Stability and preservation of a new formulation of epoprostenol sodium for treatment of pulmonary arterial hypertension

Olivier Lambert, Dirk Bandilla

Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

Background: The aim of this study was to evaluate the stability and microbiological properties of a formulation of epoprostenol sodium with L-arginine and sucrose excipients (epoprostenol AS).
Methods: The stability of the reconstituted solutions after storage at 5°C and 25°C, diluted solutions (3000–60,000 ng/mL) at controlled room temperature, and diluted solutions (3000–60,000 ng/mL) stored at 5°C and then at room temperature were evaluated. Solutions were prepared using sterile water for injection or sterile saline (sodium chloride 0.9%) for injection. Shelf-life was assessed by determining potency over time relative to initial potency. In this context, potency is synonymous with content. The antimicrobial activity of reconstituted (100,000 ng/mL for 0.5 mg vial, 300,000 ng/mL for 1.5 mg vial) and diluted (3000 ng/mL) epoprostenol AS was measured using an antimicrobial effectiveness test after inoculation with six species of bacteria, yeast, and mold.
Results: Reconstituted epoprostenol AS was stable for up to one day’s storage at 25°C or 7 days’ storage at 5°C. Epoprostenol AS was stable for up to 72 hours when diluted, depending on temperature and concentration. The maximum shelf-life of the diluted solution if the reconstituted solution had been stored for up to one day at room temperature or up to 7 days at 5°C, was between 24 and 72 hours, depending on concentration. Following storage of diluted solutions at 5°C for up to 8 days, maximum shelf-life was between one and 2 days, depending on temperature and concentration. Potency was not dependent on diluents. Preservative testing confirmed no microbial growth for any of six organisms tested for at least 14 days at 5°C or 25°C for the reconstituted solution and for at least 16 days at 5°C followed by one day at 25°C for the diluted solutions.
Conclusion: Epoprostenol AS has favorable thermal stability and does not support the growth of any micro-organism tested for up to 17 days. This extended stability under ambient conditions has the potential to improve convenience further for patients.

Keywords: epoprostenol, pulmonary arterial hypertension, potency, stability, shelf-life, microbiological activity