STUDIES ON LIPOSOME FORMULATIONS FOR INTRAARTICULAR DELIVERY OF CLODRONATE

Liposomes have been proposed as a means to target intra-articularly injected anti-flammatory agents to phagocytic cells in inflamed synovial joints. Clodronate (dichoromethylene bisphosphonate) is a new candidate for this kind of liposomal drug therapy owing to its macrophage suppressive effects and considerably increased potency through liposome-encapsulation. We undertook an investigation to assess, in vitro, liposome formulations of clodronate for intra-articular drug delivery. Brief exposure of macrophages to treatment increases the potency of liposome formulations relative to free drug; with 1-24 h exposure, the potency of liposomal clodronate was over 100-fold greater than that of free drug compared only a 58-fold difference with 48 h exposure, indicating that liposomes more rapidly affect the target cells than free drug. Fast and extensive release of calcein from highly negatively charged liposomes (25-100 mol% DSPG) with high internal osmotic pressure was observed in human plasma and synovial fluid, while lower surface charge density and iso-osmotic pressure of liposomes resulted in negligible leakage. Liposomes with neutral surface charge (100 mol% DSPC) were unable to deliver clodronate to macrophages, but inclusion of 25 mol% of DSPG in liposomes provided effective delivery of the drug regardless of internal osmotic pressure. The results indicate that the balance between liposome stability in biological fluids and effective drug delivery in cells is provided by using liposomes containing 10-25 mol% of DSPG and having an aqueous phase iso-osmotic with surrounding medium.