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研究生： 林思妤
Lin, Sih-Yu
論文名稱： 溫度敏感型聚酯類水膠作為免疫抑制藥物傳遞系統之應用
Thermosensitive Polyester Hydrogel for Application of Immunosuppressive Drug Delivery
指導教授： 朱一民
Chu, I-Ming
口試委員: 劉繼賢
Liu, Chi-Hsien
姚少凌
Yao, Chao-Ling
學位類別： 碩士
Master
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2018
畢業學年度： 106
語文別： 中文
論文頁數： 60
中文關鍵詞： 溫度敏感型聚酯類水膠 、他克莫司
外文關鍵詞： thermosensitive polyester hydrogel
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    • 本研究選用溫度敏感型聚酯類水膠作為藥物載體，包覆疏水性免疫抑制藥物他克莫司，期望能藉由藥物控制釋放系統，達到緩慢且持續釋放的效果。材料的製備是以methoxy poly(ethylene glycol)作為起始劑，與D,L-lactide、glycolide、caprolactone進行開環聚合反應，合成出mPEG-PLGA及mPEG-PLCL兩種兩團聯共聚物，將這兩種共聚物分別配製成水膠，比較其性質與包覆效果，以找出較適合包覆他克莫司之藥物載體。
    合成所得的產物，透過核磁共振氫譜、凝膠滲透層析儀和傅立葉轉換紅外線光譜儀確認其化學結構和分子量，並針對水膠之溶膠相轉換作測試，以觀察各濃度之成膠溫度範圍，結果顯示15wt% mPEG-PLGA及18wt% mPEG-PLCL能夠在常溫為液態而在體溫狀態形成膠體。體外藥物釋放則是利用水膠包覆他克莫司，以高效能液相層析儀分析確認是否能夠有效包覆藥物並達到緩慢長效釋放。實驗結果顯示，藥物與mPEG-PLGA水膠溶液混合時會有析出的現象，而mPEG-PLCL能較良好的包覆藥物並維持穩定釋放長達三個月，因此mPEG-PLCL比mPEG-PLGA更適合作為包覆疏水性免疫抑制藥物他克莫司之藥物載體。

    In this research, thermosensitive polyester hydrogels were used as drug carriers to encapsulate tacrolimus (FK506). It is expected that the drug release system will achieve a slow and sustained release effect. Two types of diblock copolymers, mPEG-PLGA and mPEG-PLCL, were synthesized by ring-opening polymerization, in which methoxy poly(ethylene glycol) was used as the initiator to react with different types of ester monomers: D,L-lactide, glycolide, and caprolactone. The two copolymers were formulated into hydrogels, and their properties and encapsulation efficiency were compared to find the most suitable drug carrier for tacrolimus.
    The chemical structure and molecular weight of copolymers were confirmed by nuclear magnetic resonance spectroscopy, gel permeation chromatography and Fourier transform infrared spectroscopy. The sol-gel-sol phase transition of hydrogels showed that 15 wt% mPEG-PLGA and 18 wt% mPEG-PLCL have good sol-gel-sol behavior. Drug release experiment was performed using a high-performance liquid chromatography, in which the encapsulation efficiency and the capability of hydrogels to achieve sustained drug release can be characterized. The results showed that mPEG-PLCL was more suitable than mPEG-PLGA as a drug carrier for encapsulating tacrolimus.

    第一章 文獻回顧 1 1.1 水膠簡介 1 1.1.1 水膠定義 1 1.1.2 水膠材料 2 1.1.3 交聯方式 3 1.2 溫度敏感型水膠(Thermosensitive hydrogels) 4 1.2.1 溫度敏感型聚酯類水膠(Thermosensitive polyester hydrogels) 6 1.2.2 相轉變行為(Phase transition behavior) 8 1.2.3 聚酯類水解機制(Hydrolysis) 10 1.3 藥物傳遞系統 11 1.3.1 藥物控制釋放方式 12 1.3.2 藥物釋放速率影響因子 13 1.4 移植排斥(Transplant rejection) 14 1.5 他克莫司(Tacrolimus, FK506) 15 第二章 研究動機 17 第三章 實驗藥品與設備 18 3.1 實驗藥品 18 3.2 實驗設備 19 第四章 實驗步驟與方法 20 4.1 實驗架構 20 4.2 mPEG-polyesters 兩團聯共聚物製備 21 4.2.1 mPEG-PLGA 21 4.2.2 mPEG-PLCL 22 4.3 化學結構鑑定與性質分析 23 4.3.1 氫原子核磁共振光譜儀(1H-NMR) 23 4.3.2 凝膠滲透層析儀(Gel permeation chromatography, GPC) 23 4.3.3 傅立葉轉換紅外線光譜儀(Fourier transform infrared spectroscopy, FTIR) 24 4.3.4 臨界微胞濃度測定(Critical micelle concentration, CMC) 24 4.3.5 微胞粒徑分析 25 4.3.6 微胞型態觀察 25 4.3.7 水膠相轉變行為測定(Sol-gel-sol phase transition) 26 4.3.8 水膠黏度分析 26 4.4 藥物傳遞系統之應用 27 4.4.1 藥物配方測試 27 4.4.2 Tacrolimus濃度標準曲線建立 27 4.4.3 體外降解實驗(Degradation test in vitro) 28 4.4.4 體外藥物釋放實驗(Drug release in vitro) 28 4.4.5 生物相容性測試 29 4.5 動物實驗 30 4.5.1 體內皮下試驗 31 4.5.2 體內藥物釋放實驗 31 第五章 實驗結果與討論 32 5.1 兩團聯共聚物結構與性質分析 32 5.1.1 NMR結構鑑定 32 5.1.2 GPC分子量之量測 34 5.1.3 全反射傅立葉轉換紅外光譜鑑定(FT-IR) 35 5.1.4 臨界微胞濃度(CMC) 36 5.1.5 微胞粒徑量測 37 5.1.6 微胞型態觀察 38 5.1.7 水膠相轉變行為 38 5.1.8 水膠黏度分析 40 5.2 藥物傳遞系統之應用 41 5.2.1 配方測試 41 5.2.2 體外降解實驗 44 5.2.3 體外藥物釋放實驗 46 5.2.4 生物相容性測試 48 5.3 動物實驗 50 5.3.1 水膠之體內相容性 50 5.3.2 水膠之體內藥物釋放 51 5.3.3 水膠之體內降解 52 5.3.4 含藥水膠之體內相容性 53 第六章 結論及未來展望 54 6.1 結論 54 6.2 未來展望 55 第七章 參考資料 56 Appendix 59 Appendix A HPLC分析Tacrolimus標準曲線 59 Appendix B 含藥水膠於大鼠體內第七天之H&E組織切片染色照片 60

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