臺灣博碩士論文加值系統

本研究以polyoxazoline、poly (acrylic acid)及polylactide 三種具良好生物適應性之高分子為主要材料，將其製備成具環境應答性之網狀互穿型(interpenetrating polymer nwtwork)生醫水膠，其能在高pH如小腸之中性pH下膨潤釋放藥物，低pH如胃之pH下收縮保護藥物，將其對環境應答產生之特性應用於藥物傳釋上，能有效的控制藥物之釋放，達到治療之效果。
在本研究中，分別製備POx/PAA IPN/SIPN、PEG-b-PLA /PAA SIPN兩種水膠，其對外在環境之刺激變化特別是pH之改變所產生之應答效果非常明顯且快速，屬於一種快速應答型水膠。由膨潤測試之結果顯示無論是POx/PAA或PEG-b-PLA /PAA 水膠，皆能在人體之生理環境下(pH 7-7.4、溫度37℃)膨潤，低溫低pH下收縮，形成一種可逆之膨潤收縮現象。由藥物制放實驗結果，證實本研究所設計之水膠皆能有效的控制釋放藥物，不論是小分子之Theophylline或是巨分子之蛋白質藥物(bovine serum albumin，BSA)，且能形成一種智慧型”On-Off”之藥物制放機制。藉由細胞毒性之實驗，可以評估水膠之生物適應性，從實驗結果得知POx/PAA和PEG-b-PLA /PAA水膠其細胞之存活率高達80﹪以上具有良好之生物適應性。除此之外，本研究所製備之PEG-b- PLA/PAA水膠還具有分解之特性，能在生理環境下分解成小分子乳酸、聚丙烯酸被人體吸收代謝。藉由體外分解實驗，證實能藉由水解過程而分解代謝，且於一個月內完全分解。
由研究之結果，證實所合成之POx/PAA IPN/SIPN、PEG-b-PLA /PAA SIPN 能對環境產生應答效果且能有效地控制藥物之釋放，作為良好之口服藥物載體，特別是能應用於腸胃道之藥物

The objective of our research is to prepare environmental responsibility bio-hydrogel with good biocompatibility based on interpenetrating polymer networks constructed with polyoxazoline、poly(acrylic acid) and polylactide. The prepared hydrogel swell to release the drug at high pH such as the neutral pH of intestine, and shrink to protect the drug at low pH such as the pH of stomach. The characterization of swelling dependence on environmental responsibility can be applied in drug delivery systems (DDS), and effectively controlled release drug to reach the purpose of therapy.
In our study, POx/PAA IPN and PEG-b-PLA/PAA SIPN are synthesized, respectively. The response of these prepared hydrogel by environmental stimuli especially in pH stimuli is obvious and fast. Hence, these prepared hydrogel belong to fast responsibility hydrogel. According to the result of swelling test, no mater POx/PAA IPN or PEG-b-PLA /PAA SIPN swell at physiology environment (pH 7-7.4, 37℃) and shrink at low temperature/pH, which form reversibly swelling/shrinking. According to the confirmation of drug controlled release experiment, these prepared hydrogel can effectively controlled release drug, no mater small molecule drug like theophylline or large molecule drug like bovine serum albumin (BSA) can be released from that, and form the intelligential “On-Off “ drug release profile. The biocompatibility of these hydrogel is evaluated by in vitro cytotoxicity test. According to the result of cytotoxicity test, the survival ratio of cultured cell can reach above 80%. In addition PEG-b-PLA/PAA SIPN have the characterization of degradable, which degrade upon hydrolysis of the polylactide regions into PEG、the lactic acid and PAA at physiology environment in one month .

目錄
英文摘要 …………………………………………………………I
中文摘要 …………………………………………………………II
目錄 …………………………………………………………III
圖目錄 …………………………………………………………VII
表目錄 …………………………………………………………XVI
Scheme 目錄………………………………………………………XVII
第一章 序論.……………………………………………………1
1-1研究背景與目的……………………………………1
1-2實驗內容簡介………………………………………2
第二章 文獻回顧……………………………………………… 6
2-1環境應答型水膠的介紹……………………………6
2-1-1水膠的定義及類型………………………………6
2-1-2溫度應答型水膠…………………………………19
2-1-3 pH應答型水膠…………… ……………………12
2-1-4葡萄糖應答型水膠………………………………17
2-1-5電流應答型水膠…………………………………21
2-1-6光應答型水膠……………………………………23
2-2 生物分解性水膠………………………………… 25
2-3 水膠在藥物傳遞的應用………………………… 27
2-4 高分子網狀互穿結構…………………………… 31
2-5 藥物制放………………………………………… 33
2-5-1藥物傳釋系統……………………………………34
2-5-2藥物動力學………………………………………38
第三章 實驗部分……………………………………………… 40
3-1實驗藥品與實驗儀器………………………………40
3-1-1實驗藥品…………………………………………40
3-1-2 實驗儀器……………………………………… 41
3-2 合成部分………………………………………… 44
3-2-1 藥品純化……………………………………… 44
3-2-2 合成步驟(Part I)…………………………… 44
3-2-3 合成步驟(Part II)……………………………48
3-3 結構鑑定………………………………………… 53
3-4 水膠平衡膨潤率測定…………………………… 54
3-5 毒性測試………………………………………… 55
3-5-1 藥品配置……………………………………… 55
3-5-2 毒性測試實驗步驟…………………………… 56
3-6 藥物之制放……………………………………… 56
3-7 分解實驗………………………………………… 57
第四章 結果與討論………….…...………………………… 59
第一部份 POx/PAA IPN and SIPN
4-1 結構鑑定………………………………………… 59
4-1-1 1H-NMR核磁共振儀分析結果………………… 59
4-1-2 紅外線光譜儀(FT-IR)分析的結果……………62
4-1-3 分子量(GPC)的分析結果………………………62
4-1-4 DSC分析結果……………………………………63
4-1-5 元素分析(EA)分析結果……………………… 69
4-2 水膠膨潤的結果與因素探討…………………… 69
4-2-1 溫度和pH對膨潤率的影響…………………… 69
4-2-2 pH值可逆膨潤性質探討……………………… 71
4-2-3 溫度可逆膨潤性質探討……………………… 72
4-3 藥物之控制釋放………………………………… 75
4-4 細胞毒性測試…………………………………… 81
第二部分PEG-b-PLA macromer / PAA SIPN
4-6 結構鑑定………………………………………… 84
4-6-11H-NMR核磁共振儀分析結果……………………84
4-6-2 紅外線光譜儀(FT-IR)分析的結果……………90
4-6-3 分子量(GPC)之測試……………………………96
4-6-4 DSC之測試………………………………………96
4-7 水膠膨潤的結果與因素探討…………………… 100
4-7-1溫度和pH對膨潤率的影響………………………100
4-7-2 pH值可逆膨潤性質探討……………………… 101
4-7-3 溫度可逆膨潤性質探討……………………… 101
4-8 藥物之控制釋放………………………………… 105
4-9 細胞毒性測試…………………………………… 112
4-10 分解測試…………………………………………115
第五章 結論…………………………………………………… 124
第六章 參考資料……………………………………………… 128

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