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DA-5018, a receutly synthesized capsaicin analog, appears to possess potent analgesic activity when administered topically. The objective of thls study is to test the feasibility of the topical administration of this compound. Specifically our identify vehicle system that permit a reasonable transdermal permeation of the compouud in mice. Among the vehicles examined, isopropyl myristate(IPM) showed the largest in vitro permeability across the intact skin (83.6 ± 5.42mcl/cm2/h). However due to the limited solubility of DA-5018 in IPM (0.53 mg/ml), the maximal flux from the IPM medium remained at only 44.3 ± 2.87mcg/cm2/hr. In order to increase the flux, addition of better solvents for DA-5018 was attempted, under the assumption that flux is the result of both solubility and permeability. Ethozydiglycol (EC) and oleic (OA) were seleted as examples of good solvents. The addition of EG or OA to IPM at a 1:1 volume ratio resulted in a comparable increase in the solubility of the compound (I.e., to 61.1 and 50.2mg/ml for EG and OA, respectively). However the addition of IC at a 1:1 volume ratio, for example,increased the flux 6.3 fold (I.e., 279mcg/cm2hr), while OA, at a 1:1 volume ratlo, decreased the flux 5 fold (I.e., 9.26g/cm2/hr). The mechanism of this discrepancy between EG and OA was investigated by measuring the permeabilty of DA-5018 across the stratum corueum- removed strain of the mouse, under the hypothesis that the viable skin layer may serve as a barrier for the permeation oi lipophilic substances such as DA-5018. The permeability of DA-5018, from the medium of EG or OA, across the viable skin differed greatly for EG (0.41mcl/cm2hr) and OA (0.086mcl/cm2hr), suggesting that a higher permeability across the viable skin layer is needed for the second slovent. The maximum flux across the intact skin was achieved for Dh-5018 when EG was added to IPM at a 1:1 volute ratoo. Thus, the use of a binary system appears to be the best approach for realizining the transdermal delivery of Dh-5018 at a reasonable rate.
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