臺灣博碩士論文加值系統

研究目的
本實驗目的在發展出lovastatin奈米微粒的製備方法，於清醒、可以自由活動的大白鼠之動物模式下，探討lovastatin奈米微粒是否能改善lovastatin的口服吸收，並且進一步探討lovastatin奈米微粒之藥物動力學與藥效學。
研究方法
對於藥物動力學的研究，使用自動採血系統以進行大白鼠血液的採集，而大白鼠的糞便則是利用代謝籠來採集。血液與糞便中lovastatin的分析是利用高效液相層析系統進行分析，並且使用串聯質譜儀來進行確認。高效液相層析系統的分析條件之移動相比率是乙氰胺比10 mM NaH2PO4為60比40，流速設定在1 ml/min，血液與糞便的回歸曲線分別在濃度0.05至100 □g/mL和0.1至100 □g/mL呈現線性。Lovastatin奈米微粒是利用chitosan的陽離子與tripolyphosphate的陰離子以離子鍵結所形成；奈米微粒粒徑大小和zeta電位的確認是分別利用多波長的粒徑分析儀和雷射都卜勒電位測定器進行分析，而藥物包埋率的測量則是使用高效液相層析系統。在清醒、可以自由活動的大白鼠之動物模式下，藉由分析大白鼠血漿中lovastatin的濃度時間曲線，以探討lovastatin奈米微粒是否能改善lovastatin的口服吸收。對於藥效學的研究，lovastatin、pravastatin、紅麴、綠茶、綠茶-紅麴膠囊和lovastatin奈米微粒在高膽固醇血症小鼠的降低膽固醇作用，以及lovastatin、pravastatin、chitosan、oligo-chitosan和lovastatin奈米微粒的減低高膽固醇血症發生率之預防作用是藉由分析小鼠血漿中的總膽固醇含量和小鼠體重以進行探討。
結果
由藥物動力學的分析，可以發現給予lovastatin (500 mg/kg, p.o.)後120分鐘，會達到血漿中lovastatin的最高濃度1.2 □g/mL，給藥後的48小時，便有相當於給藥劑量78％的lovastatin被經由糞便排出。甲殼素奈米微粒的粒徑大小是介於200至300奈米之間，並且表面帶正電位。藥效學方面，藥物降低血漿中總膽固醇作用的效力是lovastatin奈米微粒 > pravastatin > 紅麴 > lovastatin > 綠茶 > 綠茶-紅麴膠囊；藥物對於預防高膽固醇血症的效力是lovastatin奈米微粒 > oligo-chitosan > pravastatin > chitosan > lovastatin > 紅麴。
結論
對於利用高效液相層析搭配串聯質譜儀以快速、高靈敏性分析大白鼠血液和糞便中lovastatin含量的方法已經成功被建立。根據藥物動力學與藥效學的實驗結果可以發現，lovastatin奈米微粒能增加lovastatin的口服吸收，並且對於小鼠高膽固醇血症具有很好的治療與預防作用。

Purpose. The objectives of this study were to develop a new procedure of preparing lovastatin-loaded nanoparticles to improve the oral absorption of lovastatin in awake and freely moving rats and the pharmacokinetic and pharmacodynamic of lovastatin-loaded nanoparticles.
Methods. For the pharmacokinetic, the blood samples are collected by means of the automated blood sampling system DR-II and the fecal samples are collected by a metabolic cage. The concentration of lovastatin is determined by a reversed-phase liquid chromatographic system and verified by LC-MS-MS. The mobile phase of HPLC system contains acetonitrile and 10 mM NaH2PO4 in the proportions 60:40 (v/v) with a flow-rate of 1 ml/min. The calibration curve is found to be linear in concentration ranges of 0.05-100 □g/mL and 0.1-100 □g/mL for lovastatin in blood and fecal sample, respectively. Lovastatin-loaded nanoparticles were prepared by ionotropic gelation of chitosan with tripolyphosphate anions. They were characterized for particle size and zeta potential by multi-wavelength particle size analyzer and laser Doppler anemometry, respectively. Lovastatin loading and releasing were determined by a reversed-phase HPLC/UV system. The ability of lovastatin-loaded nanoparticles to enhance the oral absorption of lovastatin was investigated in conscious and freely moving rat model by monitoring the concentration-time profile of lovastatin in rat plasma. For the pharmacodynamic, the cholesterol-lowering effect of lovastatin, pravastatin, lovastatin-loaded nanoparticles, red koji and green tea were estimated in hypercholesterolemia mice and the preventive effect of lovastatin, lovastatin-loaded nanoparticles, pravastatin, chitosan and oligo-chitosan in reducing the morbidity of hypercholesterolemia were studied in mice fed with the high cholesterol food by determining the plasma total cholesterol.
Results. Following pharmacokinetic analysis, the maximum plasma concentration was around 1.2 □g/mL at peak time 120 min and almost 78 % of loading dose was cumulative in the feces within 48 h after lovastatin administration (500 mg/kg, p.o.). Chitosan nanoparticles had a size in the range of 200-300 nm and a positive surface. The cholesterol-lowing effect of the four drugs tested produced the following rank order; lovastatin-loaded nanoparticles > pravastatin > red koji > lovastatin > green tea. The preventive effect of the five drugs in reducing the morbidity of hypercholesterolemia tested produced the following rank order; lovastatin-loaded nanoparticles > oligo-chitosan > pravastatin > red koji > chitosan > lovastatin.
Conclusion. The method of fast and sensitive liquid chromatographic system coupled with LC-MS-MS to measured lovastatin in rat blood and feces has been developed successfully. According to the pharmacokinetic and pharmacodynamic results, the lovastatin-loaded nanoparticles have the ability to enhance the oral absorption of lovastatin and have the excellent cholesterol-lowing effect and preventive effect for hypercholesterolemia.

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