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研究生:郭華良
研究生(外文):Kuo, Hualiang
論文名稱:探討影響製備分散性佳之球形SBA-15之因素及其於蛋白質藥物釋放系統之應用
論文名稱(外文):Investigating the effects on the preparation of monodisperse SBA-15 microsphere and its applications for protein drug delivery.
指導教授:顧野松
指導教授(外文):Gu, Yesong
口試委員:林松池杜景順楊怡寬楊芳鏘顧野松
口試委員(外文):Lin Sung-ChyrDo Jing-ShanYang I-KuanYabg Fan-ChiangGu Ye-Song
口試日期:2011-07-05
學位類別:碩士
校院名稱:東海大學
系所名稱:化學工程與材料工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:137
中文關鍵詞:球形SBA-15藥物釋放牛血清蛋白溶菌酶
外文關鍵詞:spherical SBA-15drug delivery systermBSAlysozyme
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由於SBA-15粒子的形貌及分散性好壞,會影響其生物相容性與在藥物釋放系統之應用。因此,本研究主要以探討分散性良好之球形SBA-15之製備條件,並將其應用於大分子藥物,蛋白質之藥物釋放系統。
綜合研究成果可知,對三嵌段高分子P123在溶液中形成的微胞而言,鹽酸濃度會影響溶液中的離子強度,除了使兩性高分子P123親疏水鏈段之性質差異明顯外,亦能使後續添加的TMB能均勻分散的進入微胞中心,因而獲得孔道形態均一及孔徑分佈窄之SBA-15。此外,隨著氫離子濃度的增加存在著兩項相反的結果,適當的氫離子濃度(2 M)能增加SBA-15粒子表面電位,因而獲得分散性良好的球形SBA-15。而過高的氫離子濃度(3 M),卻會造成縮合聚合速率過快,使得合成過程中粒子容易因碰撞而產生聚集,因而合成出團聚現象嚴重之SBA-15粒子。
鹽類的添加主要是額外的增加溶液中的離子強度,除了能讓疏水鏈段PPO去溶劑化(脫水),增強疏水鏈段的聚集程度使微胞穩定外,亦能使擴孔劑TMB均勻分散的進入微胞中心(PPO區域),使微胞不因TMB的分散不均而造成微胞形態的多變,而造成SBA-15粒子形態迥異。
擴孔劑TMB的添加能改變微胞的尺寸,進而調控SBA-15的外觀形態及孔徑大小。同時,TMB進入微胞中心分散的好壞,主要依上述兩項因素(鹽酸、鹽類濃度)的影響,而TMB於中心鏈段的分散性會影響到微胞的形態,因而改變了SBA-15的粒子外貌、孔道均一性及孔徑分布。研究中所製備的球形SBA-15其單顆粒徑主要落在2 ~ 4 μm之間,主要孔徑分佈則為20 ~ 22 nm。在改變TMB添加量進行調控孔徑且同時能形成微球SBA-15之條件下,其可調控孔徑範圍落在18 ~ 22 nm 之間。
研究中亦指出載體與蛋白質間的帶電性,對載體吸附蛋白質的結果有很大的影響。以本文中之例子而言,當載體與蛋白質(lysozyme)為異性電荷時其吸附量(248.3 mg/g)較同性電荷之蛋白質(BSA)之吸附量(78.84 mg/g)高出3倍之多。且因載體與蛋白質間靜電力的作用,使SBA-15在進行lysozyme之釋放速率測試時,觀察到緩釋現象。因此,證明了以SBA-15作為大分子藥物-蛋白質之調控釋放系統之可行性。

The morphology and dispersion of SBA-15 particles could influence the biocompatibility and the applications for drug delivery systems. Therefore, this study is to investigate the conditions to synthesize well-dispersed spherical SBA-15 for drug delivery system and apply it to immobilize protein.
The components used for SBA-15 should be introduced, at the first the research has shown that the concentration of hydrochloric acid could influence ionic strength of the reaction solution, and influence both hydrophobic and hydrophilic chain of triblock copolymer P123. Besides, TMB would be easy to enter into the center of micelle, and then obtain a consistent pore morphology and narrow pore distribution. Furthermore, we found an appropriate concentration (2 M HCl) could increase zeta-potential of SBA-15 and well-dispersed spherical SBA-15 was obtained. However the higher hydrogen concentration (3 M HCl) caused the fast condensation polymerization, and resulted in serious aggergation.
The ionic strength of solution can also be increased by adding various salts. Salts could lead the desolvation (dehydration) of the hydrophobic chain, and stabilize the micelle by enhancing the assembling of hydrophobic chain. Besides, it is also making the swelling-agent TMB into the center of micelle well.
Adding swelling-agent TMB can change the micelle size, then to control the morphology and pore size distribution of SBA-15. At the same time, the difference of TMB to enter into micelle center is dependening on hydrochloric acid and salts concentrations.
This study has also shown that the charge between the carrier and protein would have a great influence on protein adsorption by carrier. For example, when the carrier and lysozyme displaced opposite different charges on their surface, the amount of protein adsorbed will be 3 times higher than that for the carrier and BSA in which has same charge type. Because of the electronstatic force between carrier and protein, we can clearly observe drug slow-release phenomenon on lysozyme releasing test. Therefore, it proves the feasibility for SBA-15 as a carrier for macromolecular drugs (protein) delievery system.


目錄
中文摘要 I
Abstract III
目錄 V
圖目錄 IX
表目錄 XII
第一章 緒論 1
1.1 前言 1
1.2 藥物調控釋放系統之介紹 4
1.2.1 藥物調控釋放系統之概述 4
1.2.2 藥物新劑形之簡介 5
1.2.3 奈米藥物技術簡介 8
1.3 蛋白質藥物之介紹 10
1.3.1 牛血清蛋白(BSA)之簡介 10
1.3.2 溶菌酶(Lysozyme)之簡介 11
1.4 中孔洞矽材SBA-15之介紹 12
1.4.1 嵌段共聚物溶液自組裝之簡介 12
1.4.2 中孔洞矽材SBA-15之介紹 13
1.5 蛋白質與載體的結合 19
第二章 文獻回顧 21
第三章 實驗材料與儀器原理 29
3.1 實驗藥品 29
3.2 實驗設備與原理 31
3.2.1 實驗設備 31
3.2.2 場發掃描式電子顯微鏡(FE-SEM) 33
3.2.3 氮氣吸附 36
3.2.4 Bio-Rad蛋白質定量分析 42
3.2.5 熱重分析法 43
3.2.6 Zeta-potential 44
第四章 實驗方法 46
4.1 球形SBA-15實驗程序 46
4.1.1 合成過程攪拌與否之實驗步驟 46
4.1.2 探討鹽酸濃度影響之實驗步驟 47
4.1.3 鹽類種類及濃度影響之實驗步驟A 48
4.1.4 添加20 mmole KCl於不同鹽酸濃度影響之步驟 49
4.1.5 鹽類種類及濃度影響之實驗步驟B 50
4.1.6 3 M鹽酸添加定量不同種鹽類之影響實驗步驟 51
4.1.7 鹽酸濃度對縮合聚合速率影響之實驗步驟 51
4.1.8 探討TMB濃度影響之實驗步驟 52
其他分析儀器操作步驟 53
4.1.9 BET操作步驟 53
4.1.10 SEM樣品前處理步驟 53
4.1.11 Zeta-potential測量實驗步驟 54
4.2 SBA-15載體吸附蛋白質之實驗 55
4.2.1 於不同pH的磷酸緩衝液下吸附蛋白質 55
4.2.2 以熱重分析法量測蛋白質吸附量之步驟 57
4.2.3 藥物釋放速率之步驟 58
第五章 結果與討論 60
5.1 形成球形SBA-15之各項因素探討 60
5.1.1 合成過程攪拌之影響 60
5.1.2 鹽酸濃度之影響 63
5.1.3 鹽類種類及濃度於1.2 M鹽酸中之影響 69
5.1.4 添加20 mmol KCl於不同鹽酸濃度之影響 77
5.1.5 鹽類種類及濃度於2 M鹽酸中之影響 83
5.1.6 3M鹽酸添加定量不同種鹽類之影響 89
5.1.7 鹽酸濃度對縮合聚合速率之影響 91
5.1.8 TMB濃度之影響 96
5.2 球形SBA-15吸附蛋白質 102
5.3 球形SBA-15藥物釋放之測試 111
第六章 結論與建議 113
參考文獻 118


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