肝素(Heparin)藥物在臨床治療上，通常施以靜脈注射方式給藥。注射方式給藥對於病人的接受度不佳，亦造成給藥的不便。口服藥物是一理想的給藥方式。但是多數藥物在口服傳遞上，經由腸胃道途徑(Gastrointestinal tract, GI tract)吸收，其效果並不佳。原因在於口服傳遞藥物，必須經過腸胃道的不同pH生理環境；藥物成功到達小腸後，又需要透過小腸上皮細胞(Epithelial cell)層，才得以進入微血管。藥物透過小腸上皮細胞層的方式，主要分為兩種；直接穿過細胞膜(Transcellular pathway)通過上皮細胞層；或經由細胞與細胞之間的空隙(Paracellular pathway)通過上皮細胞層。由於細胞膜主要是由脂雙層所構成，因此親水性藥物(肝素)無法直接穿過疏水性的細胞膜，必須經由paracellular pathwayw穿透小腸上皮細胞層。位於上皮細胞之間的蛋白質錯合物Tight junction為paracellular pathway的主要屏障，其功用為選擇性地讓一些親水性分子進出上皮細胞。因為tight junction的阻礙，造成以往經由口服投藥的親水性藥物在小腸無法有效地吸收，進而影響藥物治療疾病的功效。
據文獻記載幾丁聚醣能夠暫時性地打開Tight junction。在本實驗室先前研究中，也證明幾丁聚醣(Chitosan)與聚麩氨酸(γ-poly-glutamic-acid)所形成之表面帶正電荷奈米微粒有作為口服藥物載體的可行性。所以本篇研究要以幾丁聚醣(Chitosan)包覆肝素形成奈米微粒，作為肝素口服傳遞之研究。
本篇研究的實驗分為兩大部分，體外評估與體內評估。體外評估分又為兩大部分，奈米微粒製備與穿透小腸上皮細胞層能力評估。在奈米微粒製備方面，先將大分子量幾丁聚醣以NaBO3去聚合為小分子量幾丁聚醣，再以小分子量幾丁聚醣與肝素反應，形成離子鍵結型奈米微粒。進而分析奈米微粒的性質、表面型態、藥物包覆效率、不同pH環境穩定性及藥物體外釋放效果。在穿透小腸上皮細胞層能力評估方面，本篇研究以培養結腸癌細胞(Caco-2 cell)模擬小腸上皮細胞，藉由量測transepithelial electrical resistance (TEER)值，評估tight junction是否被打開；並以共軛焦顯微鏡觀察奈米微粒與Caco-2 cell monolayers之間的關係。體內評估是以Male Sprague-Dawley Rats實驗動物，將包覆肝素之奈米微粒以餵食針對老鼠給藥，再偵測血液中肝素濃度。
研究結果顯示，幾丁聚醣經由NaBO3去聚合，分子量可達到~30kDa，所製備的奈米微粒之表面型態為球形，粒徑大小為100~200 nm，pH穩定性範圍為pH 1.2~7.0，藥物包覆效率接近100%。體外藥物釋放結果顯示奈米藥物載體有pH敏感性釋放，亦呼應奈米微粒pH穩定性。在小腸上皮細胞層穿透能力評估方面，亦證實奈米微粒可打開tight junction；共軛焦顯微鏡觀察之結果證實肝素確有進入細胞層，而ZO-1 protein有斷裂情形，藥物輸送主要是paracellular pathway。動物實驗結果證實口服奈米微粒後，確有肝素存於血液中，而肝素濃度亦達到最低有效治療濃度；與靜脈注射肝素效果比較，所達到的絕對生物體可利用率(Absolute bioavailability)為20.5%。這些實驗結果證明以小分子幾丁聚醣包覆肝素形成奈米微粒進行口服肝素藥物傳遞的評估是可行的。

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