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研究生:丘宏治
研究生(外文):Andy Hong-Jey Chiou
論文名稱:超臨界流體於Felodipine微包埋與微粒化之研究
論文名稱(外文):The Study of Microencapsulation and Micronization of Felodipine using a Supercritical Fluid Process
指導教授:王大鵬王大鵬引用關係
指導教授(外文):Da-Peng Wang
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:99
中文關鍵詞:水難溶性藥物快速膨脹超臨界溶劑微粒
外文關鍵詞:poorly water-soluble drugrapid expansion of supercritical solutionsmicroparticles
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Felodipine (FLD)是一種水難溶性藥物。為改善FLD之溶離速率,本研究擬以快速膨脹超臨界溶劑(rapid expansion supercritical solution,RESS)法將FLD製備為微米級藥粒,並將此藥粒包埋於poly-(ethylene glycol) 4000 (PEG 4000)中。於本研究中,我們想要明瞭FLD微粒被包埋於PEG 4000中之特性 ,故進行一系列分析方法以確定其物化性質,這些方法包括光學顯微鏡檢、電子顯微鏡檢、熱示差分析掃描、X-ray粉晶繞射儀、傅立葉轉換紅外線光譜儀分析與溶離釋出行為之探討。FLD微粒是經由超臨界二氧化碳流體之製程(高度壓力與適當溫度)而製備完成。不論FLD-PEG 4000微粒或是FLD微粉 ,皆可適用於RESS法以降低粒徑。於比較微粒形態方面,我們以掃描式電子顯微鏡分別觀察FLD-PEG 4000微粒與FLD微粒之表面形態,發現兩者有相當明顯之差異,前者為斑點形狀;而後者為類似爆玉米花形狀。經由本研究中RESS法製備之FLD微粒我們發現微粒具有雙重特性:粒徑分佈窄與粒徑均一。此外,由熱示差分析與傅立葉轉換紅外線光譜儀分析掃描FLD-PEG 4000微粒之結果得知,FLD與PEG 4000分子間並無交互作用發生,然而,不論是FLD-PEG 4000微粒或是FLD微粒 皆無多晶型與非晶型之現象發生。由溶離釋出結果表明,FLD-PEG 4000微粒之溶離速率較FLD微粉為快。經由這些數據顯示: RESS法能成功被運用於製備FLD-PEG 4000微粒(2-6 µm)並可增快其溶離速率。 此外,應用felodipine微粒於錠劑之體外與生體評估亦於本文一併探討。
Felodipine (FLD) is a poorly water-soluble drug. To improve its dissolution rate, we used the rapid expansion of supercritical solutions (RESS) technique to prepare micronized FLD drug particles, which we encapsulated in poly-(ethylene glycol) 4000 (PEG 4000). We characterized the physical properties of the encapsulated drug particles by a variety of analytical methods, including optical light microscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC) powder X-ray diffraction (powder-XRD) and fourier transform infrared (FT-IR), and studied the dissolution behavior of FLD in the microparticles. The supercritical condition of micronized FLD occurred at a relatively high pressure and moderate temperature. FLD–PEG 4000 microparticles compared well with micronized FLD. RESS was effective in reducing the particle size of FLD; we observed spot-shaped micronized FLD and popcorn-shaped FLD–PEG 4000 microparticles. The particulate properties of the microparticles included a narrow distribution and uniform size. The results of thermodynamic analysis and FT-IR showed no molecular interaction between FLD and PEG 4000 molecules, neither polymorphism nor amorphous state in the micronized FLD or FLD–PEG 4000 microparticles. FLD–PEG 4000 microparticles had a significantly faster drug dissolution rate than micronized FLD. These data show that RESS can be used to prepare FLD–PEG 4000 microparticles with small particle size (2–6 µm) and enhanced dissolution rate. Additionally, the in vitro and in vivo evaluation of felodipine microparticles for tablet formulation is also to explore in this study.
正文目錄

頁次
目錄…………………………………………………………………………….Ⅰ
表目錄…………………………………………………………………………Ⅴ
圖目錄….………………………………………………………………………Ⅵ
『附錄』目錄………………………..…………………………………………Ⅷ
中文摘要………………………………………………………………………Ⅸ
英文摘要………………………………………………………………………Ⅹ
第ㄧ章 緒言……………………………………………………………………1
第一節、 研究背景…………………………………………………………..1
第二節、 超臨界流體之簡介………………………………………………..3
壹、 定義、發展及歷史沿革……………………………………………....3
貳、 二氧化碳超臨界流體簡介…………………………………………....7
參、 超臨界流體微粒化系統之簡介…………………………………...…11
第三節、 水難溶藥物felodipine之簡介………………………..………….18
壹、 水難溶藥物之簡介…………………………………………………...18
貳、 Felodipine之簡介…………………………………………………….19
第四節、 研究目的………………………………………………………….23
第二章 材料與方法…………………………………………………………24
第一節、 藥品與試劑……………………………………………………….24
壹、 藥品…………………………………………………………………..24
第二節、 儀器………………………………………………………….……25
壹、 超臨界流體萃取裝置………………………………………………..25
貳、 高效能液相層析儀裝置……………………………………………..25
第三節、 其他儀器……………….…………………….…………………..26
壹、 其他儀器……………………………………………………………..26
第四節、 HPLC分析方法……….…………………………………………28
第五節、 RESS微粒化與微包埋….…………………………………….…31
壹、 微粒化操作………………….……………………………………….31
貳、 FLD-PEG 4000微包埋操作…………………………………………31
第六節、 光學顯微鏡檢與掃描式電子顯微鏡檢….….…………………..36
第七節、 粒徑分佈測量………………………………….………………...36
第八節、 X-ray粉晶繞射分析…………………………….…………….....36
第九節、 傅立葉轉換紅外線光譜儀分析…………………………………37
第十節、 熱示差掃描分析………………………………….……………..37
第十一節、 微粒之溶離試驗……………………………………………...37
第十二節、 口服錠劑之製備………….…………………………………..38
第十三節、 口服錠劑之評估………….…………………………………..39
壹、 錠劑中藥物含量測定……...………………………...............………39
貳、 崩散試驗……………………………………………………………..41
第十四節、 錠劑之溶離試驗……………………………………………..41
第十五節、 藥物動力學實驗……………………………………………..41
壹、 動物實驗…………………………………………………………..… 41
貳、 分析條件之設定……………………………………………….……..42
參、 標準曲線之製備……………………………………………………...42
一、標準曲線之製備…………………………………………………42
二、血漿中標準曲線之製備………………………………………....43
三、回收率之計算……………………………………………………43
四、血液檢品之處理…………………………………………………44
五、資料之處理與統計分析…………………………………………44
第三章 結果……………………………………………………………….45
第一節、 HPLC分析方法……………………………………………...45
第二節、 RESS製程參數效應與felodipine微粒之關係…….……....48
第三節、 微粒表面形態之觀察……………..………………………....49
第四節、 微粒之粒徑分佈……………………………………………..49
第五節、 微粒之熱示差掃描分析……………..……………………....54
第六節、 微粒之X-ray粉晶繞射儀分析…………………..………….56
第七節、 微粒之傅立葉轉換紅外線光譜儀分析………….………….58
第八節、 微粒之溶離釋出曲線……………….……………………….58
第九節、 錠劑劑型之製備與評估…..………….……………………...61
第十節、 錠劑之溶離釋出試驗……..…………………………………65
第十一節、 動物實驗………………………...……..………………..….65
第四章 討論…………………………………….…………………….....75
第一節、 探討RESS效應對felodipine微粒之影響……….…………75
第二節、 微粒物化性質之探討………………………………..…….....80
第三節、 微粒溶離釋出行為之探討……………….………………......86
第四節、 錠劑劑型評估之探討……………………….……………......87
第五節、 綜合討論………………………………………………….…..88
第五章 結論………………………………………………………………..90
第六章 參考文獻…………………………………………………………..91

表目錄
頁次
表1、二氧化碳超臨界流體與其液、氣相物化特性比較表………………..6
表2、應用超臨界流體降低藥物粒徑或包覆之文獻摘要表….………….....8
表3、超臨界流體裝置原理比較表………….……………….………………17
表4、RESS微粒化之溫度、壓力與操作參數表…………….……………..33
表5、RESS微包埋之溫度、壓力與操作參數表…………….……………..35
表6、Felodipine錠劑配方之劑型設計表…………….…………….….…….40
表7、同日間與異日間標準曲線之精密度試驗結果…….….........................47
表8、Felodipine微粒之粒徑分佈表………………………………………....53
表9、Felodipine原料藥、felodipine微粒與FLD-PEG 4000等三種錠劑之
藥物含量………..………………………………………………….….63
表10、Felodipine原料藥、felodipine微粒與FLD-PEG 4000等三種錠劑
之崩散試驗結果………………………………………………………64
表 11、血漿中萃取felodipine回收率之實驗結果…………………………71
表12、紐西蘭大白兔經口服投與felodipine原料藥錠劑、含felodipine微粒
錠劑與含FLD-PEG 4000錠劑此三種錠劑後,由血中felodipine 經時變化計算之藥物動力學參數值……………………………….….73



圖目錄

頁次
圖1、二氧化碳之三相圖…………………….…….……………………...5
圖2、奈粒化製程增加表面積示意圖………………….…………………9
圖3、二氧化碳於自然界之循環圖….……………….…………………..10
圖4、超臨界流體裝置示意圖….………………………………………...12
圖5、Felodipine化學結構式……………………….…………………….20
圖6、超臨界流體RESS萃取裝置……………………………………32
圖7、Felodipine加速裂解檢品之分析結果….…….……………………46
圖8、觀察felodipine原料藥粉末之外觀與粒徑之光學顯微鏡照片…..50
圖9、Felodipine微粒掃描式電子顯微鏡照片…….…………………….51
圖10、Felodipine之粒徑分佈圖…………………………………………52
圖11、Felodipine熱式差掃描分析圖譜…………………………………55
圖12、Felodipine經RESS處理之粉晶X-ray光繞射圖譜.….………...57
圖13、Felodipine經RESS處理之傅立葉轉換紅外線光譜儀圖譜…....59
圖14、經RESS製備之felodipine微粒與FLD-PEG 4000微粒之溶離釋
放曲線…………………………………………………………….60
圖15、經不同RESS條件製備之felodipine微粒溶離釋放曲線………62
圖16、Felodipine錠劑之溶離釋出曲線……………….…………………...66
圖17、血漿中felodipine之HPLC-ECD層析圖譜………………………..67
圖18、Felodipine之空白標準曲線…………………………………………68
圖 19、Felodipine之血漿中之標準曲線…………………………………...69
圖20、口服餵食大白兔之felodipine原料藥錠劑、含felodipine微粒錠劑與
含FLD-PEG 4000錠劑此三種劑型之血漿中藥物濃度經時曲線... 72
圖21、超臨界流體對比壓力-對比密度之關係圖………………………….77
圖22、felodipine多晶型之傅立葉紅外線光譜儀圖譜………………….….84

『附錄』目錄

頁次
附錄一、 論文投稿SCI期刊接受函………………………………….. 附錄一
附錄二、 投稿期刊SCI排名……………………………………………附錄二
附錄三、 發表期刊原文(封面)…………………………………………附錄三
第六章參考文獻

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