Norepinephrine Compositions And Methods Therefor

What is this patent about?

’508 is related to the field of pharmaceutical formulations, specifically addressing the stability of norepinephrine solutions. Norepinephrine, a crucial medication for treating hypotension and cardiac arrest, faces challenges in maintaining its efficacy during storage. Existing formulations often require dilution, lack long-term stability, or contain antioxidants like sodium metabisulfite, which can cause allergic reactions. This patent aims to overcome these limitations by providing a ready-to-inject, antioxidant-free norepinephrine composition with improved stability.

The underlying idea behind ’508 is to formulate a stable norepinephrine solution by carefully controlling the pH and incorporating a chelating agent to minimize degradation and isomerization. The inventors discovered that a specific pH range, combined with a chelating agent and a tonicity agent, allows for a ready-to-inject formulation that remains stable over an extended period without the need for antioxidants. This approach focuses on preventing degradation pathways rather than masking them with additives.

The claims of ’508 focus on a ready-to-administer norepinephrine composition. This composition consists of an aqueous solution with a pH between 3.7 and 4.3, containing norepinephrine at a concentration of 10–100 μg/ml, where the initial norepinephrine is at least 95% the R-isomer. The solution also includes a tartrate bicarboxylic acid chelating agent at a concentration of 10–100 μg/ml and a tonicity agent. Crucially, the formulation is substantially free of antioxidants and maintains at least 90% R-isomer content after three months of storage.

In practice, the invention involves preparing an aqueous solution with a pH in the specified range, adding norepinephrine (preferably as the R-isomer), a tartrate bicarboxylic acid chelating agent, and a tonicity agent to adjust osmolality. The solution is then sterilized, often by autoclaving, and packaged for direct injection. The chelating agent binds to trace metal ions that can catalyze norepinephrine degradation, while the controlled pH minimizes both oxidation and isomerization. The absence of antioxidants reduces the risk of adverse reactions.

This formulation differentiates itself from prior approaches by eliminating the need for antioxidants while still achieving long-term stability. Previous attempts to stabilize norepinephrine involved adding antioxidants or adjusting the pH to very low levels, both of which have drawbacks. The ’508 invention provides a more elegant solution by focusing on the root causes of degradation and isomerization, resulting in a safer and more convenient ready-to-inject norepinephrine product. The use of a tartrate bicarboxylic acid as the chelating agent is also a key differentiator.