S. Takada et al., UTILIZATION OF AN AMORPHOUS FORM OF A WATER-SOLUBLE GPIIB IIIA ANTAGONIST FOR CONTROLLED-RELEASE FROM BIODEGRADABLE MICROSPHERES/, Pharmaceutical research, 14(9), 1997, pp. 1146-1150
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.