Transdermal delivery of naltrexone by minimally invasive microneedle array application: Permeation enhancement of a water soluble compound across a lipophilic barrier

Opiate and alcohol addiction are common problems in the United States and around the world. Pharmacotherapy of these diseases is available to patients but many adverse side effects, inconsistent delivery, and compliance issues decrease effectiveness of motivated patient treatment. Naltrexone (NTX), an opiate antagonist is currently prescribed for alcohol and opiate addiction as an oral tablet (ReViaRTM and DepadeRTM) or a monthly depot injection (VivitrolRTM) but is limited by the aforementioned adversities. The aim of the present study was to provide an alternative transdermal form of naltrexone to the currently marketed forms of naltrexone. Previous attempts have been explored to increase permeation NTX and 6-beta-naltrexol (NTXOL) as either prodrugs or codrugs (NTX linked to buproprion). Both prodrug and codrug approaches showed promise in enhancing skin permeation, however, only 1 prodrug and no codrug has penetrated the skin at a therapeutic rate. Thus, an approach utilizing a physical skin enhancement aid to create micro pores in the skin to deliver a water soluble form of either NTX or NTXOL was investigated.;The microneedle (MN), a micromechanical device conceptualized in the 1970's but developed in the late 1990's has progressed as a useful technique is enhancing permeation of both large and small molecules. Early in vivo studies showed a linear correlation between the number of MN insertions to the corresponding flux through the skin. Later in vitro studies of the aqueous forms (hydrochloride salt and ionized state) of NTX and NTXOL revealed therapeutic rates of permeation as well as indicated the need for a highly soluble compound to permeate through the aqueous channels created by the MN. In vivo studies allowed the determination of the aqueous channel lifetime (48--72 h) after insertion by microscopic visualization transepidermal water loss and by pharmacokinetic analysis.;Human studies with MN aided delivery of NTX·HCl gave a therapeutic plasma level (2.5 +/- 1.0 ng/mL) over a 2 d period while patients treated only with the drug system and no MN showed no levels of NTX in plasma. In vitro/in vivo correlations in the guinea pig and human were excellent with a 93% and 76% correlation, respectively.;Keywords. Percutaneous absorption, microneedle, naltrexone, skin, human...