Background Norepinephrine is a potent α-sympathomimetic drug which plays an important role in the acute treatment of hypotension and shock in an intensive care unit. Commercially available norepinephrine solutions contain sodium metabisulfite (Na2S2O5) as an antioxidant. However, the cyclic olefin polymer syringe used in our hospital is not compatible with sodium metabisulfite due to brown colourisation of the syringe during sterilisation.
Purpose To develop a new formulation of 0.1 mg/ml norepinephrine solution without sodium metabisulfite which is chemically stable and sterile.
Material and methods Pre-formulation tests were performed with 0.1 mg/ml norepinephrine solution with 0, 0.05% and 0.1% ascorbic acid added as an antioxidant. Other excipients were 0.1 mg/ml edetate sodium, 8 mg/ml sodium chloride and water for injections. The syringes were filled under nitrogen gassing, stored at room temperature and protected from daylight. Concentration of norepinephrine was measured at day 0, 8, 21 and 51, and 3 and 5 months with an UHPLC system with diode array detection. Based on the pre-formulation test results, the final formulation was defined and stability testing was performed measuring concentration of norepinephrine, pH, clarity, colour of solution, subvisible particles and sterility at time intervals according to ICH guidelines.
Results The norepinephrine concentration in the pre-formulation tests were 98.4%, 96.4% and 96.4% at t=5 months for, respectively, no ascorbic acid added, and 0.10% and 0.05% ascorbic acid added. Validation batches were produced with norepinephrine, edetate sodium, sodium chloride and water for injections filled under nitrogen gassing. Preliminary results show a concentration of 108.8% and 109.0% norepinephrine (10% more norepinephrine was added due to possible degradation during sterilisation based on historical data) at t=3 months.
Conclusion Norepinephrine (0.1 mg/ml) solution without sodium metabisulfite in a sterilised syringe stored at room temperature protected from daylight, is stable for at least 3 months.
Reference and/or acknowledgements Larmené-Beld K, Kuiper A, van Berkel S, et al. A science- and risk-based strategy to qualify sterilised prefilled syringes as primary packaging material in a hospital pharmacy. Abstract submitted for 24th EAHP Congress 2019.
No conflict of interest.