Abstract
Purpose. The purpose of this work was to study the effect of electroporation on iontophoretic transport of two β-blockers, timolol (lipophilic) and atenolol (hydrophilic), and to have a better understanding of the mechanism of combination.
Methods. The transdermal delivery of these β-blockers through human stratum corneum was studied in three-compartment diffusion cells. The transport of mannitol was evaluated to assess the electroosmotic flow.
Results. The iontophoretic transport of timolol was decreased by electroporation because the high accumulation of the lipophilic cation timolol in the stratum corneum resulted in a decrease of electroosmosis. In contrast, electroosmosis was not affected by atenolol, and the iontophoretic transport of atenolol was increased by electroporation.
Conclusions. Using two different β-blockers, we showed that lipophilicity and positive charges affect the electrotransport of drugs. Understanding the effect of the physicochemical properties of the drug, as well as the electrical parameters, is thus essential for the optimization of transdermal drug delivery by a combination of electroporation and iontophoresis.
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REFERENCES
M. R. Prausnitz, V. G. Bose, R. Langer, and J. C. Weaver. Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc. Natl. Acad. Sci. USA 90:10504-10508 (1993).
R. Vanbever, N. Lecouturier, and V. Préat. Transdermal delivery of metoprolol by electroporation. Pharm. Res. 11:1657-1662 (1994).
R. H. Guy, Y. N. Kalia, M. B. Delgado-Charro, V. Merino, A. López, and D. Marro. Iontophoresis: electrorepulsion and electroosmosis. J. Control. Rel 64:129-132 (2000).
S. Mitragotri. Synergistic effect of enhancers for transdermal drug delivery. Pharm. Res. 17:1354-1359 (2000).
D. Bommannan, J. Tamada, L. Leung, and R. Potts. Effects of electroporation on transdermal iontophoretic delivery of leutinizing hormone releasing hormone. Pharm. Res. 11:1809-1814 (1994).
S. Chang, G. Hofmann, L. Zhang, L. Deftos, and A. Banga. The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. J. Control. Rel 66:127-133 (2000).
S. Bose, W. R. Ravis, Y. J. Lin, L. Zhang, G. A. Hofmann, and A. K. Banga. Electrically-assisted transdermal delivery of buprenorphine. J. Control. Rel 73:197-203 (2001).
A. V. Badkar and A. K. Banga. Electrically enhanced transdermal delivery of a macromolecule. J. Pharm. Pharmacol. 54:907-912 (2002).
H. Y. Zhao, J. M. Zheng, Y. Pan, and J. D. Song. Effect of electroporation and iontophoresis on skin permeation of Defibrase, a purified thrombin-like enzyme from the venom of Agkistrodon halys ussuriensis Emelianov. Pharmazie 57:482-484 (2002).
R. Conjeevaram, A. K. Banga, and L. Zhang. Electrically modulated transdermal delivery of fentanyl. Pharm. Res. 19:440-444 (2002).
J. Y. Fang, T. L. Hwang, Y. B. Huang, and Y. H. Tsai. Transdermal iontophoresis of sodium nonivamide acetate. V. Combined effect of physical enhancement methods. Int. J. Pharm. 235:95-105 (2002).
P. Modamio, C. F. Lastra, and E. L. Mariño. A comparative in vitro study of percutaneous penetration of β-blockers in human skin. Int. J. Pharm. 194:249-259 (2000).
J. Hirvonen, L. Murtomaki, and K. Kontturi. Experimental verification of the mechanistic model for transdermal transport including iontophoresis. J. Control. Release 56:169-174 (1998).
N. Kanikkannan, J. Singh, and P. Ramarao. Transdermal iontophoretic transport of timolol maleate in albino rabbits. Int. J. Pharm. 197:69-76 (2000).
N. Kanikkannan, J. Singh, and P. Ramarao. In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species. J. Control. Release 71:99-105 (2001).
D. G. Fatouros and J. A. Bouwstra. Iontophoretic enhancement of timolol maleate across human skin in vitro: effect of current density. In Proceedings in Perspectives in Percutaneous Penetration, Antibes Juan-les-Pins, 2002, pp. 68.
J. Jacobsen. Buccal iontophoretic delivery of atenolol.HCl employing a new in vitro three-chamber permeation cell. J. Control. Release 70:83-95 (2001).
A.-R. Denet and V. Préat. Transdermal delivery of timolol by electroporation through human skin. J. Control. Rel 88:253-262 (2003).
A. Kim, P. G. Green, G. Rao, and R. H. Guy. Convective solvent flow across the skin during iontophoresis. Pharm. Res. 10:1315-1320 (1993).
R. Vanbever, M. A. Leroy, and V. Préat. Transdermal permeation of neutral molecules by skin electroporation. J. Control. Rel 54:243-250 (1998).
M. B. Delgado-Charro and R. H. Guy. Characterization of convective solvent flow during iontophoresis. Pharm. Res. 11:929-935 (1994).
J. Hirvonen and R. H. Guy. Iontophoretic delivery across the skin: electroosmosis and its modulation by drug substances. Pharm. Res. 14:1258-1263 (1997).
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Denet, AR., Ucakar, B. & Préat, V. Transdermal Delivery of Timolol and Atenolol Using Electroporation and Iontophoresis in Combination: A Mechanistic Approach. Pharm Res 20, 1946–1951 (2003). https://doi.org/10.1023/B:PHAM.0000008041.86042.c0
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DOI: https://doi.org/10.1023/B:PHAM.0000008041.86042.c0