Stability and microbiological properties of a new formulation of epoprostenol sodium when reconstituted and diluted

Abstract

Olivier Lambert1, Dirk Bandilla1, Rupa Iyer2, Leonore Witchey-Lakshmanan3, Nagesh Palepu41Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; 2TPM Laboratories Inc, Cherry Hill, NJ, USA; 3Pharma CMC/IP, Piscataway, NJ, USA; 4SciDose LLC, Amherst, MA, USAPurpose: Epoprostenol, used for the treatment of pulmonary arterial hypertension (PAH), has a number of limitations related to its short half-life in aqueous solution. The aim of this study was to evaluate the stability and microbiological properties of a new formulation, namely epoprostenol sodium with arginine and mannitol excipients (epoprostenol AM; Veletri®; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland).Methods: Stability and microbiological properties of epoprostenol AM were investigated at 5°C, 25°C, and 30°C over a range of concentrations (3000–30,000 ng/mL) when reconstituted and immediately diluted with sterile water for injection (SWI) or sterile saline (sodium chloride 0.9%) for injection (SSI). Stability (change in potency over time) for up to 72 hours at 25°C and 30°C was measured immediately following dilution and after storage at 5°C. Shelf-life was assessed by determining the maintenance of potency over time relative to initial potency. For microbiological testing, diluted samples of epoprostenol AM were inoculated with a range of bacteria, yeasts, and molds for up to 14 days at 5°C or 4 days at 25°C.Results: Epoprostenol AM reconstituted and immediately diluted to the required concentration with SWI or SSI was stable for up to 3 days at 25°C and up to 7 days at 5°C depending on the concentration. None of the diluted epoprostenol AM solutions supported microbial growth for any of the six organisms tested for up to 14 days.Conclusions: Epoprostenol AM has improved thermal stability and does not support the growth of any microorganism tested for up to 14 days. This extended stability under ambient conditions has the potential to improve convenience for patients.Keywords: stability, epoprostenol, formulation, microbial activity, diluents, pulmonary arterial hypertension