H-2 NMR EVIDENCE FOR DYNAMIC DISORDER IN HUMAN SKIN INDUCED BY THE PENETRATION ENHANCER AZONE

Penetration enhancers mediate trans-dermal drug delivery. The penetrat ion enhancer dodecyl-azacycloheptanone (Azone(R)) was characterized in situ with H-2 NMR on human stratum corneum treated with either unifor mly deuterated Azone(R) or penetration enhancer with only the entire c hain deuterated, in both cases in propylene glycol. The H-2 NMR spectr um at ambient temperature constitutes a single narrow line only 180 Hz wide. This contrasts with the complex lineshapes 1-25 kHz wide common ly observed for methylene deuterons of lipids in a bilayer gel phase, Hence there is no evidence for differences in orientational behaviour between different deuterons at ambient temperature. The narrow line tr anslates into a low overall order parameter S-CD < 0.0008, for all deu terons, revealing rapid motion of the entire enhancer with correlation times tau(c) much less than 6 x 10(-6) s, in all possible directions. At temperatures of about 150 K a H-2 NMR pattern characteristic for a random isotropic powder was observed on samples of stacked stratum co rneum sheets at different orientations with respect to the magnetic fi eld. This provides strong evidence for random isotropic freezing of th e Azone(R) molecules upon cooling. The H-2 NMR data suggest than incub ation with Azone(R) in propylene glycol provokes dynamic structural di sorder of the intercellular lamellar lipid structure throughout the st ratum corneum and possibly even the creation of fluid domains involvin g the intercellular lipids, which may be essential for the penetration enhancing effect.