METHODS: The stability study method was conceived according to International Council for Harmonisation guidelines. For propylene syringes, six different mixtures of morphine-bupivacaine and ziconotide were assessed over seven days. Two storage temperatures were tested (5 °C ± 3 °C and 25 °C ± 2 °C). For implantable pumps, nine different mixtures were assessed over 60 days and stored at 37 °C. Assays were performed using ultrahigh-pressure liquid chromatography. Turbidity and pH also were measured throughout the study.
RESULTS: Results confirmed excellent physicochemical stability for morphine and bupivacaine in the study for all conditions investigated (pumps at 37 °C, polypropylene syringes at 5 °C ± 3 °C and 25 °C ± 2 °C). Concerning ziconotide, after seven days, our study showed that every 95% confidence interval calculated had lower bounds >90% for all mixtures stored in polypropylene syringes. In implantable pumps, a decrease of the concentration was observed in all the mixtures studied. Moreover, the appearance of a degradation product confirmed the ziconotide degradation.
CONCLUSIONS: All results are in favor with a physicochemical stable preparation for six mixture profiles when stored in polypropylene syringes at 5 °C ± 3 °C and 25 °C ± 2 °C. For mixtures stored in implantable pumps, the efficacy should decrease over time owing to the degradation of ziconotide. A trade-off between high morphine concentration and increased refill interval will need to be found by clinicians.
方法:稳定性研究方法是根据国际协调理事会指南构思的。对于丙烯注射器,在7天内对6种不同的吗啡-布比卡因和齐康诺肽混合物进行了评估.测试两个储存温度(5°C±3°C和25°C±2°C)。对于植入式泵,在60天内评估九种不同的混合物,并在37°C下储存。使用超高压液相色谱法进行测定。在整个研究中还测量浊度和pH。
结果:结果证实,在研究的所有条件下,吗啡和布比卡因在研究中具有优异的物理化学稳定性(泵在37°C,聚丙烯注射器在5°C±3°C和25°C±2°C)。关于ziconotide,七天后,我们的研究表明,对于储存在聚丙烯注射器中的所有混合物,计算出的每95%置信区间的下限>90%.在植入式泵中,在所有研究的混合物中观察到浓度的降低。此外,降解产物的出现证实了齐科诺肽的降解。
结论:当在5°C±3°C和25°C±2°C下储存在聚丙烯注射器中时,对于六种混合物曲线的物理化学稳定制备,所有结果都是有利的。对于储存在可植入泵中的混合物,由于齐托诺肽的降解,功效应随着时间的推移而降低。临床医生需要在高吗啡浓度和增加的再填充间隔之间进行权衡。