Losartan胃滯留控釋劑型之開發研究以及在不同CYP2C9基因多型性之健康受試者於臨床上之研究評估

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題名:	Losartan胃滯留控釋劑型之開發研究以及在不同CYP2C9基因多型性之健康受試者於臨床上之研究評估 Development of Gastric Retained System for Losartan and its Clinical Relevance in Healthy Volunteers with CYP2C9 Polymorphism
作者:	游喬雅 Yu, Chiao-Ya
貢獻者:	藥學研究所
關鍵詞:	羥乙基纖維素羧甲基纖維素鈉碳酸氫鈉胃滯留劑型 CYP2C9基因多型性 hydroxyethylcellulose 250HHX (HEC 250HHX) sodium carboxymethylcellulose (SCMC) sodium bicarbonate gastroretentive dosage form CYP2C9 Polymorphism
日期:	2007
上傳時間:	2009-09-11 17:03:14 (UTC+8)
摘要:	傳統Losartan速放劑型可用於治療高血壓或心衰竭，口服後可快速被吸收，然後約有14%經CYP2C9被代謝成活性代謝物E3174。Losartan生體可用率不佳可能因吸收不完全以及首度代謝等原因，而相較於同劑量之速放劑型，胃滯留劑型之設計可延長胃滯留時間並明顯改善Losartan之生體可用率。本試驗目的即為開發新穎之Losartan胃滯留控釋劑型，以每天一次每次50公絲的方式使用。由於Losartan主要經由CYP2C9代謝成作用更強之活性代謝物E3174，因此將對Losartan胃滯留控釋劑型在不同CYP2C9基因多型性之健康受試者之影響加以研究評估。羥乙基纖維素、羧甲基纖維素鈉及碳酸氫鈉將配合不同打錠壓力用於製備錠片以進行體外膨脹特性及懸浮能力試驗。而50公絲的模式藥物Losartan再與適當處方混合，以直打法製備出600公絲之錠片，進行體外及體內臨床試驗。混合碳酸氫鈉至基質中可使錠片懸浮於模擬胃液上方16小時以上，且在3到6小時內膨脹至直徑2公分。此外，Losartan從錠片溶離之速率會受到酸鹼值影響。於臨床試驗中，4位受試者之藥物血中濃度測定將利用高效能液相層析法(HPLC)定量，並評估個體之CYP2C9酵素活性。進行臨床試驗前，共32位受試者參與CYP2C9基因多型性篩選，依聚合酶鏈鎖反應及限制酶片段長度多型性之技術(PCR-RFLP)可篩選出30位CYP2C91/1(快速代謝型)之受試者及2位CYP2C91/3(中間代謝型)之受試者，之後再隨機選出2位CYP2C91/1之受試者及2位CYP2C91/3之受試者進行臨床試驗，以研究CYP2C9基因多型性在Losartan藥物動力學上的影響。研究結果顯示胃滯留劑型GRD-A(羥乙基纖維素91.67%, 碳酸氫鈉 3.33%, Loartan 8.33%) 相對於速放劑型Cozaar®可改善生體可用率約166%，且MRT、tmax增加、Cmax減少。而CYP2C91/1之受試者其Losartan血中濃度較CYP2C91/3者低，可能與酵素活性差異有關。而Losartan之代謝途徑與代謝比例則可能受到Losartan血中濃度及代謝酵素活性交互影響。總結本研究，胃滯留劑型GRD-A應有延長胃滯留時間之效果，利用胃滯留劑型口服投予Losartan的確可改善其生體可用率。 Conventional immediate release dosage forms of losartan has been used to treat hypertension or heart failure. Following oral administration, losartan was rapidly absorbed, and then approximately 14% of a losartan dose was metabolized to the active carboxylic acid metabolite (E3174) by CYP2C9. The low bioavailability of losartan could be due to a combination of incomplete absorption and variable first-pass metabolism. Accordingly, the gastric retained dosage form was designed to prolong gastric residence time and provide for an enhanced bioavailability of losartan relative to an equal dose of an immediate release formulation. The aim of this study was to develop a novel gastric retained losartan dosage for administering losartan 50mg on an once-daily basis. Since the conversion of losartan to E3174 was mediated by the CYP2C9, the influence of gastric retained losartan dosage on healthy human volunteers with different CYP2C9 polymorphism was also investigated. Hdroxyethylcellulose 250HHX (HEC 250HHX), sodium carboxymethylcellulose (SCMC), and sodium bicarbonate were used to formulate tablets at various compression pressure for the evaluation of in vitro swelling characteristics and floating capacity. Then, 50 mg of the model drug losartan was incorporated in the optimal formulations to prepare 600 mg tablets by direct compression method for in vitro and in vivo characterization. Results demonstrated that incorporation of sodium bicarbonate into matrix resulted in the tablet floating over simulated gastric fluid for more than 16 h and swelling to 2 cm at 3 to 6 h. Moreover, the release pattern of losartan from these tablets was pH-dependent. In the clinical trial, plasma concentrations of 4 volunteers were quantified with the HPLC method to evaluate CYP2C9 activity. There were 32 subjects participated in CYP2C9 genotyping by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Eventually, comprising 2 CYP2C91/3 (intermediate metabolizers) subjects and 30 CYP2C91/1(extensive metabolizers) subjects. 2 CYP2C91/3 subjects and 2 CYP2C91/1 subjects were recruited for studying the influence of CYP2C9 polymorphism on pharmacokinetics with Losartan. Results showed that the mean bioavailability from formulation GRD-A (HEC 91.67%, sodium bicarbonate 3.33%, Loartan 8.33%) was approximately 166%, relative to the immediate-release product (Cozaar®). MRT, tmax values were greater and Cmax values were lower for the gastric-retentive tablets compared with the immediate-release product. The lower bioavailability of losartan in the CYP2C91/1 subjects than CYP2C91/3 subjects could be due to the variety of enzyme activity. The metabolic ratios and passways of losartan may be influenced by losartan plasma concentration and enzyme activity. In conclusion, this study indicated that the use of gastric retained dosage form for oral delivery of losartan could be an alternative to improve its systemic availability.
資料類型:	thesis
顯示於類別:	[藥學系] 博碩士論文

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