Abstract
Electroporation, i.e., the creation of transient “pores” in lipid membranes leading to increased permeability, could be used to promote transdermal drug delivery. We have evaluated metoprolol permeation through full thickness hairless rat skin in vitro following electroporation with an exponentially decaying pulse. Application of electric pulses increased metoprolol permeation as compared to diffusion through untreated skin. Raising the number of twin pulses (300 V, 3 ms; followed after 1 s by 100 V, 620 ms) from 1 to 20 increased drug transport. Single pulse (100 V, 620 ms) was as effective as twin pulse application (2200 V, 1100 V or 300 V, 3 ms; followed after 1 s by 100 V, 620 ms). In order to investigate the effect of pulse voltage on metoprolol permeation, 5 single pulses (each separated by 1 min) were applied at varying voltages from 24 to 450 V (pulse time 620 ms). A linear correlation between pulse voltage and cumulative metoprolol transported after 4 h suggested that voltage controls the quantity of drug delivered. Then, the effect of pulse time on metoprolol permeation was studied by varying pulse duration of 5 single 100 V pulses from 80 to 710 ms (each pulse also separated by 1 min). Cumulative metoprolol transported after 4 h increased linearly with the pulse time. Therefore, pulse time was also a control factor of the quantity of drug delivered but to a lesser extent than the voltage at least at 100 V. The mechanisms behind improved transdermal drug delivery by electroporation involved reversible increased skin permeability, electrophoretic movement of drug into the skin during pulse application, and drug release from the skin reservoir formed by electroporation. Thus, electroporation did occur as shown by the increased transdermal permeation, on indicator of structural skin changes and their reversibility. Electroporation has potential for enhancing transdermal drug delivery.
Similar content being viewed by others
REFERENCES
J. Hadgraft and R. Guy (Eds). Transdermal Drug Delivery. Developmental Issues and Research Initiatives, Marcel Dekker Inc, 1989
R. Guy (Ed) Iontophoresis Adv Drug Delivery Rev. 9:119–317 (1992)
D. Chang, B. Chassy, J. Saunders, A. Sowers (Eds). Guide to Electroporation and Electrofusion, Academic Press Inc. 1992.
J. Weaver, K. Powell and R. Langer. Transport of molecules across tissue using electroporation. PCT Patent WO 89/06555
K. T. Powell, A. W. Morgenthaler and J. Weaver. Tissue elec-troporation-Observation of reversible electrical breakdown in viable frog skin. Biophysical J. 56:1163–1171 (1989)
M. Prausnitz, V. Bose, R. Langer and J. Weaver. Transdermal drug delivery by electroporation. Proceed Intern. Symp. Control Rel. Bioact. Mater, 19:232–233 (1992).
D. Bommannan, L. Leung, J. Tamada, J. Sharifi, W. Abraham and R. Potts. Transdermal delivery of luteinizing hormone releasing hormone: comparison between electroporation and iontophoresis. Proceed. Intern. Control. Rel. Bioact. Mater. 20:97–98 (1993).
M. Prausnitz, V. Bose, C. Lee, J. Pang, R. Langer and J. Weaver, Effects of electroporation conditions on transdermal delivery. Proceed. Intern. Control. Rel. Bioact. Mater. 20:95–96 (1993).
M. Prausnitz, V. Bose, R. Langer and J. Weaver, Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc. Natl. Acad. Sci. USA 90:10504–10508 (1993).
J. Tamada, J. Sharifi, D. Bommannan, L. Leung, N. Azimi, W. Abraham and R. Potts. Effect of electroporation on the iontophoretic delivery of peptides in vitro. Pharm. Res. 10:S-257 (1993).
S. Thysman, V. Préat and M. Roland, Factors affecting iontophoretic mobility of metoprolol. J. Pharm. Sci. 81:670–675 (1992)
J. Godbillon and M. Duval. Determination of two metoprolol metabolites in human urine by HPLC. J. Chromatogr. 309:198–202 (1984)
V. A. Klenchin, S. I. Sukharev, S. M. Serov, L. V. Chernomordik and Y. A. Chizmadzhev. Electrically induced DNA uptake by cells is a fast process involving DNA electrophoresis. Biophys. J. 60:804–811 (1991)
V. Préat and S. Thysman. Transdermal iontophoretic delivery of sufentanil, Int. J. Pharm. 96:189–196 (1993)
S. Thysman, C. Tasset and V. Préat. Transdermal iontophoresis of fentanyl: delivery and mechanistic analysis. Int. J. Pharm. 101:105–113 (1994)
L. M. Mir, S. Orlowski, J. Jr. Belehradek and C. Paoletti. Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses. Eur. J. Cancer. 27:68–72 (1991)
A. V. Titomirov, S. Sukharev and E. Kistanova. In vivo electroporation and stable transformation of skin cells of newborn mice by plasmic DNA. Biochim. Biophys. Acta 1088:131–134 (1991)
M. Belehradek, C. Domenge, B. Luboinski, S. Orlowski, J. Belehradek and L. M. Mir. Electrochemotherapy, a new antitumor treatment: first clinical phase I–II trial. Cancer. 72-12: 3694–3700 (1993)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vanbever, R., Lecouturier, N. & Préat, V. Transdermal Delivery of Metoprolol by Electroporation. Pharm Res 11, 1657–1662 (1994). https://doi.org/10.1023/A:1018930425591
Issue Date:
DOI: https://doi.org/10.1023/A:1018930425591