EFFECT OF VEHICLES ON TOPICAL DELIVERY OF 5-FLUOROURACIL (5FU) BY 1-ACYL-5FU PRODRUGS

The solubilities of selected 1-alkylcarbonyl prodrugs of 5-FU and of 5 -FU in isopropyl myristate (IPM), miglyol-812 (MG), tributyrin (TB) an d triacetin (TA) were determined. The solubilities were correlated wit h the solubility parameters of the prodrugs, delta(i) and the vehicles , delta(v). The stabilities of the prodrugs in the vehicles in contact with hydrated skin were also determined. The rates of delivery of 5-F U through hairless mouse skin (transdermal delivery) by suspensions of 5FU and the prodrugs, and the accumulation of 5-FU in the skins (derm al delivery) were determined. In addition, the damage done to the skin s by the application of 5-FU or its prodrugs in the vehicles was estim ated from the rates of delivery (J(j)) of a standard solute (theophyll ine) from a nondamaging vehicle (propylene glycol-PG) subsequent to th e application of 5-FU or its prodrugs. 5-FU and its prodrugs were less soluble in the more lipophilic vehicles: S-IPM < S-MG < S-TB < S-TA. On the other hand, the hydrolytically unstable prodrugs were more stab le in the more highly hydrophobic vehicle, IPM. The prodrugs delivered more 5-FU through (J,) and accumulated more 5-FU in the skins from th e more lipophilic vehicles in which they were less soluble. However, m ore damage was also done to the skins by the more lipophilic vehicles: IPM > MG > TB > TA. Thus, the greater delivery of 5-FU by the prodrug s from the more lipophilic vehicles was predominantly due to greater d amage done to the skins by the more lipophilic vehicles. On the other hand, the ratios of delivery of j FU to damage (J,IJ,) were greater fo r 1-acetyl-5FU (1) and 1-hexanoyl-5FU (2) from IPM than those from MG and TB, and 1 and 2 were less soluble in IPM than in MG and TB, so tha t an apparent inverse relationship between rates of delivery and solub ility exists for those solute/vehicle combinations. (C) 1997 Elsevier Science B.V.