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Transdermal Iontophoresis of Rotigotine Across Human Stratum Corneum in Vitro: Influence of pH and NaCl Concentration

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Abstract

Purpose. The aim of this study was to characterize the influence of pH and NaCl concentration on the transdermal iontophoretic transport of the dopamine receptor agonist rotigotine across human stratum corneum (HSC).

Methods. Rotigotine transport was studied in vitro in side by side diffusion cells according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis, and 5 h of passive diffusion. A current density of 0.5 mA cm−2 was used. The influence of donor phase pH (4, 5, and 6) and different concentrations of NaCl (0.07 and 0.14 M) on rotigotine iontophoretic flux were examined. The acceptor phase was phosphate-buffered saline (PBS) at pH 7.4 except in one series of experiments aimed to study the effects of rotigotine solubility on its iontophoretic transport. In this study, PBS at pH 6.2 was used. In separate studies, 14C-mannitol was used as a marker to determine the role of electro-osmosis during iontophoresis.

Results. The estimated iontophoretic steady-state flux (Fluxss) of rotigotine was influenced by the pH of the donor solution. At a drug donor concentration of 0.5 mg ml−1, the iontophoretic flux was 30.0 ± 4.2 nmol cm−2 h−1 at pH 6 vs. 22.7 ± 5.5 nmol cm−2 h−1 at pH 5. However, when the donor concentration was increased to 1.4 mg ml−1, no significant difference in iontophoretic rotigotine transport was observed between pH 5 and 6. Increase of NaCl concentration from 0.07 M to 0.14 M resulted in a decrease of the rotigotine Fluxss from 22.7 ± 5.5 nmol cm−2 h−1 to 14.1 ± 4.9 nmol cm−2 h−1. The contribution of electro-osmosis was estimated less than 17%. Probably due to the lipophilic character of the drug, impeding the partitioning of rotigotine from HSC to the acceptor compartment, steady-state transport was not achieved during 9 h of iontophoresis.

Conclusions. Both pH and NaCl concentration of the donor phase are crucial on the iontophoretic transport of rotigotine. Electro-repulsion is the main mechanism of the iontophoretic transport of rotigotine.

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references

  1. A. Lledo. Dopamine agonists: the treatment for Parkinson's disease in the XXI century? Parkinsonism Relat. Disord. 7:51–58 (2000).

    Google Scholar 

  2. J. Van der Weide, J. B. de Vries, P. G. Tepper, D. N. Krause, M. L. Dubocovich, and A. S. Horn. N-0437: a selective D-2 dopamine receptor agonist in in vitro and in vivo models. Eur. J. Pharmacol. 147:249–258 (1988).

    Google Scholar 

  3. V. P. Calabrese, K. A. Lloyd, P. Brancazio, E. Cefali, P. Martin, J. J. Wall, and D. Sica. N-0923, a novel soluble dopamine D2 agonist in the treatment of parkinsonism. Mov. Disord. 13:768–774 (1998).

    Google Scholar 

  4. T. K. Gerding, B. F. Drenth, H. J. Roosenstein, R. A. de Zeeuw, P. G. Tepper, and A. S. Horn. The metabolic fate of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin in rats after intravenous and oral administration. I. Disposition and metabolic profiling. Xenobiotica 20:515–524 (1990).

    Google Scholar 

  5. T. K. Gerding, B. F. Drenth, R. A. de Zeeuw, P. G. Tepper, and A. S. Horn. The metabolic fate of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in rats after intravenous and oral administration. II. Isolation and identification of metabolites. Xenobiotica 20:525–536 (1990).

    Google Scholar 

  6. P. J. Swart and R. A. de Zeeuw. Extensive gastrointestinal metabolic conversion limits the oral bioavailability of the dopamine D2 agonist N-0923 in freely moving rats. Pharmazie 47:613–615 (1992).

    Google Scholar 

  7. P. J. Swart, W. E. Oelen, A. P. Bruins, P. G. Tepper, and R. A. de Zeeuw. Determination of the dopamine D2 agonist N-0923 and its major metabolites in perfused rat livers by HPLC-UV-atmospheric pressure ionization mass spectrometry. J. Anal. Toxicol. 18:71–77 (1994).

    Google Scholar 

  8. D. R. Friend. Transdermal delivery of contraceptives. Crit. Rev. Ther. Drug Carrier Syst. 7:149–186 (1990).

    Google Scholar 

  9. J. T. Hutton, L. V. Metman, T. N. Chase, J. L. Juncos, W. C. Koller, R. Pahwa, P. A. LeWitt, A. Samii, J. K. Tsui, D. B. Calne, C. H. Waters, V. P. Calabrese, J. P. Bennett, R. Barrett, and J. L. Morris. Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson's disease with N-0923 TDS: a double-blind, placebo-controlled study. Mov. Disord. 16:459–463 (2001).

    Google Scholar 

  10. L. V. Metman, M. Gillespie, C. Farmer, F. Bibbiani, S. Konitsiotis, M. Morris, H. Shill, W. Bara-Jimenez, M. M. Mouradian, and T. N. Chase. Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease. Clin. Neuropharmacol. 24:163–169 (2001).

    Google Scholar 

  11. P. J. Swart, W. L. Weide, and R. A. de Zeeuw. In vitro penetration of the dopamine D2 agonist N-0923 with and without Azone. Int. J. Pharm. 87:67–72 (1992).

    Google Scholar 

  12. B. H. Sage. Iontophoresis. In E. W. Smith and H. I. Maibach (eds.), Percutaneous Penetration Enhancer, CRC Press Inc., Boca Raton, 1995, pp. 351–368.

    Google Scholar 

  13. A. Luzardo-Alvarez, M. B. Delgado-Charro, and J. Blanco-Mendez. Iontophoretic delivery of ropinirole hydrochloride: effect of current density and vehicle formulation. Pharm. Res. 18:1714–1720 (2001).

    Google Scholar 

  14. R. Van der Geest, M. Danhof, and H. E. Bodde. Iontophoretic delivery of apomorphine. I: In vitro optimization and validation. Pharm. Res. 14:1798–1803 (1997).

    Google Scholar 

  15. G. L. Li, M. Danhof, and J. A. Bouwstra. Effect of elastic liquid-state vesicle on apomorphine iontophoresis transport through human skin in vitro. Pharm. Res. 18:1627–1630 (2001).

    Google Scholar 

  16. G. L. Li, M. Danhof, and J. A. Bouwstra. Iontophoretic delivery of apomorphine in vitro: physicochemic considerations. Pharm. Res. 18:1509–1513 (2001).

    Google Scholar 

  17. G. L. Li, R. Van der Geest, L. Chanet, E. van Zanten, M. Danhof, and J. A. Bouwstra. In vitro iontophoresis of R-apomorphine across human stratum corneum. Structure-transport relationship of penetration enhancement. J. Control. Rel. 84:49–57 (2002).

    Google Scholar 

  18. G. L. Li, M. Danhof, P. M. Frederik, and J. A. Bouwstra. Pretreatment with a water-based surfactant formulation affects transdermal iontophoretic delivery of R-apomorphine in vitro. Pharm. Res. 20:653–659 (2003).

    Google Scholar 

  19. R. Van der Geest, T. Van Laar, J. M. Gubbens-Stibbe, H. E. Bodde, and M. Danhof. Iontophoretic delivery of apomorphine. II: an in vivo study in patients with Parkinson's disease. Pharm. Res. 14:1804–1810 (1997).

    Google Scholar 

  20. G. L. Li. Transdermal Iontophoretic Delivery of R-Apomorphine for the Treatment of Patients with Parkinson's Disease, Ph.D. Thesis, Leiden University, Leiden, The Netherlands, 2003.

    Google Scholar 

  21. R. Van der Geest, M. Danhof, and H. E. Bodde. Validation and testing of a new iontophoretic continuous flow through transport cell. J. Control. Rel. 51:85–91 (1998).

    Google Scholar 

  22. N. Kanikkannan, J. Singh, and P. Ramarao. In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species. J. Control. Rel. 71:99–105 (2001).

    Google Scholar 

  23. S. Y. Oh, S. Y. Jeong, T. G. Park, and J. H. Lee. Enhanced transdermal delivery of AZT (Zidovudine) using iontophoresis and penetration enhancer. J. Control. Rel. 51:161–168 (1998).

    Google Scholar 

  24. Anonymous. N-0923 Hydrochloride General Information and Properties, internal report, Schwarz Pharma, 2001.

  25. L. Wearley and Y. W. Chien. Enhancement of the in vitro skin permeability of azidothymidine (AZT) via iontophoresis and chemical enhancer. Pharm. Res. 7:34–40 (1990).

    Google Scholar 

  26. L. Wearley, L. Jue-Chen, and Y. W. Chien. Iontophoresis-facilitated transdermal delivery of verapamil I. In vitro evaluation and mechanistic studies. J. Control. Rel. 8:237–250 (1989).

    Google Scholar 

  27. D. Marro. R. H. Guy and, M. B. Delgado-Charro. Characterization of the iontophoretic permselectivity properties of human and pig skin. J. Controlled Release 70:213–217 (2001).

    Google Scholar 

  28. J. Hirvonen and R. H. Guy. Iontophoretic delivery across the skin: electro-osmosis and its modulation by drug substances. Pharm. Res. 14:1258–1263 (1997).

    Google Scholar 

  29. D. Marro, Y. N. Kalia, M. B. Delgado-Charro, and R. H. Guy. Contributions of electromigration and electro-osmosis to iontophoretic drug delivery. Pharm. Res. 18:1701–1708 (2001).

    Google Scholar 

  30. M. J. Pikal. The role of electroosmotic flow in transdermal iontophoresis. Adv. Drug Deliv. Rev. 46:281–305 (2001).

    Google Scholar 

  31. A. Jadoul, L. M. Dunbar, D. Ellis, and V. Preat. Modification induced on stratum corneum structure after in vitro iontophoresis: ATR-FTIR and X-ray scattering studies. J. Control. Rel. 42:165–173 (1996).

    Google Scholar 

  32. A. Jadoul, J. A. Bouwstra, and V. Preat. Effects of iontophoresis and electroporation on the stratum corneum. Review of the biophysical studies. Adv. Drug Deliv. Rev. 35:89–105 (1999).

    Google Scholar 

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Authors and Affiliations

  1. Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, 2300 RA, Leiden, The Netherlands

    Akhmad Kharis Nugroho, Gai Ling Li & Joke A. Bouwstra

  2. Faculty of Pharmacy, Gadjah Mada University, Sekip Utara Yog- yakarta, 55281, Indonesia

    Akhmad Kharis Nugroho

  3. Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, 2300 RA, Leiden, The Netherlands

    Meindert Danhof

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  1. Akhmad Kharis Nugroho
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  4. Joke A. Bouwstra
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Correspondence to Joke A. Bouwstra.

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Nugroho, A.K., Li, G.L., Danhof, M. et al. Transdermal Iontophoresis of Rotigotine Across Human Stratum Corneum in Vitro: Influence of pH and NaCl Concentration. Pharm Res 21, 844–850 (2004). https://doi.org/10.1023/B:PHAM.0000026438.57787.10

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