AbstractA novel dexamethasone palmitate liposomal long‐circulating (DPL long‐circulating) drug delivery system was established. The DPL long‐circulating and DPL (dexamethasone palmitate liposomal) systems were prepared by film‐distributed extrusion with phospholipid and cholesterol. The formulation stability of DPL long‐circulating and DPL were investigated. The anti‐inflammatory activity and acute toxicity of DPL long‐circulating, DPL and dexamethasone sodium phosphate injection (DSP) were evaluated with mice. The DPL long‐circulating systems were successfully prepared by film‐distributed extrusion methods. The experimental results showed that the DPL long‐circulating had uniform particle size and stable property. The DPL long‐circulating and DPL showed stronger anti‐inflammatory effect than DSP in an anti‐inflammatory test. Acute toxicity tests showed that DSP injection had lower toxicity than the DPL long‐circulating and DPL, which suggested that DPL long‐circulating and DPL had higher bioavailability with passive targeting efficacy of liposomes. The DPL long‐circulating formulation product can meet quality requirement. This formulation had stronger anti‐inflammatory effect and higher acute toxicity.