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研究生:薛成燁
研究生(外文):Cheng-Yeh Hsueh
論文名稱:利用微流體系統包覆疏水性藥物成高分子微胞
論文名稱(外文):Encapsulation of hydrophobic drug in polymer micelles by microfluidic system
指導教授:蔡碩文蔡碩文引用關係
指導教授(外文):Shuo-Wen Tsai
口試委員:劉沛芬陳睿能
口試委員(外文):Pei-Fen LiuRui-Neng Chen
口試日期:2015-07-16
學位類別:碩士
校院名稱:國立中興大學
系所名稱:食品暨應用生物科技學系所
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:97
中文關鍵詞:高分子微胞
外文關鍵詞:polymer micelles
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高分子微胞的包覆技術的目的是在於包覆目標物,並賦予微小化以及顆粒化,以改善其反應能力以及便利使用。以不同的素材包覆亦提供新的表面性質,提供保護樣品或是標靶性釋放及傳送。此一技術已被應用於化學工業和醫療藥學系統多年。本研究開發一個微流體晶片平台,以高分子微胞技術包覆疏水性藥物,並檢討其效果。使用微流體通道系統時,需要考量晶片設計、液體流速、流體性質與晶片材料的特性。此半橢圓微流體晶片,是由半橢圓形的側邊注入通道、中間注入通道及產物出口通道所組成。系統內,由側邊通道注入含Pluronic F127 ( 5、10 % ) 的水相溶液,由中間通到注入含Gliclazide (1 %, w / w ) 的大豆油溶液;當兩者匯集後,產物由出口通道流出。通道以十字型設計匯集,在剪切力與線性流的作用下,中間流道的油相溶液會受側邊通道水相溶液的擠壓形成液滴。水相中的介面活性劑會在油水介面分別與水相與油相產生交互作用,從而穩定產生的液滴。當中間油相通道流速設定為0.4 μL/mL,側邊通道含5 % Pluronic F127的水相流速設定為0.5 mL/min,產出之液滴平均粒徑為633 nm。當中間油相通道流速設定為0.4 μL/mL,側邊通道含10 % Pluronic F127的水相流速設定為0.8 mL/min,產出之高分子微胞平均粒徑為101 nm。研究中發現,在側邊通道以高流速注入時會出現雙夾流現象,並且觀察到微胞粒徑大小會隨著雙夾流的出現而下降。以高效能液相層析儀檢測得目標藥物Gliclazide的包覆率為70 %,相較於傳統法要來高。
本研究開發的微流體平台系統,展現優秀的連續生產性及穩定性,並可依需求,調節微胞囊尺寸。未來可以應用於包覆修飾不同特性的藥物,或是機能性食品成分,以達到增加吸收率或樣品保護的效果。


The purpose of using polymer micelle technology is to miniaturize and to granulate an object so that not only its applicability and convenience can be enhanced simultaneously. Coating the different materials on micelle surface provides a new surface properties that can provide sample protection, targeted release and targeted transfer. This technique has been used in chemical industry and medical systems for many years. We developed a new microfluidic chip to capsule a hydrophobic drug by polymeric micelle and discussed its effectiveness in this study. Using the microfluidic channel system needs to consider variable conditions, including the design of structure, liquid flow rate, fluid properties and characteristics of the material. The semielliptical microfluidic chip is composed of the side injection channel, the middle injection channel and the product export channel. In this system, we injected the aqueous solution of Pluronic F127(5 %、10 %) into side channel and injected the Gliclazide of soybean oil (1 %, w/w )into middle channel. When the two solution interact, the products will be released from the product export channel. Due to the design of the cross-shaped chip, the solution of the middle channel will be pressed from both side of the channel and formed into droplets according to the effect of the laminar flow and shearing force. The surfactant of aqueous phase interacted with aqueous phase and oil phase respectively in the oil-water interface, thereby the stable droplets were produced. When the middle channel velocity is set as 0.4 μL/min and the side channel velocity is set as 0.5 mL/min, the formed droplet minimum size up to 633nm.(Pluronic F127( 5 %)) Then, we test group of the side channel flowed into Pluronic F127(10 % ). When the middle channel velocity is set as 0.4 μL/min and the side channel velocity is set as 0.8 mL/min, the formed droplet minimum size up to 101 nm. We found that double-clip flow will appear when we injected into the side channels with high flow rate. And we discovered particle size of the micelles were decreased as double-clip flow will appeared. The capsule encapsulation efficiency of target drug by high performance liquid chromatography was 70 %, and its efficiency was higher than other traditional methods.
This microfluidic system show advantage on the continuous production, reliable and can adjust the micelle’s size on demand. That can be implemented on modifying the different characteristic of the drug or function food and let it have a great uptake efficiency or sample protection capability in the future.



目次
謝誌 i
中文摘要 ii
英文摘要 iv
目次 xi
圖目錄 vi
表目錄 x
第一章 前言 1
1.1 緒論 1
1.2 Pluronic F127 2
1.2.1 Pluronic F127簡介 2
1.2.2 Pluronic f217的化學結構 4
1.3 Gliclazide(Gliclazide) 7
1.3.1Gliclazide簡介 7
1.4 高分子微胞簡介 8
1.5生物晶片 14
1.5.1流體生物晶片簡介 14
1.5.2微流體形成液滴之簡介 15
1.5.2.1 三種常見之微流體通道 15
1.5.2.2 毛細數Ca(capillary number) 16
1.5.2.3 體積流率比Q 17
1.5.2.4微流體液滴之應用 18
1.6以介面活性劑 Pluronic F127包埋Gliclazide製備高分子微胞 19
1.6.1 蜜克龍製備高分子微胞之製程 19
1.6.2微流體通道結構的選擇 21
第二章 材料與方法 23
2.1 實驗設計與流程 23
2.2 實驗材料 24
2.2.1 實驗藥品 24
2.2.2 實驗設備 25
2.3 實驗方法 27
2.3.1 微流體晶片製作 27
2.3.1.1 玻璃基板之清潔 27
2.3.1.2 光罩製作 28
2.3.1.3 微顯影技術 32
2.3.2 以介面活性劑Pluronic F127做為包覆藥材之材質 35
2.3.2.1 以介面活性劑Pluronic F127做為壁材之液滴形成 35
2.3.2.2疏水性PDMS微流體晶片進行親水性表面修飾 39
2.3.3 以天然大豆油為核心基底之液滴製備 41
2.3.3.1 核心油相液滴製備 41
2.3.3.2 蠕動幫浦液體輸送穩定之策略 45
2.3.3.3 液滴粒徑分析 50
2.3.3.4 Gliclazide含量標準曲線 50
2.3.3.5 含液滴之包埋率測試 51
2.3.3.6 Gliclazide高分子微胞冷凍乾燥 52
2.3.3.7 以螢光染劑代替Gliclazide偵測高分子微胞結構 54
2.3.3.8 膠囊壁材強化 55
第三章 結果與討論 57
3.1 微流體晶片製造 57
3.1.1光罩製程 57
3.1.2 微流體通道製程 58
3.2 以介面活性劑Pluronic F127做為包覆藥材包覆材質 60
3.2.1 以介面活性劑Pluronic F127做為壁材製程高分子微胞 60
3.2.2 親水性修飾與未修飾晶片之比較 63
3.3 以天然大豆油為核心基底之液滴製備 65
3.3.1 包覆Gliclazide之材料更換 65
3.3.2 微流體晶片設計改良 66
3.3.2.1 原晶片需改良部分 66
3.3.2.2 改良過後原晶片通道與新晶片通道之比較 67
3.3.2.3 以自製之控壓裝備穩定蠕動幫浦運輸 68
3.3.2.4 微流體晶片之使用比較 70
3.4 高分子微胞之各項分析及測量 72
3.4.1 螢光染色測試 72
3.4.2 液滴粒徑分析 73
3.4.3液滴成品圖 81
3.4.4 Gliclazide含量標準曲線製作 82
3.4.5 含Gliclazide大豆油核心液滴包埋率測定 83
3.4.6 液滴壁材之強化 84
3.4.6.1 聚天門冬胺酸之製作 84
3.4.6.2 Gliclazide高分子微胞之凍乾 85
3.4.6.3 以聚天門冬胺酸修飾壁材 86
第四章 結論與未來展望 89
第五章 參考文獻 91



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