Lambert Olivier, Bandilla Dirk, Iyer Rupa, Witchey-Lakshmanan Leonore, Palepu Nagesh
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Drug Des Devel Ther. 2012;6:61-70. doi: 10.2147/DDDT.S29916. Epub 2012 Mar 28.
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).
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.
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.
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.
依前列醇用于治疗肺动脉高压（PAH），但因其在水溶液中的半衰期短而存在诸多局限性。本研究的目的是评估一种新制剂的稳定性和微生物学特性，该制剂为含精氨酸和甘露醇辅料的依前列醇钠（依前列醇AM；Veletri®；瑞士阿勒斯维尔的Actelion制药有限公司）。
当用注射用水（SWI）或注射用无菌生理盐水（0.9%氯化钠，SSI）复溶并立即稀释后，在5℃、25℃和30℃下，对一系列浓度（3000 - 30,000 ng/mL）的依前列醇AM的稳定性和微生物学特性进行研究。在25℃和30℃下，稀释后立即以及在5℃储存后，测量长达72小时的稳定性（效价随时间的变化）。通过确定效价相对于初始效价随时间的维持情况来评估保质期。对于微生物学检测，将依前列醇AM的稀释样品接种一系列细菌、酵母菌和霉菌，在5℃下培养长达14天，或在25℃下培养4天。
用SWI或SSI复溶并立即稀释至所需浓度的依前列醇AM，根据浓度不同，在25℃下稳定长达3天，在5℃下稳定长达7天。在所测试的六种微生物中，任何一种的依前列醇AM稀释溶液在长达14天的时间内均未支持微生物生长。
依前列醇AM具有改善的热稳定性，并且在长达14天的时间内不支持所测试的任何微生物生长。这种在环境条件下延长的稳定性有可能提高患者的便利性。
