In vitro assessment of the influence of intravenous extension set materials on insulin aspart drug delivery

Abstract

Insulin is a frequently prescribed drug in hospitals and is usually administered by syringe pumps with an extension line which can be made of various materials. Two insulin solutions were studied: an insulin analogue, Novorapid® which contains insulin aspart and two phenolic preservatives (e.g. phenol and metacresol) and Umuline rapide® with human insulin and metacresol as preservative. Some studies have indicated interactions between insulin, polyvinyl chloride (PVC) and polyethylene (PE). The aim of this work was to study such interactions between Novorapid® or Umuline rapide® and infusion extension line materials (PVC, PE and coextruded (PE/PVC)). Insulin solution at 1 IU/mL was infused at 2 mL/h over 24 hours with 16 different extension lines (8 in PVC, 3 in PE and 5 in PE/PVC). Ultra-Fast Liquid Chromatography with diode array detection (UFLC-DAD) was performed to quantify insulin (human and aspart) and preservatives (metacresol and phenol). Limited human insulin sorption was observed thirty minutes after the onset of infusion: 24.3 ± 12.9%, 3.1 ± 1.6% and 18.6 ± 10.0% for PVC, PE and PE/PVC respectively. With insulin aspart, sorption of about 5% was observed at the onset of infusion for all materials. However, there were interactions between phenol and especially metacresol with PVC, but no interactions with PE and PE/PVC. This study shows that insulin interacts with PVC, PE and PE/PVC at the onset of infusion. It also demonstrates that insulin preservatives interact with PVC, which may result in problems of insulin conservation and conformation. Some more studies are required to understand the clinical impact of the latter during infusion.

Capacity of Infusion Lines for Insulin Adsorption: Effect of Flow Rate on Total Adsorption

“…13 Within the Masse et al data, insulin NovoRapid recovery maintained a steady state at 98%-99% for close to 20 hours, so a slightly lower input concentration than nominally intended is a reasonable assumption. Hewson et al 7 Fuloria et al 6 Masse et al 13 Zahid et al 10 Insulin In general, for each individual experiment the adsorption capacity is higher at the higher flow rate. Despite this, there is an overall trend for lower adsorptive capacity with higher flow rate, as shown in Figure 2(b).…”

“…The data from Masse et al 13 demonstrates the importance of flow rates when considering total adsorption. Higher flow rates at high concentrations may amplify measurement error or input uncertainty with regard to the steady state, significantly affecting AUC as demonstrated in the 311.5 vs 37.7 U/m 2 adsorption capacity values.…”

“…First documented in the 1960s-1970s, [1][2][3][4][5] it has recently returned to prominence with a second burst from the late 1990s to present. [6][7][8][9][10][11][12][13][14] Importantly, while the phenomenon is well documented, no methods to quantify, predict, and thus manage this loss have emerged. Given the dangers of hypoglycemia [15][16][17] and glycemic variability, [18][19][20] as well as those of line blockages for wearable insulin pumps, [21][22][23] it is a potentially significant gap with implications for modern precision insulin therapy systems.…”

Impact of alternative materials to plasticized PVC infusion tubings on drug sorption and plasticizer release

“…This hypothesis is in good agreement with data reported by Masse et al . 3 , who showed a sorption phenomenon involving metacresol and phenol of a Novorapid diluted solution (1 UI/mL) when in contact with PVC tubings. Based on this result, drugs with an adsorption only profile such as therapeutic peptides or monoclonal antibodies should not be tested in static condition, as a dynamic test at a low flow rate appeared to be more suitable.…”

“…It can affect drug solutions by releasing compounds into the infusate or by retaining the drug (sorption) thus potentially affecting infusion safety and effectiveness. Sorption phenomena can cause a loss of active pharmaceutical ingredient (API) 1,2 or protective excipients 3 and are mediated by different physicochemical parameters/properties 4–6 that are still incorrectly evaluated. The phenomena can be detailed in two steps: adsorption then absorption.…”