腸道炎症 (inflammatory bowel disease; IBD) 是一種於腸道組織產生慢性發炎的疾病，伴隨著腹瀉、腹痛、血便等症狀。其致病機制尚未完全被了解。一般認為是受到腸道微生物感染、生活習慣、心理壓力或基因等因素所影響。病症起因主要為腸道黏膜組織受傷後，腸道微生物入侵受損組織進而引起急性發炎反應，若病灶處無法及時抑止該急性發炎，則可能發展成慢性之腸道炎症。
近年來硫化氫 (hydrogen sulfide; H2S) 在生物體內做為信息傳遞物質的作用機制已逐漸被解開，文獻指出硫化氫能夠藉由抑制促發炎因子 (諸如 TNF-α, IL-1β, IL-8, IFN-γ等) 來緩和生物體內之發炎反應。此外，硫化氫也被發現能抑制免疫細胞貼附血管壁進入發炎組織，進而有效地抑止發炎訊號後續之放大程度。
大蒜素 (diallyl trisulfide; DATS) 是一種常見的疏水有機性硫化氫前驅物，可經由蔥蒜類植物萃取獲得。DATS進入細胞內後可被 glutathione 等還原劑代謝產生硫化氫。由於 DATS 的低水溶特性，臨床上常需搭配一定劑量的界面活性劑 (如 Tween 80) 來增加其分散性，卻也產生了額外的細胞毒性及相關副作用。因此開發一高安全性載體，且能夠將疏水性的 DATS 有效地分散於大面積且病灶位置廣泛之腸道炎症進行治療，是一重要課題。
在本研究中，我們已完成一可自我塗布給藥的膠囊產氣系統，在膠囊內填充一產酸劑 (diethylene triamine pentaacetic acid; DTPA)、一產泡劑 (sodium bicarbonate; SBC)、一界面活性劑 (sodium dodecyl sulfate; SDS)、以及硫化氫前驅物 DATS，以肛門塞劑的方式給藥於IBD大鼠。此系統利用大鼠直腸內的濕潤環境融化膠囊後，水分將與 DTPA作用形成一酸性微環境，SBC遇酸後產生CO2氣體，在SDS界面活性劑的穩定作用下，產生一CO2氣泡載體攜帶疏水的DATS。隨著氣泡載體的產生與分散，將可有效地將DATS藥物均勻的塗佈於腸道壁內，提升DATS的吸收效率。在載體研發方面，我們分析了膠囊系統產生CO2氣泡過程、氣泡結構以及其最佳組成比例等，並模擬腸道環境來觀察此膠囊系統均勻分散疏水藥物DATS的能力。在細胞實驗方面，我們觀察膠囊系統對於 LPS 誘導後的巨噬細胞之免疫抑制情形，以及其抑制巨噬細胞貼附於血管內皮細胞的效果。在動物實驗方面，我們藉由餵食 dextrane sulfate sodium (DSS) 來建構大鼠 IBD 模型，並以疾病復原指標、活體影像系統、組織切片等實驗方式，來評估本產氣系統自動塗布疏水藥物 DATS 於大鼠腸道之效率。我們預期本膠囊系統，將能有效達到治療 IBD 發炎症狀之功效。

關鍵字:發炎性腸症, DATS, 硫化氫, 產氣系統, 肛門塞劑

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that is induced by the uncontrolled activation of the mucosal immune system in the colon tract. Physiologically, hydrogen sulfide (H2S) is an endogenous gasotransmitter with multiple biological functions, which can serve as an anti-inflammatory mediator, diminishing the expression of a number of pro-inflammatory cytokines. As H2S is an ephemeral gaseous molecule, many researchers have attempted to administer exogenous H2S donors to enhance its biological function. Diallyl trisulfide (DATS), a nature-origin compound isolated from garlic, has been commonly used as an exogenous H2S donor, which can be reduced by glutathione to release H2S intracellularly. In this study, a bubble-carrier system that can effectively deliver DATS to the large and uncertain IBD locations is proposed. This bubble-carrier system comprises compounds of an acid initiator [diethylene triamine pentaacetic acid (DTPA) dianhydride], a foaming agent (sodium bicarbonate; SBC), a surfactant (sodium dodecyl sulfate; SDS), and the poorly water-soluble DATS, which are thoroughly mixed and filled in a gelatin capsule. Following administration of the gelatin capsule into a rat model bearing IBD via suppository delivery and its dissolution in the colon, DTPA dianhydride is exposed to the intestinal fluid and an acidic environment is created, in which SBC decomposes to form CO2 bubbles that are stabilized by a monolayer of surfactant molecules (SDS) that can carry the hydrophobic DATS molecules. The massively formed DATS-laden CO2 bubbles can be expanded freely in the colon tract until they come in contact with the mucosal layer, eventually bursting and releasing their loaded DATS. It is expected that this novel bubble-carrier system can effectively distribute the hydrophobic DATS to cover/coat the colon tract, enhancing its bioavailability and treating IBD.

Keywords: drug delivery, inflammatory bowel disease, ulcerative colitis, H2S, capsule

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