Enhanced skin permeation of a new capsaicin derivative (DA-5018) from a binary vehicle system composed of isopropyl-myristate and ethoxydiglycol

DA-5018, a recently synthesized capsaicin analog, appears to possess potent analgesic activity when administered topically. The objective of this stud y is to test the Feasibility of the topical administration of this compound . Specifically, our goal was to identify vehicle system that permit a reaso nable transdermal permeation of the compound in mice. Among the vehicles ex amined, isopropyl myristate (IPM) showed the largest in vitro permeability across the intact skin (83.6 +/- 5.42 mul/cm(2)/h). However, due tea due li mited solubility of DA-5018 in IPM (0.53 mg/ml), the maximal flux from the IPM medium remained at only 44.3 +/- 2.87 mug/cm(2)/hr. In order to increas e the flux, addition of better solvents for DA-5018 was attempted, under th e assumption that flux is the result of both solubility and permeability. E thoxydiglycol (EC) and oleic acid (OA) were selected as examples of good so lvents. The addition of EC 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 5 0.2 mg/ml for EG and OA, respectively). However, the addition of EG at a 1: 1 volume ratio, for example, increased the flux 6.3 fold (i.e., 279 mug/cm( 2)/hr), while OA, at a 1:1 volume ratio, decreased the flux 5 fold (i.e., 9 .2 mug/cm(2)/hr). The mechanism of this discrepancy between EC and OA was i nvestigated by measuring the permeabilty of DA-5018 across the stratum corn eum-removed skin of the mouse, under the hypothesis that the viable skin la yer may serve as a barrier for the permeation of lipophilic substances such as DA 5018. The permeability of DA-5018, from the medium of EC or OA, acro ss the viable skin differed greatly for EC (0.41 mul/cm(2)/hr) and OA (0.08 6 mul/cm(2)/hr), suggesting that a higher permeability across the viable sk in layer is needed for the second solvents. The maximum flux across the int act skin was achieved for DA-5018 when EG was added to IPM at a 1:1 volume ratio. Thus, the use of a binary system appears to be the best approach for realizing the transdermal delivery of DA-5018 at a reasonable rate.