Parenteral formulation development of renin inhibitor Abbott-72517.

Abstract

Abbott-72517 is an inhibitor of human renin and is being investigated for the treatment of hypertension. It is an orally bioavailable candidate which is being developed for oral as well as intravenous use. The preclinical development of this molecule involved studies to evaluate irritation at the site of injection in an animal model. Several formulation variables such as drug concentration, types of buffer (citrate or acetate), addition of cosolvent (ethanol) to enhance drug solubility, and tonicity modifiers such as glycerin or mannitol were evaluated. Additionally, in vitro formulation--whole blood hemolysis and plasma precipitation studies were conducted. Based on these studies, a liquid formulation containing 1.2 mg/mL Abbott-72517.HCl as base, 0.01M citrate buffer, pH 3.7, in 0.45% sodium chloride containing 2.5% mannitol was recommended for preclinical studies. Various processing and administration parameters were evaluated including filter qualification and compatibility of the drug with typical infusion fluids and administration sets. The liquid formulation was further characterized for physical and chemical stability. It was shown that it has acceptable stability at ambient temperature. Based on the accelerated temperature storage results, T90 at 25 degrees C is > 1 year for the ready-to-use liquid formulation. Additionally, a lyophilized version of the liquid formulation was evaluated.