2-苯基-4-■■酮(YT-1)的溶離改善及其藥物動力學之研究; Dissolution Improvements and Pharmacokinetic Studies of 2-Phenyl-4-quinolone(YT-1)

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題名:	2-苯基-4-■■酮(YT-1)的溶離改善及其藥物動力學之研究;Dissolution Improvements and Pharmacokinetic Studies of 2-Phenyl-4-quinolone(YT-1)
作者:	黃太鴻;Tai-Hung Huang
貢獻者:	中國醫藥學院藥物化學研究所
關鍵詞:	2-苯基-4-酮;固體分散;檸檬酸;蘋果酸;藥物動力學;2-Phenyl-4-quinolone;Solid dispersion;Citric acid;Malic acid;Pharmacokinetic;YT-1
日期:	1990
上傳時間:	2009-12-03 09:30:56 (UTC+8)
摘要:	2-苯基-4-■■酮( 2-phenyl-4-quinolone，YT-1 )為■■酮類衍生物，具有抗多種腫瘤細胞之強效細胞毒性作用，也可以抑制 neutrophil respiratory burst 及局部水腫，並具有 aspirin-like 抗血小板凝集等活性，是具有相當開發價值之化合物，但是其溶解性不佳，為能提供臨床給藥之應用，進行開發前之相關研究。因此，首先擬建立一簡單、高感度和精確之分析方法。並對其理化性質加以探討，且製成固體分散物，藉由體外溶離試驗檢討溶離改善的程度並進行動物體內藥物動力學之探討。為定量增溶劑增溶後及動物血清中之 YT-1 濃度，首先開發 HPLC 分析方法。所開發之方法是簡單、高感度和精確之高效液相層析法，可同時用以定量個種增溶劑增溶試驗及動物服藥後血清中之 YT-1 濃度。本分析法係以 RP-18 層析管柱，移動相為乙?－水 ( 45：55 ) 經階梯沖堤十分鐘後其比率改變為 60：40 ，流速 0.7 mL/min ，檢測波長為 254 nm ， butylparaben 為內標準。血清檢品經水解與不水解處理後，注入管柱分析。血清中最低檢測濃度及最低定量濃度分別為 0.05 mg/mL及 0.10 mg/mL，在 0.1-100.0 mg/mL 濃度範圍具有良好的線性關係。經由示差掃描熱分析儀 ( DSC ) 及傅立葉轉換紅外線光譜儀( FTIR ) 之測定， YT-1 與檸檬酸或蘋果酸 ( 1：4 ) 可形成非晶形之固體分散物，故可使用檸檬酸或蘋果酸為載體 ( carrier ) 進一步進行溶離與藥品動力學研究。 YT-1 與檸檬酸及蘋果酸之固體分散物於模擬人工胃液中溶離試驗比較結果發現，使用檸檬酸之固體分散物比用蘋果酸者有更大的溶離速率。將溶離效果最好之 YT-1－檸檬酸 (1：4) 及 YT-1－蘋果酸之固體分散物 (1：4) 進行動力學研究，結果發現兔子口服檸檬酸固體分散物之生體可用率可達84 ﹪ ，比口服 YT-1 或 YT-1－蘋果酸之固體分散物，其生體可用率分別為 43 ﹪及 49 ﹪更佳。靜脈注射後之血中藥物濃度經時過程配適為二室性吸收模式，而口服給藥之數據則配適為一室性吸收模式。綜合以上結果，證明以檸檬酸做為增溶劑，可增加YT-1 之溶離及其生體可用率。; 2-Phenyl-4-quinolone (YT-1) is a quinolone derivative, which has been shown to demonstrate potent cytotoxic activities, positive inotropic effect, inhibit the neutrophil respiratory burst, local edema formation and possess aspirin-like antiplatelet activity. In this study, an HPLC method for the determination of YT-1 in formulation and in serum was developed. A reversed-phase RP-18 column was used. The gradient elution system comprises of solvent A (water) and B (acetonitrile), starting from 45% to 60% of B in 10 min and then from 60% to 45% of B in 6 min. Butylparaben was used as the internal standard. The flow rate was 0.7 mL/min. The absorbance was monitored at 254 nm. Linearity was found between the concentrations of 0.1 μg/mL - 100.0 μg/mL. The limit of detection and the limit of quantitation were 0.05 μg/mL and 0.1 μg/mL, respectively. The solid dispersions of YT-1 were prepared, then dissolution tests and animal studies were carried out to investigate the improvement on dissolution and absorption. By comparing the results from differential scanning calorimetry and FT-IR, it was found that the solid dispersions of YT-1 with citric acid or malic acid at the ratio of 1:4 exhibited amorphous state. The dissolution rate of YT-1 with citric acid was much higher than that of YT-1 with malic acid. The solid dispersions of YT-1 with citric acid and malic acid were used for pharmacokinetic studies. A two-compartment model can best describe the serum YT-1 concentration-time profile after intravenous administration, whereas one compartment model is best fitted for that after oral administration of various formulations. The glucuronide/sulfate conjugates of YT-1 were accounted for 62%, 83% and 86% of the total YT-1 in plasma for YT-1/citric acid, YT-1 and YT-1/malic acid formulations, respectively. The bioavailability of YT-1/citric acid, YT-1 and YT-1/malic acid formulation were 84%, 43% and 49% respectively, indicating that YT-1/citric acid formulation showed greater absorption in rabbit. In conclusion, citric acid can be used as a solubilizing agent to increase the dissolution and the bioavailability of YT-1.
顯示於類別:	[藥物化學研究所] 博碩士論文

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