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

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          Abstract

          Purpose

          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.

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          Most cited references 20

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          A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.

          Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.
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            Guidelines for the diagnosis and treatment of pulmonary hypertension.

             ,  J-L Vachiery,  M Beghetti (2009)
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              Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival.

              We sought to determine the factors associated with long-term survival in patients with primary pulmonary hypertension (PPH) treated with continuous epoprostenol infusion. Epoprostenol improves survival in patients with PPH in New York Heart Association (NYHA) functional class III or IV. However, some patients do not benefit from epoprostenol and must be considered for lung transplantation. The best timing for listing these patients on a lung transplantation program is currently unknown. Between December 1992 and January 2001, 178 patients with PPH in NYHA functional class III or IV were treated with epoprostenol. The 6-min walk test (WT) and right-sided heart catheterization were performed at baseline, after three months on epoprostenol and thereafter once a year. Overall survival rates at one, two, three, and five years were 85%, 70%, 63%, and 55%, respectively. On univariate analysis, the baseline variables associated with a poor outcome were a history of right-sided heart failure, NYHA functional class IV, 6-min WT or=12 mm Hg, and mean pulmonary artery pressure 30%, relative to baseline, were associated with poor survival. Survival of patients with PPH treated with epoprostenol depends on the severity at baseline, as well as the three-month response to therapy. These findings suggest that lung transplantation should be considered in a subset of patients who remain in NYHA functional class III or IV or in those who cannot achieve a significant hemodynamic improvement after three months of epoprostenol therapy, or both.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2012
                28 March 2012
                : 6
                : 61-70
                Affiliations
                [1 ]Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
                [2 ]TPM Laboratories Inc, Cherry Hill, NJ, USA
                [3 ]Pharma CMC/IP, Piscataway, NJ, USA
                [4 ]SciDose LLC, Amherst, MA, USA
                Author notes
                Correspondence: Olivier Lambert, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123, Allschwil, Switzerland, Tel +41 61 565 6751, Fax +41 61 565 6366, Email olivier.lambert@ 123456actelion.com
                Article
                dddt-6-061
                10.2147/DDDT.S29916
                3340107
                22563237
                © 2012 Lambert et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

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