Site-specific immunosuppression using a new formulation of topical cyclosporine A with polyethylene glycol-8 glyceryl caprylate caprate

Purpose. Dermal application of immunosuppressants can be an effective means of achieving site-specific immunosuppression (SITE) on skin allografts in burn wound management and in the treatment of various immune skin disorders . We have previously reported success with topical cyclosporine A (tCsA) in the treatment of skin allograft rejection in rats. Using a new tCsA formul ation with a penetration enhancer (PE), polyethylene glycol-8 (PEG-8) glyce ryl caprylate/ caprate (Labrasol, Gattefosse, St. Priest, France), in a tri nary drug delivery system, we hypothesized that we would induce SITE and si gnificantly delay rejection of dual skin allografts in rats. Methods. Dual rat skin allografts from Lewis x Brown-Norway (LBN) donors we re grafted to Lewis (Lew) recipients. Experimental animals (EXP, n = 7) rec eived a 10-day course of systemic cyclosporine (sCsA, 8 mg/kg/day) followed by topical application. One of the two allografts on each experimental ani mal received tCsA/PE application (5 mg/kg/day) until sacrifice (tCsA/PE-tre ated), The other allograft received vehicle only (vehicle-treated). Allogen eic controls (ALLO-CON, n = 9) received no sCsA or tCsA. First signs of rej ection were determined based on the initial observation of erythema, hair l oss, flakiness, and/or scabs. Results. The mean time to rejection for ALLO-CON allografts was 6.3 +/- 0.7 days (t test, P = 0.0013); for vehicle-treated allografts, 12.3 +/- 3.8 da ys (paired t test, P = 0.0146); and for tCsA/PE-treated allografts, 25.6 +/ - 5.4 days. The disparity of days to rejection between dual allografts in t he ALLO-CON group was 0.0 +/- 0.0 day and that between the tCsA/PE- and veh icle-treated dual allografts was 13.3 +/- 3.9 days (t test, P = 0.0016). Conclusions. A new formulation of tCsA in a trinary drug delivery system is successful at delaying the onset of rejection in dual skin allografts in r ats by SITE, and PEG-8 glyceryl caprylate/caprate may represent a potential ly effective transdermal penetration enhancer. (C) 1999 Academic Press.