A novel prodrug approach for tertiary amines. 2. Physicochemical and in vitro enzymatic evaluation of selected N-phosphonooxymethyl prodrugs

Quaternary amine prodrugs resulting from N-phosphonooxymethyl derivatizatio n of the tertiary amine functionality of drugs represents a novel approach for improving their water solubility. Separate reports have demonstrated th e synthetic feasibility and rapid and quantitative prodrug to parent drug c onversion in rats and dogs. This work is a preliminary evaluation of the ph ysicochemical and in vitro enzymatic reversion properties of selected prodr ugs. The loxapine prodrug had over a 15 000-fold increase in aqueous solubi lity relative to loxapine free base at pH 7.4. The loxapine prodrug was als o shown to be quite stable at neutral pH values. The time for degradation p roduct (parent drug) precipitation from an aqueous prodrug formulation woul d be expected to dictate the shelf life. Using this assumption, together wi th solubility and elevated temperature chemical stability studies, the shel f life of a parenteral formulation of the loxapine prodrug was projected to be close to 2 years at pH 7.4 and 25 degrees C. In addition, the prodrugs of cinnarizine and loxapine have been shown to be substrates for alkaline p hosphatase, an enzyme found throughout the human body, and revert to the pa rent compound in its presence. The results from these evaluations demonstra te that the derivatives examined have many of the ideal properties required for potential clinical application.