European Journal of Pharmaceutical Sciences 2008-04-23

In vivo evaluation of a transdermal codrug of 6-beta-naltrexol linked to hydroxybupropion in hairless guinea pigs.

Paul K Kiptoo, Kalpana S Paudel, Dana C Hammell, Mohamed O Hamad, Peter A Crooks, Audra L Stinchcomb

Index: Eur. J. Pharm. Sci. 33(4-5) , 371-9, (2008)

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Abstract

6-Beta-naltrexol is the major active metabolite of naltrexone, NTX, a potent mu-opioid receptor antagonist used in the treatment of alcohol dependence and opioid abuse. Compared to naloxone, NTX has a longer duration of action largely attributed to 6-beta-naltrexol. This study was carried out in order to determine percutaneous absorption of a transdermal codrug of naltrexol, 6-beta-naltrexol-hydroxybupropion codrug (CB-NTXOL-BUPOH), in hairless guinea pigs as well as to evaluate the safety of 6-beta-naltrexol for development as a transdermal dosage form. This codrug may be useful in the simultaneous treatment of alcohol dependence and tobacco addiction. The carbonate codrug traversed the skin at a faster rate than 6-beta-naltrexol. 6-Beta-naltrexol equivalent steady state plasma concentrations of 6.4 ng/ml were obtained after application of the codrug as compared to 1.2 ng/ml from 6-beta-naltrexol base. The steady state plasma concentration of hydroxybupropion after codrug application was 6.9 ng/ml. Skin sensitization and irritation tested in the hairless guinea pigs using the Buehler method revealed that 6-beta-naltrexol had no skin sensitizing potential. The method was validated with a known sensitizer, p-phenylenediamine, which induced sensitization in 90% of the animals. 6-beta-Naltrexol caused only mild transient skin irritation after the initial application of the patch. During subsequent applications, erythema was slightly increased but no skin damage was observed. In conclusion, a transdermal codrug of 6-beta-naltrexol could be a viable alternative treatment for alcohol and opiate abuse.