最大速率裂解溫度 (Tmax)以及碳焦殘餘量 (C.Y.)	77
表4-7不同P(NP-co-VAm)於pH7.4、37 C下的粒徑尺寸	88
表4-8不同組成之P(NP-co-VAm)之起始重量損失溫度 (Td, 5%)、最大速率裂解溫度 (Tmax)以及碳焦殘餘量 (C.Y.)	92
表4-9進料比NP：NVF為19：1以自由基聚合法合成不同NMA含量的PFA之官能基紅外線吸收峰位置整理	97
表4-10 不同組成之水凝膠經熱交聯及水解後之CS/PVA比例、PVA之凝膠比率(GFPFA)與平衡膨潤率(ESR)	106
表4-11不同組成的CS/PVA水凝膠在不同溫度及pH 5.5緩衝液中的平衡膨潤率 (ESR, %)	108
表4-12不同組成的CS/PVA水凝膠在不同溫度及pH 7.4緩衝液中的平衡膨潤率 (ESR, %)	108
表4-13不同組成的水凝膠在不同溫度下(25與37 oC)之平衡膨潤率差異百分比 (SRD，%)	110
表4-14不同組成的水凝膠在不同溫度下 (25與45 oC)之平衡膨潤率差異百分比 (SRD，%)	110
表4-15不同組成之CS2/PVA水凝膠之起始重量損失溫度 (Td, 5%)、最大速率裂解溫度 (Tmax)以及碳焦殘餘量 (C.Y.)	111

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