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研究生: 謝季辰
Ji-Chen Shie
論文名稱: 溫敏型寡聚聚乙二醇單甲醚/聚乳酸-甘醇酸雙團聯共聚物水膠之相變化、微胞性質及藥物釋放行為
Phase Transition、Micelle Properties and Drug Release Behavior in Thermosensitive Oligomeric Monomethoxy Poly(ethylene glycol) -Poly(D,L-lactic-co-glycolic acid) (mPEG-PLGA) Diblock Copolymer Gels
指導教授: 胡孝光
Shiaw-Guang Hu
口試委員: 童世煌
none
朱一民
none
何明樺
none
學位類別: 碩士
Master
系所名稱: 工程學院 - 材料科學與工程系
Department of Materials Science and Engineering
論文出版年: 2013
畢業學年度: 101
語文別: 中文
論文頁數: 99
中文關鍵詞: 雙團聯共聚物相變化微胞性質藥物釋放
外文關鍵詞: Diblock Copolymer, Phase Transition, Micelle Properties, Drug Release
相關次數: 點閱:280下載:11
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  • 本研究合成一系列不同疏水鏈段聚合度(聚合度NPLGA=17.59 ~ 23.75)之聚乙二醇單甲醚(mPEG, NmPEG=12.50)/聚乳酸-甘醇酸(PLGA)雙團聯共聚物(具約等莫耳數乳酸與甘醇酸單體單位),並使用翻轉試管法及流變法求得共聚物溶液之相圖,藉由可控溫型紫外光/可見光分光光譜儀及染料溶入法測定共聚物於水溶液中的臨界微胞濃度,並計算其熱力學參數,利用動態光散射儀測量微胞粒徑。採用Leibler臨界微胞濃度理論,探討疏水鏈段與水的Flory-Huggins 交互作用參數 PLGA-water。最後以紫外光/可見光分光譜儀測量雙團聯共聚物水膠中包覆藥物aminoguanidine hydrochloride的濃度,測量37℃從水膠釋放至水中的藥物釋放率,探討藥物釋放率如何受水膠中高分子結構、濃度影響。
    使用翻轉試管法及流變法求得共聚物溶液之相圖,結果顯示,使用流變法可求得三個相(sol, gel and precipitate),使用翻轉試管法只可觀察出兩個相(sol and gel),兩種方法求得的相變溫度之相對誤差為0.2~2.02%,而採用流變法測量臨界成膠溫度較翻轉試管法略高,且隨著共聚物疏水鏈段長度的增加,臨界成膠溫度下降,而臨界成膠濃度明顯減少;溶液中共聚物濃度愈高,黏度愈大,成膠範圍愈大。藉由共聚物於水溶液中的臨界微胞濃度與溫度的關係,計算其熱力學參數。發現隨著共聚物疏水鏈段長度的增加,臨界微胞濃度減少,而微胞化標準焓(負值)的絕對值減少,微胞化標準熵(正值)增加,微胞化自由能(負值)減少,有利於微胞的形成。結果顯示微胞半徑隨著疏水鏈段聚合度增加,且求得微胞半徑與疏水鏈段聚合度的冪次關係的指數為0.38次方。採用Leibler臨界微胞濃度理論,結果發現 PLGA-water隨疏水鏈段長度增加而增加。
    利用mPEG-PLGA水膠做為藥物載體,改變mPEG-PLGA的疏水鏈段長度,以及在相同疏水鏈段長度下,改變mPEG-PLGA水膠濃度,aminoguanidine hydrochloride藥物通過透析袋,進行釋放。起初aminoguanidine hydrochloride因mPEG-PLGA疏水鏈段愈長,濃度愈高,水膠黏度愈大,釋放遲滯時間愈長;在最後達平衡時,疏水鏈段愈長,最終釋放率愈低。水膠濃度愈高,最終釋放率愈低。因為疏水鏈段愈長,濃度愈高,水膠與aminoguanidine hydrochloride交互作用愈強。


    Monomethoxy poly(ethylene glycol)-Poly(D,L-lactic-co-glycolic acid) (mPEG-PLGA) diblock copolymers with fixed mPEG length (degree of polymerization =12.50) and various PLGA lengths (degree of polymerization = 17.59 to 23.75) were synthesized. The molar ratio of DLLA and GA is 58:42 to 55:45 . Phase diagrams were determined by the tube inverting method and rheometry. The critical micelle concentrations (CMC) and micellar radius were determined by UV/Vis spectroscopy with dye solubilization and dynamic light scattering, respectively . Based on Leibler theory for CMC, we calculated the Flory-Huggins interaction parameter between hydrophobic segments and water, χmPEG-PLGA .Using the mPEG- PLGA as the drug loading carrier for the drug that was aminoguanidine hydrochloride.The drug release experiment was performed at 37℃, the drug release amount was determined by UV/Vis spectroscopy. It was aimed at investigating how the drug release amount was affected by structure of hydrophobic blocks in mPEG-PLGA and mPEG-PLGA concentration in solution.
    Rheomety showed three phases (sol, gel and precipitate) in copolymer solutions, whereas the tube inverting method two phases (sol and gel). Relative difference between phase transition temperatures from two methods can vary between 0.2~2.02%. As the length of hydrophobic blocks in copolymers increased, the critical gel temperatures (CGC) decreased slightly, but the critical gel concentrations (CGC) decreased significantly. Also the higher copolymer concentrations gave a wider temperature range for gelation. Thermodynamic parameters calculated from CMC indicate that the micellization process was driven by entropy gain. The micellar radius increases with the PLGA length and micellar radius was proportional to the 0.38th power of PLGA block length. Upon increasing the hydrophobic length, the Flory-Huggins interaction parameters between hydrophobic segments and water were increased . Aminoguanidine hydrochloride in mPEG-PLGA gels with various hydrophobic block lengths or copolymer concentrations in solution release through the dialysis bags. Initially, the longer hydrophobic blocks in mPEG-PLGA or the higher concentrations of copolymer solutions gave rise to the longer time lag. In the equilibrium, the longer hydrophobic blocks or the higher concentrations offered the stronger interactions between aminoguanidine hydrochloride and copolymers , hence the lower fractional release of drug . The lower release rate of drug was caused by the longer hydrophobic blocks or the higher copolymer concentrations , owing to the higher viscosity of copolymer solutions.

    目錄 中文摘要..........................I 英文摘要..........................III 誌謝.............................VI 目錄.............................VII 圖表索引..........................IX 溫敏型寡聚聚乙二醇單甲醚/聚乳酸-甘醇酸雙團聯共聚物水膠之相變化、微胞性質及藥物釋放行為 一、 前言 ..........................1 二、 實驗方法..........................7 2.1 mPEG-PLGA雙團聯共聚物的製備.............7 2.2 凝膠滲透層析儀分析......................8 2.3 質子核磁共振光譜分析.....................8 2.4由翻轉試管法量測相圖......................9 2.5由流變法量測相圖.........................9 2.6 臨界微胞濃度(critical micelle concentration)量測...10 2.8 Aminoguanidine hydrochloride溶液標定...............11 2.9 Aminoguanidine hydrochloride藥物釋放實驗............11 三、 結果與討論......................................13 3.1 mPEG-PLGA雙團聯共聚物之組成分析.......................13 3.2 相圖分析...........................................15 3.2.1 mPEG-PLGA雙團聯共聚物中改變親水鏈段長度對於成膠影響....15 3.2.2由翻轉試管法求得相圖................................15 3.2.3由流變法求得相圖...................................16 3.2.4經由流變法比較 S-1 25%和20%凝膠的相結構..............18 3.2.5翻轉試管法與流變法相圖數據比較 ......................19 3.2.6臨界成膠性質......................................19 3.3臨界微胞濃度........................................20 3.3.1 雙團聯共聚物之臨界微胞濃度..........................20 3.3.2 雙團聯共聚物之微胞熱力學性質影響................... 21 3.3.3 臨界微胞濃度與微胞核鏈段聚合度關係..................23 3.3.4 微胞半徑與微胞核鏈段聚合度關係......................23 3.3.5 由動態光散射觀測出mPEG-PLGA微胞聚集............... 24 3.4 Flory-Huggins交互作用參數........................…24 3.4.1 親、疏水鏈段間Flory-Huggins交互作用參數............24 3.4.2疏水鏈段與水的Flory-Huggins交互作用參數............…26 3.5在不同疏水鏈段比例與不同濃度mPEG- PLGA,aminoguanidine hydrochloride釋放速率探討...................................................31 四、 結論.........................................33 五、 參考文獻......................................35

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