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標題: 阿托伐他汀鈣自乳化口服新劑型之開發
Development of Self-Emulsified New Oral Dosage Forms for Atorvastatin Calcium
作者: 羅元均
Lo, Yuan-Chun
Contributors: 賴秉杉
化學系所
關鍵字: 高血脂;阿托伐他汀;生體可用率;自奈米乳化藥物傳遞系統
Hypercholesterolemia;Atorvastatin;Bioavailability;Self-nanoemulsion drug delivery system
日期: 2013
Issue Date: 2013-11-07 13:21:09 (UTC+8)
Publisher: 化學系所
摘要: 根據世界衛生組織的報告,近年來全球十大死因之首為心血管疾病,其中包含很多的病症,例如:高血壓、動脈硬化、心絞痛及中風,然而造成此疾病的主要原因為高血壓及高血脂。人體內膽固醇主要由肝臟合成,其合成的早期步驟係由3-羥基-3-甲基麩胺醯輔酶A還原酶(HMG-CoA reductase)負責催化3-羥基-3-甲基麩胺醯輔酶A轉變為甲羥戊酸(mevalonate),此步驟亦是速率決定步驟,其中3-羥基-3-甲基麩胺醯輔酶A還原酶是肝細胞合成膽固醇過程中的限速酶,因此抑制3-羥基-3-甲基麩胺醯輔酶A還原酶能減少內源性膽固醇合成。他汀類(statins)藥物是3-羥基-3-甲基麩胺醯輔酶A還原酶的選擇性競爭抑制劑,其中成效較佳的為阿托伐他汀(atorvastatin calcium)。然而阿托伐他汀的低水溶液溶解度導致其在體液中的有效濃度及生體可用率僅有14 %,這對現今的藥物傳遞系統是一主要挑戰。目前用以克服低溶解度和低生體可用率的方法有微粒化、環糊精複合物、固態分散和自奈米乳化系統。近期自奈米乳化藥物傳遞系統(self-nanoemulsion drug delivery system)顯示能成功促進低水溶性和親脂性藥物之口服生體可用率,故本研究在一般錠劑製程前端結合油/水乳化及溶劑揮發的方法,使得錠劑於溶離後可自行產生具有均一尺寸的藥物奈米液滴,開發新劑型錠劑。預期提升主成分藥物的溶解度和吸收效率,改善藥物生體可用率,進而減少藥物使用量。
According to the report of World Health Organization, the top ten causes of death in recent years of the first is cardiovascular diseases. Cardiovascular diseases contain many symptoms for instance, hypertension, arteriosclerosis, angina and stroke. However, the vital reasons to cause the diseases are hypertension and hypercholesterolemia. The cholesterol in our body are mainly synthesized by liver, 3-hodroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) catalyzes HMG-CoA convert to mevalonate (MVA) is the early step to synthesize cholesterol, which is also the rate-determining step. In cholesterol synthesis process, HMG-CoA reductase is the rate-limiting enzyme of hepatocytes synthesized cholesterol, thus the inhibition of HMG-CoA reductase could reduce the production of endogenous cholesterol. Statins are the selective competitive inhibitor of HMG-CoA reductase, and the most effective Statins is Atorvastatin. But the poor water solubility, led to very low valid concentration in biofluids and rarely bioavailability; that is a major problem for drug delivery. Nowadays, some methods were used to overcome the poor solubility and low bioavailability, for example: micronization, complexation with cyclodextrin, solid dispersions and self-nanoemulsion system. Recently, self-nanoemulsion drug delivery system has shown the success of bioavailability improvement for poor water soluble drugs and hydrophilic drugs. In this study, we combined the methods of emulsion and solvent evaporation with general tablets manufacturing process. When the new formulation fabricated tablets dissolution it can become nanoemusion droplets in uniform size, so we expect to overcome bioavailability problems and therefore enhance efficiency of drug absorption.
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