Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
권호 표지
DOI QR코드

DOI QR Code

Iontophoretic Delivery of Levodopa: Permeation Enhancement by Oleic Acid Microemulsion and Ethanol

Levodopa의 이온토포레시스 경피전달: 올레인산 아이크로에멀젼 및 에탄올의 투과증진

  • Published : 2008.12.20
Download PDF
⟨ Previous Next ⟩

Abstract

In order to develop optimal formulation and iontophoresis condition for the transdermal delivery of levodopa, we have evaluated the effect of two permeation enhancers, ethanol and oleic acid in microemulsion, on transdermal delivery of levodopa. In vitro flux studies were performed at $33^{\circ}C$, using side-by-side diffusion cell and full thickness hairless mouse skin. Current density applied was $0.4\;mA/cm^2$ and current was off after 6 hours application. Levodopa was analysed by HPLC at 280 nm. The o/w microemulsions of oleic acid in buffer solution (pH 2.5 & 4.5) were prepared using oleic acid, Tween 80 and ethanol. The existence of microemulsion regions were investigated in pseudo-ternary phase diagrams. Contrary to our expectation, cumulative amount of levodopa transported from microemulsion (pH 2.5) for 10 hours was similar to that from aqueous solution in all delivery methods (passive, anodal and cathodal). When pH of the micro-emulsion was pH 4.5, cumulative amount of levodopa transported for 10 hours increased about 40% (anodal) to 50% (cathodal), when compared to that from aqueous solution. Flux from pH 4.5 microemulsion showed higher value than that from pH 2.5 in all delivery methods. These results seem to indicate that electroosmosis plays more dominant role than electrorepulsion in the flux of levodopa at pH 2.5. The effect of ethanol on iontophoretic flux was studied using pH 2.5 phosphate buffer solution containing 3% or 5% (v/v) ethanol. Flux enhancement was observed in passive and anodal delivery as the concentration of the ethanol increased. Without ethanol, cathodal delivery showed higher flux than anodal delivery. Anodal delivery increased the cumulative amount of levodopa transported 1.6 fold by 5% ethanol after 10 hours. However, in cathodal delivery, no flux enhancement of levodopa was observed during current application and only marginal increase in cumulative amount transported after 10 hours was observed by 5% ethanol. These results seem to be related to the decrease in dielectric constant of the medium and the lipid extraction of the ethanol, which decrease the electroosmotic flow, and thus decrease the flux. Overall, the results provide important insights into the role of electroosmosis and electrorepulsion in the transport of levodopa through skin, and provide some useful informations for optimal formulation for levodopa.

Keywords

References

  1. Y.N. Kalia, A. Naik, J. Garrison and R.H. Guy, Iontophoretic drug delivery, Advanced Drug Delivery Reviews, 56, 619-658 (2004) https://doi.org/10.1016/j.addr.2003.10.026
  2. R.C. Scott, R.H. Guy and J. Hadgraft, Prediction of percutaneous penetration: Methods, Measurements and Modelling, IBC technical Services, London, UK, pp. 19-33 (1990)
  3. G.L. Flynn, R.L. Bronaugh and H.I. Mailbach, Percutaneous absorption, Marcel Dekker, New York, U.S.A., pp. 27-51 (1989)
  4. H.A.E. Benson, Transdermal drug delivery: penetration enhancement technique, Current drug delivery, 2(1), 23-33 (2005) https://doi.org/10.2174/1567201052772915
  5. S.A. Jung, H.S. Gwak, I.K. Chun and S.Y. Oh, Levodopa transport through skin using iontophoresis: the role of electroosmosis and electrorepulsion, J. Kor. Pharm. Sci., 38(1), 31-38 (2008)
  6. K. Sugibayashi, K. Nakayama, T. Seki, K. Hosoya and Y. Morimoto, Mechanism of skin penetration-enhancing effect by laurocapram, J. Pharm. Sci., 81, 58 (1992) https://doi.org/10.1002/jps.2600810112
  7. B. Ongpippattanakul, R.R. Burnette, R.O. Potts and M.L. Francoeur, Evidence that oleic acid exists in separate phase eithin stratum corneum lipids, Pharm. Res., 8(3), 350-354 (1991) https://doi.org/10.1023/A:1015845632280
  8. M.L. Francoeur, G.M. Golden and R.O. Potts, Oleic acid: Its effect on stratum corneum in relation to (trans) dermal drug delivery, Pharm. Res., 7, 621-627 (1990) https://doi.org/10.1023/A:1015822312426
  9. S.Y. Oh and R.H. Guy, The effect of oleic acid and propylene glycol on the electrical properties of skin, J. Kor. Pharm. Sci., 24(4), 281-287 (1994)
  10. D. Van der Merwe and J.E. Riviere, Comparative studies on the effects of water, ethanol and water/ethanol mixtures on chemical partitioning into porcine stratum corneum and silastic membrane, Toxicology in vitro, 19(1), 69-77 (2005) https://doi.org/10.1016/j.tiv.2004.06.002
  11. S.I. Yum, Permeation enhancement with ethanol : In drug permeation enhancement, D.S. Hsieh (Ed.), Marcel Dekker, New York, U.S.A., pp. 3-17 (1994)
  12. J.M. Sarciaux, L. Acar and P.A. Sado, Invited review ; using microemulsion formulations for oral drug delivery of therapeutic peptides, Int. J. Pharm., 120, 127-136 (1995) https://doi.org/10.1016/0378-5173(94)00386-J
  13. M. Jumaa and B.W. Mller, The stabilization of parenteral fat emulsion using non-ionic ABA copolymer surfactant, Int. J. Pharm., 174, 29-37 (1998) https://doi.org/10.1016/S0378-5173(98)00222-1
  14. P. Becher, Encyclopedia of emulsion technology, vol. 3, Marcel Dekker, New York, U.S.A., pp. 137 (1998)
  15. L.M. Prince, Theory and practice : in Microemulsions, L.M. Prince (Ed.), Academic Press, New York, U.S.A., pp. 1 (1997)
  16. I. Shoulson, G.A. Glaubiger and T.N. Chase, On-off response. Clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients, Neurology, 25(12), 1144-1148 (1975) https://doi.org/10.1212/WNL.25.12.1144
  17. J.G. Hardman, L.E. Limbird, P.D. Molinoff, R.W. Ruddon and A.G. Gilman, Goodman and Gilman's the pharmacological basis of therapeutics, 9th ed., McGraw-Hill, New York, U.S.A., pp. 506-513, 1562, 1754 (1996)
  18. C.W. Olanow and W.C. Koller, An algorithm (decision tree) for the management of Parkinson's disease: treatment guidelines, Neurology, 50(Suppl. 3), pp. S1-S57 (1998) https://doi.org/10.1212/WNL.50.1.1
  19. H.D. Kao, A. Traboulsi, S. Itoh and A. Hussain, Enhancement of the systemic and CNS specific delivery of L-dopa by nasal administration of its water soluble prodrugs, Pharm.Res., 17, 978-984 (2000) https://doi.org/10.1023/A:1007583422634
  20. J. Jankovic and M. Stacy, Medical Management of Levodopa-Associated Motor Complications in Patients with Parkinson's Disease, CNS drugs, 21(8), 677-692 (2007) https://doi.org/10.2165/00023210-200721080-00005
  21. J.E. Riviere and M.C. Heit, Electrically-assisted transdermal drug delivery, Pharm. Res., 14(6), 687-761 (1997) https://doi.org/10.1023/A:1012129801406
  22. O.D. Uitto and H.S. Henry, Electroosmotic pore transport in human skin, Pharm. Res., 20(4), 646-652 (2003) https://doi.org/10.1023/A:1023259102279
  23. V. Merino, A. Lopez, Y.N. Kalia and R.H. Guy, Electrorepulsion versus electroosmosis : effect of pH on the iontophoresis flux of 5-fluorouracil, Pharm. Res., 16(5), 758-761 (1999) https://doi.org/10.1023/A:1018841111922
  24. J. Hirvonen and R.H. Guy, Transdermal iontophoresis: modulation of electroosmosis by polypeptides, J. Control.Rel., 50, 283-289 (1998) https://doi.org/10.1016/S0168-3659(97)00150-8
  25. S. Oh, Effect of formulation additives on the electroosmosis during iontophoresis, Abrtracts, The fifth asian international symposium on biomaterials, Biomaterial society of China, pp. 308 (2006)
  26. P. Xu G. Tan, L. Lawson, L. Freytag, J. Clements and V. John, Stratum corneum microstructure and implications to size dependent penetration, Abrtracts, 34th CRS annual meeting & exposition, Controlled release society, (2007)
  27. J.E. Gorton and R.F. Jameson, Complexes of doubly chelating ligands. proton and copper(II) complexes of LDOPA, J. Chem. Soc. A, 2615-2618 (1968) https://doi.org/10.1039/j19680002615
  28. V. Merino, A. Lopez, Y.N. Kalia and R.H. Guy, Electrorepulsion versus electroosmosis : effect of pH on the iontophoresis flux of 5-fluorouracil, Pharm. Res., 16(5), 758-761 (1999) https://doi.org/10.1023/A:1018841111922
  29. D. Marro, R.H. Guy and M.B. Delgado-Charro, Characterization of the iontophoretic properties of human and pig skin, J. Control. Rel., 70, 213-217 (2001) https://doi.org/10.1016/S0168-3659(00)00350-3
  30. B.D. Bath, H.S. White and E.R. Scott, Visualization and Analysis of Electroosmotic Flow in Hairless Mouse Skin, Pharm. Res., 17(4), 471-475 (2000) https://doi.org/10.1023/A:1007589306661
  31. M. Al-Khaili, V.M. Meidan2 and B.B Michniak, Iontophoretic Transdermal Delivery of Buspirone Hydrochloride in Hairless Mouse Skin, AAPS PharmSci., 5(2) Article 14, (2003)
  32. A. Sze, D. Erickson, L. Ren and D. Li, Zeta-potential measurement using the Smoluchowski equation, and the slope of the current-time relationship in electroosmotic flow, J. Colloid Interface Sci., 261 402-410 (2003) https://doi.org/10.1016/S0021-9797(03)00142-5
  33. S. K. Rastogi and J. Singh, Lipid extraction and transport of hydrophilic solutes through porcine epidermis, Int. J.Pharm., 225, 75-82 (2001) https://doi.org/10.1016/S0378-5173(01)00766-9
  34. D.Bommannan, R.O. Potts and R.H.Guy, Examination of the effect of ethanol on human stratum corneum using infrared spectroscopy, J. Cont. Rel., 16, 299-304 (1991) https://doi.org/10.1016/0168-3659(91)90006-Y
  35. S.Y.Oh and R.H.Guy, Effect of enhancers on electrical properties of skin : The effect of Azone and Ethanol. J. Kor.Pharm. Sci., 24(3), S41-47 (1994)