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

Abstract

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

Acknowledgments

The authors would like to thank Roberta Bucci and Stefano Bovani (Patheon Italia SpA, Ferentino, Italy), and Anne Muller, Anne Schirmer, Elodie Barret, and Marta Polin (Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) for their support with high-performance liquid chromatography measurements.

Disclosure

Both OL and DB are employees of Actelion Pharmaceuticals Ltd, manufacturer of both epoprostenol AM and epoprostenol AS. Editorial assistance was provided by Lisa Thomas from Elements Communications Ltd, Westerham, UK, and funded by Actelion Pharmaceuticals Ltd.