Assessment of the Mixing Efficiency of Neutral Protamine Hagedorn Cartridges

Abstract

Abbreviations: (HPLC) AbstractReliable application of neutral protamine Hagedorn (NPH) insulin requires previous resuspension of the suspension by tipping over the cartridge 20 times. This procedure is considered annoying by patients. The goal of this investigation was to assess the efficiency of the mixing procedure when performed less frequently than recommended. Neutral protamine Hagedorn insulin cartridges from five different manufacturers (sanofi-aventis, Lilly, Berlin-Chemie, B. Braun, and Novo Nordisk) were emptied with doses of 28 IU in the morning and the evening over 5 days. While the first dose was obtained after a regular resuspension procedure (20× tipping over), the consecutive doses were obtained after 3, 6, 10, or 20 mixing procedures (12 cartridges per experimental series, two doses/day). Insulin concentrations of doses 1, 2, 6, and 10 were determined by highpressure liquid chromatography. Between dosing, cartridges were stored at room temperature in a horizontal position. Comparable insulin concentrations were seen in the first correctly prepared doses. Pronounced and substantial deviations from the selected dose were observed with most of the cartridges, in particular when resuspending only 3 and 6 times. Mean absolute percentage deviations when tipping 3 times and maximally observed overdoses were: Insuman basal: 1.1 ± 1.0%/4 IU, Humulin N: 2.6 ± 3.4%/19 IU, Berlinsulin H basal: 4.4 ± 6.0%/26 IU, Insulin B. Braun basal: 10.4 ± 8.9%/38 IU, and Protaphane: 4.7 ± 4.1%/19 IU (all p < 0.05 vs Insuman basal). Only one cartridge with three metal mixing bullets (sanofi-aventis) was resuspended efficiently with only a few mixing procedures. All other cartridges with fewer bullets were shown to deliver potentially harmful doses if used for treatment when the mixing procedure was less frequent than demanded in the instructions for use.

Pharmacokinetics and Pharmacodynamics of NPH Insulin in Type 1 Diabetes: The Importance of Appropriate Resuspension Before Subcutaneous Injection

“…The wide fluctuations in plasma glucose control reported in subjects with T1DM who do not adequately resuspend NPH insulin before injection (10) are likely explained by the PK/PD results of the current study. A large part of the reported variability of NPH insulin (5-7,10,18) is possibly explained by a lack of or insufficient resuspension before injection, as shown in the current study; thus, the variability of NPH insulin might be substantially decreased in the everyday life of patients with diabetes by simply adhering to the long-well-known recommendation of resuspending NPH insulin before injection, no matter the manufacturer (19). In fact, the major insulin companies all recommend injecting NPH insulin at room temperature after full resuspension obtained with at least 10-20 times of tipping the pen to allow full movement of the small glass ball present in the Novo Nordisk FlexPen and Lilly KwikPen or the three small metal balls of the Sanofi Lantus SoloSTAR pen.…”

“…However, the fact that differences are quite evident with so few subjects speaks in favor of the importance of the resuspension process as a main factor in determining PK/PD of injected NPH insulin. The study examined NPH insulin from only one manufacturer (Novo Nordisk), but it is assumed that NPH insulin from other manufacturers would result in similar characteristics (19) and action profiles at least in subjects without diabetes (24). In the present study, the effect of NPH insulin was examined for 24 h after administration of a 0.35 units/kg dose, mimicking the subjects' prior daily basal insulin need (Supplementary Table 1).…”

Comparison of Insulin Degludec/Insulin Aspart and Biphasic Insulin Aspart 30 in Uncontrolled, Insulin-Treated Type 2 Diabetes: A Phase 3a, Randomized, Treat-to-Target Trial

“…Therefore, IDegAsp provides full 24-h coverage of basal insulin requirements as shown by a distinct peak action due to prandial IAsp and separate and stable basal action from IDeg (20). The low variability of the IDeg component reported at steady state over a 24 h period (12,21) could further contribute to the low rates of hypoglycemia observed with IDegAsp.…”

“…As a soluble coformulation, IDegAsp does not require resuspension, which eases administration (11) and, more importantly, eliminates the risk of incomplete mixing and therefore increased hypoglycemia (12). In solution, the individual components of IDegAsp exist separately as di-hexamers (IDeg) and hexamers (IAsp) (13).…”

An Analysis of the Mixing Efficiency of Neutral Protamine Hagedorn Cartridges

“…In this issue of Journal of Diabetes Science and Technology, Kaiser and colleagues 11 conducted an investigation to identify variations in the delivered dose of several different NPH insulin brands that use glass and metal bodies ("bullets") to facilitate mixing. Using a strategy where multiple pens from each of five different NPH insulin products (Insuman Basal, sanofi-aventis, three metal bullets; Humulin N, Lilly, one glass bullet; Berlinsulin H Basal, Berlin-Chemie, one glass bullet; Insulin B. Braun Basal, two glass bullets; and Protaphane Penfill, NovoNordisk, one glass bullet) were compared at multiple sampling points and over a range of mixing procedures (3, 6, 10, and 20 times), the authors identified deviations in the delivered dose of insulin at initial use and with repeated dosing.…”