跳到主要內容

臺灣博碩士論文加值系統

(44.201.99.222) 您好!臺灣時間:2022/12/04 01:10
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:張齡云
研究生(外文):Ling-Yun Chang
論文名稱:Adenosine analogue自發性微乳化給藥系統
論文名稱(外文):Self- microemulsifying drug delivery system for oral delivery of an adenosine analogue
指導教授:許明照許明照引用關係
指導教授(外文):Ming-Thau Sheu
口試委員:蔡義弘林山陽謝堅銘
口試委員(外文):Yi-Hung TsaiShan-Yang LinChien-Ming Hsieh
口試日期:2013-07-17
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學院生技製藥產業碩士專班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:78
中文關鍵詞:腺苷類似物亨丁頓氏舞蹈症自發性微乳化釋藥系統Caco-2細胞藥物動力學試驗
外文關鍵詞:adenosine analogueHuntington’s diseaseSMEDDSCaco-2 cellspharmacokinetics
相關次數:
  • 被引用被引用:0
  • 點閱點閱:77
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
目的:腺苷類似物來源中國藥材萃取出來,在動物模型已被證明能延緩亨丁頓氏舞蹈症的進展。然而,腺苷類似物之水溶解度差,且口服生體可用率低。為了提高腺苷類似物溶解度及口服生體可用率,進行SMEDDS(自發性微乳化釋藥系統)開發。

方法:為了獲得合適的自發性微乳化釋藥系統,進行脂質、表面活性劑和輔助表面活性劑組成的三相圖構建。 在28天內利用粒徑儀 (N5 submicron particle size analyzer) 測量SMEDDS在水性介質中形成的液滴大小。利用高效能液相層析法(HPLC)測量溶液中腺苷類似物的溶液濃度之方法開發。此外,利用超高效液相色譜-串聯質譜(UPLC-MS/MS)測定在大鼠腺苷類似物血漿中的濃度也被開發和驗證。SMEDDS利用Caco-2細胞進行體外模擬測試腺苷類似物於小腸穿透率。最後口服給予腺苷類似物於雄性Sprague - Dawley大鼠,進行藥物動力學試驗。

結果與結論:油相、界面活性劑、輔助介面活性劑所組成之自發性微乳化劑能顯著提高藥物的溶解度。在28天內在水介質中形成液滴的大小約200 nm左右。腺苷類似物自發性微乳化劑通過Caco-2細胞之穿透率較對照組溶液高。此外,自發性微乳化劑口服給予雄性Sprague - Dawley大鼠進行藥物動力學試驗,顯示出自發性微乳化劑對於水不溶性藥物腺苷類似物略提高其口服生體可用率。
Purpose: An adenosine analogue isolated from a Chinese medicinal herb has been shown to delay the progression of Huntington’s disease in an animal model. However, the solubility of this adenosine analogue is poor with very low oral bioavailability. In order to improve the oral bioavailability of the adenosine analogue, a solubility enhancement system SMEDDS (Self Microemulsifying Drug Delivery System) was developed. SMEDDS is a strategy for the delivery of hydrophobic drugs that are insoluble in water in order to improve the oral bioavailability.

Methods: In order to obtain a suitable SMEDDS, ternary phase diagrams composed of lipids, surfactants, and co-surfactants were constructed. SMEDDS in aqueous media formed droplet size from day 1 within 28 days by N5 submicron particle size analyzer. A simple and reproducible high performance liquid chromatography (HPLC) method for determining the concentration of the adenosine analogue in the solution was developed and validated. UPLC-MS/MS (Ultra Performance Liquid Chromatography-tandem mass spectrometry method for determination the concentration of the adenosine analogue in rat plasma was also developed and validated. The permeation of the adenosine analogue SMEDDS in vitro studies using Caco-2 cells was tested. Oral absorption of the adenosine analogue SMEDDS was evaluated the pharmacokinetics and bioavailability in male Sprague - Dawley rats.

Results and conclusions: The SMEDDS composed of oil phase, surfactant phase and co-surfactant phase was able to significantly increase the drug solubility. The SMEDDS in aqueous media formed droplet size around 200 nm from day 1 within 28 days. The permeability of the adenosine analogue SMEDDS compound through Caco-2 cells was more than the permeability of the adenosine analogue solution. In male Sprague-Dawley rats, this study illustrated the potential use of SMEDDS to improve bioavailability of the water - insoluble drug by oral route.
目錄 I
致謝 Ⅳ
附圖目錄 Ⅴ
附表目錄 Ⅷ
中文摘要 Ⅸ
Abstract ⅩI
壹、緒論 1
第一節、研究背景介紹 1
一、自發性微乳化給藥系統(SMEDDS) 6
二、疾病介紹 11
三、模式藥物adenosine analogue 14
第二節、研究目的 19
貳、實驗材料與方法 20
第一節、實驗材料與儀器設備 20
第二節、實驗方法 24
一、Adenosine analogue分析方法 24
二、分析方法確效 27
第三節、溶解度試驗 28
第四節、自發性微乳化給藥系統處方製備…………………….29
第五節、Adenosine analogue SMEDDS通過腸道的穿透率實驗………………………………………………………32
第六節、Adenosine analogue SMEDDS於大鼠體內之藥物動力學實驗……………………………………………………35
參、結果與討論 38
第一節、實驗方法之確效 38
一、Adenosine analogue高效液相層析(HPLC)之分析方法… ………………………………………………………….38
二、 Adenosine analogue UPLC-MS/MS 超高效液相與串聯質譜聯用血漿中之分析方法 40
三、Adenosine analogue在大白鼠血漿中的回收率……….44
四、Adenosine analogue溶液分析方法確效……………….46
五、Adenosine analogue血漿分析方法確效………………..51
第二節、溶解度試驗 56
第三節、自發性微乳化給藥系統三相圖建立 58
第四節、Adenosine analogue SMEDDS通過腸道的穿透率實驗 (Caco-2 cell permeability) 65
第五節、Adenosine analogue SMEDDS於大鼠體內之藥物動力學實驗 67
肆、結論 74
伍、參考文獻 75
1.Mandal, S. and Mandal. S.S., Microemulsion drug delivery system: A platform for improving dissolution rate of poorly water soluble drug. Int. J. Pharm. Sci. Nanotechnol., 2011,vol 3: 1214-1219.
2.van Hoogevest P, Liu X, Fahr A., Drug delivery strategies for poorly water-soluble drugs: the industrial perspective., Expert Opin Drug Deliv. 2011 Nov;8(11):1481-500.
3.Pouton, C.W., Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. Eur. J. Pharm. Sci., 2006, 29: 278-287.
4.Akhlaquer R., Arshad H., Sarfaraj H., Mohd. A.M., and Zeenat I., Role of excipients in successful development of self- emulsifying /microemulsifying drug delivery system (SEDDS/ SMEDDS), Drug Development and Industrial Pharmacy, 2012, 1–19.
5.Gershanik, T., Haltner E. and Benita S., Charge-dependent interaction of self-emulsifying oil formulations with Caco-2 cells monolayers: binding, effects on barrier function and cytotoxicity. Int. J. Pharm., 2000, 211: 29-36.
6.Chakraborty S, Shukla D, Mishra B, Singh S. , Lipid--an emerging platform for oral delivery of drugs with poor bioavailability, Eur J Pharm Biopharm. 2009 Sep;73(1):1-15.
7.Tan, A., Simovic S., Davey A.K., Rades T. and Prestidge C.A., Silica-lipid hybrid (SLH) microcapsules: A novel oral delivery system for poorly soluble drugs, J. Control. Release. 2009, 134: 32-70
8.Mullertz A, Ogbonna A, Ren S, Rades T., New perspectives on lipid and surfactant based drug delivery systems for oral delivery of poorly soluble drugs, J Pharm Pharmacol. 2010 Nov;62(11):1622- 36.
9.Gursoy, N.R. and S. Benita, Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophylic drugs. J. Biomed. Pharmacother. 2004, 58: 173-182.
10.亨丁頓氏舞蹈症關懷http://www.hdc.org.tw/about/about01.asp
11.行政院衛生署食品藥物管理局, 罕見疾病藥物資料庫, http://www.pharmaceutic.idv.tw/
12.Up To DateR 2013, Huntington disease : Management.
13.鍾瑩慧, 中藥學堂-天麻, 藥師週刊1730期
14.行政院衛生署中醫藥委員會官網 http://www.ccmp.gov.tw
15.Jung TY, Suh SI, Lee H, et al. Protective Effects of Several Components of Gastrodia elata on Lipid Peroxidation in Gerbil Brain Homogenates. Phytotherapy Research 2007; 21: 960-964
16.Huang NK, Chern YJ, Fang JM, et al. Neuroprotective principles from Gastrodia elata., Journal of Natural products 2007; 70: 571-574
17.Kim DSHL, Kim JY, Han YS, Alzheimer’ s disease drug discovery from herbs: neuroprotectivity from β-Amyloid (1-42) Insult. The Journal of Alternative and Complementary Medicine 2007; 13(3): 333-340.
18.Chen PJ, Hsieh CL, Su KP, et al. The Antidepressant Effect of Gastrodia elata Bl. the Forced-Swimming Test in Rats. The American Journal of Chinese Medicine 2008; 36(1): 95-106.
19.Ahn EK, Jeon HJ, Lim EJ, et al. Anti-inflammatory and anti-angiogenic activities of Gastrodia elata Blume. Journal of Ethnopharmacology 2007; 110(3): 476-482.
20.Lee JY, Jang YW, Kang HS, et al. Anti-inflammatory action of phenolic compounds from Gastrodia elata root. Archives of Pharmacal Research 2006; 29(10): 849-858.
21.Heo JC, Woo SU, Son M, et al. Anti-tumor activity of Gastrodia elata Blume is closely associated with a GTP-Ras-dependent pathway. Oncology Reports 2007; 18(4): 849-853.
22.沈佳錚, 中藥學堂-中藥天麻之現代研究進展, 藥師週刊1767、1768、1769、1770期
23.Huang NK, Lin JH. et.al. , A New Drug Design Targeting the Adenosinergic System for Huntington’s Disease, PLoS One. 2011;6(6):e20934
24.ISODA Lab, Bioassay http://isodalabtsukubaen.wordpress.com/ bioassay/
25.Schulze JD, Waddington WA, Eli PJ, Parsons GE, Coffin MD, Basit AW., Concentration-dependent effects of polyethylene glycol 400 on gastrointestinal transit and drug absorption., Pharm Res. 2003 Dec;20(12):1984-8.
26.Basit AW, Podczeck F, Newton JM, Waddington WA, Ell PJ, Lacey LF., Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine, Pharm Res. 2002 Sep;19(9):1368-74.
27.Miller JM, Beig A, Carr RA, Webster GK, Dahan A., The solubility-permeability interplay when using cosolvents for solubilization: revising the way we use solubility-enabling formulations., Mol Pharm. 2012 Mar 5;9(3):581-90. doi: 10.1021/ mp200460u. Epub 2012 Feb 22.
電子全文 電子全文(本篇電子全文限研究生所屬學校校內系統及IP範圍內開放)
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top