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) and triacetin (TA) were determined. The solubilities were correlated with 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-FU through hairless mouse skin (transdermal delivery) by suspensions of 5FU and the prodrugs, and the accumulation of 5-FU in the skins (dermal delivery) were determined. In addition, the damage done to the skins by the application of 5-FU or its prodrugs in the vehicles was estimated from the rates of delivery (J(j)) of a standard solute (theophylline) from a nondamaging vehicle (propylene glycol-PG) subsequent to the 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 stable in the more highly hydrophobic vehicle, IPM. The prodrugs delivered more 5-FU through (J,) and accumulated more 5-FU in the skins from the more lipophilic vehicles in which they were less soluble. However, more 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 prodrugs from the more lipophilic vehicles was predominantly due to greater damage 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 for 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 that an apparent inverse relationship between rates of delivery and solubility exists for those solute/vehicle combinations. (C) 1997 Elsevier Science B.V.