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研究生:蘇容潔
研究生(外文):Rong Jia Su
論文名稱:兩性AB雙嵌段接枝共聚物聚己內酯/(聚己內酯接枝烯類)之合成與微胞性質探討
論文名稱(外文):Synthesis of (PαN3CL-g-alkyne)-b- PCL block-graft copolymers and their micelles characterization
指導教授:呂彥禮李仁盛
指導教授(外文):Y. L. LeuR. S. Lee
學位類別:碩士
校院名稱:長庚大學
系所名稱:天然藥物研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:100
中文關鍵詞:雙嵌段接枝共聚物微胞兩性偶合反應
外文關鍵詞:block-graft copolymermicellesclick chemistryamphiphiles
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本研究著重於利用胺基酯類PMHEC作為起始劑、SnOct2作為催化劑,和乙-氯己內酯進行開環聚合後,再與己內酯進行聚合得不同莫耳比例雙嵌段共聚物(PαClCL-b-PCL),PαClCL-b-PCL接著再進行疊氮化及炔類接枝反應,最後得雙嵌段接枝兩性共聚物。改變不同的接枝側官能基,使得雙嵌段共聚物材料本身的親、疏水性改變。藉由開環聚合反應得到的AB兩性雙嵌段團聯接枝共聚物,以凝膠滲透層析儀、核磁共振儀、微差掃描熱卡計等儀器鑑定,得到當聚己內酯鏈段比例增加,共聚物的熔點會降低或是玻璃轉移溫度上升。利用共聚物在水中自我組裝的特性,以透析方式製備微胞,使用螢光判斷共聚物是否形成微胞,進而計算出共聚物微胞的臨界微胞濃度是介於5~40 mg/L之間,再利用穿透式顯微鏡觀察共聚物微胞形態,與雷射光散射儀測得微胞粒徑大小相比對,微胞形態具備core-shell結構,粒徑大小約為30~230 nm,隨著PCL鏈段比例增加,微胞的尺寸也隨著變大。進而探討接枝3-(2-methoxyethoxy) propyne共聚物微胞包覆indomethacin的微胞包埋率,當共聚物/藥物的重量比值越大,所得到entrapment efficiency由34.6%增加到53.5%,但drug loading content則由23.0%降低到17.9%。
A straightforward strategy is proposed for the synthesis of amphamiphilic block-graft (PαN3CL-g-alkyne)-b-PCL degradable copolymers. First, the ring-opening copolymerization of α-chloro-ε-caprolactone (αClεCL) with ε-caprolactone (εCL) was initiated with hydroxy-terminated initiator phenylmethyl-N-(2-hydroxyethyl) carbamate with SnOct2 as catalyst. In the second step, pendent chlorides were converted into azides by reaction with sodium azide. Finally, various of terminal alkynes were reacted with pendent azides by “ click reaction”. These copolymers were characterized by differential scanning calorimetry (DSC), 1H NMR, gel premeation chromatography (GPC). The molecular weight and compositions of block-graft copolymers were controlled by molar ratios of αClCL and CL to the initiator and the grafting efficiency. CMC values were detected by fluorescence probe technique. An increase of the length of hydrophobic segment in amphophilic block-graft copolymers produced a lower CMC values. The block-graft copolymers formed micelles in the aqueous phase with critical micelle concentrations (CMCs) in the range of 5-40 mg L-1. The morphology of the micelles exhibited a spindle or spherical shape depending on the length of hydrophilic block. DLS experiments showed that the mean hydrodynamic diameters of the micelles were 30~230 nm. The drug loading content increased when the feed weight ratio of indomethacin to the polymer and the drug entrapment efficiency was the opposite.
目錄
指導教授推薦書…………………………………………………i
口試委員審定書…………………………………………………ii
長庚大學碩士紙本論文著作授權書……………………………iii
誌謝………………………………………………………………iv
中文摘要…………………………………………………………vi
Abstract…………………………………………………………vii
目錄………………………………………………………………viii
表目錄……………………………………………………………xiv
圖目錄……………………………………………………………xv
第一章 緒論 ………………………………………………………1
1.1 生物可降解性材料……………………………………………2
1.2 聚合物微胞的特性……………………………………………3
1.3 微胞的應用……………………………………………………4
1.4 藥物載體設計…………………………………………………5
1.5 藥物控制釋放…………………………………………………6
1.6 indomethacin藥物使用………………………………………7
第二章 文獻回顧 …………………………………………………8
2.1 團鏈/接枝共聚物 ……………………………………………8
2.2 側官能基 ……………………………………………………10
2.3 click reaction ……………………………………………11
2.4 聚己內酯 ……………………………………………………13
2.5 研究目的與動機 ……………………………………………13
第三章 實驗設計與方法…………………………………………16
3.1 實驗流程 ……………………………………………………16
3.2 實驗藥品 ……………………………………………………16
3.3 分析儀器 ……………………………………………………17
3.4 實驗步驟 ……………………………………………………20
3.4.1起始物αClCL合成…………………………………………20
3.4.2 3-(2-methoxyethoxy) propyne的合成步驟……………20
3.4.3 1-propargyl 2-methoxy poly(ethylene glycol)的合成步驟 ……………………………………………………………………21
3.4.4團聯共聚物 PαClCL 的聚合步驟 ………………………21
3.4.4.1 胺基酯類PMHEC與αClCL聚合步驟……………………21
3.4.4.2 甲基聚乙二醇 MPEG550與αClCL聚合步驟 …………22
3.4.5 雙嵌段團聯共聚物 PαClCL- b-PCL聚合步驟…………23
3.4.5.1 雙嵌段團聯共聚物 PMHEC-PαClCL-b-PCL之聚合步驟 ……………………………………………………………………23
3.4.5.2雙嵌段團聯共聚物 MPEG550-PαClCL-b-PCL之聚合步驟…………………………………………………………………24
3.4.6 利用azide取代雙嵌段共聚物上官能基chloride 反應…………………………………………………………………24
3.4.7 click reaction…………………………………………26
3.4.7.1 PMHEC-PαN3CL-b-PCL與propargyl benzoate進行click reaction…………………………………………………………25
3.4.7.2 MPEG550-PN3CL-b-PCL與propargyl benzoate進行click reaction…………………………………………………………26
3.4.7.3 PMHEC-PN3CL-b-PCL與3-(2-methoxyethoxy) propyne進行click reaction…………………………………………………27
3.4.7.4 PMHEC-PN3CL-b-PCL與1-propargyl 2-methoxy poly(ethylene glycol)進行click reaction ………………28
3.4.8 氫化去除雙嵌段共聚物的保護基………………………29
3.4.9 微胞溶液製備……………………………………………30
3.4.9.1偵測臨界微胞濃度 ……………………………………30
3.4.9.2 微胞粒徑大小與型態測試……………………………30
3.4.9.3 微胞1H NMR樣品製備…………………………………30
3.4.10 藥物包埋樣品製備 ……………………………………31
3.4.10.1 藥物包埋後的微胞粒徑大小與型態測試 …………32
3.4.10.2 釋放藥物的樣品製備 ………………………………32
3.4.11 體外水解樣品製備 ……………………………………33
3.4.12 測接觸角樣品製備 ……………………………………34
第四章 實驗結果與討論 ………………………………………35
4.1 起始物 αClCL合成結果與鑑定 …………………………35
4.2聚合物合成結果與鑑定 ……………………………………35
4.2.1 PMHEC-PαClCL聚合結果與鑑定 ………………………35
4.2.2 MPEG550- PαClCL聚合結果與鑑定……………………36
4.3 雙嵌段共聚物的聚合條件…………………………………37
4.3.1 PαClCL-b-PCL 聚合結果與鑑定………………………39
4.3.1.1 PMHEC- PαClCL-b-PCL雙嵌段聚合物………………39
4.3.1.2 MPEG550- PαClCL-b-PCL雙嵌段聚合物……………40
4.4 雙嵌段共聚物azide取代側鏈chloride反應 ……………41
4.4.1 PMHEC- PαN3CL-b-PCL 1H NMR確認結構 ……………42
4.4.2 MPEG550- PαN3CL-b-PCL 1H NMR確認結構 …………43
4.5雙嵌段共聚物之click reaction …………………………43
4.5.1 PMHEC-PαN3CL-b-PCL coupling with propargyl benzoate 1H NMR結構鑑定…………………………………………………44
4.5.2 PMHEC-PαN3CL-b-PCL coupling with 3-(2-methoxyethoxy) propyne 1H NMR結構鑑定………………………………………45
4.5.3 PMHEC-PαN3CL-b-PCL coupling with 1-propargyl 2-methoxy poly(ethylene glycol) 1H NMR結構鑑定………45
4.5.4 MPEG550-PαN3CL-b-PCL coupling with propargyl benzoate 1H NMR結構鑑定 ……………………………………46
4.6去雙嵌段共聚物的benzyl保護基 …………………………47
4.7雙嵌段共聚物物化性質 ……………………………………50
4.7.1不同類型不同比例的雙嵌段共聚物熱學性質比較 ……50
4.7.2不同類型同比例的雙嵌段共聚物熱學性質比較 ………52
4.7.3雙嵌段共聚物接觸角比較 ………………………………53
4.7.4雙嵌段共聚物水解速率 …………………………………55
4.8雙嵌段共聚物微胞特徵 ……………………………………57
4.8.1臨界微胞濃度 ……………………………………………57
4.8.2微胞的粒徑大小及形態 …………………………………60
4.8.3雙嵌段共聚物形成微胞後的1H NMR圖譜 ............64
4.9雙嵌段共聚物微胞的藥物包埋 ……………………………66
4.9.1雙嵌段共聚物微胞的藥物包埋率 ………………………66
4.9.2包埋藥物後的微胞大小及型態 …………………………68
4.10雙嵌段共聚物微胞的藥物控制釋放………………………68
第五章 結論……………………………………………………71
參考文獻…………………………………………………………74
表目錄
表4-1……………………………………………………………36
表4-2……………………………………………………………38
表4-3……………………………………………………………41
表4-4……………………………………………………………44
表4-5……………………………………………………………47
表4-6……………………………………………………………51
表4-7……………………………………………………………52
表4-8……………………………………………………………54
表4-9……………………………………………………………60
表4-10 …………………………………………………………62
表4-11 …………………………………………………………66
圖目錄
Scheme 2-1……………………………………………………12
流程一…………………………………………………………15
Scheme 3-1……………………………………………………20
Scheme 3-2……………………………………………………21
Scheme 3-3……………………………………………………21
Scheme 3-4……………………………………………………22
Scheme 3-5……………………………………………………23
Scheme 3-6……………………………………………………24
Scheme 3-7……………………………………………………24
Scheme 3-8……………………………………………………25
Scheme 3-9……………………………………………………26
Scheme 3-10 …………………………………………………26
Scheme 3-11 …………………………………………………28
Scheme 3-12 …………………………………………………29
Scheme 3-13 …………………………………………………30
圖4-1 …………………………………………………………35
圖4-2 …………………………………………………………36
圖4-3 …………………………………………………………37
圖4-4 …………………………………………………………39
圖4-5 …………………………………………………………40
圖4-6 …………………………………………………………41
圖4-7 …………………………………………………………42
圖4-8 …………………………………………………………42
圖4-9 …………………………………………………………43
圖4-10…………………………………………………………44
圖4-11…………………………………………………………45
圖4-12…………………………………………………………46
圖4-13…………………………………………………………46
圖4-14…………………………………………………………48
圖4-15…………………………………………………………48
圖4-16…………………………………………………………49
圖4-17…………………………………………………………50
圖4-18…………………………………………………………56
圖4-19…………………………………………………………57
圖4-20…………………………………………………………58
圖4-21…………………………………………………………59
圖4-22…………………………………………………………62
圖4-23…………………………………………………………63
圖4-24…………………………………………………………64
圖4-25…………………………………………………………65
圖4-26…………………………………………………………68
圖4-27…………………………………………………………69
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