口服投藥對病患來說，是一最舒適且高接受度的給藥方式。然而口服疏水性藥物在腸道內由於容易自我聚集而無法被有效地分散和吸收，進而導致口服之生物可利用率普遍偏低。因此本研究建立一能於小腸內自我乳化脂質奈米油珠載體於口服難吸收之藥物，用以改善上述問題。此載體系統共包含四種材料: paclitaxel, capric acid, sodium bicarbonate, 與citric acid。paclitaxel為疏水性小分子抗癌藥物且應用於胰臟癌之第一線抗癌療程。脂質capric acid大量的存在於天然椰子油與動物乳奶中，而sodium bicarbonate與citric acid 為市面上泡騰片(effervescent tablet)之常見成分。這些材料，僅需在充分混合後，即可填充於一膠囊中，做成一創新的口服劑型。此一腸溶膠囊在口服後，通過食道、胃到了小腸後，膠囊外的腸溶衣在偏中性的環境下開始溶解，膠囊內的citric acid遇到腸液後隨即釋出質子(proton)產生一酸性環境。此酸性環境促使sodium bicarbonate裂解產生CO2氣泡，而腸道內之膽鹽(bile salt)具有界面活性劑的特性可隨之穩定CO2氣泡結構，並以其形成的氣泡載體攜帶脂質capric acid與疏水藥物paclitaxel。此載體在腸道內會由氣泡主動推散，當超過氣泡所能承受之表面張力時，氣泡會破裂進而自我乳化形成一脂質奈米油珠載體來裝載疏水藥物，使得疏水小分子藥物在此載體的幫助下能有效地分散在腸道之中減少疏水藥物的聚集現象，藉此大幅提升腸道吸收效率。於biodistribution實驗結果可推測疏水藥物可藉由腸淋巴系統運輸至胰臟。未來將利用此口服載體用以投遞藥物至胰臟以提升胰臟癌之治療效果，並在大鼠胰臟癌模型進一步探討此載體搭載paclitaxel治療胰臟癌之功效。

Oral therapeutic agents offer the advantages of greater convenience, ease of administration, and their associated complications and costs. Among all of the oral therapeutic agents, small molecule hydrophobic drugs have poor water solubility, and oral delivery of such drugs is limited by difficulties, including poor solubility, low permeability, instability, and rapid metabolism, all of which cause low oral bioavailability. To address these issues, we developed a self-emulsified lipid oil drops drug delivery system, the system including four compounds — sodium bicarbonate (SBC), citric acid, capric acid, together with hydrophobic drug (paclitaxel). The powder mixture can self-assembly undergo 3-stage structural transformations after encountering intestinal fluid: First, the test powder produces a CO2 bubble carrier system in aqueous phase where capric acid and paclitaxel encapsulated in the hydrophobic tail of bile salt. Next, these bubble carriers gradually float to the air-water interface due to their density with structural transition of which capric acid and paclitaxel is distributed from single layer to double layer once exposing to air. Finally, those of bubble carriers burst owing to their surface tension, and followed by a capric acid and paclitaxel loaded carriers with a particle size range around 200 nm mechanically emulsified in intestinal fluid. This carrier system can facilitate paclitaxel uptake through M-cellular endocytosis, which locate on the intestinal tract and can be visualized by CLSM. Afterward, the IVIS results suggested that those of delivered hydrophobic drug were underwent lymphocyte and then were specifically shipped into lymphatic system nearby pancreas tissue through the lymphatic drainage between intestinal and pancreas lymphatic channel. It is a niche to orally treat pancreas disease like pancreatic cancer.

摘要 1
Abstract 2
Contents 3
List of Figures 4
一、緒論 5
1.1 口服投遞 5
1.2紫杉醇 6
1.2.1 紫杉醇作用機制 6
1.2.2 紫杉醇副作用與投遞難題 7
1.3 自我乳化脂質奈米油珠載體 7
1.3.1 脂質油珠載體之優勢與吸收途徑 8
1.4 胰臟與胰臟癌 9
1.5 實驗架構 10
二、材料與方法 12
2.1 材料 12
2.2 劑型製備 12
2.3 脂質奈米油珠載體特性 12
2.3.1 材料比例與產泡能力 12
2.3.2 分散性與乳化效果-自我乳化機制 13
2.3.4 脂質油珠載體粒徑與電荷 13
2.4 紫杉醇吸收 13
2.4.1 動物體內疏水螢光藥物定性分布 13
2.4.2 動物體內紫杉醇定量分布 13
2.4.3 吸收機制-小腸與Peyer’s Patch 14
2.4.4 吸收機制-Lymphatic Inhibitor 14
2.4.5 吸收機制-胰臟與腸繫膜淋巴結 15
2.5 原位胰臟癌模型建立 15
2.5.1 原位胰臟癌癌細胞注射誘導 15
2.5.2 原位胰臟癌腫瘤組織植入誘導 15

三、實驗結果與討論 16
3.1 脂質奈米油珠載體特性 16
3.1.1 材料比例與產泡能力 16
3.1.2 分散性與乳化效果-自我乳化機制 17
3.1.3 脂質油珠載體粒徑與電荷 18
3.2 紫杉醇吸收 19
3.2.1 動物體內疏水螢光藥物定性分布 19
3.2.2 動物體內紫杉醇定量分布 21
3.3.3 吸收機制-小腸與Peyer’s Patch 21
3.3.4 吸收機制-Lymphatic Inhibitor 22
3.3.5 吸收機制-胰臟與腸繫膜淋巴結 23
3.3 原位胰臟癌模型建立 24
3.3.1 原位胰臟癌癌細胞注射誘導 24
3.3.2 原位胰臟癌腫瘤組織植入誘導 24
四、結論 28
五、參考文獻 29

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