臺灣博碩士論文加值系統

藥物治療的效果，與藥物釋放的位置及藥物在患處所釋放的濃度有關。一個理想的藥物控制釋放元件，須具備以下條件：適用於廣泛的藥物並能儲存大量的藥物、在“off”的狀態下能夠釋放較少甚至零藥物通量、在“on”的狀態下能夠重複性的控制脈衝式藥物釋放，在釋放的過程中不會對藥物釋放元件產生機械性的破壞及在釋放的過程中可有效地藉由刺激的強度改變釋放速率。

在本研究中我們成功地開發出一種利用電場驅動覆膜式藥物控制釋放元件。此控制釋放元件可廣泛地適用於離子型藥物，可使用的藥物分子量範圍為300~40000 道爾吞。利用電場移動帶電藥物分子的釋放機制，其電場刺激的時間對於釋放量的響應迅速，且可成功控制藥物達到脈衝式藥物釋放系統的效果。本系統採用覆膜式儲藥槽，所製造出的控制釋放元件在釋放過程中，不會對元件的結構產生破壞並可重複脈衝式釋放達4次以上。對於不同細胞毒性層級的藥物，控制釋放元件的釋放速率可以由實驗設計的參數改變，即使用不同類型的阻隔膜使控制釋放速率達到一個數量級的差異(10~100 ng / hr)，以符合不同藥物對人體的治療效果。除了藉由實驗設計的參數改變，也可藉由施加不同的外加電壓強度，達到一個數量級(100~1000 ng / hr)的差異之控制釋放速率。此外，也可以藉由設計不同電壓波形，依需求控制釋放速率。在此論文所呈現的系統，對於在生物材料、組織工程、移植科技及生物感測器上有極大的應用潛力。

Drug therapy efficacy depends on therapeutic concentrations of drugs at disease sites. An ideal controlled drug delivery device should safely contain a large quantity of drugs, release little or no drug in the “off ” state, be repeatedly switchable to the “on” state without mechanically disrupting the device, and can actively control release rates. In this thesis, an electro-stimulated membrane-based drug delivery device was developed to release drugs on demand. Drugs over a broad range of molecular weights (300-40000 Da) and different charge properties can be delivered by the same drug delivery approach. Ionic drug molecules were electrically ejected from polyelectrolyte hydrogels into bulk solution in vitro, the response time between electric stimulus and release amounts was fast, and without mechanically disrupting the membrane-based drug delivery device .We showed that the dose of drug delivered across drug delivery device could be tuned by different material of membrane, the strength of applied voltage, and the waveform of applied voltage, allowing for pulsatile drug delivery system of model drug, we could control the release rate at 1 order of magnitude (100~1000 ng / hr) during release processes. The system reported here has great potential for use in biomaterials, tissue engineering, implant technology, and biosensors for biomedical applications.

目錄
口試委員審定書 i
誌謝 I
摘要 II
英文摘要 III
目錄 IV
圖目錄 VI
表目錄 VIII
物理符號意義 IX
第一章、緒論 1
1-1藥物釋放元件的發展 3
1-2覆膜式微型藥槽 5
1-3總結 14
1-4研究動機 15
第二章、藥物釋放機制 18
2-1藥物控制釋放理論 18
2-2電遷移理論 18
2-3薄膜阻力控制釋放 22
第三章、實驗藥品流程與元件設計 25
3-1實驗藥品與儀器 25
3-1.1實驗藥品 27
3-1.2實驗儀器 28
3.2實驗流程 28
3-2.1藥品配製 28
3-2.2磷酸緩衝溶液 30
3-2.3蠟紙製作 30
3-2.4藥物釋放實驗 31
3-3藥物釋放元件製作 34
第四章、藥物釋放元件特性分析 41
4-1以軟體模擬在儲藥槽中所建立的電場分佈 41
4-2藥物釋放元件測試 47
4-2.1以洋菜膠為藥物載體之藥物元件測試 48
4-2.2以洋菜膠為藥物載體做連續性控制釋放實驗 49
4-2.3以洋菜膠為藥物載體做脈衝式控制釋放實驗 50
4-2.4以洋菜膠為藥物載體做胰島素藥物釋放實驗 52
4-3以三仙膠藥物載體之藥物釋放實驗 60
4-3.1連續性施加電壓控制釋放實驗 61
4-3.2脈衝式控制釋放實驗 62
4-3.3胰島素的脈衝式控制釋放實驗 63
第五章、藥物釋放元件實驗結果與討論 69
5-1不同阻隔膜材料對藥物釋放行為之影響 71
5-1-1連續施加電壓控制藥物釋放速率 71
5-1-2脈衝式施加電壓控制藥物釋放速率 73
5-1-3阻隔模材料的結構與特性分析 74
5-2以PTFE阻隔膜在不同施加電壓下對藥物釋放之影響 80
5-3不同施加電壓對脈衝式藥物釋放之影響 82
5-4 FITC-dextran脈衝式藥物釋放之影響 88
第六章、結論 90
第七章、未來展望 91
參考文獻 92
 
圖目錄
圖1-1、血液中藥物濃度與時間的關係 2
圖1-2、脈衝式藥物釋放系統 4
圖1-3、藥物釋放機制[37] 6
圖1-4、藥物釋放機制[32] 7
圖1-5、藥物釋放機制[33] 8
圖1-6、藥物釋放機制[30, 34] 9
圖1-7、藥物釋放元件結構[10] 11
圖1-8、藥物釋放機制[23] 12
圖1-9、藥物釋放元件結構[21] 13
圖1-10、實驗規劃圖 17
圖2-1、釋放機制(I) 23
圖2-2、釋放機制(II) 24
圖3-1.1-1、the structure of FITC-dextran 26
圖3-1.1-2、the structure of methylene blue 26
圖3-1.1、亞甲基藍校正曲線 32
圖3-1.2、胰島素校正曲線 32
圖3-1.3、FITC-dextran校正曲線 33
圖3-3-1、(A)藥物釋放元件結構(鋁材) 37
圖3-3-1、(B)藥物釋放元件結構 37
圖3-3-2、元件爆炸圖 38
圖3-3-3、實驗步驟示意圖 39
圖3-3-4、元件成品 40
圖4-1.1、元件幾何結構設計圖 42
圖4-1.2、邊界條件 44
圖4-1.3、電力線分佈圖 46
圖4-2.1、亞甲基藍藥物釋放實驗(I) 55
圖4-2.2、亞甲基藍藥物釋放實驗(II) 55
圖4-2.3、亞甲基藍施加脈衝式釋放曲線 56
圖4-2.4、亞甲基藍脈衝式藥物釋放(I) 57
圖4-2.5、亞甲基藍脈衝式藥物釋放(II) 58
圖4-2.6、胰島素脈衝式藥物釋放實驗 59
圖4-3.1、亞甲基藍藥物釋放實驗(三仙膠) 66
圖4-3.2、亞甲基藍脈衝式藥物釋放 67
圖4-3.3、胰島素脈衝式藥物釋放 68
圖5-1、實驗流程 70
圖5-1.1、比較蠟紙與PTFE阻隔膜 75
圖5-1.2、比較蠟紙與PTFE阻隔膜之脈衝式藥物釋放 76
圖5-1.3、比較PTFE (上圖)與蠟紙(下圖)阻隔膜之SEM圖 78
圖5-1.4、比較蠟紙與PTFE阻隔膜之接觸角 79
圖5-2.1、連續施加電壓PTFE阻隔膜亞甲基藍之藥物釋放 81
圖5-2.2、脈衝式釋放實驗測試 85
圖5-3、PTFE阻隔膜亞甲基藍之脈衝式藥物釋放 86
圖5-4、PTFE阻隔膜FITC-dextran之脈衝式藥物釋放 89
 
表目錄
表3-1.1、實驗藥品 25
表3-1.2、實驗儀器 27
表3-1-1、校正方程式 33
表4-1、參數設定 43
表4-2、邊界條件設定 45
表4-2.1、以洋菜膠為藥物載體的實驗操作條件 54
表4-3.1、以三仙膠為藥物載體的實驗操作條件 65
表4-3.2、三仙膠洋菜膠的比較 65
表5-1、實驗條件 69
表5-1、蠟紙與PTFE比較表 77
表5-2、PTFE阻隔膜亞甲基藍之連續性藥物釋放 81
表5-3、PTFE阻隔膜亞甲基藍之脈衝式藥物釋放 87

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