- 學位論文
白藜蘆醇滴丸製備與藥物動力學評估
Preparation and pharmacokinetic evaluation of resveratrol dripping pills
摘要
本篇研究的目的是利用固體分散的原理，將白藜蘆醇（3,5,4′-trihydroxystilbene, Resveratrol）製備成滴丸處方劑型，以提高白藜蘆醇之溶解度與溶離釋出累積百分率，進而提高其口服生體可用率。 以23實驗設計法來設計出適當的滴丸處方，設定的三個變因為：Poloxamer 188含量、Cremophor EL含量及Capryol 90含量，以及兩個層級，製作出八組不同處方，並探討白藜蘆醇滴丸之性質，包括：溶解度試驗、體外溶離試驗、重量差異試驗、圓度分析、平均粒徑大小、崩散時間試驗、含量試驗、示差掃描熱量分析、掃描式電子顯微鏡以及貯存安定性試驗。最後選擇較佳之白藜蘆醇滴丸處方六（50 mg/kg）、白藜蘆醇粉末（300 mg/kg）以及靜脈輸注白藜蘆醇溶液（30 mg/kg），來進行大鼠之口服體內藥物動力學試驗。 實驗結果發現白藜蘆醇滴丸之溶解度比白藜蘆醇粉末約可以增加14倍，而體外溶離試驗之白藜蘆醇釋出累積百分率於pH 1.2鹽酸溶液及pH 6.8磷酸鹽緩衝溶液中，分別比白藜蘆醇粉末約提高3倍及4倍；白藜蘆醇滴丸具有良好的重量均一度，外觀呈現深咖啡色光澤感，粒徑大小約在3.5 mm且圓整度均勻，每粒滴丸的白藜蘆醇含量約在0.37 mg且皆於5分鐘內完全崩散；DSC分析證明製作成滴丸劑型後，白藜蘆醇已均勻分散於賦形劑中呈現非晶型的狀態；SEM觀察白藜蘆醇粉末的內部呈現針狀結晶型態且表面粗糙，而滴丸的內部均皆呈現非晶型的狀態且表面平滑；安定性試驗中，滴丸經過6個月的加速試驗後，滴丸處方六仍然具有良好的安定性，顯示白藜蘆醇的含量在92％以上。藥物動力學試驗結果顯示，白藜蘆醇滴丸可以有效的提高相對生體可用率達11.22倍以及絕對生體可用率達11.41％，因此將白藜蘆醇製成滴丸後可形成一個穩定的藥物傳遞系統，可顯著的增加藥物的溶解度、溶離釋出累積百分率以及提升口服生體可用率，是一種具有實用性的劑型。
並列摘要
The purpose of this study is to use solid dispersion technique to develop a resveratrol (3,5,4′-trihydroxystilbene) dripping pills formulation which could enhanced the aqueous solubility, the dissolution rate, and the oral bioavailability of resveratrol. We applied a 23 fractional experiment design to get an optimized formulation, and effects of cremophor EL, capryol 90, and poloxamer 188, on the dripping pills were investigated in this study. The characterization of reveratrol dripping pills included solubility, dissolution rate, weight variation, roundness, average particle size, disintegration time, measurement of drug content, differential scanning calorimetry (DSC), scanning electron microscope (SEM) and stability. Resveratrol concentration analysis was achieved by HPLC, and the in-vitro dissolution rates between resveratrol dripping pills and resveratrol powder were compared. The size of resveratrol dripping pill was approximately 3.5 mm and the weight was about 29 mg per pill. The physicochemical properties of resveratrol dripping pills was examined by DSC and SEM. Unlike the resveratrol powder, resveratrol dripping pills had a smooth surface and existed an amorphous form of drug. In pharmacokinetics study, we evaluated resveratrol dripping pills (50 mg/kg) oral administration, resveratrol powder (300 mg/kg) oral administration, and resveratrol solution (30 mg/kg) intravenous administration in Sprague-Dawley rats. The results of our study indicated that the solubility test of resveratrol dripping pills was about 14-fold higher than resveratrol powder. Moreover, we found that the dissolution rate of resveratrol dripping pills at pH 1.2 HCl solution and pH 6.8 phosphate buffer were significantly 3-fold and 4-fold higher than resveratrol powder. Moreover, in the pharmacokinetics study, resveratrol dripping pills significantly increased 11.22-fold relative bioavailability compared to resveratrol powder, and the absolute bioavailability was 11.41%. In conclusion, we utilized solid dispersion technique to develop a resveratrol dripping pills formulation that could significantly enhanced the solubility, dissolution rate, and oral bioavailability of resveratrol.