Preparation and characterization of solid dispersion of novel dual antiplatelet agent BF061 for oral use

Abstract

Combined antiplatelet therapy has been widely used to treat arterial thrombotic diseases with improved efficacy and safety. In our pursuit to seek more efficacious and safer antiplatelet drugs, we developed a novel antiplatelet agent BF061 targeting both P2Y12 and phosphodiesterase. In FeCl3 induced mouse mesenteric arterial thrombosis model, BF061 intravenous administration effectively prevented thrombus formation similarly to clopidogrel with significantly less bleeding. BF061 oral administration is ineffective due to low plasma concentration. To increase BF061 plasma concentration, we developed several solid dispersions (SD) of BF061. Among them, a mixture of BF061/Soluplus (1:5) prepared by hot-melt extrusion significantly enhanced BF061 plasma concentration in rats after oral administration. Differential scanning calorimetry (DSC) and X-ray powder diffraction (PXRD) demonstrated the formation of amorphous BF061. Using rat arterio-venous (A-V) shunt arterial thrombosis model, BF061 SD1 100 mg/kg oral administration prevented thrombosis similarly to clopidogrel (10 mg/kg, p.o.). Notably, at the doses achieving antithrombotic effects similar to clopidogrel, BF061 SD1 oral administration did not significantly increase bleeding time in rats (15.9 ± 3.7 min, compared to 11.2 ± 1.0 min in saline group), in contrast to the significantly increased bleeding time in clopidogrel group (more than 60 min). In conclusion, we successfully prepared a solid dispersion of an efficacious and safe antiplatelet agent for oral use. Given the success of combined antiplatelet therapy in clinical practice and the bleeding concern, BF061 which targets both P2Y12 and phosphodiesterase without significant bleeding deserves further development.