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研究生： 高尚成
Kao, Shang-Cheng
論文名稱： 以新型微流體晶片製作雙重乳化PLGA複合藥物微球進行藥物釋放控制
Production of double emulsion PLGA based microparticles using newest microfluidics chip for the controlled drug release
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： 76
中文關鍵詞： 微流體晶片 、PLGA複合藥物微球 、藥物釋放 、共傳輸
外文關鍵詞： Microfluidic chip, PLGA multi-drug microparticles, Drug release, Co-delivering
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    • 隨著科技的發展，在現今的年代中，因為生活及環境的改變，人們也患有越來越多的疾病，造成人們每年在醫療上的支出持續地增長，而在這些疾病當中，癌症是令人們非常頭痛的疾病之一，因此本篇研究決定利用新型微流體晶片來製作雙重乳化PLGA複合藥物微球，並能有一次性完成及尺寸均勻的效果，最後利用複合藥物微球進行階段性及長效性的雙重藥物釋放。
    本研究經由改善研究團隊中的微流體晶片設計來達成研究目的，第一階段流道採用原研究團隊所設計之菱形柱狀陣列晶片來進行第一次乳化，第二階段流道則採用突擴型流體聚焦結構來進行第二次的乳化，在實驗的乳化過程中，僅改變第一階段的連續相與分散相中所含之藥物量，藉以製作出包覆不同藥物及藥物濃度之藥物微球，隨後比較不同藥物微球間的差異，其中包括尺寸、載藥率、包覆率及其藥物釋放之情形。
    由實驗結果可得知，藥物濃度對藥物釋放的影響上，薑黃素會受到藥物濃度影響而產生不同的釋放趨勢，而阿黴素則較不易受到藥物濃度的影響；複合藥物微球相較於單藥物微球，其可有效地降低藥物的初始爆發值，並使整體的釋放曲線更為緩和。未來團隊若能解決薑黃素初始爆發值的問題，以及能使複合藥物微球以最佳比例釋放藥物的話，相信能在生醫領域上有巨大的貢獻。

    In this study, we fabricated the composite PLGA microparticles for curcumin and doxorubicin co-delivering. We utilized the microfluidic double emulsion device which was published for our group. This microfluidc device comprised two different parts, the micromixer with diamond-shaped pillar arrays and flow-focusing droplet generator. In the emulsification process of the experiment, we only change the concentrations of the doxorubicin and curcumin in dispersed phase and continuous phase during first emulsion to produce microspheres with different drug contents and drug release behavior. We discussed the differences between these microspheres, including size, drug loading capacity, encapsulation efficiency and drug release. The experimental data showed that the release curve of the curcumin would be affected by different concentrations of the drug, and then, the release of the curcumin would perform the different release curve. On the contrary, the release of doxorubicin always had the same trend of release with many kinds of changes in drug concentrations. The multi-drug microspheres compared to the single-drug microspheres, having a significantly effect to decrease the burst release, and letting the whole release curve smoother and slower. On this basis, we developed a composited PLGA particles which can achieve the co-delivery of curcumin and doxorubicin and could be helpful in the clinical cancer treatment in the future.

    摘要 i Abstract ii 致謝 x 圖目錄 xiii 表目錄 xvii 符號索引 xviii 第一章 緒論 1 1.1研究背景 1 1.2研究動機與目的 3 第二章 文獻回顧 5 2.1 PLGA藥物微球製作 6 2.2藥物介紹 13 2.2.1阿黴素(小紅莓) 13 2.2.2薑黃素 14 2.2.3 提升療效&抑制副作用 14 2.3藥物釋放 18 2.3.1 藥物釋放特徵與機制 18 2.3.2 影響藥物釋放曲線因素 19 2.4文獻回顧小結 29 第三章 研究方法 30 3.1微流體晶片設計 31 3.2微流體晶片製作 33 3.2.1 流道材料選擇 33 3.2.2 光罩製作 33 3.2.3 流道晶片模型製作 33 3.2.4 流道翻模與接合 39 3.2.5 流道改質 41 3.3實驗儀器配置 42 3.4實驗流程 44 3.4.1 PLGA藥物微球製備 44 3.3.2 PLGA微球表面觀察 46 3.3.3 PLGA微球大小量測 47 3.3.4 PLGA微球包覆率與載藥率量測 47 3.3.5 建立藥物釋放標準曲線 48 3.3.6 PLGA微球藥物釋放測量 54 第四章 實驗結果與討論 56 4.1微流道雙重乳化液珠生成 56 4.1.1 流率選擇 56 4.1.2 氯化鈣添加問題 58 4.1.3 載藥、藥物濃度對生成液珠尺寸之影響 59 4.2 冷凍乾燥藥物微球表徵 60 4.2.1 添加海藻酸鈉對藥物微球之影響 60 4.2.2藥物微球表徵比較 61 4.2.3有瑕疵之藥物微球 63 4.3 載藥率、包覆率比較 64 4.4 藥物釋放比較 65 4.4.1 藥物濃度對藥物釋放之影響 65 4.4.2 複合藥物微球對藥物釋放之影響 70 4.4.3 以最佳藥物濃度比所製作之複合藥物微球(M1、M2) 71 第五章 結論與未來展望 72 5.1 結論 72 5.2 未來展望 72 參考文獻 74

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