UTILIZATION OF AN AMORPHOUS FORM OF A WATER-SOLUBLE GPIIB IIIA ANTAGONIST FOR CONTROLLED-RELEASE FROM BIODEGRADABLE MICROSPHERES/

Purpose. We prepared injectable microspheres for controlled release of TAK-029, a water-soluble GPIIb/IIIa antagonist and discussed the char acteristics of controlled release from microspheres. Methods. Copoly(d l-lactic/glycolic)acid (PLGA) microspheres were used for controlled re lease of TAK-029 lglycyl)3-methoxycarbonyl-2-oxopiperazine-1-acetic ac id]. They were prepared with a solid-in-oil-in-water (S/O/W) emulsion solvent evaporation technique using either a crystalline form or an am orphous form of the drug. Results. An amorphous form of TAK-029 gave m ore homogeneous S/O dispersion and higher viscosity than its crystalli ne form when added to dichloromethane solution of PLGA, resulting in a high drug entrapment into microspheres and a well-controlled release of the drug. Additions of sodium chloride into an external aqueous pha se and L-arginine into an oil phase also increased entrapment of the d rug, and reduced initial bunt of the drug from the microspheres. The m icrospheres demonstrated a desirable plasma level profile in therapeut ic range (20-100 ng/ml) for 3 weeks in rats after single subcutaneous injection. Conclusions. A well-controlled release of TAK-029, a water- soluble neutral drug, with small initial burst was achieved by utilizi ng its amorphous form as a result of possible interaction with PLGA an d L-arginine.