EFFECT OF VARIOUS ENHANCERS ON TRANSDERMAL PENETRATION OF INDOMETHACIN AND UREA, AND RELATIONSHIP BETWEEN PENETRATION PARAMETERS AND ENHANCEMENT FACTORS

The enhancing capacity of various chemicals, which are widely recognized as enhancers, for the transdermal penetration into full-thickness rat skin of a model lipophilic drug [indomethacin (IND)] and a hydrophilic permeant (urea) was estimated by an in vitro technique. In addition, the fluidity of the stratum corneum lipids, the partitioning of IND into skin, the lipid (ceramides) extraction from the stratum corneum by enhancers, and the IND solubility in enhancer vehicle were measured and related to the enhancing capacity. In vitro permeation experiments with hairless rat skin unequivocally revealed that the enhancers varied in abilities to enhance the fluxes of both agents. Laurocapram, isopropylmyristate (IPM), sodium oleate, and cineol increased fluxes of both agents to a great extent, but N-methyl-2-pyrrolidone (NMP), N,N-diethyl-m-tolamide (DEET), and oleyl oleate were less effective acclerants. Many enhancers increased the fluidity of the lipids [with a threshold of similar to 0.6-0.8 ns at 37 degrees C in the rotational correlation time (tau(c))], the skin partitioning of IND, the extraction of ceramides from the cornified cells, and the thermodynamic activity of IND in vehicle (calculated from the solubility) to varying extents. A good correlation was observed between the increase in the fluidity of stratum corneum lipids and the partitioning of IND into skin, between the increase in the fluidity and the flux or the decrease in lag time for IND, between the removal of ceramides and the skin partitioning of IND, and between the removal of ceramides and the flux of urea (p < 0.05 in all cases). The enhancement diagram, a novel concept based on the four factors just mentioned, was introduced. This diagram was used to compare enhancer activities towards IND penetration, which in turn provided a measure of the activity of a penetration enhancer and a comparison of the activities of various enhancers. The order of the enhancement potency of enhancers tested with IND was laurocapram > oleic acid > monoolein > sodium oleate > cineol and IPM, and the order of potency of enhancers tested with urea was n-octanol > cineol > laurocapram = monoolein = oleic acid > sodium oleate > D-limonen > IPM.