Long-circulating liposomes for i.v. targeted delivery of glucocorticoids in arthritis.

Glucocorticoids are highly potent anti-arthritic drugs. However, despite their efficacy a major drawback is their non-specific activity, which can result in a variety of adverse effects. We encapsulated prednisolone phosphate in PEG-liposomes aiming at enhanced local therapeutic activity at inflammatory sites and reduced systemic activity upon i.v. injection. Whole body radioscintigraphy in rats with experimental arthritis showed that glucocorticoid-liposomes are stable in the circulation and that, besides liver and spleen uptake; preferential targeting to inflamed joints is realized. Both in rat and in murine arthritis models, a strong anti-arthritic effect of i.v. liposomal prednisolone was observed. Fast, complete and lasting disappearance of joint inflammation was achieved with a single dose of 10 mg/kg and lasted up to a week post-injection. Unencapsulated prednisolone was not effective when administered at the same dose. Even an intensive daily dosing regimen of free drug could not match the anti-arthritic activity of a single dose liposomal prednisolone. In subsequent experiments, it was found that despite some localization and activity of glucocorticoid-liposomes in the inflamed spleen, rather the localization in the inflamed joints is decisive for the therapeutic effect. Liposomal dexamethasone proved to be five times more effective than liposomal prednisolone, which corresponds with their relative potency. However, significant weight loss and enhanced blood glucose values were observed with dexamethasone liposomes. These phenomena are known adverse effects of free glucocorticoid and could be associated with relatively high systemic plasma levels of released dexamethasone after injection of the liposomal formulation. The clearance rate of the released glucocorticoid appeared to determine the systemic plasma levels. For humans liposomal encapsulation of rapidly cleared topical glucocorticoids may therefore be preferable. An important representative of this group is budesonide. We achieved stable liposomal encapsulation with budesonide phosphate, a newly synthesized derivative. In subsequent therapeutic studies, liposomal budesonide proved to be as effective as liposomal dexamethasone while lower systemic levels of free glucocorticoid and less adverse effect were observed. In conclusion, besides an increased therapeutic activity, encapsulation of glucocorticoids in PEG-liposomes also results in an enhanced benefit-risk ratio. This