OPTIMIZATION OF IN-VITRO FLUX THROUGH HAIRLESS MOUSE SKIN OF CIDOFOVIR POTENT NUCLEOTIDE ANALOG

The in vitro flux (4-8 h) of cidofovir [(S)-3-hydroxy-2-(phosphonometh oxy)propy]cytosine) was measured across full-thickness hairless mouse skin to evaluate potential formulations for local treatment of herpes virus infections. The effects of propylene glycol, isopropyl alcohol, oleic acid, pH, and cidofovir concentration were examined. In addition , several prototype aqueous gel formulations were studied. Flux Values (4-8 h) increased linearly with cidofovir concentration in both solut ion and gel formulations. Removal of the stratum corneum by tape strip ping increased the flux by similar to 400-fold, whereas pH (4.5 versus 7) had little effect on flux. The presence of propylene glycol, isopr opyl alcohol, or their combination did not significantly increase mean flux (p greater than or equal to 0.05). Pretreatment of the skin with oleic acid resulted in a significant enhancement of cidofovir flux (p less than or equal to 0.01). From the measured flux values, the calcu lated concentration of cidofovir achievable in the viable epidermis fr om a 1% cidofovir gel formulation was similar to 14 mu g/mL, which is comparable to the in vitro 50% inhibitory dose (ID50) values for herpe s simplex viruses HSV-1 and HSV-2.