Stabilization of eptifibatide by cosolvents

Abstract

Eptifibatide is a potent and highly specific inhibitor of platelet receptor glycoprotein IIb/IIIa and is indicated in the treatment of acute coronary syndrome. The commercial product Integrilin® (eptifibatide) Injection requires a cold/refrigerator storage condition. In an effort to improve the drug stability for room temperature storage and transportation, this study proposed a semi-aqueous formulation that contains 2 mg/ml dose, 10% ethanol, 40% propylene glycol and 50% 0.025 M citrate buffer. A carefully designed stability study was conducted in the pH range 4.25-6.25 under accelerated temperatures: 48°C, 60°C, 72.5°C. The results indicate that the proposed semi-aqueous vehicles greatly increased eptifibatide stability in comparison with aqueous vehicles. The pH-rate profiles of eptifibatide are V-shaped with the curves for semi-aqueous vehicles lower all over the test pH range. The pH of drug maximum stability is 5.25 in the aqueous vehicle, and it is shifted to 5.75 in the semi-aqueous vehicle. Studies indicate that eptifibatide degradation may involve a few different mechanisms: the specific acid catalyzed hydrolysis which is dominant in the acidic region, and a pH-dependent oxidation which is likely to be dominant in the basic region of the test pH range. The predicted drug shelf-life T90 at 25°C shows that an almost 2-fold increase can be achieved by formulating eptifibatide in the semi-aqueous vehicle, which is 60 months at its maximum stability pH 5.75 as opposed to the 33 months in the aqueous vehicle at its maximum stability pH 5.25.