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研究生:陳雯馨
研究生(外文):Wen Hsin Chen
論文名稱:甲氧基聚乙二醇/官能性聚己內酯/聚己內酯兩性嵌段共聚物的合成與其微胞性質之探討
論文名稱(外文):Synthesis of methoxy poly(ethyleneglycol) / functional poly(ε-caprolactone) / poly(ε-caprolactone) amphiphilic block copolymers and characterization of their micelles
指導教授:華沐怡李仁盛
指導教授(外文):M.Y. HuaR.S. Lee
學位類別:碩士
校院名稱:長庚大學
系所名稱:化工與材料工程研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
論文頁數:67
中文關鍵詞:甲氧基聚乙二醇官能性聚己內酯聚己內酯嵌段共聚物微胞藥物負載
外文關鍵詞:methoxy poly(ethyleneglycol)functional poly(ε-caprolactone)poly(ε-caprolactone)block copolymersmicellesdrug-loading
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這研究目的是在發展聚己內酯(PCL)區塊上具有官能側基團的嵌段共聚物合成及微胞的形成。我們利用甲氧基聚乙二醇(MPEG,Mn=550 g mol-1)為巨起始劑與單體γ-芐氧基-ε-己內酯(BOCL)以SnOct2當催化劑,在溫度140℃下進行開環聚合反應48小時去合成MPEG-b-PBOCL雙嵌段共聚物。而MPEG-b-PBOCL-b-PCL三嵌段共聚物的合成是利用MPEG-b-PBOCL雙嵌段共聚物與ε-己內酯(ε-CL)以SnOct2當催化劑,在溫度110℃下進行開環聚合反應48小時。接著,將所獲得的三嵌段共聚物進行氫化反應,使PBOCL區塊上的芐基去除,以氫氧基團代替,增加其親水性。這些共聚物藉由微凝膠滲透層析(GPC)、核磁共振儀(1H NMR)及示差掃描熱量計(DSC)描述其特徵。而氫化後的三嵌段共聚物以IR和1H NMR去判斷其氫化程度。結果顯示,雙嵌段共聚物的熱性質(Tg和Tm)依賴聚合物的成份做改變。以MPEG-b-PBOCL雙嵌段共聚物而言,只有Tg存在,當PBOCL鏈長增加其Tg隨之增加;而MPEG-b-PBOCL -b-PCL三嵌段共聚物,其疏水段中PCL比例增加,則Tg減少和Tm增加。以油/水乳化法製備微胞水溶液,藉由螢光光譜儀,穿透式電子顯微鏡(TEM),和動態光散射法(DLS)進行研究微胞特徵。所得結果,臨界微胞濃度(CMCs)範圍為0.76× 10-3 ~ 9.77×10-3 g L-1;微胞平均直徑範圍:未包覆藥物(AM)的微胞為87.0 ± 0.680 ~ 193.2 ± 6.406 nm,包覆藥物(AM)的微胞為89.4 ± 0.497 ~ 134.8 ± 1.262 nm;未包覆藥物微胞的Zate-電位為-2.3 ± 0.054 ~ -20.7 ± 0.994 mV;而微胞形態隨組成成份的比例不同形成長短不同的紡錘體。並測定微胞的藥物補集效率和微胞的藥物載荷含量,隨組成成份的不同而有所變化。
The purpose of study was to develop the synthesized and micelles-forming of (MPEG-b-PCL)-based block copolymers bearing functional side groups on the PCL block. MPEG-b-PBOCL diblock copolymers were synthesized by ring-opening polymerization of γ-Benzyloxy-ε-caprolactone(BOCL)using monomethoxy poly(ethylene glycol)(MPEG, Mn = 550 g mol-1)as the macroinitiator and SnOct2 as the catalyst. MPEG-b-PBOCL-b-PCL triblock copolymers were either synthesized by ring-opening polymerization of ε-caprolactone(ε-CL)using MPEG-b-PBOCL diblock copolymers and SnOct2 as the catalyst. The diblock or triblock copolymers were characterized by DSC, GPC, and 1H NMR. The Tg and Tm of block copolymers depend on the composition of block copolymers. For MPEG-b-PBOCL diblock copolymers exhibited only Tg that are amorphous. The length of PBOCL block was increased, the Tgs of MPEG-b-PBOCL were increased either. The length of PCL block was increased, the Tgs of MPEG-b-PBOCL-b-PCL were decreased and Tms of that were increased. The micelles of diblock or triblock copolymers in an aqueous phase were characterized by fluorescence, TEM, and DLS. The range of CMCs values were 0.76× 10-3 ~ 9.77×10-3 g L-1. The sizes of polymeric micelles were in the range of 87.0 ± 0.680 ~ 193.2 ± 6.406 nm. And the sizes of AM-loading micelles were in the range of 89.4 ± 0.497 ~ 134.8 ± 1.262 nm. However, the Zeta-potential of polymeric micelles were -2.3 ± 0.054 ~ -20.7 ± 0.994 mV. The shapes of micelles vary with the composition of block polymers were different length of spindle. The drug entrapment efficient and the drug-loading content of micelles depending on the composition of block polymers were described.
目錄
指導教授推薦書…………………………………………………..
口試委員會審定書………………………………………………..
授權書…………………………………………………………….. iii
誌謝……………………………………………………………….. iv
中文摘要………………………………………………………….. v
英文摘要………………………………………………………….. vi
目錄……………………………………………………………….. vii
第一章 緒論……………………………………………………… 1
1.1 前言…………………………………………………………... 1
1.2 研究動機……………………………………………………... 1
1.3 藥物控制釋放系統…………………………………………... 2
1.4 嵌段共聚物(Block copolymers)………………………….. 3
1.5 聚合物微胞(Polymeric micelles)………………………… 4
第二章 文獻回顧………………………………………………… 13
2.1 聚合物材料簡介……………………………………………... 13
2.2 MPEG-b-PCL嵌段共聚物…………………………………… 15
2.3 MPEG-b-PCL嵌段共聚物中PCL區塊的改質……………... 17
第三章 實驗設計與方法………………………………………… 19
3.1 實驗流程……………………………………………………... 19
3.2 實驗藥品……………………………………………………... 20
3.3 分析儀器……………………………………………………... 22
3.4 實驗步驟……………………………………………………... 24
3.4.1 嵌段共聚物的合成步驟………………………………... 24
3.4.1.1 單體γ-芐氧基-ε-己內酯的製備………………….. 24
3.4.1.2 雙嵌段共聚物MPEG-b-PBOCL的合成………… 24
3.4.1.3 三嵌段共聚物MPEG-b-PBOCL-b-PCL的合成… 25
3.4.2 三嵌段共聚物MPEG-b-PBOCL-b-PCL之氫化……… 25
3.4.3 嵌段共聚物微胞的特徵………………………………... 26
3.4.3.1 臨界微胞濃度(CMCs)的樣品製備……………. 26
3.4.3.2 微胞的粒徑大小、Zeta-電位和形態之樣品製備
………………………………………………………………. 27
3.4.4 微胞包覆藥物(AM)的特徵………………………...... 27
3.4.4.1 微胞包覆藥物的粒徑大小和形態之樣品製備….... 27
3.4.4.2 藥物負載含量和藥物補集效率的樣品製備…….... 28
3.4.4.2.1 藥物Amitriptyline hydrochloride(AM)…..... 28
3.4.4.2.2 藥物5-Fluorouracil(5-Fu)…………………... 29

第四章結果與討論………………………………………………… 30
4.1 嵌段共聚物的合成…………………………………………... 30
4.1.1 單體γ-芐氧基-ε-己內酯的製備結果…………………... 30
4.1.2 雙嵌段共聚物MPEG-b-PBOCL的合成結果與鑑定..... 31
4.1.3 三嵌段共聚物MPEG-b-PBOCL-b-PCL的合成結果與
鑑定…………………………………………………………..... 32
4.2 三嵌段共聚物MPEG-b-PBOCL-b-PCL之氫化檢測……… 33
4.3 嵌段共聚物的熱學性質……………………………………... 35
4.4 嵌段共聚物微胞的特徵……………………………………... 38
4.4.1 臨界微胞濃度(CMCs)………………………………. 38
4.4.2 微胞的粒徑大小和形態………………………………... 40
4.5 微胞包覆藥物(AM)的特徵………………………………. 41
4.5.1 微胞包覆藥物的粒徑大小、Zeta-電位和形態………... 41
4.5.2藥物負載含量和藥物補集效率………………………… 45
4.5.2.1 藥物Amitriptyline hydrochloride(AM)……….. 45
4.5.2.1 藥物5-Fluorouracil(5-Fu)………... ……….. …. 46
第五章 結論……………………………………………………… 48
參考文獻………………………………………………………...... 49

表目錄
表 1-1 影響微胞安定性的因素…………………………………. 12
表 4-1 嵌段共聚物的合成結果…………………………………. 36
表 4-2 嵌段共聚物微胞的特性…………………………………. 41
表 4-3 微胞之藥物(AM)補集效率和藥物負載含量的比較... 46
表 4-4 微胞之藥物(5-Fu)補集效率和藥物負載含量的比較… 47

圖目錄
圖 1-1 藥物在血液中濃度對時間的變化……………………… 3
圖 1-2 兩性共聚物自組裝成微胞的簡圖……………………… 5
圖 1-3 嵌段共聚物在不同濃度下微胞形成機制……………… 6
圖 1-4 微胞溶液的製備方法:直接溶解法和透析法………… 7
圖 1-5 微胞溶液的製備方法:油/水乳化法…………………... 8
圖 1-6 嵌段共聚物微胞的簡圖…………………………………. 9
圖 1-7 理想微胞的性質…………………………………………. 10
圖 3-1 嵌段共聚物MPEG-b-PBOCL、MPEG-b-PBOCL-b-PCL
和MPEG-b-POHCL/PBOCL-b-PCL的合成……………………. 26
圖 4-1 單體γ-芐氧基-ε-己內酯(BOCL)的1H NMR光譜(in
CDCl3)………………………………………………………….... 30
圖 4-2 雙嵌段共聚物MPEG12-b-PBOCL27的1H NMR光譜(in
CDCl3)…………………………………………………………… 32
圖 4-3 三嵌段共聚物MPEG12-b-PBOCL27-b-PCL48的1H NMR
光譜(in CDCl3)………………………………………………… 33
圖 4-4 三嵌段共聚物MPEG12-b-POHCL23/PBOCL4-b-PCL89的
1H NMR光譜(in CDCl3)………………………………………. 34
圖 4-5 三嵌段共聚物(A)MPEG12-b-PBOCL30- b-PCL89(氫
化前)(B)MPEG12-b-POHCL23/PBOCL4-b-PCL89(氫化後)
的IR光譜………………………………………………………… 35
圖 4-6 三嵌段共聚物(A)MPEG12-b-PBOCL30- b-PCL89(氫
化前)(B)MPEG12-b-POHCL23/PBOCL4-b-PCL89(氫化後)
的GPC圖譜……………………………………………………… 35
圖 4-7 嵌段共聚物的DSC圖譜………………………………... 36
圖 4-8 不同濃度的MPEG12-b-PBOCL12-b-PCL33嵌段共聚物
之pyrene溶液的螢光激發光譜(λem = 390 nm)……………… 39
圖 4-9 雙嵌段共聚物之不同濃度pyrene溶液的螢光激發光譜
(λem = 390 nm)I339 / I334 vs Log C……………………………… 39
圖 4-10 三嵌段共聚物之不同濃度pyrene溶液的螢光激發光譜
(λem = 390 nm)I 338 / I334 vs Log C……………………………… 40
圖 4-11 嵌段共聚物微胞形態的TEM照片(倍率:30 K)…. 43
圖 4-12 嵌段共聚物微胞形態的TEM照片(倍率:30 K)…. 44
圖 4-13 嵌段共聚物氫化後之微胞形態的TEM照片(倍率:
30 K)……………………………………………………………… 45
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