Prefilled Cyclic Olefin Sterilized Syringes of Norepinephrine Injection Solution Do Not Need to Be Stabilized by Antioxidants.

ABSTRACT

Norepinephrine is a potent α-sympathomimetic drug which plays an important role in the acute treatment of hypotension and shock. Commercially available norepinephrine solutions contain sodium metabisulfite (Na2S2O5) as an antioxidant. However, prefilled cyclic olefin polymer syringes are not compatible with sodium metabisulfite. The aim of this study was to develop a new formulation of 0.1-mg/mL norepinephrine solution without sodium metabisulfite which is chemically stable and sterile and can be stored in prefilled polymer syringes. Formulation studies were performed with 0.1-mg/mL norepinephrine solution with 0, 0.05, or 0.1% ascorbic acid added as antioxidant. The syringes were filled under nitrogen gassing, stored at 20 ± 5°C, and protected from daylight. Based on the formulation test results, the final formulation was defined and stability testing at 20 ± 5°C was performed measuring norepinephrine concentration, pH, clarity, color of the solution, subvisible particles, and sterility at time intervals up to 12 months. The norepinephrine concentrations at t = 22 weeks were 100.4%, 95.4%, and 92.2% for the formulations with no ascorbic acid and with 0.05% and 0.10% ascorbic acid, respectively. Three batches for the stability study were produced containing norepinephrine, sodium edetate, sodium chloride, and water for injections filled under nitrogen gassing and stored at 20 ± 5°C. Norepinephrine concentrations were respectively 98.8%, 98.6%, and 99.3% for batches 1, 2, and 3 at t = 12 months. It can be concluded that norepinephrine (0.1 mg/mL) solution without metabisulfite is stable for at least 12 months at room temperature when protected from daylight.