FLUORESCENT-PROBE STUDIES OF THE INTERACTIONS OF 1-ALKYL-2-PYRROLIDONES WITH STRATUM-CORNEUM LIPID LIPOSOMES

Previously, the effects of a series of 1-alkyl-2-pyrrolidones (APs; C2 -C8) on the lipoidal pathway of hairless mouse skin (HMS) were studied with a parallel pathway skin model. At their isoenhancement concentra tions, these 1-alkyl-2-pyrrolidones induce the same transport enhancem ent (isoenhancement factor, E(HMS)) on the lipoidal pathway of the str atum corneum for the probe permeants studied. In the present study, th e fluidizing effects of APs upon the stratum corneum lipid liposome (S CLL) bilayer were investigated under these isoenhancement conditions u sing steady-state anisotropy and fluorescence lifetime studies with fl uorescent probes 2-, 6-, and 9-(9-anthroyloxy)stearic acids, 16-(9-ant hroyloxy)palmitic acid, and 1,6-diphenyl-1,3,5-hexatriene to examine a possible correlation between the fluidizing properties of APs and the ir enhancement effects on transdermal drug transport. Time-resolved fl uorescence decay studies were also conducted to further investigate th e fluidizing properties of APs and add support to the steady-state flu orescence results. Under an isoenhancement condition of E(HMS) = 10, t hese APs fluidized the alkyl chains of the lipids at intermediate dept hs (C6-C9) in the SCLL bilayer (a 40-50% decrease in the rotational co rrelation times) but did not significantly change the fluidity in the deep hydrophobic region of the bilayer. Three rotational correlation t imes were deduced from the global simultaneous analysis in time-resolv ed fluorescence decay measurements. The slowest of these (greater than 1000 ns) was attributed to the global motion of SCLLs and is probably related to the static component of steady-state anisotropy. The other two rotational correlation times (on the order of nanoseconds) were i n the range expected for the local motion of the fluorophores and may correspond to their vibrational and rotational motions. When the conce ntrations of APs were increased (increasing the E(HMS) value), the sta tic component (a) decreased. This suggests that APs might induce a gen eral fluidizing effect upon the lipid bilayer (i.e., a decrease in the order of the lipid bilayer). The decrease in the longer rotational co rrelation time (on the order of nanoseconds) with increasing E(HMS) va lue, on the other hand, indicates a possible increase in the ''cavity volume'' for the hindered motions of the fluorophores (i.e., an increa se in the free volume at intermediate depths in the bilayer).