Fluorouracil prodrugs for the treatment of proliferative vitreoretinopathy:: formulation in silicone oil and in vitro release of fluorouracil

Three new N-1-alkylcarbonyl-5-fluorouracil derivatives that are prodrugs of 5-fluorouracil (FU), one of them being a co-drug FU-retinoic acid (RA), were studied as potentially effective drugs against postsurgical proliferative vitreoretinopathy (PVR). The stability of N-1-octenoylFU (3), N-1-lauroylFU (2), and N-1-retinoylFU (4) in aqueous medium, their solubility in silicone oil (SiO). the kinetics of FU release in an in vitro system were determined. Compound 3 is very rapidly soluble in SiO. Its saturation concentration, reached after 6 h, is 233 +/- 13 mug g(-1) SiO. Compound 2 is not very soluble in SiO but its kinetic of solubilization is fast. Its saturation concentration, reached after 2 days, is 27 +/- 2 mug g(-1) SiO. Compound 4 is poorly soluble in SiO. A concentration plateau, with a mean value of 4 mug g(-1) SiO, is reached after 4 days. The addition in SiO of 5% of a perfluorinated perhydrogenated alkene greatly improves the solubilization of compound 4. Two different types of FU release are observed. For compound 3, the release is fast and is achieved after I day. For compounds 2 and 4, the release is slower and is ended at 10 and 27 days, respectively. The solubility of the prodrugs in SiO is not correlated with their lipophilicity, whereas the release rate of FU decreased with increased lipophilicity of the prodrug. The most promising prodrug is compound 4 that slowly releases two active drugs (FU and RA) with a t(1/2release) of 5.8 days. It might be interesting for the treatment of PVR. However, an in vivo study on an animal model of PVR is necessary to prove the efficacy of this formulation and to study its toxicity. (C) 2003 Elsevier Science B.V. All rights reserved.