STUDIES ON LIPOSOME FORMULATIONS FOR INTRAARTICULAR DELIVERY OF CLODRONATE

Liposomes have been proposed as a means to target intra-articularly in jected anti-flammatory agents to phagocytic cells in inflamed synovial joints. Clodronate (dichoromethylene bisphosphonate) is a new candida te for this kind of liposomal drug therapy owing to its macrophage sup pressive effects and considerably increased potency through liposome-e ncapsulation. We undertook an investigation to assess, in vitro, lipos ome formulations of clodronate for intra-articular drug delivery. Brie f exposure of macrophages to treatment increases the potency of liposo me formulations relative to free drug; with 1-24 h exposure, the poten cy of liposomal clodronate was over 100-fold greater than that of free drug compared only a 58-fold difference with 48 h exposure, indicatin g that liposomes more rapidly affect the target cells than free drug. Fast and extensive release of calcein from highly negatively charged l iposomes (25-100 mol% DSPG) with high internal osmotic pressure was ob served in human plasma and synovial fluid, while lower surface charge density and iso-osmotic pressure of liposomes resulted in negligible l eakage. Liposomes with neutral surface charge (100 mol% DSPC) were una ble to deliver clodronate to macrophages, but inclusion of 25 mol% of DSPG in liposomes provided effective delivery of the drug regardless o f internal osmotic pressure. The results indicate that the balance bet ween liposome stability in biological fluids and effective drug delive ry in cells is provided by using liposomes containing 10-25 mol% of DS PG and having an aqueous phase iso-osmotic with surrounding medium.