Utilization of an amorphous form of a water-soluble GPIIb/IIIa antagonist for controlled release from biodegradable microspheres.
OBJECTIVE
We prepared injectable microspheres for controlled release of TAK-029, a water-soluble GPIIb/IIIa antagonist and discussed the characteristics of controlled release from microspheres.


METHODS
Copoly(dl-lactic/glycolic)acid (PLGA) microspheres were used for controlled release of TAK-029 [4-(4-amidinobenzoylglycyl)-3-methoxycarbonyl-2-oxopiperazine++ +-1-acetic acid]. They were prepared with a solid-in-oil-in-water (S/O/W) emulsion solvent evaporation technique using either a crystalline form or an amorphous form of the drug.


RESULTS
An amorphous form of TAK-029 gave more homogeneous S/O dispersion and higher viscosity than its crystalline 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 phase and L-arginine into an oil phase also increased entrapment of the drug, and reduced initial burst of the drug from the microspheres. The microspheres demonstrated a desirable plasma level profile in therapeutic 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 utilizing its amorphous form as a result of possible interaction with PLGA and L-arginine.
Takada
S
S
DDS Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan. Takada_Shigeyuki@takeda.co.jp
Kurokawa
T
T
Miyazaki
K
K
Iwasa
S
S
Ogawa
Y
Y
D000818:Animals; D001120:Arginine / Q000737:chemistry; D001672:Biocompatible Materials / Q000737:chemistry*; D016503:Drug Delivery Systems; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics*; D006146:Guanidines / Q000493:pharmacokinetics*; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011719:Pyrazines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001672:Biocompatible Materials; D005343:Fibrinolytic Agents; D006146:Guanidines; D011108:Polymers; D011719:Pyrazines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D001120:Arginine; C099142:TAK 029