Microneedles permit transdermal delivery of a skin-impermeant medication to humans

doi:10.1073/pnas.0710355105

Microneedles permit transdermal delivery of a skin-impermeant medication to humans

Departments of *Pharmacy Practice and Science and
^‡Pharmaceutical Sciences, College of Pharmacy; and
^§Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY 40536; and
^¶Wallace H. Coulter Department of Biomedical Engineering and
^‖School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332

Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved December 21, 2007 (received for review October 31, 2007)

Abstract

Drugs with poor oral bioavailability usually are administered by hypodermic injection, which causes pain, poor patient compliance, the need for trained personnel, and risk of infectious disease transmission. Transdermal (TD) delivery provides an excellent alternative, but the barrier of skin's outer stratum corneum (SC) prevents delivery of most drugs. Micrometer-scale microneedles (MNs) have been used to pierce animal and human cadaver skin and thereby enable TD delivery of small molecules, proteins, DNA, and vaccines for systemic action. Here, we present a clinical study of MN-enhanced delivery of a medication to humans. Naltrexone (NTX) is a potent mu-opioid receptor antagonist used to treat opiate and alcohol dependence. This hydrophilic and skin-impermeant molecule was delivered from a TD patch to healthy human subjects with and without pretreatment of the skin with MNs. Whereas delivery from a standard NTX TD patch over a 72-h period yielded undetectable drug plasma levels, pretreatment of skin with MNs achieved steady-state plasma concentrations within 2 h of patch application and were maintained for at least 48 h. The MNs and NTX patch were well tolerated with mild systemic and application site side effects. The MN arrays were painless upon administration and not damaged during skin insertion, and no MNs were broken off into the skin. This human proof-of-concept study demonstrates systemic administration of a hydrophilic medication by MN-enhanced TD delivery. These findings set the stage for future human studies of skin-impermeant medications and biopharmaceuticals for clinical applications.

Footnotes

^†To whom correspondence should be addressed. E-mail: dwermel{at}uky.edu
Author contributions: D.P.W., S.L.B., H.S.G., M.R.P., and A.L.S. designed research; D.P.W., S.L.B., D.A.H., H.S.G., and J.G. performed research; H.S.G. and M.R.P. contributed new reagents/analytic tools; D.P.W., S.L.B., H.S.G., J.G., and A.L.S. analyzed data; and D.P.W., S.L.B., and M.R.P. wrote the paper.
Conflict of interest statement: D.P.W., S.L.B., D.A.H., and J.G. have no conflicts to disclose. H.S.G. and M.R.P. are inventors on microneedle-based patents that have been licensed to companies. In addition, M.R.P. is a consultant and advisor to companies working on microneedles. S.L.B. and A.L.S. are inventors on patents related to naltrexone and transdermal delivery.
This article is a PNAS Direct Submission.