跳到主要內容

臺灣博碩士論文加值系統

(3.235.185.78) 您好!臺灣時間:2021/07/30 00:27
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:吳信賢
研究生(外文):Shin-Shian Wu
論文名稱:利用數值模型定量尿素經皮吸收之滲透係數
論文名稱(外文):Quantification of Porcine Skin Diffusivity in Transdermal Diffusion with a Numerical Model
指導教授:張厚謙
學位類別:碩士
校院名稱:國立中興大學
系所名稱:化學工程學系所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:68
中文關鍵詞:尿素滲透係數數值模型
外文關鍵詞:TransdermalPermeabilityUreaIn vitro
相關次數:
  • 被引用被引用:4
  • 點閱點閱:277
  • 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
藥物經皮輸送系統為新的藥物傳遞應用方法,目前藥物經皮輸送系統發展中,皮膚表皮的角質層被視為藥物經皮滲透最大的阻礙,為了降低藥物分子傳遞的阻礙與提高經皮吸收的效率,針對角質層的結構與特性加以研究,發展促進藥物滲透的方法,其中包含物理性與化學性等多類型的方法。
本篇研究以尿素溶液為藥物分子,在體外模式進行藥物滲透豬皮的全皮組織實驗,而尿素屬於化學性促滲劑之ㄧ,促滲劑主要作用於角質層,藉由改變角質細胞及細胞間脂質的組成與結構,使藥物分子更容易穿透角質層深入皮下。尿素溶液加入尿素分解酶反應後,可以利用簡單快速的電導度法進行定量分析,測得溶液電導度後經由標準曲線求得尿素溶液濃度。實驗裝置使用垂直式Franz Diffusion Cell(FDC)與水平式Side by Side Diffusion Cell(SDC)兩種滲透儀器,比較體外滲透實驗下完整的全皮樣品,尿素經皮滲透的結果。
實驗結果以尿素累積滲透量對實驗時間作圖,觀察尿素累積滲透的情形,再加入數值模型量化尿素滲透全皮組織的表觀滲透係數,結果FDC與SDC的滲透係數分別為6.1×10-6cm/s與6.9×10-6cm/s,與相關研究文獻進行比對與討論,除了不同藥物分子的莫爾體積會影響滲透係數,仍有許多因素會影響藥物分子對皮膚的滲透係數,都是未來必須進行研究與確認尿素經皮滲透的模式與皮膚的滲透係數。
Transdermal Diffusion 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.

Commonly known as chemical enhancer in TDDS, urea alters the structure and composition of corneocyte and intracellular lipids, and thus makes it easier for molecules to penetrate through stratum corneum. In this research, however, urea itself is employed as a tracer to diffuse through whole porcine skin in vitro. The diffusion process is recorded as the conductivity variation in time course. Concentration of urea is easily converted from its conductivity with aid of calibration curves predetermined. Experimental results show the accumulation of tracer quantity diffused through the skin sample as time proceeds. In parallel, a simple diffusion model is developed, attempting to describe this mass transport process in mathematical point of view. Output of the comparison between model data and experimental results generates the apparent diffusivity of the whole skin, which quantify the molecular mobility through the skin. Results are 6.1×10-6cm/s and 6.9×10-6cm/s for diffusions in vertical and horizontal cells respectively. The former is validated against literature data(2×10-7cm/s) and discussed from molecular viewpoint theoretically.

This study builds up a quantitative base for the upcoming researches aiming at improvement of TDDS.
摘要 i
Abstract ii
目錄 iii
圖目錄 v
表目錄 vii
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 3
第三節 皮膚構造 6
一、 表皮層 7
二、 真皮層 7
三、 皮下組織 7
第四節 經皮滲透途徑 8
一、 穿透細胞路徑(Transcellular Route) 9
二、 細胞間隙路徑(Intercellular Route) 9
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 11
第六節 促進經皮吸收方法 12
一、 物理性方法 13
二、 化學性方法 14
第七節 定量與定性分析 15
第三章 實驗材料與方法 18
第一節 實驗方法 18
第二節 皮膚處理 21
第三節 體外經皮滲透實驗步驟 21
一、 垂直式FDC 21
二、 水平式SDC 21
三、 FDC取樣 22
四、 SDC取樣 22
五、 電導度測定 23
第四節 尿素定量分析 23
一、 電導度(Electrical Conductivity,EC) 23
二、 標準曲線 24
第五節 數值模型分析擬合流程 24
第六節 實驗藥品 27
第七節 實驗儀器 28
第四章 實驗結果與討論 29
第一節 標準曲線 29
第二節 尿素累積滲透量 30
一、FDC實驗數據 30
二、SDC實驗數據 34
第三節 數值模型模擬結果 39
第四節 量化FDC滲透係數 41
第五節 量化SDC滲透係數 48
第六節 滲透係數與時間關係 54
第七節 研究結果與文獻比較 56
一、滲透係數 56
二、電導度法精確度 60
第五章 結論與未來展望 62
第六章 參考文獻 63
附錄 69
1. Abrams, K., Harvell, J.D., Shriner, D., Wertz, P., Maibach, H., Maibach, H.I. and Rehfeld, S.J., “Effect of Organic Solvents on In Vitro Human Skin Water Barrier Function,” Journal of Investigative Dermatology, Vol.101, pp.609-613 (1993).
2. Barry, B.W., “Mode action of penetration enhancers in human skin,” Journal of Controlled Release, Vol.6, pp.85-97 (1987).
3. Bashir, S.J., Chew, A.L., Anigbogu, A., Dreher, F. and Maibach, H.I., “Physical and physiological effects of stratum corneum tape stripping,” Skin Research and Technology, Vol.7, pp.40-48 (2001).
4. Benson, H.A.E., “Transdermal Drug Delivery Penetration Enhancement Techniques,” Current Drug Delivery, Vol.2, pp.22-33 (2005).
5. 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).
6. Chin, W.T. and Kroontje, W., “Conductivity method for determination of urea,” Analytical chemistry, Vol.33, No.12, pp.1757-1760 (1961).
7. 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).
8. Cooper, E.R., “Increased skin permeability for lipophilic molecules.” Journal of pharmaceutical sciences, Vol.73, pp.1153-1156 (1984).
9. Cullander, C., “What are the pathways of iontophoretic current flow through mammalian skin?” Advanced Drug Delivery Reviews, Vol.9, pp.119-135 (1992).
10. 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).
11. EI-Kattan, A.F., Asbill, C.S., Kim, N., and Michniak, B.B., “The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities,” International Journal of Pharmaceutics, Vol.215, pp. 229-240 (2001).
12. 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).
13. 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).
14. Franz, T.J., “Percutaneous Absorption on the Relevance of in Vitro Data,” The Journal of Investigative Dermatology, Vol.64, pp.190-195 (1975).
15. Franz, T.J. and Lehman, P.A., The skin as a barrier: structure and function, CRC Press LLC, pp.15-31 (2000).
16. 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).
17. Golden, G.M., McKie, J.E., and Potts, R.O., “Role of stratum corneum Lipid fluidity in transdermal drug flux,” Journal of Pharmaceutical Sciences, Vol.76, pp.25-28 (1987).
18. 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).
19. Grubauer, G., Elias, P.M. and Feingold, K.R., “Transepidermal water loss: the signal for recovery of barrier structure and function,” Journal of Lipid Research, Vol.30, pp.323-333 (1989).
20. Grubauer, G., Feingold, K.R., Harris, R.M. and Elias, P.M., “ Lipid content and lipid type as determinants of the epidermal permeability barrier,” Journal of Lipid Research, Vol.30, pp.89-96 (1989).
21. 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).
22. Hadgraft, J., “Passive enhancement strategies in topical and transdermal drug delivery,” International Journal of Pharmaceutics, Vol.184, pp.1-6 (1999).
23. Hadgraft, J., and Valenta, C., “pH, pKa and dermal delivery”, International Journal of Pharmaceutics, Vol.200, pp.243-247 (2000).
24. Harrison, J.E., Watkinson, A.C., Green, D.M., Hadgraft, J. and Brain, K., “The relative effect of Azone and transcutol on permeant diffusivity and solubility in human stratum corneum,” Pharmaceutical Research, Vol.13, pp.542-546 (1996).
25. Ilic, L., Gowrishankar, T.R., Vaughan, T.E., Herndon, T.O. and Weaver, J.C., “Spatially constrained skin electroporation with sodium thiosulfate and urea creates transdermal microconduits,” Journal of Controlled Release, Vol.61, pp.185-202(1999).
26. Illel, B., Schaefer, H., Wepierre, J., and Doucet, O., “Follicles play an important role in percutaneous absorption,” Journal of Pharmaceutical Sciences, Vol.80, pp.424-427 (1991).
27. 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).
28. 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).
29. 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).
30. Machet, L. and Boucaud, A., “Phonophoresis: efficiency, mechanisms and skin tolerance,” International Journal of Pharmaceutics, Vol.243, pp.1-15 (2002).
31. 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).
32. McAllister, D.V., Wang, P.M., Davis, S.P., Park, J.H., Canatella, P.J., Allen, M.G., and Prausnitz, M.R., “Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies,” Proceedings of the National Academy of sciences of the united states of America, Vol.100, pp. 13755-13760 (2003).
33. Mitragotri, S., “Synergistic effect of enhancers for transdermal drug delivery,” Pharmaceutical Research, Vol.17, No.11, pp.1354-1359 (2000).
34. 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).
35. Pinnagoda, J., Tupker, R.A., Agner, T.and Serup, J., “Guidelines for transepidermal water loss (TEWL) measurement,” Contact Dermatitis, Vol.22, pp.164-178 (1990).
36. 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).
37. Prausnitz, M.R., Mitragotri, S. and Langer, R., “Current status and future potential of transdermal drug delivery,” Nature reviews. Drug discovery, Vol.3, pp.115-124 (2004).
38. Pugh, W.J., Degim, I.T., and Hadgraft, J., “Epidermal permeability–penetrant structure relationships: 4,QSAR of permeant diffusion across human stratum corneum in terms of molecular weight, H-bonding and electronic charge,” International Journal of Pharmaceutics, Vol.197. pp.203-211 (2000).
39. Roberts, M.S. and Walters, K.A., Dermal Absorption and Toxicity Assessment, Inform Health Care (1998).
40. 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).
41. 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).
42. 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).
43. 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).
44. Shah, V.P., Midha, K.K., Dighe1, S., McGilveray, I.J., Skelly1, J.P., Yacobi, A., Layloff, T., Viswanathan, C.T., Cook, C.E., McDowall, R.D., Pittman, K.A. and Spector, S., “Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies,” Pharmaceutical Research, Vol.9, pp.588-592(1992).
45. Shah, V.P., Midha, K.K., Findlay, J.W.A., Hill, H.M., Hulse, J.D., McGilveray, I.J., Mckay, G., Miller, K.J., Patnaik, R.N., Powell, M.L., Tonelli, A., Viswanathan, C.T. and Yacobi, A., “Bioanalytical Method Validation-A Revisit with a Decade of Progress,” Pharmaceutical Research, Vol.17, pp.1151-1157(2000).
46. 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).
47. Suhonen, T.M., Bouwstra, J.A. and Urtti, A., “Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations.” Journal of Controlled Release, Vol.59, pp.149-161 (1999).
48. 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).
49. Van der Molen, R.G., Spies, F., van ''t Noordende, J.M., Boelsma, E., Mommaas, A.M. and Koerten, H.K., “Tape stripping of human stratum corneum yields cell layers that originate from various depths because of furrows in the skin,” Archives of Dermatological Research, Vol.289, pp.514-518 (1997).
50. Vavrova, K., Lorencova, K., Klimentova, J., Novotny, J., and Hrabalek, 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).
51. Walker, R.B. and Smith, E.W., “ The role of percutaneous penetration enhancers,” Advanced Drug Delivery Reviews, Vol.18, pp.295-301 (1996).
52. 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).
53. Wertz, P.W., “Lipids and barrier function of the skin,” Acta Dermato-Venereologica, Vol.80, pp.7-11 (2000).
54. Wilke, C.R. and Chang, P., “Correlation of diffusion coefficients in dilute solutions,” AIChE Journal, Vol.1, pp.264-270(1955).
55. Williams, A.C. and Barry, B.W., “Penetration enhancers,” Advanced Drug Delivery Reviews, Vol.56, pp.603-618 (2004).
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊