Shields David E, Aclan Jennifer, Szatkowski Aaron
Elan Pharmaceuticals, Inc., South San Francisco, California.
Int J Pharm Compd. 2008 Sep-Oct;12(5):463-6.
Although the U.S. Food and Drug Administration has not approved the combined use of intrathecal medications, practitioners frequently prescribe combination intrathecal therapy for patients who do not experience adequate analgesia with a single intrathecal agent; however, the chemical stability of an analgesic combination may influence the frequency of pump refills necessary to maintain safe and efective pain control. This investigation was performed to evaluate the chemical stability of admixtures containing 25 mcg/mL ziconotide and either 1000 mcg/mL fentanyl citrate or 1000 mcg/mL sufentanil citrate during simulated intrathecal infusion under laboratory conditions at 37 deg C. Admixtures were prepared from commercial ziconotide (25 mcg/mL) and lyophilized powders of the opioid drugs, sparged with nitrogen to remove dissolved oxygen, and stored in implantable intrathecal pumps at 37 deg C. Samples obtained at various intervals over the course of 40 days were assessed for drug concentrations by using high-performance liquid chromatography. The periods of time that the admixtures retained > or = 90% and > or = 80% of the initial concentrations of each drug (i.e., the 90% and 80% stabilities) were determined by using linear regression and 95% confidence intervals. At study end, ziconotide concentrations averaged 87.5% of the initial concentration in the ziconotide/fentanyl admixture and 89.3% of the initial concentration in the ziconotide/sufentanil admixture; opioid concentrations were unchanged. Ziconotide was 90% stable for 26 days and 80% stable for 58 days (extrapolated) when combined with fentanyl; when combined with sufentanil, ziconotide was 90% stable for 33 days and 80% stable for 68 days (extrapolated). The opioids were stable throughout the study. At the concentrations used in this study, ziconotide/fentanyl and ziconotide/sufentanil admixtures were relatively stable.
尽管美国食品药品监督管理局尚未批准鞘内药物联合使用，但对于使用单一鞘内药物镇痛效果不佳的患者，医生经常会开出鞘内联合治疗的处方；然而，镇痛合剂的化学稳定性可能会影响维持安全有效的疼痛控制所需的泵注药频率。本研究旨在评估在37℃实验室条件下模拟鞘内输注过程中，含25 mcg/mL齐考诺肽与1000 mcg/mL枸橼酸芬太尼或1000 mcg/mL枸橼酸舒芬太尼的混合液的化学稳定性。混合液由市售齐考诺肽（25 mcg/mL）和阿片类药物冻干粉末配制而成，用氮气吹扫以去除溶解氧，并储存在37℃的植入式鞘内泵中。在40天的过程中，每隔一段时间采集的样本用高效液相色谱法评估药物浓度。通过线性回归和95%置信区间确定混合液中每种药物保持初始浓度≥90%和≥80%的时间（即90%和80%稳定性）。在研究结束时，齐考诺肽/芬太尼混合液中齐考诺肽浓度平均为初始浓度的87.5%，齐考诺肽/舒芬太尼混合液中齐考诺肽浓度平均为初始浓度的89.3%；阿片类药物浓度未变。齐考诺肽与芬太尼联合时，90%稳定26天，80%稳定58天（外推）；与舒芬太尼联合时，齐考诺肽90%稳定33天，80%稳定68天（外推）。在整个研究过程中，阿片类药物均稳定。在本研究使用的浓度下，齐考诺肽/芬太尼和齐考诺肽/舒芬太尼混合液相对稳定。
