以離子電透入法與電破法促進非固醇類抗發炎藥物於體外與體內 之經皮吸收的研究

The In Vitro and In Vivo Transdermal Delivery of NSAIDs Enhanced by Iontophoresis and Electroporation

王仁俊(Ren-Jiunn Wang)

指導教授 ： 蔡義弘

共同指導教授 ： 吳寶珠(Pao-Chu Wu)

高雄醫學大學/藥學院/藥學研究所/博士(2007年)

https://doi.org/10.6832/KMU.2007.00098

摘要

本研究之目的在於探討離子電透入法、電破法與兩促進法之合併法對藥物經皮穿透之影響。NSAIDs（non-steroid anti-inflammatory drugs）中的diclofenac 鹽類、indomethacin、ketoprofen、piroxicam 、ketorolac 與 meloxicam之鹽類（鈉鹽與鉀鹽）被選為模式藥物。其中indomethacin與meloxicam之鹽類則進一步研究之，以纖維半透膜、大白鼠皮、豬皮與人類表皮（human epidermal membrane，HEM）進行體外實驗，並以Wistar大白鼠進行體內實驗。
初步研究發現物理性與化學性促進法之效果因條件而異，不過物理性促進法可大幅減少藥物輸送之延滯時間。藥物在離子電透入法、電破法與合併法促進下之流通量（flux）與藥物分子量呈現反比之關係，而合併法必須在電破法有足夠的電壓與離子電透入法在可接受的電流密度下才能產生協同效應（synergistic effect）。
離子電透入法與合併法可顯著促進indomethacin於體外與體內之經皮穿透，不過電破法的促進效果有限。合併法之促進更產生了協同效應。
離子電透入法與合併法亦可顯著促進meloxicam之鈉鹽與鉀鹽於體外與體內之經皮穿透，不過單獨使用電破法亦可促進其在體內之經皮穿透。合併法在體外與體內實驗卻無協同效應產生。鉀鹽在離子電透入法與電破法促進下較鈉鹽更具經皮穿透之優勢。
合併法於促進藥物經皮穿透時引起大白鼠皮膚顯著的經皮水分散失（TEWL），然而此現象可於短期間恢復。不過，離子電透入法與電破法單獨使用時無此現象。
總之，離子電透入法與合併法可顯著促進藥物之經皮穿透，不過，電破法的促進效果與合併法之協同效應則因藥物而異。

關鍵字

非固醇類抗發炎藥物 ； 經皮吸收 ； 離子電透入法 ； 電破法

並列摘要

The aim of this present study was to investigate the influence of iontophoresis, electroporation and their combination on the transdermal permeation. Several NSAIDs including diclofenac, indomethacin, ketoprofen, ketorolac, piroxicam and two meloxicam salts were chosen as model drugs. Indomethacin and meloxicam were both chosen to carry out the in vitro and in vivo study. Cellulose membrane, Wistar rat skin, pig skin, and HEM (human epidermal membrane) were chosen as the barrier of in vitro study. Wistar rat was chosen as the animal model of in vivo study.
In comparison of chemical enhancers and physical enhancers on the release of ketoprofen, the enhancement effect depended on the condition. However, the physical enhancers could reduce the lag time of the release of ketoprofen.
The flux resulted from iontophoresis, electroporation and combination protocol was reversely dependent on the M.W. of model drug. It was also found that the synergistic effect of combination protocol presented in the condition of enough voltage of electroporation with maximally acceptable value of current density of iontophoresis in the preliminary study.
Iontophoresis and combination protocol could enhance the in vitro and in vivo transdermal permeation of indomethacin, but the enhancement of electroporation was limited. The combination protocol produced synergistic effect.
Iontophoresis and combination protocol could also enhance the in vitro and in vivo transdermal permeation of meloxicam salts. However, electroporation could also enhance the permeation in the in vivo study. Meloxicam potassium might benefit more from the electrical protocols than meloxicam sodium.
Rather than the individual protocols, the combination of electroporation/iontophoresis induced more TEWL (transepidermal water loss), and the phenomenon could return to normal.
It was concluded that iontophoresis and combination protocol could enhance the transdermal permeation of model drugs. The enhancement of electroporation and the synergistic effect of combination protocol depended on the drug.

並列關鍵字

NSAIDs ； transdermal ； iontophoresis ； electroporation

參考文獻

Banga A. K., Bose S., Ghosh T. K., Iontophoresis and electroporation: comparisons and contrast. Int. J. Pharm. 179: 1-19. 1999.

Barry B. W., Is transdermal drug delivery research still important today? Drug Discov. Today 6: 967-971. 2001A.

Barry B. W., Novel mechanisms and devices to enable successful transdermal drug delivery. Eur. J. Pharm. Sci. 14: 101-14. 2001B.

Brand R. M., Iversen P. L., Iontophoretic delivery of a telomeric digonucleotide. Pharm. Res. 13: 851-854. 1996.

Chang J. S., Wu P. C., Huang Y. B., Tsai Y. H., In vitro evaluation of meloxicam permeation using response surface methodology. J. Food Drug Anal. 14: 236-241. 2006.