TRANSDERMAL DELIVERY OF DRUGS WITH DIFFERING LIPOPHILICITIES USING AZONE ANALOGS AS DERMAL PENETRATION ENHANCERS

Six model drugs were selected for this study based on their degree of lipophilicity as represented by their log P values (range = -0.95 to 3 .51). They included 2,4-dihydroxy-5-fluoropyrimidine (5-fluorouracil); 1,3,7-trimethylxanthine (caffeine); [(2-hydroxybenzoyl)amino]acetic a cid (salicyluric acid); 2-hydroxybenzoic acid (salicylic acid); 9 alph a-fluoro-1 6 alpha-hydroxyprednisolone 16 alpha,17 alpha-acetonide (tr iamcinolone acetonide); and alpha-methyl-4-[2-methylpropyl]benzeneacet ic acid (ibuprofen). Six dermal penetration enhancers [Azone or 1-dode cylhexahydro-2H-azepin-2-one (1), N-dodecyl-2-pyrrolidinone (2), N-dod ecyl-2-piperidinone (3), N-dodecyl-N-(2-methoxyethyl)acetamide (4), N- (2,2-dihydroxyethyl)dodecylamine (5), and 2-(1-nonyl)-1,3-dioxolane (6 )] were tested in vitro across full-thickness hairless mouse skin with each of the drugs. The relationship between lipophilicity (log P) and efficacy (represented by the enhancement ratio of flux) of the drugs when coadministered with the enhancers was examined using linear regre ssion. The three cyclic enhancers (1-3) exhibited linear relationships , indicating that they were more effective at enhancing the penetratio n of hydrophilic drugs (R(l) = 0.8997 for 1, 0.8801 for 2, and 0.804 f or 3) when evaluating all the model drugs except triamcinolone acetoni de (TA). The two acyclic enhancers (4 and 5) showed a similar relation ship, but their correlation coefficients were lower at 0.6463 for 4 an d 0.6213 for 5. Studies with the dioxolane (6) yielded no relationship between the lipophilicity of the drug and the efficacy of the enhance r, with an R(l) of 0.002. Overall, 6 was the least effective enhancer studied. The steroid TA was not included in the linear regression anal yses. Of the six model drugs studied, TA exhibited the largest increas e in transdermal delivery when enhancers 1-6 were used.