LIPOSOME AND MULTIPLE EMULSION FORMULATIONS AUGMENT THE ANTICALCIFYING EFFICACY OF PHOSPHOCITRATE IN A CUTANEOUS CALCERGY MODEL

The anticalcifying agent phosphocitrate was incorporated into phosphat idylcholine/cholesterol liposomes by reverse-phase evaporation. The co mpound was entrapped to the extent of 11.6% (mol mol(-1) of lipid) and the liposomes exhibited prolonged retention of the compound when incu bated with rat plasma. Phosphocitrate's ionic contribution in solution adversely influenced the encapsulation efficiency but improvements we re made through ion-pairing with the quaternary ammonium detergent cet rimide, or with the inclusion of stearylamine in the lipid phase. The liposomal dose that could be practically administered in-vivo was rest ricted to 2.5 mg phosphocitrate kg(-1) day(-1). The formulation of a m ultiple emulsion preparation of phosphocitrate, however, offered an al ternative delivery mode permitting infrequent dosing to be successfull y investigated. In a rat calcergy model, both vehicles effectively red uced the formation of induced subcutaneous calcified plaques at doses for which the phosphocitrate salt alone was inactive. The current form ulations demonstrate that the therapeutic efficacy of phosphocitrate c an be markedly improved through an appropriately designed drug deliver y system, signalling a new approach for the future therapeutic applica tion of this compound.