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

• Published in: European journal of pharmaceutical sciences 2008-04, Vol.33 (4), p.371-379
• Main Authors: Kiptoo, Paul K., Paudel, Kalpana S., Hammell, Dana C., Hamad, Mohamed O., Crooks, Peter A., Stinchcomb, Audra L.
• Format: Article
• Language: English
• Subjects: 6-β-Naltrexol; Administration, Cutaneous; Alcohol-Related Disorders - drug therapy; Animals; Bioconversion; Bupropion - administration & dosage; Bupropion - adverse effects; Bupropion - analogs & derivatives; Bupropion - chemistry; Bupropion - pharmacokinetics; Chromatography, High Pressure Liquid; Codrug; Drug Delivery Systems - methods; Female; Guinea Pigs; Hairless guinea pig; Male; Mass Spectrometry; Molecular Structure; Naltrexone - administration & dosage; Naltrexone - adverse effects; Naltrexone - analogs & derivatives; Naltrexone - chemistry; Naltrexone - pharmacokinetics; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Sensitization; Skin - drug effects; Skin Absorption - drug effects; Skin Irritancy Tests; Smoking Cessation - methods; Transdermal
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2008.01.006

6-β-Naltrexol is the major active metabolite of naltrexone, NTX, a potent μ-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-β-naltrexol. This study was carried out in order to determine percutaneous absorption of a transdermal codrug of naltrexol, 6-β-naltrexol-hydroxybupropion codrug (CB-NTXOL-BUPOH), in hairless guinea pigs as well as to evaluate the safety of 6-β-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-β-naltrexol. 6-β-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-β-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-β-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-β-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-β-naltrexol could be a viable alternative treatment for alcohol and opiate abuse.