臺灣博碩士論文加值系統

本研究選用meloxicam為實驗的模式藥物，評估其製成穿皮輸藥系統之可行性。Meloxicam是一種長效性非固醇類抗發炎藥物，由於具備水難溶性，故實驗首先以複合溶劑系統(co-solvent system)來尋求具高溶解度的溶媒組合，並利用超臨界二氧化碳微粒化技術降低藥物顆粒大小，以增加藥物
溶解度，結果顯示，meloxicam微粒化後粒徑由23.6 μm降為0.95 μm，可使溶解度提高約1.2倍。同時利用meloxicam原料藥製成以pluronic F-127或chitosan為基劑之水膠時，meloxicam自pluronic F-127水膠的釋出量遠大於自chitosan水膠的釋出量，因而選用pluronic F-127作為配方之主要基劑。在不同藥物濃度配方釋出量的比較上，以含有5％藥物的配方可得到最佳的釋出量。而在以大白鼠皮膚進行的體外穿皮測試中，不同作用機制的穿皮促進劑，以Sodium oleate的穿皮促進作用最好，可增加穿皮作用約 81.3倍；在原料藥與微粒化粉末最佳配方的通透量比較上，兩者之通透量無明顯差異；同時在體內動物試驗中，原料藥與微粒化粉末配方皆可以經皮輸藥發揮meloxicam的抗發炎作用。

The objective of this study is to explore the possibility of developing an effective meloxicam transdermal delivery system without association of adverse effects. Meloxicam is a new representative of the oxicam class of non-steroidal anti-inflammatory drugs (NSAID). Due to the very poor aqueous solubility of meloxicam, in the study we used the techniques of “co-solvent system”and“supercritical fluid carbon dioxide micronization”to enhance meloxicam’s solubility and to reduce its particle size. Results showed that, after micronization, the particle size of meloxicam was reduced from average 23.6 μm to 0.95 μm, and consequently its aqueous solubility was increased about 1.2 folds. Also, various hydrogel formulations composed of either chitosan or pluronics as the base and raw meloxicam as the drug were prepared to test drug release profiles using Franz cells. The results disclosed that the formulation with pluronics as the base, 5% w/w drug concentration, and sodium oleate as the penetration enhancer had the best transdermal properties, an overall 81.3-folds increase in terms of the penetration amount. Hence, this formulation was further tested in vivo for its anti-inflammatory efficacy. Without discrimination in flux, both raw and micronized meloxicam formulation delivered the anti-inflammatory efficacy of meloxicam via the transdermal route in vivo.

正文目錄
頁次
正文目錄……………………………………………………………………..... .I
表目錄………………………………………………………………………....VII
圖目錄……………………………………………………………………….... IX
中文摘要…………………………………………………………………….... XI
英文摘要……………………………………………………………………... XII

第一章 緒論………………………………………………………………... 1
第一節 皮膚之結構…………………………………………………….. .3
壹、表皮……………………………………………………………….. .3
貳、真皮……………………………………………………………….. .4
參、皮下組織………………………………………………………….. .4
第二節 藥物穿透皮膚之理論………………………………………….. .5
壹、藥物穿透皮膚之途徑…………………………………………….. .5
貳、穿皮輸藥系統藥物經由皮膚釋放之原理……………………….. .5
第三節 幾丁聚醣之簡介……………………………………………..... .11
壹、幾丁聚醣之來源與製備…………………………………………. .11
貳、物理化學特性……………………………………………………. .11
參、生理特性.............................................................................................14
第四節 Pluronic®之簡介...............................................................................17壹、Pluronic® 產品之介紹........................................................................17
貳、微膠粒(micelle)及膠體(gel)的形成………………………………....19
參、Pluronic polymer之毒性………………………………………….....20
第五節 Meloxicam 之簡介…………………………………………….....21
壹、Meloxicam物化性質之介紹…………………..................................21
貳、藥理作用及適應症……………………………………………….....22
參、Mx之藥物動力學參數………………………………………….......22
一、吸收(Absorption)……………………………………………….....22
二、分佈(Distribution)………………………………………………....22
三、代謝(Metabolism)………………………………………………....24
四、排除(Elimination)………………………………………………....24
第六節 超臨界流體之簡介…………………………………………….....28
壹、超臨界流體之定義及性質…………………………………...….......28
貳、超臨界二氧化碳之RESS系統…………………………………......31
一、RESS微粒化系統…………………………………………….......31
二、RESS系統架構………………………………………………........31
第七節 研究內容……………………………………………………….....34
第二章 材料與方法……………………………………………………….....35
第一節 儀器與試藥…………………………………………………….....35
壹、儀器……………………………………………………………….....35
一、高效能液相層析儀裝置(HPLC)…………………………….........35
二、超臨界流體萃取裝置…………………………………………......35
三、其它儀器………………………………………………………......35
貳、材料與試藥………………………………………………………......36
第二節 實驗方法……………………………………………………….....39
壹、Meloxicam體外經皮吸收之分析方法………………………….......39
一、高效能液相層析儀系統條件之設定………………………….....39
二、標準曲線之製作、同日間（within day）及異日間（between
day）之精密度（precision）、準確度（accuracy）及靈敏度
（sensitivity）之測量…………………………………………….....39
貳、配方之製備及其物化性質之測定………………………………......41
一、親水性凝膠之製備……………………………………………......41
二、Mx於不同基劑中其物化性質之測定……………………............42
參、Meloxicam微粒化之方法……………………………………….......42
一、超臨界二氧化碳之RESS系統裝置………………………….......42
二、Mx微粒化之步驟…………………………………………….......42
肆、Mx原料藥與微粒之分析……………………………………….......42
一、光學顯微鏡之觀察…………………………………………….....43
二、掃描式電子顯微鏡之觀察…………………………………….....43
三、粒徑分佈……………………………………………………….....43
四、X-ray粉末繞射分析………………………………………….......43
伍、Mx於人工膜之體外釋出試驗………………………………….......44
一、直立式穿皮試驗裝置…………………………………………......44
二、Mx於不同比例ethanol/pH 7.4 phosphate buffer中溶解度之
測定…………………………………………………………….....44
陸、Mx於大白鼠皮之體外穿透試驗…………………………………..48
一、直立式穿皮試驗裝置………………………………………….....48
二、動物皮之取得…………………………………………………. ...48
柒、Mx經皮吸收參數之測定……………………………………….......48
一、通透量(Flux，J)………………………………………………......48
二、藥物穿透累積量………………………………………………......49
捌、Mx於大白鼠體內之抗發炎作用之試驗…………………………...49
第三章 結果……………………………………………………………….....53
第一節 Meloxicam體外經皮吸收分析方法之建立……………………....53
壹、標準曲線之製作、同日間( intraday )及異日間( interday )之精密
度( precision )、準確度( accuracy )及靈敏度( sensitivity )之測量..53
一、標準曲線之建立……………………………………………….....53
二、同日間及異日間於精密度及準確度之評估………………….....57
三、靈敏度之測定………………………………………………….....57
第二節 Meloxicam外用凝膠劑配方之篩選…………………………......61
壹、Mx於不同基劑中其物化性質之測定………………………….......61
一、pH值之測定……………………………………………………....61
二、黏度之測定……………………………………………………......61
貳、Meloxicam微粒化之條件設定………………………………….......61
參、Mx原料藥與微粒之分析……………………………………….......64
一、光學顯微鏡之觀察……………………………………………......64
二、掃描式電子顯微鏡之觀察……………………………………......64
三、粒徑分佈……………………………………………………….......66
四、X-ray粉末繞射分析……………………………………………....66
肆、Mx於人工膜之體外釋出試驗……………………………………....71
一、評估Mx於不同基劑中之體外釋出情形…………………….......71
二、Mx於不同比例ethanol/pH 7.4 phosphate buffer中溶解度之測
定………………………………………………………………….74
三、評估不同藥物濃度之體外釋出情形…………………………….74
伍、Mx於大白鼠皮之體外穿透試驗…………………………………...80
一、不同作用機制的穿皮促進劑對經皮吸收之影響………………..80
陸、Mx穿皮配方於大白鼠之抗發炎效果................................................92
第四章 討論………………………………………………………………….94
壹、不同基劑對Mx釋出之影響………………………………………..94
貳、Mx於不同比例ethanol/pH 7.4 phosphate buffer中溶解度之測
定………………………………………………………………….....95
參、評估不同藥物濃度之體外釋出情形…………………………….....97
肆、不同種類的界面活性劑對穿皮吸收之影響………..........................97
伍、其他不同類別的穿皮促進劑對Mx經皮吸收之影響……………....98
陸、Mx原料藥與微粒化粉末通透量之比較……………………………99
柒、Mx於大白鼠體內之抗發炎作用之試驗…………………………..100
第五章 結論………………………………………………………………...102
第六章 參考文獻…………………………………………………………...104








表 目 錄
頁次
表1、幾丁聚醣物理化學性質……………………………………………........15
表2、幾丁聚醣之生理特性……………………………………………….......16
表3、Pluronic類聚合物分子結構關係表（pluronic grid）……………........18
表4、不同流體下之基本物理性質……………………………………….......29
表5、常作為超臨界流體之物質其臨界溫度及其臨界壓力…………….......30
表6、Meloxicam分析方法同日間精確度及準確度之評估……………........59
表7、Meloxicam分析方法異日間精確度及準確度……………………........60
表8、Mx於不同基劑中之配方組成……………………………………….....62
表9、不同基劑之物化性質……………………………………………….......63
表10、粒徑測量結果………………………………………………………....68
表11、Mx於不同比例ethanol/pH 7.4 phosphate buffer中之溶解度……....76
表12、不同藥物濃度之配方組成…………………………………………....77
表13、配方組成……………….........................................................................81
表14. 不同種類界面活性劑增進穿透鼠皮通透量(Flux)、24小時穿透累
積量、促進比例(Enhancement Ratio，ER)之比較…………………......84
表15. 不同種類穿皮促進劑增進穿透鼠皮通透量(Flux)、24小時穿透累
積量、促進比例(Enhancement Ratio，ER)之比較……………………..88
表16、Mx原料藥與微粒化粉末配方穿透鼠皮通透量(Flux)、24小時穿
透累積量、延遲時間之比較……………………………………….... 91

































圖 目 錄
頁次
圖1、藥物穿透皮膚之途徑……………………………………………….........6
圖2、藥物以擴散方式穿透膜之簡圖…………………………………….........7
圖3、(a) 幾丁質分子結構式 (b) 幾丁聚醣分子結構式……………….........12
圖4、幾丁聚醣之製造流程簡圖………………………………………….......13
圖5、Meloxicam之化學結構式…………………………………………........23
圖6、Meloxicam之藥理作用機轉………………………………………........25
圖7、純物質之典型三相圖……………………………………………….......28
圖8、超臨界二氧化碳之微粒化系統………………………………….............33
圖9、超臨界二氧化碳萃取裝置及其他配件圖………………………............46
圖10、直立式穿皮試驗裝置簡圖……………………………………….........47
圖11、穿皮累積量與時間之關係圖…………………………………….........50
圖12、Mx於大白鼠體內抗發炎作用之實驗過程……………………….......52
圖13、Meloxicam之HPLC圖譜……………………………..........................54
圖14、以HPLC分析法所建立之( a )同日間及( b )異日間之Meloxicam
標準曲線圖………………………………………………………….....55
圖15、光學顯微鏡圖……………………………………………………….....65
圖16、掃描式電子顯微鏡圖…………………………………………….........67
圖17、粒徑分佈圖…………………………………………………….............69
圖18、X-ray粉繞射分析圖………………………………………………......70
圖19、不同濃度Pluronic F-127釋出累積量之比較……………………......72
圖20、Mx凝膠劑之通透量與Pluronic F-127濃度之關係…………….......73
圖21、不同藥物濃度釋出累積量之比較……………………………............78
圖22、不同藥物濃度通透量之比較……………………………………........79
圖23、不同種類界面活性劑對增進藥物穿透鼠皮之影響…………………82
圖24、不同種類界面活性劑增進穿透鼠皮通透量的比較……………........83
圖25、不同種類穿皮促進劑對增進藥物穿透鼠皮之影響…………………86
圖26. 不同種類穿皮促進劑增進穿透鼠皮通透量的比較…………….........87
圖27、Mx原料藥與微粒化粉末配方之藥物穿透累積量………………….89
圖28、Mx原料藥與微粒化粉末其穿透鼠皮之通透量的比較…………......90
圖29、大鼠右足蹠以皮下注射carrageenan誘導急性發炎反應後之足蹠
腫脹率……………………………………………………………….....93

第六章 參考文獻

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