Preparation of ONO-1301-loaded poly(lactide-co-glycolide) microspheres and their effect on nerve conduction velocity

The aim of this study was to prepare poly(lactide-co-glycolide) (PLGA) microspheres containing ONO-1301, a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity, with 10% of drug released in the initial burst and a sustained-release period of about 3 weeks after administration. The effect of PLGA type (molecular weight and the lactide/glycolide (L/G) ratio in PLGA), the preparative conditions and the particle size on the in-vitro release profile were examined. The effect of optimized ONO-1301-loaded PLGA microspheres on delayed nerve condition velocity (NCV) was investigated in streptozotocin (STZ) induced diabetic rats.

ONO-1301 PLGA microspheres were produced by the oil-in-water emulsion/solvent evaporation method. Drug release from the prepared microspheres was monitored in phosphate buffer solution at 37°C for 4 weeks by high-performance liquid chromatography. The in-vivo study was performed in STZ-induced diabetic rats treated with optimized ONO-1301 PLGA microspheres (10 mg/kg by intramuscular or subcutaneous injection every 3 weeks). NCV was measured in the thigh 4, 8 and 12 weeks after induction.

The molecular weights of PLGA, the L/G ratio in PLGA and the particle diameter all affected the length of the sustained release period. Drug release from microspheres containing PLGA 5050 (MW 50,000, L/G 50/50), with an average diameter of about 30 µm, could be sustained for 3 weeks in vitro. In the in-vivo study, delayed NCV was significantly increased by treatment with these ONO-1301 PLGA microspheres once every 3 weeks, in comparison with vehicle only.

Local intramuscular injection of sustained-release ONO-1301 PLGA microspheres improved delayed NCV in STZ-induced diabetic rats.