PHASE-TRANSITIONS OF RAT STRATUM-CORNEUM LIPIDS BY AN ELECTRON-PARAMAGNETIC-RESONANCE STUDY AND RELATIONSHIP OF PHASE STATES TO DRUG PENETRATION

In order to relate barrier function to stratum corneum structure and t he thermal transitions of corneum lipids, samples from hairless rat sk in were investigated by using ESR and drug penetration techniques. The phase transition of stratum corneum lipids was estimated using a deep er probe (16-doxyl-stearic acid) inserted in the lipid bilayers and me asuring the rotational correlation time, tau(c). Results of ESR study showed that stratum corneum lipids underwent thermal transitions at 39 .3 +/- 2.6 degrees C and 63.6 +/- 2.6 degrees C roughly similar to the data obtained by differential scanning calorimetry measurements. Chol esterol oxidase treatment decreased the fluidity of the lipids at lowe r temperatures. The treatment of stratum corneum with laurocapram (1%) and isopropyl myristate (IPM, 2%) little changed both phase transitio n temperatures, although the treatment highly increased the molecular motion of the lipids. The flux (J(s)) of lipophilic drugs (beta-estrad iol, indomethacin and betahistine) through the skin was enhanced with increasing temperatures, with an increase in the diffusion constant wi thin skin and a decrease in the lag time. There was a good relationshi p between log J(s) or log permeability coefficient (K-p) and 1/tau(c) in the temperature range of 45 to 64 degrees C. The calculated activat ion energy (Delta E) for diffusion of these drugs across skin was 17-4 0 kcal/mol. Judging from our data, stratum corneum lipids of rat proba bly exist as the gel, crystalline state below 39 degrees C, the mesomo rphic state between 39 and 64 degrees C and the fluid, liquid-crystall ine state at temperatures of 64 degrees C or above. These results are in line with that the permeability of these lipophilic drugs through t he intercellular lipids disordered is highly increased.