蛋白質藥物傳遞系統之研究 : 纖維蛋白微球體及微乳劑
蛋白質藥物傳遞系統研究以開發具有生物體可分解性，生體相配性的高分子材質之外，天然的聚合 物和脂質亦是發展方向。本研究在設計蛋白質藥物傳遞系統則採用天然聚合物—纖維蛋白質及脂質 系統—微乳劑作為蛋白質藥物的載體。
纖維蛋白微球體的備製，仍利用纖維蛋白原可被凝血酵素轉化成纖維蛋白此一溫和生化反應原理，
以乳化方式成功地備製出纖維蛋白微球體。藉由加入不同量的油酸當作界面活性劑，控制介於兩相 之間的介面張力，便可容易達到控制粒子大小。蛋白質以旋轉或震盪方法做安定性實驗，結果顯示 選擇以振盪並添加 0.5%NaN3 當作防腐劑的 Tris Buffer 作為蛋白質滲透和釋放實驗的條件。從滲透 和釋放實驗結果可知，蛋白質的滲透或釋放是與纖維蛋白微球體大小有關 ; 較小的纖維蛋白微球體
，則蛋白質的滲透或釋放速率愈快，且釋放速率大於滲透速率 ; 除了 Lysozyme 外，蛋白質的分子 量愈大，蛋白質擴散係數愈小。與理論上大分子的擴散係數與其分子量的關係相符合。 Lysozyme 因與纖維蛋白之間電荷吸引作用而吸附在纖維蛋白表面，阻礙 Lysozyme 擴散。所以控制大分子蛋 白質從微纖維蛋白微球體滲透和釋放，是受到纖維蛋白微球體粒子大小分佈，和蛋白質對纖維蛋白 微球體擴散性質所影響。
微乳劑是具有熱力學上安定性、透明澄清、自發乳化作用形成，以及具有助溶能力及維持長時間動 力學上安定的微小乳滴的性質，已逐漸應用在藥劑學上研究。本研究採用去離子純水當作水相， C aptex 300 當做油相，以及數種具口服安全性和依順性的聚甘油脂肪酸酯的材質，以單獨或複合或與 短鏈醇類 (C2~C4) 一起合併使用當做界面活性劑來製備微乳劑。結果顯示，僅有加入短鏈醇類當做 輔助乳化劑才能獲得微乳劑，而且微乳劑處方的範圍受到醇類鏈長的影響。因此醇類可以修飾乳化 劑的 HLB 值去達到一適中 HLB 值以利形成微乳劑。本實驗所配製微乳劑，無論是粘度、相的平衡 皆能維持長時間的安定性 ; 胰島素在微乳劑中無論是 4 ﾟ C 或室溫下儲存，亦能保持一段安定期間。
而含胰島素微乳劑在 37 ﾟ C ， 0.1 N HCl 人工胃酸下，微乳劑則具有保護胰島素的功能。
Study of Protein Drugs Delivery System: Microspheric Fibrin System and Microemulsion System
Many biodegradable and biocompatible synthetic polymers have been developed as protein drug delivery system. But natural polymer and lipids may be utilized with inherent advantages. In this study, the feasibility of using natural polymers –fibrin an d lipid system—microemulsion for protein drug carrier was examined.
An emulsion method was employed in this study to prepare fibrin microsphere. By utilizing a mild biochemical reaction betw een fibrinogen and thrombin to yield the fibrin polymer, fibrin microspheres were successfully prepared. As expected, by vary ing the amount of oleic acid as surfactant added in oil phase to lower the interfacial tension between phases, size of fibrin micr ospheres could be easily controlled.
The stability of macromolecules either rotating or shaking in the medium with various amount of preservative was examined.
The results indicated that shaking conditions and adding 0.2% NaN3 as preservative was able to keep the macromolecules sta ble long enough for studying their diffusion characteristics. A dependence on the size of fibrin microspheres was noticed; the smaller the size of fibrin microspheres, the faster the penetration or release rate of macromolecules would be. It also showed t hat the release rate of macromolecules from fibrin microspheres was faster than the penetration rate into the same size of micr ospheres. As expected, diffusion coefficient is a function of molecular size of macromolecules. As a result, the larger the mole cular weight of macromolecules, the smaller the diffusion coefficient is. But Lysozyme showed some deviation from this pred iction. Since chargeattration forces between Lysozyme and fibrin, Lysozyme is adsorbed on the surface of fibrin microsphere or kept inside the microsphere. More resistance to diffuse for Lysozyme was realizable. In conclusion, the penetration and the release of macromolecules in fibrin microsphere system was controlled by the size an dits distribution of microsphere and diff usion characteristics of macromolecules.
