臺灣博碩士論文加值系統

本研究使用羥丙基甲基纖維素琥珀酸醋酸鹽﹙HPMCAS﹚作為腸溶性硬膠囊的腸溶膠體，目的在於用腸衣膠囊的特性，使阿斯匹靈不在胃中崩解，待膠囊移動至腸中後再釋放藥效，達到不傷害胃的功能。研究內容包括腸衣膠體配方的探討，膠囊成品的崩散試驗、溶離試驗、腸衣膠囊的安定性等品管規範的探討，並與市售阿斯匹靈腸衣錠做比較。
實驗結果顯示，膠體配方中的二氯甲烷可降至9%，且阿斯匹靈膠囊成品其崩散試驗、溶離試驗及安定性結果都符合藥典規定，因此食用阿斯匹靈腸溶性硬膠囊可以有同樣的療效並減少副作用發生的可能性。分析方法其回歸取線的相關係系數﹙R2﹚為Aspirin 0.9994與水楊酸0.9999，專一性及精密度試驗所得之相對標準偏差﹙R.S.D﹚均在1.5%以下。由實驗結果可知此分析方法有高靈敏度且可快速偵測Aspirin及水楊酸，證明此分析方法之可行性。

This research uses hydroxypropyl methylcellulose acetate succinate﹙HPMCAS﹚ to made the intestine dissolved colloid as the coating material of the hard capsule. The purpose of this coating is using its characteristic to prevent the aspirin capsule breaking up in the stomach, until the capsule migrate to intestine and breaks up to the drug. The aspirin would not to injure the stomach by this way. The research including the discussion of the intestine dissolved colloid formula, the disintegration test and, the dissolution test of capsules, as well as the stability of the enteric coated capsules, and its comparison with aspirin enteric coated tablet in drugstore.
The experimental results showed that in the colloid formula the dichloromethane can reduce to 9%. All results of disintegration tests, the dissolution tests, and the stability tests of the aspirin enteric-coated capsules conforms to the stipulation of pharmacopoeia, therefore the edible aspirin enteric coated hard capsules may have the same curative effect, and reduce the risk of side effects. The correlation coefficients of linear calibration in this analysis method for aspirin and salicylic acid are 0.9994 and 0.9999. The relatively standard deviation﹙R.S.D﹚of the specific and accuracy test obtained are both below 1.5%. The experimental results the high of sensitivity and fast detection of aspirin and the salicylic acid also proves the feasibility of this analysis method.

中文摘要.........................................................................................................Ⅰ
Abstract...........................................................................................................Ⅱ
誌謝.................................................................................................................Ⅲ
目錄.................................................................................................................Ⅳ
表目錄..........................................................................................................VIII
圖目錄.............................................................................................................IX
第一章 緒論.....................................................................................................1
1-1 前言..........................................................................................................1
1-2 相關成分介紹..........................................................................................3
1-2-1 阿斯匹靈 ﹙Aspirin﹚..........................................................................3
1-2-2 羥丙基甲基纖維素琥珀酸醋酸鹽﹙HPMCAS﹚................................5
1-2-3 二氯甲烷 ﹙Dichloromethane﹚...........................................................8
1-3 高效能液相層析儀介紹 ﹙HPLC﹚.........................................................9
1-3-1 高效能液相層析儀原理..................................................................10
1-3-2 高效能液相層析儀基本構造..........................................................12
第二章 實驗部分...........................................................................................13
2-1 實驗藥品................................................................................................13
2-2 實驗儀器................................................................................................14
2-3 腸溶性披覆膠體....................................................................................16
2-3-1 HPMCAS型腸衣膠囊腸溶性披覆膠體的配製..........................16
2-4 二氯甲烷添加量....................................................................................19
2-5 膠囊的厚度及膠體重量........................................................................20
2-5-1 厚度試驗..........................................................................................20
2-5-2 重量差異試驗..................................................................................21
2-6 崩散試驗................................................................................................21
2-6-1 崩散溶液配製..................................................................................23
2-7 膜衣安定性試驗....................................................................................23
2-8 阿斯匹靈腸溶膠囊................................................................................23
2-9 阿斯匹靈腸溶膠囊安定性試驗............................................................24
2-9-1 溶離試驗..........................................................................................25
2-9-2 崩散試驗..........................................................................................26
2-9-3 含量分析..........................................................................................26
2-10 HPLC分析方法與條件之確立............................................................27
2-10-1 Aspirin標準品配製.........................................................................30
2-10-2 水楊酸標準品配製........................................................................30
2-10-3 稀釋液配製....................................................................................30
2-10-4 樣品之配製....................................................................................31
2-11 分析方法確效......................................................................................31
2-11-1 專一性試驗.....................................................................................31
2-11-2 儀器精密度試驗.............................................................................32
2-11-2-1 Intra-day試驗...........................................................................32
2-11-2-2 Inter-day試驗...........................................................................32
2-11-3 儀器偵測極限與定量極限﹙LOD、LOQ﹚......................................32
第三章 結果與討論.......................................................................................34
3-1腸衣膠囊配方探討.................................................................................34
3-1-1 助溶劑含量探討..............................................................................34
3-1-2 腸衣重量與厚度探討......................................................................36
3-1-3 膠囊崩散試驗的探討......................................................................39
3-1-4 二氯甲烷理論含量..........................................................................41
3-1-5 膜衣安定性試驗..............................................................................41
3-2阿斯匹靈腸溶膠囊.................................................................................42
3-2-1 市售阿斯匹靈定量分析..................................................................42
3-2-2 市售阿斯匹靈崩散試驗..................................................................43
3-2-3 市售阿斯匹靈溶離試驗..................................................................46
3-2-4 自製阿斯匹靈腸溶膠囊安定性探討..............................................46
3-2-4-1 常溫試驗...................................................................................46
3-2-4-2 45℃加速型試驗........................................................................48
3-4-2-3 含量分析...................................................................................48
3-4-2-4 膠囊外觀變化.........................................................................50
3-3 分析方法確效.......................................................................................50
3-3-1 專一性試驗......................................................................................50
3-3-2 儀器精密度探討..............................................................................55
第四章 結論...................................................................................................60
附錄一.............................................................................................................61
﹙1﹚二氯甲烷對人體危害.......................................................................61
﹙2﹚溶離試驗數據計算方法...................................................................63
參考文獻.........................................................................................................65

1. Jay Walker、James Robinson、Jamie Stewart、Samuel Jacob，“ Does enteric-coated aspirin result in a lower incidence of gastrointestinal complications compared to normal aspirin? ”Interactive CardioVascular and Thoracic Surgery 2007,doi:10.1510/icvts.2007.155788
2. Els Mehuys、Jean-Paul Remon、Chris Vervaet，“Production of enteric capsules by means of hot-melt extrusion” European Journal of Pharmaceutical Sciences 24 (2005) 207–212
3. Ewart T. Cole、Robert A. Scott、Alyson L. Connor、Ian R. Wilding、
Hans-U. Petereit、Carsten Schminke、Thomas Beckert、Dominique Cade，“Enteric coated HPMC capsules designed to achieve intestinal targeting” International Journal of Pharmaceutics 231 (2002) 83–95
4. 原著：Wingard、Brody、Larner、Schwartz；合譯：楊聖信、許桂森、林君穎、張國志；校閱：楊春茂，“人體藥理學上冊” p.407-411，藝軒出版社﹙1998﹚。
5. 陳世凱，“腸衣被覆硬膠囊配方及品管方法的開發”朝陽科技大學應用化學系碩士論文﹙2005﹚。
6. 原著：Robert Carola、John P. Harley、Charles R. Noback；編譯：李玉菁、何杏梤、黃玉琪、陳秋媛、李意、阮大盛、徐玉華，“人體解剖學”p.537-545，麥格羅希爾出版﹙2000﹚。
7. 洪肇宏，“天麻錠劑之配方研究”中國醫藥大學藥物化學系碩士論文﹙2004﹚。
8. Eiji Fukui、Nobuteru Miyamura、Katsuji Uemura、Masao Kobayashi，“Preparation of enteric coated timed-release press-coated tablets and evaluation of their function by in vitro and in vivo tests for colon targeting”International Journal of Pharmaceutics 204 (2000) 7–15
9. 編輯出版：The United States Pharmacopeial Convention，“U.S. Pharmacopeia / National Formulary”﹙1994﹚。
10. 行政院衛生署中華藥典編修委員會編纂，“中華藥典第四版”，衛生署出版﹙1995﹚。