Improved delivery through biological membranes. LXI: Design, synthesis, and evaluation of a lipolol-based intradermal drug targeting system for 5-fluorouracil.

This report describes initial studies with the lipolyl ester of 1-carboxypropylcarbamoyl-FU (LE-CPCFU) which was designed to enhance the dermal delivery of the antitumor agent 5-fluorouracil (FU). The design of LE-CPCFU was based upon our previous observation that sulfur-based chemical drug targeting systems were localized within the skin and improved the delivery of the parent drug to the dermal tissue (Chikhale et al., 1993; Bodor et al., 1982; Bodor and Sloan, 1982). In the in vitro test system that used freshly-excised guinea-pig skin, LE-CPCFU was found to enhance FU delivery to the skin 2- to 5-fold compared to underivatized FU. Neither LE-CPCFU nor its acid metabolite 1-carboxypropylcarbamoyl-FU (CPCFU) could be detected in the skin or receiver during the diffusion experiments even though LE-CPCFU and CPCFU were found to be reasonably stable in aqueous pH 7.4 buffer and during the analytical procedure. FU which was released from LE-CPCFU in the skin subsequently diffused into the receiver. Thus, LE-CPCFU was observed to improve FU delivery to the skin during the initial time period of the study (0-4 hr). This study indicates that LE-CPCFU in the guinea-pig skin was hydrolyzed to form FU in the skin serving as an intradermal drug delivery system for the antitumor agent. Thus, LE-CPCFU could prove to reduce the systemic toxicity of FU by enhancing the local skin concentration and minimizing the systemic concentration of the antitumor agent as compared to underivatized FU.