Compatibility and Stability of Hyaluronidase and Hydromorphone

Abstract

ABSTRACT The stability and compatibility of the combination of three different hydromorphone concentrations (2 mg/ml, 10 mg/mL and 40 mg/mL) and hyaluronidase (150 U/mL) was evaluated over a seven day period. In addition to physical inspection and pH, solutions were assayed for hydromorphone content using a validated stability-indicating liquid chromatographic method and hyaluronidase activity using hyaluronic acid as the substrate. Each test was performed at time zero and after 1, 2, 4 and 7 days storage at 4°C, room temperature (23°C), and 37°C. The solutions were all observed to be physically compatible over the seven day study period and there was no change in the hydromorphone concentration, all concentrations remaining within 10% of the initial concentration. However, hyaluronidase activity was substantially reduced by hydromorphone during storage. The reduction in activity was dependent on the hydromorphone concentration (as the hydromorphone concentration increased there were greater reductions in hyaluronidase activity) and storage temperature (at higher temperatures hyaluronidase activity was lost at a faster rate). We conclude that although the combination is physically compatible, the chemical incompatibility which results in reduced hyaluronidase activity is such that the practice of mixing these two medications cannot be recommended. Rather, we would support the practice recommended by the manufacturer which involves injecting hyaluronidase subcutaneously into the site prior to the start of hypodermoclysis or priming the intravenous tubing with hyaluronidase. RESUME On a determine la stabilite et la compatibilite des melanges de trois concentrations differentes d'hydromorphone (2 mg/mL, 10 mg/mL et 40 mg/mL) et d'hyaluronidase (150 U/mL) sur une periode de sept jours. En plus de proceder a un examen physique et de determiner le pH des solutions, on a dose l'hydromorphone au moyen d'une technique de chromatographie en phase liquide eprouvee indiquant la stabilite de la solution et mesure l'activite de l'hyaluronidase en prenant l'acide hyaluronique comme substrat. Chaque essai a ete effecte au temps de depart et apres 1, 2, 4 et 7 jours d'entreposage a 4 °C, a temperature ambiante (23°C) et a 37°C. Les solutions sont restees physiquement compatibles durant la periode de sept jours et on n'a decele aucune modification de la concentration d'hydromorphone, celle-ci demeurant constamment a 10% de la concentration initiale. L'hydromorphone a neanmoins reduit de facon appreciable l'activite de l'hyaluronidase au cours de l'entreposage. La baisse d'activite depend de la concentration d'hydromorphone (a mesure qu'elle augmente, l'activite de l'hyaluronidase diminue) et de la temperature d'entreposage (l'activite de l'hyaluronidase diminue plus rapidement avec la hausse de la temperature). On en conclut que si les deux composes sont physiquement compatibles, l'incompatibilite chimique a l'origine de l'activite reduite de l’hyaluronidase ne permet pas de recommander la pratique qui consiste a melanger les deux medicaments. On appuierait plutot la recommandation du fabricant, a savoir injecter l'hyaluronidase sous la peau au site d'inoculation, avant de commencer l'hypodermoclyse, ou amorcer la perfusion avec l'hyaluronidase dans la tubulure.