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研究生: 傅誠耀
Fu, Cheng-Yao
論文名稱: 以微流體雙重乳化晶片製備PLGA多孔性藥物微球
Preparation of Porous PLGA Microparticles from Microfluidic Double Emulsified Chip
指導教授: 葉思沂
Yeh, Szu-I
學位類別: 碩士
Master
系所名稱: 工學院 - 航空太空工程學系
Department of Aeronautics & Astronautics
論文出版年: 2020
畢業學年度: 108
語文別: 中文
論文頁數: 79
中文關鍵詞: 微流體晶片藥物釋放控制PLGA藥物微球多孔結構藥物微球
外文關鍵詞: Microfluidic chip, Drug release, Porous PLGA microspheres, PLGA microsphere
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  • 微流體乳化晶片廣泛應用於石油、化妝品、生醫以及製藥等領域,並具有傳統乳化方式所沒有的優點,本研究將沿用本研究團隊在過去開發的雙重乳化微流體晶片,透過調整注射幫浦控制流道入口的各相流率參數,以改變液珠生成的尺寸及孔洞的疏密程度,以製備不同結構的藥物微球。固定第一階段總流率(Qt,1)改變第一階段連續相以及分散相流率比(R1)以及外部水相流率(Qo)製作多種孔隙率以及多種幾何尺寸的PLGA藥物微球,實驗結果發現R1越小其孔洞程度越密集,Qo越大藥物微球尺寸越小。非多孔結構以及R1=3所製作出來的PLGA藥物微球其藥物包覆率(E.E.)及載藥率(L.C.)值不會隨著Qo的改變而有明顯改變,但R1=5及R1=7所製作出來的PLGA藥物微球其E.E.及L.C.值會隨著Qo的升高而逐漸下降。以恆溫培養箱以及迴轉震盪器模擬生物體內環境,進行藥物釋放實驗,較大尺寸的PLGA藥物微球有更高的初始藥物釋放,而由R1=3及R1=7所製作出來的藥物微球中,無論其藥物微球尺寸大小,R1=3所製作出來的藥物微球之初始釋放速率始終大於R1=7所製作出來的藥物微球,因R1=5所製作出來的藥物微球因內外部相連通的孔洞結構以及相較R1=3所製作出來的藥物微球來的稀疏的孔洞密度,使自催化作用具有相對高的影響,因此R1=5所製作出來的藥物微球其釋放曲線具有初始釋放速率不隨著藥物微球尺寸改變而改變的特性。本研究成功製作出多種不同結構的藥物微球,並具有廣泛的藥物釋放特性,未來在藥物載體或藥物釋放的實驗中,可利用微流體裝置製作少量且精確的藥物微球以進行實驗,以大幅減少實驗成本。

    In this research, the double emulsion microfluidic chip was used to make the porous PLGA microspheres. The PLGA microspheres with multiple porosities and multiple sizes was fabricated by operation parameters, which includes the 1st flow rate ratio (R1) and external water phase flow rate (Qo). The experimental results showed that the Porosity of PLGA microsphere increases as R1 decreases; the size of PGLA microsphere decreases as Qo increases. The drug entrapment efficiency (E.E.) and drug loading capacity (L.C.) of non-porous PLGA microsphere (R1=∞) and porous PLGA microspheres made by R1 = 3 do not change significantly with the change of Qo. The E.E. and L.C. of the porous PLGA microspheres made by R1 = 5 and R1 = 7 decrease with the increase of Qo. Use a constant temperature incubator and a rotary oscillator to simulate the biological environment for drug release experiments. The results verified that larger PLGA microspheres have higher initial drug release rate even with porous structure. Regardless of the size of the porous PLGA microspheres made by R1=3 and R1=7, the initial release rate of the porous PLGA microspheres made by R1=3 is always higher than that of the porous PLGA microspheres made by R1=7. The porous PLGA microspheres made by R1=5 initial release rate does not depend on the size of the PLGA microspheres. In the future, the presented microfluidic devices and the fabrication process can be used to make small quantities of precise PLGA microsphere for clinical or pharmaceutical test.

    摘要 i Abstract ii 致謝 xiii 目錄 xiv 圖表目錄 xvii 符號索引 xxiii 第一章 前言 1 1-1研究背景 1 1-2 研究目的 4 第二章 文獻回顧 5 2-1液珠式微流體系統(Microfluidics System) 5 2-1.1 微流體系統 5 2-1.2液珠生成機制 7 2-1.3 T型流道結構 8 2-1.4 流動聚焦型流道結構 9 2-1.5 同軸型流道結構 10 2-1.6 雙重乳化型流道結構 11 2-2 製備多孔結構藥物微球 13 2-2.1 鹽浸成孔法 14 2-2.2 氣體成孔法 15 2-2.3 滲透壓成孔法 16 2-3 PLGA藥物微球釋藥機制 17 2-3.1 PLGA藥物微球尺寸對釋放影響 17 2-3.2 PLGA共聚物成份比例對釋放藥物之影響 20 2-3.3 PLGA藥物微球孔隙率對釋放藥物之影響 21 小結 23 第三章 研究方法 24 3-1多孔結構PLGA藥物微球製備 25 3-1.1 雙重乳化微流體晶片參考與設計 25 3-1.2 微流體晶片材料與製作流程 27 3-1.3 微流體晶片表面改質方法 35 3-1.4 PLGA藥物微球製備 36 3-2 實驗結果觀測與分析 40 3-2.1 乳化觀測平台 40 3-2.2 多孔結構藥物微球之幾何外型觀測 41 3-2.3 多孔結構藥物微球吸水率測量 42 3-2.4 多孔結構藥物微球包覆率及載藥率測量 43 3-2.5 多孔結構藥物微球之藥物釋放率測量 46 第四章 實驗結果與討論 49 4-1 雙重乳化液珠生成 49 4-1.1 第一階段總流率對液珠尺寸之影響 49 4-1.2 第一階段連續相及分散相流率對液珠生成的影響 51 4-1.3 第二階段外部水相流率對液珠生成之影響 52 4-1.4 液珠生成品質不穩定現象 56 4-2 多孔結構PLGA藥物微球表徵 56 4-3 多孔結構PLGA藥物微球之吸水率 59 4-4 藥物微球之藥物包覆率及載藥率 60 4-5 多孔及非多孔結構PLGA藥物微球之藥物釋放 62 4-5.1 PLGA藥物微球尺寸對釋放之影響 63 4-5.2 PLGA藥物微球之孔洞率對藥物釋放之影響 67 第五章 結論與未來展望 73 5-1 結論 73 5-2 未來展望 74 參考文獻 76

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