臺灣博碩士論文加值系統

本研究首次以改良式酒精注射法形成活性成分A奈米粒子，並添加D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-Tocopheryl polyethylene glycol 1000 succinate, TPGS)以改善活性成分A奈米粒子分散液的穩定性。另外，與添加維生素E (α-Tocopherol, VE)於活性成分A奈米粒子相比，以探討聚乙二醇側鏈(PEG1000)的效應。以多重技術包含動態光散射儀(dynamic light scattering, DLS)、穿透式電子顯微鏡(Transmission electron microscope, TEM)、螢光光譜儀(Fluorescence spectrometer, FL)及微分掃描熱卡計(Differential scanning calorimetry, DSC)等探討不同莫耳比例下，混合A/TPGS和A/VE分散液之物化特徵。此外，藉由高效能液相層析儀(High performance liquid chromatography)探討不同濃度二硫蘇糖醇(dl-Dithiothreitol, DTT)對混合A/TPGS分散液化學穩定性之影響。以及使用Franz擴散槽進行體外經皮吸收試驗。在24℃下，結合Langmuir trough系統與螢光顯微鏡，量測氣/液界面上混合A/TPGS及混合A /VE單分子層之行為，並直接觀察單分子層間的形態。
混合A/TPGS及A /VE分散液會形成奈米粒子結構，然而，隨TPGS增加會使得活性成分A奈米粒子平均粒徑減少，其中以混合A/TPGS (6/4)分散液粒徑最小。A/TPGS (9.9/0.1)分散液可達到較多穩定天數。活性成分A主相變溫度為59.4℃，添加TPGS或VE時，使得活性成分A主要相變化熱焓量減少，尤其在XTPGS = 0.5或XVE = 0.1時相變化熱焓量即消失。比較同莫耳比例下混合A/TPGS及混合A /VE系統之結果，PEG-側鏈會使得混合分子間交互作用變大。於室溫時(活性成分A屬於膠態)，隨TPGS或VE添加皆使得活性成分A奈米粒子膜內疏水區的流動性降低，其中添加TPGS會提高活性成分A膜表面分子間流動性，表示PEG-側鏈可軟化活性成分A膜內結構。在0.01M DTT濃度下，混合A/TPGS (9/1)分散液時最具有化學穩定性。另外，添加TPGS可提高活性成分A分散液滲透度，以混合A/TPGS (9/1)奈米粒子分散液在皮膚上的滲透量最高。由單分子層結果可知混合A/TPGS單分子層較混合A /VE單分子層具延展性(Expanded)，可能因PEG立體障礙所導致。於低表面壓時，混合A/TPGS單分子層之過剩面積為負偏差，然而混合A /VE單分子層為正偏差，表示低表面壓時，PEG-側鏈可使得混合分子間排列較緊密。另外，於高表面壓時，混合A/TPGS與混合A/VE單分子層皆為正偏差，可能因此時分子間距離較小，使得鄰近PEG-側鏈易產生立體排斥力。過剩自由能和混合自由能結果顯示，混合A/TPGS單分子層分子間較具互溶性及具有熱力學上的穩定性。由螢光影像結果顯示，活性成分A分子會聚集成樹枝狀Domain，表示線張力的影響小於偶極排斥力。在固定表面壓下，添加TPGS使得活性成分A Domain變小且均勻分佈，表示TPGS會使得分子間較具延展性，另一方面，添加VE時，部分Domain變大且由樹枝狀轉成圓形狀，表示PEG立體排斥力會使得分子間較無凝聚力。

In this study, we found that compound A can form nanoparticles by a modified ethanol injection method for the first time, In order to improve the stability of compound A nanoparticles, D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) was added into compound A nanoparticles. In addition, the effects of polyethylene glycol chain (PEG1000) on compound A dispertions were investigated by compared with mixed A/α-Tocopherol (VE) nanoparticles. Physicochemical characteristics of mixed A/TPGS and A/VE nanoparticles were investigated by multi-techniques including dynamic light scattering (DLS), transmission electron microscope (TEM), fluorescence spectrometer and differential scanning calorimetry (DSC). High performance liquid chromatography (HPLC) was used to study the chemical stability of mixed A/TPGS dispersionss in different concentrations of dithiothreitol (DTT). Transdermal absorption studies of A/TPGS nanoparticles across the rat skin were investigated by using Franz diffusion cells. Furthermore, behavior of mixed A/TPGS and A/VE monolayers at the air/water interface were measured at 24 ℃ by Langmuir trough system combined with fluorescence microscopy.
Adding TPGS into compound A nanoparticles decreased average particle size among the A/TPGS systems, and mixed A/TPGS 6:4 dispersions showed the smallest average particle size. Mixed A/TPGS (9.9:0.1, mol ratio) dispersionss exhibited better storage stability than pure compound A dispersions. Main phase transition temperature of A dispersionss was found at 59.4 ℃. The phase transition temperature remained constant, and the enthalpy of the observable gel to liquid-crystalline phase transition decreased with increasing XTPGS or XVE, and the phase change enthalpy was eliminated at XTPGS = 0.5 or XVE = 0.1. By Comparing results of mixed A/TPGS with A/VE systems at the same molar ratio, PEG-chains was found to enhance the intermolecular interactions. At room temperature (compound A is under gel state), the incorporation of TPGS or VE into compound A membrane reduced the mobility in hydrocarbon chain region, and the presence of TPGS generally increased the molecular mobility of the interfacial region of the membrane. This indicated that PEG-chain may soften compound A membrane structure. The most chemical stability was found as the mixed A/TPGS (9:1) dispersions in 0.01M concentration of DTT. Adding TPGS can improve compound A dispersions permeability, and mixed A/TPGS (9/1) dispersions exhibited better transdermal efficacy absorption than pure compound A dispersionss. Monolayer results showed that mixed A/TPGS monolayers were more expanded than mixed A/VE monolayers, possibly resulting from PEG-chains steric barrier. Excess area results showed that the mixed A/TPGS monolayers were negative deviation and mixed A/VE monolayers were positive deviation at low surface pressure, implying PEG-chain makes intermolecular arrangement tighter. In addition, the mixed A/TPGS and A/VE monolayers were positive deviation at high surface pressure, which maybe caused by steric repulsive of neighboring PEG-chains. Excess Gibbs free energy and the free Gibbs energy results showed that mixed A/TPGS monolayer molecules were more miscible and thermodynamic stable than mixed A/VE monolayer. Fluorescence imaging results showed that compound A molecules aggregated into dendritic domain, indicating that the impact of line tension was less than the dipole repulsion. At constant surface pressure, adding TPGS into compound A domain make compound A Domain become smaller and uniformly distributed, indicating TPGS will make intermolecular more expaned. On the other hand, adding VE, part of the domain become large, and turn into circular shape by the dendrimers. This indicates that steric repulsion of PEG-chain will make intermolecular no cohesive interaction in mixed monolayers.

中文摘要 i
ABSTRACT iii
誌謝 v
目錄 vi
表目錄 ix
圖目錄 xi
符號說明 xvii
第一章 緒論 1
1-1前言 1
1-2研究目的與動機 2
第二章 文獻回顧 3
2-1膠體粒子 3
2-2活性成分A 4
2-3維生素E 5
2-4 D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS) 6
2-5氣/液界面單分子層 7
2-6二硫蘇糖醇 8
第三章 實驗設備與方法 14
3-1實驗藥品 14
3-2實驗方法 14
3-2-1奈米粒子分散液製備流程 14
3-2-2粒徑分佈的量測 15
3-2-3界面電位的量測 16
3-2-4穿透式電子顯微鏡的觀察 17
3-2-5螢光偏極化的量測 17
3-2-6微分掃描熱卡計的量測 18
3-2-7混合A/TPGS 奈米粒子活性含量分析 19
3-2-8混合A/TPGS 9/1 with DTT活性含量分析 20
3-2-9體外皮膚滲透實驗 20
3-2-10單分子層技術 21
第四章 結果與討論 36
4-1混合A/TPGS分散液之物化特徵 36
4-1-1粒徑及界面電位 36
4-1-2型態觀察 37
4-1-3螢光偏極化 37
4-1-4相變行為 39
4-1-5混合A/TPGS分散液之pH值與導電度評估 40
4-2混合A/VE分散液之物化特徵 40
4-2-1粒徑及界面電位 40
4-2-2型態觀察 41
4-2-3螢光偏極化 42
4-2-4相變行為 43
4-3 PEG-側鏈對混合分散液物化特性之影響 43
4-4混合A/TPGS分散液之A和TPGS含量評估 44
4-5不同濃度DTT對混合A/TPGS分散液物化特徵之影響 45
4-6混合A/TPGS分散液之表面張力 45
4-7混合A/TPGS分散液之皮膚滲透行為 46
4-8混合A/TPGS單分子層 46
4-8-1表面壓-每分子佔據面積等溫線行為 46
4-8-2熱力學性質分析 47
4-8-3可壓縮係數分析 49
4-8-4螢光單分子層之表面形態 49
4-9混合A/VE單分子層 51
4-9-1表面壓-每分子佔據面積等溫線行為 51
4-9-2熱力學性質分析 52
4-9-3螢光單分子層之表面形態 53
第五章 結論 142
參考文獻 144

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