Preparation, physicochemical properties and animal studies of new water-soluble prodrugs of carbamazepine and oxcarbazepine

The objective of this research was to develop new water-soluble prodrugs of carbamazepine (CBZ) and oxcarbazepine (OXC) that are suitable for parenteral and oral delivery. Acyl urea and sulfenamide prodrugs of CBZ and OXC were designed to overcome the poor aqueous solubility of the parent drugs and rapidly convert to parent drug and harmless side products in vivo.; Synthesis the acyl urea prodrugs of CBZ (N-Gly-CBZ) and OXC (N-Gly-OXC) involve the attachment of glycine to the urea nitrogen of the parent drug forming a peptide like acyl urea bond. The sulfenamide prodrug N-cysteamine-CBZ utilizes the ionizable promoiety cysteamine, which is attached to the urea nitrogen of CBZ forming a sulfenamide bond. The amine groups of these prodrugs can be protonated to form water-soluble salts. Acyl urea and sulfenamide prodrugs possess dramatically improved aqueous solubility relative to CBZ. Concentrated solutions of N-Gly-CBZ also showed an increased aqueous solubility of CBZ.; The chemical stabilities of these derivatives were investigated. N-Gly-OXC was found to be very unstable and its aqueous degradation was rapid and complex. It also appeared to undergo unexpected degradation reactions in the solid state. The pH-rate profiles and pKa values for N-Gly-CBZ and N-cysteamine-CBZ were determined. The pH of maximum stability was in the lower pH range for both prodrugs where they both exhibit excellent aqueous solubility. The stability of N-Gly-CBZ is insufficient for a ready-to-use parenteral formulation, but a sterile solid for reconstitution prior to administration may be possible. An Eyring plot for N-cysteamine-CBZ stability at the pH of maximum stability predicts a t90 value of 75 years at refrigerated temperature (4°C), but the actual shelf-life is likely to be limited by the precipitation of the degradation product iminostilbene from concentrated prodrug solutions.; The in vivo conversion of N-Gly-CBZ to CBZ was apparently rapid and complete following IV administration to rats. AUC values for CBZ produced from crossover IV doses of N-Gly-CBZ and from equivalent IV CBZ control were not statistically different. Oral bioavailability of CBZ from N-Gly-CBZ appears to be greater than from CBZ per se in rats.; The in vivo conversion of N-cysteamine-CBZ appeared to be instantaneous and quantitative following IV administration to rats, probably due to reaction with glutathione. The pharmacokinetic profiles of CBZ following crossover IV administration of N-cysteamine-CBZ and CBZ control were indistinguishable, and no unchanged prodrug was observed in the plasma or urine of the rats.