(3.92.96.236) 您好!臺灣時間:2021/05/07 00:54
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:王怡芳
研究生(外文):Yi-Fang Wang
論文名稱:藥物分子結構在經皮吸收過程中所扮演的角色:以水楊酸和阿斯匹靈為例
論文名稱(外文):The Role of Drug Molecular Structure on Transdermal Delivery Processes Exemplified by Salicylic Acid and Acetylsalicylic Acid
指導教授:張厚謙
指導教授(外文):Hou-Chien Chang
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生醫工程研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:76
中文關鍵詞:滲透係數數值模型分子結構活性
外文關鍵詞:effective permeabilitymathematical modelstructure-activity
相關次數:
  • 被引用被引用:4
  • 點閱點閱:465
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
藥物經皮輸送系統(TDDS),是一種藥物分子藉由局部投予的方式,控制藥物持續穿透皮膚,甚至釋放到全身血液循環,達到治療效果。TDDS最大的阻力是皮膚角質層,因此針對角質層其結構及特性,可利用物理性、化學性促進方法來提高經皮吸收效率。本研究利用垂直式Franz Diffusion Cell進行in vitro滲透實驗,使用尿素、水楊酸與阿斯匹靈藥物分子滲透豬皮組織,以高效能液相層析儀為定量工具,之將各藥物分子之累積滲透量對時間作圖,並配合數值模型量化皮膚之滲透係數。
關於尿素分子定量法,電導度法定量出的滲透係數與高效能液相層析儀定量法在同一數量級,驗證了電導度法之準確性。水楊酸與阿斯匹靈分子結構相似,但實驗結果顯示兩者滲透係數有所差異,推論原因可能為藥物分子結構活性(親脂性、分子量、分子莫爾體積大小)與滲透係數有所關聯性,並經由文獻證實其推論,未來期望可利用數值模型定量出皮膚滲透係數,控制藥物釋放行為。
Transdermal Drug Delivery System (TDDS) finds a variety of applications in drug delivery nowadays and is viewed a potential method in controlled release of drug. Currently, it is widely accepted that stratum corneum (SC) composes the major diffusional resistance in transdermal diffusion process. Therefore it demands elucidation on structure and characteristics of SC in order to improve the efficacy of drug delivery with physical and chemical protocols. The drug molecules including urea, salicylic acid and aspirin are allowed to permeate through skin sample mounted on Franz diffusion cells (FDC). In the in vitro experiment the real time concentration of the sample solution are recorded and quantified by High Performance Liquid Chromatography (HPLC). In parallel, a simple diffusion model is developed, attempting to describe this mass transport process with diffusion theories mathematically. Output of the comparison between model data and experimental results generates the permeability of the skin. Permeabilities determined with the mathematical model and HPLC in this work are checked against previous work, in which Electrical Conductivity was employed to quantify the concentration of sample solution. Comparison between them confirms the accuracy of both experimental methods (HPLC and EC). Physicochemical factors including lipophilicity, molecular weight, molar volume are elucidated for permeating probes, aiming at interpreting the potential mechanisms underlying the transdermal drug delivering process.
摘要 i
Abstract ii
目錄 ii
圖目錄 vi
表目錄 viii
第一章 前言 1
第二章 文獻回顧 2
第一節 藥物經皮輸送系統 2
第二節 藥物經皮滲透原理 4
第三節 皮膚構造 6
一、 表皮層 7
二、 真皮層 8
三、 皮下組織 8
第四節 經皮滲透途徑 10
一、 直接穿透角質細胞路徑(Transcellular Route) 10
二、 角質細胞間隙路徑(Intercellular Route) 11
三、 附屬器路徑(Appendage Route) 11
四、 其他滲透途徑 11
第五節 皮膚屏障功能 12
第六節 促進經皮吸收方法 12
一、 化學性方法 13
二、 物理性方法 14
第七節 定量與定性分析 17
第三章 實驗材料與方法 19
第一節 實驗方法 19
第二節 皮膚處理 21
第三節 體外經皮滲透實驗步驟 22
一、 垂直式FDC 22
二、 取樣 22
第四節 HPLC 分析方法 23
一、 分析方法之建立: 23
二、 操作步驟: 24
三、 分析條件: 25
第五節 數值模型分析擬合流程 28
第六節 實驗藥品 31
第七節 實驗儀器 32
第四章 研究結果 33
第一節 標準曲線 33
第二節 分析方法之確效 35
第三節 藥品累積滲透量 38
一、 尿素實驗數據 38
二、 水楊酸實驗數據 40
三、 阿斯匹靈實驗數據 42
第四節 數值模型模擬結果 44
第五節 量化藥品滲透係數 45
第六節 滲透係數與時間關係 55
第五章 討論 57
第六章 結論與未來展望 65
第七章 參考文獻 66
附錄 73
1.Akhavan, A. and Bershad, S., “Topical acne drugs: review of clinical properties, systemic exposure, and safety,” American Journal of Clinical Dermatology, Vol.7, pp.473-492 (2003).
2.Ammar, H.O., Ghorab, M., El-Nahhas, S.A. and Kamel, R. , “Design of a transdermal delivery system for aspirin as an antithrombotic drug,” International Journal of Pharmaceutics, Vol.327, pp.81–88 (2006).
3.Barratt, M. D., “Quantitative structure-activity relationships for skin permeability,” Toxicology in Vitro, Vol.9, pp.27-37 (2002).
4.Barry, B.W., “Mode action of penetration enhancers in human skin,” Journal of Controlled Release, Vol.6, pp.85-97 (1987).
5.Benson, H.A.E., “Transdermal Drug Delivery Penetration Enhancement Techniques,” Current Drug Delivery, Vol.2, pp.22-33 (2005).
6.Bronaugh, R.L., Stewart, R.F., and Congdon, E.R., “Methods for in vitro percutaneous absorption studies Ι Comparison with in vivo results,” Toxicology and Applied Pharmacology, Vol.62, pp.474-480 (1982).
7.Bronaugh, R.L., Stewart, R.F., and Congdon, E.R., “Methods for in vitro percutaneous absorption studies II. Animal models for human skin,” Toxicology and Applied Pharmacology, Vol.62, pp.481-488 (1982).
8.Chin, W.T. and Kroontje, W., “Conductivity method for determination of urea,” Analytical chemistry, Vol.33, No.12, pp.1757-1760 (1961).
9.Chin, W.T. and Kroontje, W., “Conductivity method for Estimation of urease activity,” Journal of Agricultural and Food Chemistry, Vol.10, pp.347-348 (1962).
10.Davies, M.G., Briffa, D.V. and Greaves M.W., “Systemic toxicity from topically applied salicylic acid,” British Medical Jounal, Vol.1, pp.661 (1979).
11.Degim, I.T., Pugh, W.J. and Hadgraft, J., “Skin permeability data: anomalous results,” International Journal of Pharmaceutics, Vol.170, pp.129–133 (1998).
12. Edwards, D.A., Prausnitz, M.R., Langer, R. and Weaver, J.C. , “Analysis of enhanced transdermal transport by skin electroporation,” Journal of Controlled Release, Vol.34, pp.211-221 (1995).
13.EI-Kattan, A., Asbill, C.S. and Haidar, S., “Transdermal testing: practical aspects and methods,” Pharmaceutical Science & Technology Today, Vol.3, pp.426-430 (2000).
14.Lien, E.J. and Tong, G.L., “Physicochemical properties and percutaneous absorption of drugs,” Jounal of the Society of Cosmetic Chemists, Vol.24, pp.371-384 (1973).
15.Fernandes, M., Simon, L. and Loney, N.W., “Mathematical modeling of transdermal drug-delivery systems: Analysis and applications,” Journal of Membrane Science, Vol.256, pp.184-192 (2005).
16.Ferry, L.L., Argentieri, G. and Lochner, D.H., “The comparative histology of porcine and guinea pig skin with respect to iontophoretic drug delivery,” Pharmaceutica Acta Helvetiae, Vol.70, pp.43-56 (1995).
17.Flarend, R., Bin, T., Elmore, D. and Hem, S.L., “A preliminary study of the dermal absorption of aluminium from antiperspirants using aluminium-26,” Food and Chemical Toxicology, Vol.39, pp.163–168 (2001).
18.Flynn, G.L.,“ Physicochemical determinants of skin absorption,” New York, pp.93–127 (1990).
19.Franz, T.J. and Lehman, P.A., The skin as a barrier: structure and function, CRC Press LLC, pp.15-31 (2000).
20.Godwin, D.A., Player, M.R., Sowell, J.W. and Michniak, B.B., “Synthesis and investigation of urea compounds as transdermal penetration enhancers,” International Journal of Pharmaceutics, Vol.167, pp.165-175 (1998).
21.Graaff, A.M., Li, G.L., van Aelst, A.C. and Bouwstra, J.A., “Combined chemical and electrical enhancement modulates stratum corneum structure,” Journal of Controlled Release, Vol.90, pp.49-58 (2003).
22.Guy, R.H. and Hadgraft, J., “Percutaneous penetration enhancement: physicochemical considerations and implications for prodrug design,” Drugs and the pharmaceutical sciences, Vol.53, pp.1-16 (1992).
23.Guy, R.H. and Hadgraft, J.,“Percutaneous penetration enhancement: physicochemical consideration and implications for prodrug design,” Clinical Research and Regulatory Affairs, Vol.18, pp.219-233 (2001).
24.Hadgraft, J., “Passive enhancement strategies in topical and transdermal drug delivery,” International Journal of Pharmaceutics, Vol.184, pp.1-6 (1999).
25.Hadgraft, J., and Valenta, C., “pH, pKa and dermal delivery”, International Journal of Pharmaceutics, Vol.200, pp.243-247 (2000).
26.Hadgraft, J.,“ Trans(dermal) delivery, present and future perspectives,” Drug delivery report (2003).
27.Hughes, M.F., Edwards, B.C., Mitchell, C.T. and Bhooshan, B., “In vitro dermal absorption of flame retardant chemicals,” Food and Chemical Toxicology, Vol.39, pp.1263–1270 (2001).
28.Kalia, Y.N. and Guy, R.H., “Interaction between penetration enhancers and iontophoresis: effect on human skin impedance in vivo,” Journal of Controlled Release, Vol.44, pp.33-42 (1997).
29.Kasichayanula, S., House, J.D., Wang, T. and Gu, X., “Simultaneous analysis of insect repellent DEET, sunscreen oxybenzone and five relevant metabolites by reversed-phase HPLC with UV detection: Application to an in vivo study in a piglet model,” Journal of Chromatography B, Vol.822, pp.271–277 (2005).
30.Lebwohl, M., “The role of salicylic acid in the treatment of psoriasis,” International Journal of Dermatology, Vol. 38, pp.16–24 (1999).
31.Lee, S., McAuliffe, D.J, Flotte, T.J., Kollias, N. and Doukas, A.G., “Photomechanical transdermal delivery: The effect of laser confinement,” Lasers in Surgery and Medicine, Vol.28, pp.344-347 (2001).
32.Loden, M., Andersson, A.C., Andersson, C., Frodin, T., Oman, H. and Lindberg, M., “Instrumental and dermatologist evaluation of the effect of glycerine and urea on dry skin in atopic dermatitis,” Skin Research and Technology, Vol.7, pp.209-213 (2001).
33.Lu, S.M., Chang, S.L., Ku, W.Y., Chang, H.C., Wang, J.Y. and Lee, D.J., “Urea release rate from a Scoop of coated pure urea beads: Unified extreme analysis,” Journal of the Chinese Institute of Chemical Engineers, Vol.38, pp.295-302 (2007).
34.Machet, L. and Boucaud, A., “Phonophoresis: efficiency, mechanisms and skin tolerance,” International Journal of Pharmaceutics, Vol.243, pp.1-15 (2002).
35.Manosroi, A., Kongkaneramit, L. and Manosroi, J., “Stability and transdermal absorption of topical amphotericin B liposome formulations,” International Journal of Pharmaceutics, Vol.270, pp.279-286 (2004).
36.McMahon, G.P., O’Connor, S.J., Fitzgerald, D.J. and Roy, S.l. , “Determination of aspirin and salicylic acid in transdermal perfusates,” Journal of Chromatography B, Vol.707, pp.322–327 (1998).
37.Mitragotri, S., “Synergistic effect of enhancers for transdermal drug delivery,” Pharmaceutical Research, Vol.17, No.11, pp.1354-1359 (2000).
38.Moss, G.P., Dearden, J.C., Patel, H. and Cronin, M.T.D., “Quantitative structure–permeability relationships (QSPRs) for percutaneous absorption,” Toxicology in Vitro, Vol.16, pp.299-317(2002).
39.Moghimi, H.R., Williams, A.C. and Barry, B.W., “A lamellar matrix model for stratum corneum intercellular lipids. I. Characterisation and comparison with stratum corneum intercellular structure,” International Journal of Pharmaceutics, Vol.131, pp.103-115(1996).
40.Naik, A., Kalia, Y.N. and Guy, R.H., “Transdermal drug delivery: overcoming the skin’s barrier function,” Pharmaceutical Science & Technology Today, Vol.3, pp.318-326 (2000).
41.Netzlaff, F., Kostka, K.H., Lehr, C.M. and Schaefer, U.F., “TEWL measurements as a routine method for evaluating the integrity of epidermis sheets in static Franz type diffusion cells in vitro. Limitations shown by transport data testing,” European Journal of Pharmaceutics and Biopharmaceutics, Vol.63, pp.44-50 (2006).
42.Nicolazzo, J.A., Morgan, T.M., Reed, B.L.and Finnin, B.C., “ Synergistic enhancement of testosterone transdermal delivery,” Journal of Controlled Release, Vol.103, pp. 577–585 (2005).
43.Ogura, M., Sato, S., Kuroki, M., Wakisaka, H., Kawauchi, S., Ishihara, M., Kikuchi, M., Yoshiko, M., Ashida, H. and Obara, M., “Transdermal delivery of photosensitizer by the laser-induced stress wave in combination with skin heating,” The Japan Society of Applied Physics Vol.41, pp.814-816 (2002).
44.Pirola, R., Bareggi, S.R. and Benedittis, G. D., “Determination of acetylsalicylic acid and salicylic acid in skin and plasma by high-performance liquid chromatography,” Journal of Chromatography B, Vol.705, pp.309–315 (1998).
45.Pirot, F., Kalia, Y.N., Stinchcomb, A.L., Keating, G., Bunge, A. and Guy, R.H., “Characterization of the permeability barrier of human skin in vivo,” Proceedings of the National Academy of Sciences USA, Vol.94, pp.1562-1567 (1997).
46.Reid, R.C., Prausnitz, J. M. and Poling, B. E., “The properties of gases and liquids,” New York: McGraw-Hill 4th ed. (1987).
47.Roberts, M.S., Anissimov, Y.G. and Gonsalvez, R.A., “Mathematical models in percutaneous absorption,” Journal of Toxicology: Cutaneous and Ocular Toxicology, Vol.20, pp.221-270 (2001).
48.Roxhed, N., Gasser, T.C. and Griss, P., “Penetration-enhanced ultrasharp microneedles and prediction on skin interaction for efficient transdermal drug delivery,” Jounal of microelectromechanical systems, Vol.16, pp.1429-1440 (2007).
49.Sartorelli, P., Andersen, H.R., Angerer, J., Corish, J., Drexler, H., Goen, T., Griffin, P., Hotchkiss, S.A.M., Larese, F., Montomoli, L., Perkins, J., Schmelz, M., van de Sandt, J. and Williams, F., “Percutaneous penetration studies for risk assessment,” Environmental Toxicology and Pharmacology, Vol.8, pp.133-152 (2000).
50.Schaller, M. and Korting, H.C., “Interaction of liposomes with human skin the role of the stratum corneum,” Advanced Drug Delivery Reviews, Vol.18, pp.303-309 (1996).
51.Shah, S.N.H., Rabbani, M. and Amir, M.F., “Effect of urea on topical absorption of diclofenac diethylamine through hairless rabbit skin,” Journal of Research (Science), Vol.17, pp.165-171 (2006).
52.Simon, G.A. and Maibach, H.I., “The Pig as an Experimental Animal Model of Percutaneous Permeation in Man Qualitative and Quantitative Observations. An Overview,” Skin Pharmacology and Applied Skin Physiology, Vol.13, pp.229-234 (2000).
53.Singh, S. and Singh, J., “Transdermal drug delivery by passive diffusion and iontophoresis: a review,” Medicinal Research Reviews, Vol.13, pp.569-621 (1993).
54.Sinico, C., Manconi, M., Peppi, M., Lai, F., Valenti, D. and Fadda, A.M., “Liposomes as carriers for dermal delivery of tretinoin: in vitro evaluation of drug permeation and vesicle–skin interaction,” Journal of Controlled Release, Vol.103, pp.123-136 (2005).
55.Stoeber, B. and Liepmann, D., “Arrays of hollow out-of-plane microneedles for drug delivery,” Jounal of Microelectromechanical Systems, Vol.14, pp.472-479 (2005).
56.Suzuki, T., “Development of an automatic estimation system for both the partition coefficient and aqueous solubility,” Journal of Computer-Aided Molecular Design, Vol.5, pp. 149-166 (1991).
57.Talreja, P.S., Kleene, N.K., Pickens, W.L., Wang, T.F. and Kasting, G.B., “Visualization of the Lipid Barrier and Measurement of Lipid Pathlength in Human Stratum Corneum,” AAPS PharmSci, Vol.3, E13 (2001).
58.Thong, H.Y., Zhai, H. and Maibach, H.I.,“Percutaneous penetration enhancers: an overview,” Skin Pharmacology and Physiology, Vol.20, pp.272-282 (2007).
59.Tsai, J.C., Chuang, S.A., Hsu, M.Y. and Sheu H.M., “Distribution of salicylic acid in human stratum corneum following topical application in vivo: a comparison of six different formulations,” International Journal of Pharmaceutics, Vol.188, pp.145–153 (1999).
60.Ueda, H., Ogihara, M., Sugibayashi, K. and Morimoto, Y., “Change in the electrochemical properties of skin and the lipid packing in stratum corneum by ultrasonic irradiation,” International Journal of Pharmaceutics, Vol.137, pp. 217-224 (1996).
61.Vávrová, K., Lorencová, K., Klimentová, J., Novotný, J., and Hrabálek, A.,“ HPLC method for determination of in vitro delivery through and into porcine skin of adefovir (PMEA),” Journal of Chromatography, Vol.853, pp.198-203 (2007).
62.Walker, B., and Smith, E.W., “The role of percutaneous penetration enhancers ,” Advanced Drug Delivery Reviews, Vol. 18, pp.295-301 (1996).
63.Walker, M., Hulme, T.A., Pippon, M.G., Walmsley, R.S., Gunnigle, S. and Lewin, M, “In vitro model(s) for the percutaneous delivery of active tissue repair agents,” Journal of Pharmaceutical Sciences, Vol. 86, pp.1379-1384 (1997).
64.Wertz, P.W., Abraham, W., Landmann, L. and Downing, D.T., “Preparation of Liposomes from Stratum Corneum Lipids,” Journal of Investigative Dermatology, Vol.87, pp.582-584 (1986).
65.Wilke, C.R. and Chang, P.,“Correlation of diffusion coefficients in dilute solutions,” AIChE Journal, Vol.1, pp.264-270 (1955).
66.Williams, A.C. and Barry, B.W., “Penetration enhancers,” Advanced Drug Delivery Reviews, Vol.56, pp.603-618 (2004).
67.吳信賢,中興大學化工碩士論文 (2008)。
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊
 
系統版面圖檔 系統版面圖檔