基於維持藥物活性，臨床上蛋白質藥物劑型多為針劑注射，若能開發口服劑型，將有效提升病人服藥接受度及便利性。本實驗室先前研發一自我組裝氣泡型奈米載體，將界面活性劑sodium dodecyl sulfate (SDS)、螯合劑diethylenetriaminepentaacetic acid (DTPA) dianhydride、產氣材料sodium bicarbonate (SBC)及蛋白質藥物胰島素混合裝填於酸鹼應答的腸溶衣膠囊，應用於口服胰島素傳遞。然而，SDS作為吸收增進劑是否對腸道造成損害，以及增加腸道菌內毒素侵入，一直是這個新型載體系統尚未驗證之疑慮。本研究將針對SDS的劑量調整，根據不同配方的氣泡型載體做特性分析、傳遞效率比較和毒性探討，以探析自我組裝氣泡型奈米載體之最適SDS劑量。經由載體分析、體外試驗和動物體內試驗都應證隨著SDS的劑量增加，載藥率、載體穩定度、腸道的藥物通透性皆有顯著提升；毒性方面，腸道無局部損傷也無內毒素入侵的憂慮，然而長期服用高劑量組別會有慢性毒性的疑慮，因此權衡安全性與藥物傳遞效能考量，採用中劑量SDS為載體最適劑量。經過糖尿病大鼠實驗證實，本載體系統確實能安全且成功自口服路徑投遞胰島素進入血液循環，達血糖平衡的功效，為一具前瞻性之口服蛋白質藥物傳遞平台。

In clinical, to maintain the bioavailability of protein drugs, most of them are delivered through the injection route. Therefore, development of a system that can apply protein drugs via oral route may highly improve patient compliance. Recently, we reported a self-assembling bubble carrier system which was prepared by mixing a surfactant (sodium dodecyl sulfate; SDS), diethylene triamine pentaacetic acid (DTPA) dianhydride, and a foaming agent (sodium bicarbonate; SBC) for oral insulin delivery. However, using SDS as an absorption enhancer has been questioned whether SDS would cause local intestinal toxicity and promote endotoxin invasion. To address this concern, we aim to study the importance of SDS and find out the optimized dosage for our bubble carrier system. Comparing to the effects of various SDS dose on bubble characteristics analysis, in vitro tests and in vivo tests, SDS is proved to improve loading efficiency, stabilize the bubble carrier, and enhance drug absorption as the increasing concentration. No obvious local irritation and endotoxin permeation enhanced is displayed in all SDS treated groups. But long-term toxicity should be concerned of taking highest dose of SDS daily. Therefore, moderate dose is chosen as the optimized one and carried out the following efficacy experiments. In the results of PK and PD studies, oral administration of this bubble carrier system can successfully deliver insulin into systemic circulation and exert hypoglycemic effects. In summary, the self-assembling bubble carrier with an optimal dose of SDS offering a promising and safety platform for oral protein drug delivery.

摘要 I
Abstract II
圖目錄 VI
表目錄 VII
第一章 緒論 1
1.1 糖尿病 (Diabetes Mellitus) 1
1.2 胰島素治療(Insulin-based Therapies) 2
1.2.1 胰島素投遞策略 3
1.3 生物製劑：蛋白質/胜肽藥物 5
1.3.1 開發蛋白質/胜肽藥物口服途徑的阻礙 6
1.3.2 口服藥物吸收途徑 8
1.4 自我組裝氣泡型奈米載體 (Self assembling nanobubble carriers) 9
1.4.1 Sodium dodecyl sulfate (SDS) 11
1.4.2 SDS 起泡性 (Foam property) 11
1.4.3 SDS於口服藥物的應用 12
1.4.4 SDS毒性探討 13
1.5 研究動機與目的 17
1.6 實驗設計流程圖 18
第二章 實驗材料與方法 19
2.1 實驗藥品 19
2.2 實驗儀器 19
2.3 氣泡特性探討 20
2.3.1 氣泡形態觀察 20
2.3.2 氣泡穩定度 20
2.3.3 氣泡載藥率測定 20
2.4 體外實驗 21
2.4.1 酵素降解試驗 21
2.4.2 Caco-2 permeability assay藥物穿透試驗 21
2.5 體內實驗 22
2.5.1 腸道形態及毒性傷害觀察 22
2.5.2 生物分佈觀測 23
2.5.3 藥物動力學和藥效學實驗 24
第三章 實驗結果與討論 25
3.1 氣泡特性探討 25
3.1.1 氣泡形態觀察 25
3.1.2 氣泡穩定度 26
3.1.3 氣泡載藥率測定 27
3.2 體外實驗 28
3.2.1 酵素降解試驗 28
3.2.2 Caco-2 permeability assay藥物穿透試驗 29
3.3 體內實驗 32
3.3.1 腸道形態及毒性傷害觀察 32
3.3.2 生物分佈觀測 34
3.3.3 物動力學和藥效學實驗 38
第四章 結論 40
第五章 參考資料 41

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