Sustained release of a water-soluble GP IIb/IIIa antagonist from copoly(dl-lactic/glycolic)acid microspheres

Sustained release of TAK-029 4-(4-amidinobenzoylglycyl)-3-methoxycarbonyl-2-oxopiperazine-l-acetic acid], a glycoprotein (GP) IIb/IIIa antagonist, from injectable microspheres was achieved by a W/O/W emulsion solvent evaporation technique using copoly(d-lactic/glycolic)acid (PLGA). Entrapment of the drug into microspheres increased with addition of sodium chloride into an external aqueous polyvinyl alcohol solution. Addition of l-arginine to an internal water phase dose-dependently reduced initial burst of the drug from the microspheres in vitro and in vivo, probably by forming hydrophobic diffusion barriers with rigid inner structure and increased glass transition temperature (T_g). Microspheres obtained using sodium chloride and l-arginine demonstrated sustained plasma levels of TAK-029 for 3 weeks after subcutaneous injection in rats, while causing a slight increase of its plasma levels in 2–3 weeks.