臺灣博碩士論文加值系統

本研究主要探討在聚葡萄糖水膠中，利用第一階段合成前驅高分子(dex-GMA)時加入不同含量的GMA，來改變前驅高分子的取代度(定義為在100個葡萄糖單體中接上methacrylate group的個數)，並在第二階段改變前驅高分子在溶液中反應的濃度，經過自由基聚合後形成不同交聯度及含水率的水膠，藉以探討網路結構與網目孔隙的影響。由水膠應力-應變實驗的結果顯示，水膠內有效交聯密度ve，會隨著水膠取代度的增加及含水率的減少而遞增，顯示影響水膠網路交聯包含有化學交聯及物理交聯兩種；而由應力-應變數據與slip link模型計算Ns和Nc值，結果發現，Ns呈現負值，代表水膠網路中發生物理解纏現象，Ns/Nc值並隨著水膠取代度的減少及含水率的增加，負值遞增，則解纏現象越是明顯，表示隨著水膠取代度的減少及含水率的增加，物理解纏對網路的影響越重要。而隨著水膠取代度的減少及含水率的增加，網路中化學交聯減少及物理解纏增加，使得網路交聯點間的分子量變大，水膠的網目變大。
利用BSA和Vitamin B12作為釋放實驗的溶質，藉由改變水膠的取代度及含水率，探討溶質在水膠中「擴散自由體積」與「擴散路徑長度」如何受溶質與水膠分子參數控制。根據自由體積理論，由ln(Dm/D0)對(1/H -1)作圖發現，隨著水膠取代度及交聯度的增加，高分子鏈運動性降低，則直線斜率的絕對值越大；而改變溶質的半徑發現，斜率和溶質半徑近似1.2次方成正比，此結果並不符合Yasuda自由體積理論中斜率和溶質的平方成正比，顯示溶質在水膠中擴散的速率，除了溶質半徑外，還需要考慮溶質和高分子、溶劑間的交互作用力。
當水膠取代度的減少及含水率的增加，網目變大，溶質和網目大小的比值變小，因而減少溶質在水膠中擴散的繞曲度，當溶質直徑和網目大小的比值在0.06和0.4之間，繞曲度的實驗值與Renkin理論值誤差在20％以內，而隨著λ值的增加，實驗值和理論值的差距增加，此結果符合Renkin理論中λ< 0.4的條件；此外，由Vitamin B12及BSA所計算出來的繞曲度，其回歸線無法交疊在一起，因此我們推測，影響溶質在水膠中擴散的繞曲度，除了溶質直徑和網目大小的比值外，溶質的形狀也是影響繞曲度的因素之一。

In this study, dextran hydrogels were prepared by polymerization of aqueous solution of glycidyl methacrylate derivatized dextran(dex-GMA). The compressive measurements and thermodynamic equilibrium for chain elasticity and water-polymer mixing results indicate that the effective crosslinking density (ve) increase with increasing the degrees of substitutions and decreasing the water contents of gels. The stress-strain data of hydrogels fitted with the slip-link model indicate that there are significant disentanglements in the network, which is increased with water contents. As the crosslinks decrease and disentanglements increase, the mesh sizes of gels increase.
The releases of BSA and Vitamin B12 from hydrogels varying in degrees of substitutions and water contents, are investigated to understand the “free volume of diffusion” and “length of diffusion path” in terms of the molecular parameters of diffusants and gels. In terms of the free volume theory, the slope of logarithm of normalized diffusion coefficients against the inverse hydration of gels increases with the degrees of substitutions of gels, and is nearly proportional to the radius of the solute. In addition, as the water contents decrease, the tortuosity of solutes diffusion in the gels increase. As the ratio of diameter of solutes to mesh sizes of the gels lie between 0.06 to 0.4, a deviation of about 20% between the experimental and predicted values is found. However, there’s a large deviation between the experimental and the predicted values at higher ratio.
The regression lines for the tortuosity of Vitamin B12 and BSA can’t overlap with each other, and therefore, it’s believed that the shape in solutes can also affect the tortuosity of solutes diffusion in gels.

中文摘要……………………………………....……………...Ι
英文摘要.…………….……………………………………….Ⅲ
誌謝………………………………………….………………..Ⅴ
目錄…………………………………………………..……….Ⅵ
圖表索引…………...…………………………………………Ⅷ
一、 前言………………………………………………………1
二、 實驗方法…………………………………………………7
2.1 前驅高分子的製備………………………………….7
2.2 含藥水膠的合成…………………………………….7
2.3 水膠彈性模數測定………………………………….8
2.4 藥物溶液的標定…………………………………….8
2.5 藥物釋放實驗………………….…………...……...10
2.6 分配係數測量……………………………………...10
2.7 動態膨潤與平衡膨潤測定………..……………….13
三、藥物釋放動力學………………………………………….14
四、結果討論………………………………………………….18
4.1 聚葡萄糖水膠分析........…......…………………….18
4.2 傅力葉轉換紅外線光譜儀(FTIR)分析……………18
4.3 核磁共振儀(NMR)分析……………………………22
4.4 Flory-Huggins交互作用參數………………………22
4.5 使用黏彈性-Slip link模型分析水膠網路結構……29
4.6 水膠網目大小對藥物釋放影響…………………...38
4.7 擴散係數和擴散指數的探討…………………..….44
4.8 分配係數的探討…………………………………...49
4-9-1 自由體積理論分析……………………………....51
4-9-2 多孔質模型中繞曲度(tortuosity)分析…………..57
4.10 水膠動態膨潤探討…………………..…………...63
五、結論………………………………………………………66
六、參考文獻………………………………………………….68
Table 3.1 Diffusion exponent and mechanism of drug release from various release systems……………………...17
Table 4.1(a) Preparation of precursor for dextran hydrogels various in degrees of substitutions……….….…19
Table 4.1(b) Preparation condition of dextran hydrogels with various degrees of substitutions and resulting water contents………………………..…………20
Table 4.2 Stress-Strain and Flory-Huggins parameters various in degrees of substitutions and water contents……..….31
Table 4.3 Structural parameters of dextran hydrogels in slip link model……………………………………………..…37
Table 4.4 Structure characteristics in dextran hydrogels……...45
Table 4.5 Diffusion coefficients of solutes release from a film and a cylinder various in degrees of substitutions and water contents……………..……….………..…….46
Table 4.6 Diffusion exponents and diffusion kinetic constants of solutes release in dextran hydrogels…...……………48
Table 4.7 Release contents in different dextran hydrogels……50
Table 4.8 Partition coefficients in different dextran hydrogels
………………………………………………….....52
Table 4.9 Comparison of the A values various in solutes and hydrogels…………………………………………..58
Table 4.10 The tortuosity of solutes release in dextran hydrogel
…………………………………………………….61
Figure 2.1 Reaction of Dextran with Glycidyl Methacrylate…..9
Figure 2.2 UV standard curve of BSA in pH 7.2 PBS………...11
Figure 2.3 UV standard curve of Vitamin B12 in pH 7.2 PBS...12
Figure 4.1 Transmittance FTIR spectra of (A)dextran and (B) dex-GMA………………………………………….21
Figure 4.2 1H NMR spectra of dextran………………………..23
Figure 4.3 1H NMR spectra of dex-GMA(DS9)………………24
Figure 4.4 1H NMR spectra of dex-GMA(DS18)……………..25
Figure 4.5 Stress-strain curves in different hydrogels………...28
Figure 4.6 Stress-strain curves in different hydrogels………...30
Figure 4.7 Plot of compressive reduced stress against the strain term H(η,λ) for dextran hydrogels (DS9) of various water contents…………..…………...……35
Figure 4.8 Plot of compressive reduced stress against the strain term H(η,λ) for dextran hydrogels (DS18) of various water contents…...…..……………………36
Figure 4.9 Cumulative releases of BSA from dextran hydrogels (DS9)of various contents…….……..……………39
Figure 4.10 Cumulative releases of BSA from dextran hydrogels (DS18) of various water contents………………..40
Figure 4.11 Cumulative releases of Vitamin B12 from dextran hydrogels (DS9) of various water contents……...41
Figure 4.12 Cumulative releases of Vitamin B12 from dextran hydrogels (DS18) of various water contents…….42
Figure 4.13 Logarithm of the normalized diffusion coefficient of BSA in dextran hydrogels as a function of the inverse hydrogel hydration…………………........55
Figure 4.14 Logarithm of the normalized diffusion coefficient of Vitamin B12 in dextran hydrogels as a function of the inverse hydrogel hydration…………………..56
Figure 4.15 Comparison of tortuosity in experimental and theoretical values of Vitamin B12 and BSA….....62
Figure 4.16 Water uptake of dextran hydrogels as a function of contact time for various degrees of substitutions
...…………………………………………………65

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