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研究生:林晉霆
研究生(外文):Jin-Ting Lin
論文名稱:聚乳酸-聚醚-聚乳酸三團聯共聚物之自組裝與藥物荷載: 軟段與硬段長度之影響
論文名稱(外文):Self-assembly and Drug Solubilization of Poly (L-lactic acid)/Polyether Triblock Copolymers: Effect of Soft and Hard Segment Length
指導教授:胡孝光胡孝光引用關係
指導教授(外文):Shiaw-Guang Hu
口試委員:胡孝光
口試委員(外文):Shiaw-Guang Hu
口試日期:2013-07-16
學位類別:碩士
校院名稱:國立臺灣科技大學
系所名稱:材料科學與工程系
學門:工程學門
學類:材料工程學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:97
中文關鍵詞:三團聯共聚物藥物荷載結晶軟段長度硬段長度分配係數
外文關鍵詞:triblock copolymerdrug solubilizationcrystallinesoft segment lengthhard segment lengthpartition coefficient
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本研究第一部份合成不同聚合度的聚乳酸(PLLA, 聚合度= 60~ 468)與聚丙二醇(PPG, 聚合度= 17, 34, 69)三團聯共聚物(PLLA-PPG-PLLA)。使用偏光顯微鏡方法探討不同聚合度的PLLA鏈段以及不同聚合度的PPG鏈段,對球晶成長動力學參數的影響。以Hoffman-Weeks方法估計平衡熔點(Tm˚)與增厚係數(δ),再估計平衡晶片厚度(Lc),並討論平衡晶片厚度與PLLA鏈段及PPG鏈段聚合度之標度關係。

由Hoffman-Weeks方法可知共聚物的平衡熔點隨著PLLA鏈段聚合度變小而降低,且增厚係數會隨著共聚物PLLA鏈段聚合度愈大而下降。接著利用平衡熔點求出平衡晶片厚度,討論平衡晶片厚度和PLLA鏈段聚合度之冪次關係的標度指數α,與非平衡晶片厚度所求得之標度指數α’比較,發現α較α’為大(非平衡時過冷度,其範圍在30 K到90 K之間) ;而平衡晶片厚度所求得之標度指數α,較理想理論值大。討論平衡晶片厚度與PPG聚合度之冪次關係的標度指數β,其值較非平衡晶片厚度與PPG鏈段聚合度的標度指數β’小;再將平衡晶片指數β絕對值與理論值的絕對值作比較,發現較理論值小,因為理論值皆忽略兩鏈段相連處柔軟度不同造成的局部化自由能(floc)以及結晶相硬段與非晶相軟段界面處之自由能(fint)。

另一部份將聚乳酸的聚合度固定在小範圍內(聚合度= 254~264),合成一系列聚乳酸與聚乙二醇( PEG, 聚合度=23, 46, 91)三團聯共聚物(PLLA-PEG-PLLA)。將此三團聯共聚物製備成微胞溶液,使用螢光探針法測量臨界微胞濃度,並使用動態光散射儀測量微胞粒徑,探討微胞半徑與親疏水鏈段聚合度的標度關係,利用紫外光/可見光分光光度計測得三團聯共聚物微胞溶液中包覆藥物Vitamin K3的濃度,計算藥物分配係數與藥物荷載率。

在臨界微胞濃度實驗中得知,當PLLA鏈段聚合度愈低或PEG鏈段聚合度愈高,臨界微胞濃度會愈高。當親水鏈段長度增加,疏水鏈段長度相對來說減少,導致共聚物不容易形成微胞,故臨界微胞濃度提高。動態光散射實驗中可知,PLLA鏈段聚合度愈低或PEG鏈段聚合度愈高,微胞半徑愈小。微胞半徑與親疏水鏈段聚合度之間有一標度關係式,先將親水鏈段聚合度固定,可求得PLLA鏈段聚合度之標度指數,正好介於兩理想理論值之間;再將PLLA鏈段聚合度之標度指數帶回關係式中,進而求得親水鏈段聚合度之標度指數,與理想理論值比較,發現PLLA鏈段標度指數在兩理論值範圍內,而PEG鏈段標度指數不在理論值範圍內,是由於文獻中均忽略了兩團聯間的交互作用力。藥物荷載率實驗中可知,疏水鏈段聚合度愈少或親水鏈段聚合度愈高,共聚物中疏水鏈段的比例就會減少,造成藥物荷載效率及分配係數均會下降。

由上述實驗可知界面作用力在微胞態中與結晶態中均扮演著重要角色,在結晶態中實驗所求得之標度指數與理想理論值估計的相差不大,但在微胞態中實驗求得之標度指數則與理想理論值相差甚大,結晶態與微胞態中的相間界面由團聯間交互作用力所造成,但在微胞態中此作用力會受到溶劑所影響,故相對來說,其影響大於在結晶態中。
In the first part, poly (L-lactide) –poly (propylene glycol)-poly (L-lactide) (PLLA-PPG-PLLA) triblock copolymers with various PPG (degrees of polymerization from 17 to 69) and PLLA length (degrees of polymerization from 60 to 468) were synthesized. The equilibrium melting point and spherulitic growth rate of copolymers were examined with polarizing microscopy. In conjunction with data, the Hoffman nucleation theory was used to obtain kinetic parameters such as nucleation constant (Kg), pre-exponential factor (G0), and fold surface free energy (σe). The thickness of equilibrium lamellar was calculated, via equations by Hoffman-Weeks and Gibbs-Thomson-Tammann.
The equilibrium melting point decreases with the decreasing length of PLLA segments and thickening parameter decreases with the increasing length of PLLA segments. We observe the exponent (α) in power-law relationship between equilibrium lamellar thickness and degree of polymerization of PLLA, its value is more than that for the non-equilibrium lamellar thickness (with degree of supercool ranging from 30 to 90 K). The value of the exponent (α) for equilibrium lamellar thickness, determined from the experiment, is more than that as predicted from the theory. Regarding the exponent (β) in power-law relationship between equilibrium lamellar thickness and degree of polymerization of PPG, its value is less than that for the non-equilibrium lamellar thickness. The absolute value of the exponent (β) for equilibrium lamellar thickness, determined from the experiment, is less than that as predicted from the theory. This discrepancy is because that, the theory ignores the free energy of localization (floc) caused by the different flexibility between hard and soft segments, and the interfacial free energy (fint) between crystalline phase containing hard segments and amorphous one containing the soft segments.
In the second part, poly (L-lactide) –poly (ethylene glycol)-poly (L-lactide) (PLLA-PEG-PLLA) triblock copolymers with various PEG (degrees of polymerization from 23 to 91) and PLLA length (degrees of polymerization from 254 to 264) were synthesized. The critical micelle concentrations (CMC’s), micellar radius and concentration of Vitamin K3 partitioned into the micelles for various copolymers were determined with fluorescence probe method, dynamic light scattering, and UV/Vis spectroscopy, respectively.
It is found that CMC’s increase with the decreasing length of PLLA segments or increasing length of PEG segment. Because the hydrophilic segment length increases, the length of hydrophobic segments are relatively reduced, resulting copolymers are not easy to form micelle.
The micellar radius, drug loading efficiency, and partition coefficient decrease with the decreasing length of PLLA segments or increasing length of PEG segment. We observe the exponent (a) in power-law relationship between micellar radius and degree of polymerization of PLLA, its value is between two ideal theoretical values. Regarding the exponent (b) in power-law relationship between micellar radius and degree of polymerization of PEG, its value is not between two ideal theoretical values. Because ideal theoretical values assume the interaction between the two blocks is negligible.
摘要.....................................I
Abstract................................IV
誌謝.....................................VI
目錄.....................................VII
圖表目錄..................................X
聚乳酸-聚醚-聚乳酸三團聯共聚物之自組裝與藥物荷載: 軟段與硬段長度之影響
一、前言.................................1
二、實驗方法..............................7
2.1三團聯共聚物PLLA-PPG-PLLA球晶成長實驗....7
2.1.1 三團聯共聚物PLLA-PPG-PLLA聚合反應....7
2.1.2質子核磁共振光譜分析..................7
2.1.3熔點測定............................8
2.1.4球晶成長實驗.........................8
2.2三團聯共聚物PLLA-PEG-PLLA藥物荷載實驗....9
2.2.1三團聯共聚物PLLA-PEG-PLLA聚合反應.....9
2.2.2質子核磁共振光譜分析..................10
2.2.3臨界微胞濃度測量.....................10
2.2.4配製共聚物微胞溶液...................11
2.2.5微胞粒徑之量測......................11
2.2.6 Vitamin K3溶液之標定..............11
2.2.7共聚物微胞包覆藥物實驗...............12
三、結果與討論.....................................13
3.1三團聯共聚物PLLA-PPG-PLLA聚合反應與組成分析........13
3.1.1三團聯共聚物PLLA-PPG-PLLA聚合反應..............13
3.1.2三團聯共聚物PLLA-PPG-PLLA之組成分析............13
3.2 兩高分子鏈段間Flory-Huggins交互作用參數..........14
3.3結晶動力學分析..................................16
3.3.1平衡溶點測量..................................16
3.3.2球晶成長速率..................................17
3.3.3成核分析......................................18
3.4估算平衡與非平衡晶片厚度...........................22
3.5平衡與非平衡晶片厚度與硬段和軟段聚合度之標度關係........23
3.6三團聯共聚物PLLA-PEG-PLLA組成分析..................25
3.7三團聯共聚物PLLA-PEG-PLLA之臨界微胞濃度.............27
3.8微胞半徑與微胞親疏水鏈段聚合度之標度關係...............28
3.9三團聯共聚物PLLA-PEG-PLLA中PEG鏈段長度對藥物荷載量與藥物分配係數之影響..30
3.10藥物分配係數與微胞半徑之關係........................32
四、結論............................................33
五、參考文獻.........................................36
附錄一 符號對照表.....................................72
附錄二 均聚物Gibbs-Thomson-Tammann equation推導.......76
附錄三 本體型態與表面的示意圖...........................78
附錄四 藥物分配係數推導................................79
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