- 學位論文
Adenosine analogue自發性微乳化給藥系統
Self- microemulsifying drug delivery system for oral delivery of an adenosine analogue
摘要
目的：腺苷類似物來源中國藥材萃取出來，在動物模型已被證明能延緩亨丁頓氏舞蹈症的進展。然而，腺苷類似物之水溶解度差，且口服生體可用率低。為了提高腺苷類似物溶解度及口服生體可用率，進行SMEDDS（自發性微乳化釋藥系統）開發。 方法：為了獲得合適的自發性微乳化釋藥系統，進行脂質、表面活性劑和輔助表面活性劑組成的三相圖構建。 在28天內利用粒徑儀 (N5 submicron particle size analyzer) 測量SMEDDS在水性介質中形成的液滴大小。利用高效能液相層析法（HPLC）測量溶液中腺苷類似物的溶液濃度之方法開發。此外，利用超高效液相色譜-串聯質譜(UPLC-MS/MS)測定在大鼠腺苷類似物血漿中的濃度也被開發和驗證。SMEDDS利用Caco-2細胞進行體外模擬測試腺苷類似物於小腸穿透率。最後口服給予腺苷類似物於雄性Sprague - Dawley大鼠，進行藥物動力學試驗。 結果與結論：油相、界面活性劑、輔助介面活性劑所組成之自發性微乳化劑能顯著提高藥物的溶解度。在28天內在水介質中形成液滴的大小約200 nm左右。腺苷類似物自發性微乳化劑通過Caco-2細胞之穿透率較對照組溶液高。此外，自發性微乳化劑口服給予雄性Sprague - Dawley大鼠進行藥物動力學試驗，顯示出自發性微乳化劑對於水不溶性藥物腺苷類似物略提高其口服生體可用率。
並列摘要
Purpose: An adenosine analogue isolated from a Chinese medicinal herb has been shown to delay the progression of Huntington’s disease in an animal model. However, the solubility of this adenosine analogue is poor with very low oral bioavailability. In order to improve the oral bioavailability of the adenosine analogue, a solubility enhancement system SMEDDS (Self Microemulsifying Drug Delivery System) was developed. SMEDDS is a strategy for the delivery of hydrophobic drugs that are insoluble in water in order to improve the oral bioavailability. Methods: In order to obtain a suitable SMEDDS, ternary phase diagrams composed of lipids, surfactants, and co-surfactants were constructed. SMEDDS in aqueous media formed droplet size from day 1 within 28 days by N5 submicron particle size analyzer. A simple and reproducible high performance liquid chromatography (HPLC) method for determining the concentration of the adenosine analogue in the solution was developed and validated. UPLC-MS/MS (Ultra Performance Liquid Chromatography-tandem mass spectrometry method for determination the concentration of the adenosine analogue in rat plasma was also developed and validated. The permeation of the adenosine analogue SMEDDS in vitro studies using Caco-2 cells was tested. Oral absorption of the adenosine analogue SMEDDS was evaluated the pharmacokinetics and bioavailability in male Sprague - Dawley rats. Results and conclusions: The SMEDDS composed of oil phase, surfactant phase and co-surfactant phase was able to significantly increase the drug solubility. The SMEDDS in aqueous media formed droplet size around 200 nm from day 1 within 28 days. The permeability of the adenosine analogue SMEDDS compound through Caco-2 cells was more than the permeability of the adenosine analogue solution. In male Sprague-Dawley rats, this study illustrated the potential use of SMEDDS to improve bioavailability of the water - insoluble drug by oral route.