Abstract：
OBJECTIVE: The aim of this study was to investigate the physicochemical stability of morphine-bupivacaine-ziconotide mixtures used in intrathecal analgesia in polypropylene syringes and intrathecal pumps.
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.
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.
摘要：
目的：本研究的目的是研究吗啡-布比卡因-齐科诺肽混合物用于聚丙烯注射器和鞘内泵鞘内镇痛的物理化学稳定性。
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。
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。
