Advertisement

Pharmaceutical Research

, Volume 25, Issue 7, pp 1677–1685 | Cite as

Flux Across of Microneedle-treated Skin is Increased by Increasing Charge of Naltrexone and Naltrexol In Vitro

  • Stan L. Banks
  • Raghotham R. Pinninti
  • Harvinder S. Gill
  • Peter A. Crooks
  • Mark R. Prausnitz
  • Audra L. Stinchcomb
Research Paper

Abstract

Purpose

The purpose of this investigation was to evaluate the in vitro microneedle (MN) enhanced percutaneous absorption of naltrexone hydrochloride salt (NTX·HCl) compared to naltrexone base (NTX) in hairless guinea pig skin (GP) and human abdominal skin. In a second set of experiments, permeability of the major active metabolite 6-β-naltrexol base (NTXOL) in the primarily unionized (unprotonated) form at pH 8.5 was compared to the ionized form (pH 4.5).

Methods

In vitro fluxes of NTX, NTX·HCl and ionized and unionized NTXOL were measured through microneedle treated or intact full thickness human and GP skin using a flow through diffusion apparatus. Solubility and diffusion samples were analyzed by HPLC.

Results

Both GP and human skin show significant increases in flux when treated with 100 MN insertions as compared to intact full thickness skin when treated with NTX·HCl or ionized NTXOL (pH 4.5; p < 0.05). MN increased GP skin permeability for the hydrophilic HCL salt of NTX by tenfold and decreased lag time by tenfold too. Similar results were found using human skin, such that skin permeability to NTX·HCl was elevated to 7.0 × 10−5 cm/h. Permeability of the primarily unionized (unprotonated) form of NTXOL at pH 8.5 was increased by MN only threefold and lag time was only modestly reduced. However, MN treatment with the primarily ionized (protonated) form of NTXOL at pH 4.5 increased skin permeability fivefold and decreased lag time fourfold.

Conclusion

Enhancement was observed in vitro in both GP and human skin treated with MN compared to intact skin with the salt form of NTX and the ionized form of NTXOL. We conclude that transdermal flux can be optimized by using MN in combination with charged (protonated) drugs that have increased solubility in an aqueous patch reservoir and increased permeability through aqueous pathways created by MN in the skin.

KEY WORDS

microneedle 6-β-naltrexol naltrexone protonation transdermal 

Notes

Acknowledgments

We would like to thank Dr. Mark Allen at Georgia Tech for the use of his microfabrication facilities. This research was supported in part by NIH R01DA13425 and R01EB006369. Human skin was supplied by the National Cancer Institute (NCI) Cooperative Human Tissue Network (CHTN). HSG and MRP are members of the Center for Drug Design, Development and Delivery and the Institute for Bioengineering and Bioscience at Georgia Tech. MRP is the Emerson Lewis Faculty Fellow.

References

  1. 1.
    T.L. Mark, R.M. Coffey, R. Vandivort-Warren, H.J. Harwood, and E.C. King. U.S. spending for mental health and substance abuse treatment, 1991–2001. Health Aff (Millwood). Suppl Web Exclusives:W5-133–W135-142 (2005).Google Scholar
  2. 2.
    SAMHSA. Results from the 2006 National Survey on Drug Use and Health: National Findings, Department of Health and Human Services: Substance Abuse and Mental Health Services Administration Office of Applied Studies, 2006, pp. 1–282.Google Scholar
  3. 3.
    J. A. Bouwstra, P. L. Honeywell-Nguyen, G. S. Gooris, and M. Ponec. Structure of the skin barrier and its modulation by vesicular formulations. Prog. Lipid Res. 42:1–36 (2003).PubMedCrossRefGoogle Scholar
  4. 4.
    NIDA. Treatment for Drug Abusers in the Criminal Justice System, National Institutes of Health and National Institute on Drug Abuse, July 2006.Google Scholar
  5. 5.
    ACS. Cancer Facts and Figures 2007, American Cancer Society, 2007, pp. 1–56.Google Scholar
  6. 6.
    PDR. Generics second edition. Medical Economics. New Jersey, 1996, pp. 1083–1086.Google Scholar
  7. 7.
    C. Alkermes. Vivitrol™ (naltrexone for extended-release injectable suspension). http://www.vivitrol.com/.
  8. 8.
    G. P. Galloway, M. Koch, R. Cello, and D. E. Smith. Pharmacokinetics, safety, and tolerability of a depot formulation of naltrexone in alcoholics: an open-label trial. BMC Psychiatry. 5:1–10 (2005).CrossRefGoogle Scholar
  9. 9.
    D. C. Hammell, M. Hamad, H. K. Vaddi, P. A. Crooks, and A. L. Stinchcomb. A duplex “Gemini” prodrug of naltrexone for transdermal delivery. J. Control. Release. 97:283–290 (2004).PubMedCrossRefGoogle Scholar
  10. 10.
    D. C. Hammell, E. I. Stolarczyk, M. Klausner, M. O. Hamad, P. A. Crooks, and A. L. Stinchcomb. Bioconversion of naltrexone and its 3-O-alkyl-ester prodrugs in a human skin equivalent. J. Pharm. Sci. 94:828–836 (2005).PubMedCrossRefGoogle Scholar
  11. 11.
    B. N. Nalluri, C. Milligan, J. Chen, P. A. Crooks, and A. L. Stinchcomb. In vitro release studies on matrix type transdermal drug delivery systems of naltrexone and its acetyl prodrug. Drug Dev. Ind. Pharm. 31:871–877 (2005).PubMedCrossRefGoogle Scholar
  12. 12.
    M. R. Prausnitz, S. Mitragotri, and R. Langer. Current status and future potential of transdermal drug delivery. Nat. Rev. 3:115–124 (2004).Google Scholar
  13. 13.
    M. S. Gersteland, and V. A. Place. Drug delivery device, Alza CorporationIn U. S. P. Office (ed.), Vol. 3,964,482, Alza Corporation, USA, 1976, pp. 1–13.Google Scholar
  14. 14.
    M. R. Prausnitz. Microneedles for transdermal drug delivery. Adv. Drug Deliv. Rev. 56:581–587 (2004).PubMedCrossRefGoogle Scholar
  15. 15.
    M. R. Prausnitz, J. A. Mikszta, and J. Raeder-Devens. Microneedles in percutaneous penetration enhancers. In E. Smith and H. Maibach (eds.), CRC, Boca Raton, FL, 2005, pp. 239–255.Google Scholar
  16. 16.
    S. A. Coulman, D. Barrow, A. Anstey, C. Gateley, A. Morrissey, N. Wilke, C. Allender, K. Brain, and J. C. Birchall. Minimally invasive cutaneous delivery of macromolecules and plasmid DNA via microneedles. Curr. Drug Deliv. 3:65–75 (2006).PubMedCrossRefGoogle Scholar
  17. 17.
    J. G. E. Gardeniers, J. W. Luttge, J. W. Berenschott, M. J. de Boer, Y. Yeshurun, M. Hefetz, R. van’t Oever, and A. van den Berg. Silicon micromachined hollow microneedles for transdermal liquid transport. J. MEMS. 6:855–862 (2003).Google Scholar
  18. 18.
    M. Cormier, B. Johnson, M. Ameri, K. Nyam, L. Libiran, D. D. Zhang, and P. Daddona. Transdermal delivery of desmopressin using a coated microneedle array patch system. J. Control. Release. 97:503–511 (2004).PubMedGoogle Scholar
  19. 19.
    W. Martanto, S. P. Davis, N. R. Holiday, J. Wang, H. S. Gill, and M. R. Prausnitz. Transdermal delivery of insulin using microneedles in vivo. Pharm. Res. 21:947–952 (2004).PubMedCrossRefGoogle Scholar
  20. 20.
    J. A. Mikszta, J. B. Alarcon, J. M. Brittingham, D. E. Sutter, R. J. Pettis, and N. G. Harvey. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nat. Med. 8:415–419 (2002).PubMedCrossRefGoogle Scholar
  21. 21.
    S. Kaushik, A. H. Hord, D. D. Denson, D. V. McAllister, S. Smitra, M. G. Allen, and M. R. Prausnitz. Lack of pain associated with microfabricated microneedles. Anesth. Analg. 92:502–504 (2001).PubMedCrossRefGoogle Scholar
  22. 22.
    B. R. de Costa, M. J. Iadarola, R. B. Rothman, K. F. Berman, C. George, A. H. Newman, A. Mahboubi, A. E. Jacobson, and K. C. Rice. Probes for narcotic receptor mediated phenomena. 18. Epimeric 6 alpha- and 6 beta-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5 alpha-epoxymorphinans as potential ligands for opioid receptor single photon emission computed tomography: synthesis, evaluation, and radiochemistry of [125I]-6 beta-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5 alpha-epoxymorphinan. J. Med. Chem. 35:2826–2835 (1992).PubMedCrossRefGoogle Scholar
  23. 23.
    K. S. Paudel, B. N. Nalluri, D. C. Hammell, S. Valiveti, P. Kiptoo, M. O. Hamad, P. A. Crooks, and A. L. Stinchcomb. Transdermal delivery of naltrexone and its active metabolite 6-beta-naltrexol in human skin in vitro and guinea pigs in vivo. J. Pharm. Sci. 94:1965–1975 (2005).PubMedCrossRefGoogle Scholar
  24. 24.
    J. Liu, and Z. Gong. Progress of research on naltrexol. Zhongguo Yaowu Yilaixing Zazhi. 14:89–92 (2005).Google Scholar
  25. 25.
    R. L. Bronaugh, and R. F. Stewart. Methods for in vitro percutaneous absorption studies III: hydrophobic compounds. J. Pharm. Sci. 73:1255–1258 (1984).PubMedCrossRefGoogle Scholar
  26. 26.
    M. A. Hussain, C. A. Koval, M. J. Myers, E. G. Shami, and E. Shefter. Improvement of the oral bioavailability of naltrexone in dogs: a prodrug approach. J. Pharm. Sci. 76:356–358 (1987).PubMedCrossRefGoogle Scholar
  27. 27.
    H. K. Vaddi, M. O. Hamad, J. Chen, S. L. Banks, P. A. Crooks, and A. L. Stinchcomb. Human skin permeation of branched-chain 3-0-alkyl ester and carbonate prodrugs of naltrexone. Pharm. Res. 22:758–765 (2005).PubMedCrossRefGoogle Scholar
  28. 28.
    S. Valiveti, D. C. Hammell, K. S. Paudel, M. O. Hamad, P. A. Crooks, and A. L. Stinchcomb. In vivo evaluation of 3-O-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs. J. Control. Release. 102:509–520 (2005).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Stan L. Banks
    • 1
  • Raghotham R. Pinninti
    • 1
  • Harvinder S. Gill
    • 2
  • Peter A. Crooks
    • 1
  • Mark R. Prausnitz
    • 2
    • 3
  • Audra L. Stinchcomb
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity of Kentucky College of PharmacyLexingtonUSA
  2. 2.The Wallace Coulter School of Biomedical Engineering at Georgia Tech and Emory UniversityGeorgia Institute of TechnologyAtlantaUSA
  3. 3.School of Chemical and Biomolecular EngineeringGeorgia Institute of TechnologyAtlantaUSA

Personalised recommendations