Influence of pH and temperature on ziconotide stability in intrathecal analgesic admixtures in implantable pumps and syringes

Abstract

Purpose: The aim of our study was to investigate the influence of pH and temperature on the stability of ziconotide in analgesic admixtures containing morphine and ropivacaine.

Methods: All admixtures were combined using a wide range of concentrations, in implantable pumps and syringes, using temperatures from 4°C to 37°C. Quantification was made thanks to a specific chromatographic technique. pH has also been measured throughout the study.

Results: Admixtures confirm excellent stability for morphine and ropivacaine. Concerning ziconotide, an acid hydrolysis has been observed, reducing the time of use of our admixtures in a significant way, but producing non-toxic degradation products. The degradation was linear in all conditions. Inside the implantable pumps at body temperature turned out to be the best conditions for lower protein breakdown. Finally the degradation process showed a high correlation with the pH and the morphine concentration with a median loss of concentration delay due to degradation of 3.5 days [3; 5] when pH<4.5 and 13 days [13; 24] when pH ≥ 4.5.

Conclusion: Our admixtures showed different stability depending on the drug concentrations, pH and temperature. The great majority of mixtures in real life in our institution have stability highly compatible with our practice and with the delay between two pump refilling.

Keywords: Analgesia; Intrathecal; Methionine (PubChem CID: 6137); Morphine; Morphine sulphate (PubChem CID: 5464280); Ropivacaine; Ropivacaine (PubChem CID: 175805); Stability; Ziconotide; Ziconotide (PubChem CID: 16129690).