Is insulin diluted when stored in water?

BACKGROUND: Insulin storage is a challenge in resource-poor countries. In Uganda, patients were noted to store insulin vials by submerging them in water. OBJECTIVE: To examine whether withdrawing insulin from a vial without adding air back causes a vacuum which allows water to enter the vial, resulting in insulin dilution. METHODS: Seven hundred units of insulin were withdrawn from forty 10 mL vials of 100 units/mL insulin [20 neutral protamine hagedorn (NPH), 20 regular]. In half, air was added back. The vials were weighed (baseline). Half of the vials (10 with added air, 10 without) were submerged in water for 24 h and then air-dried for 24 h. Vials that were not submerged sat at room temperature for 48 h. All vials were weighed 48 h from baseline. RESULTS: Addition of air did not impact the change in weight after submersion (air added: -0.002 ± 0.001 g or -0.2 ± 0.1 unit; no air added: -0.003 ± 0.000 g or -0.3 ± 0 unit, p = 0.57). In a subset of vials in which an additional 240 units were withdrawn before submersion for another 24 h, there was still no difference in weight change in those vials with air added (p = 0.2). CONCLUSION: Withdrawing insulin from a vial without adding air did not result in uptake of water or dilution of insulin in the submerged vial, although it made drawing up the insulin easier. This study did not address the larger concern of bacterial contamination of the rubber stopper during water storage.

Characteristics of commercially manufactured and compounded protamine zinc insulin.

OBJECTIVE: To evaluate and compare characteristics of a commercially manufactured protamine zinc insulin (PZI) product and PZI products obtained from various compounding pharmacies. DESIGN: Evaluation study. SAMPLE: 112 vials of PZI (16 vials of the commercially manufactured product and 8 vials from each of 12 compounding pharmacies) purchased over an 8-month period. PROCEDURES: Validated methods were used to analyze 2 vials of each product at 4 time points. Appearance, endotoxin concentration, crystal size, insulin concentration in the supernatant, pH, total insulin and zinc concentrations, and species of insulin origin were evaluated. RESULTS: All 16 vials of commercially manufactured PZI met United States Pharmacopeia (USP) specifications. Of 96 vials of compounded PZI, 1 (1 %) contained a concentration of endotoxin > 32 endotoxin U/mL, 23 (24%) had concentrations of insulin in the supernatant > 1.0 U/mL, and 45 (47%) had pH values < 7.1 or > 7.4; all of these values were outside of specifications. Several vials of compounded PZI (52/96 [54%]) did not meet specifications for zinc concentration (0.06 to 0.1 mg/mL for 40 U of insulin/mL, 0.075 to 0.12 mg/mL for 50 U of insulin/mL, and 0.15 to 0.25 mg/mL for 100 U of insulin/mL), and total insulin concentration in 36 [38%] vials was < 90% of the labeled concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Only 1 of 12 compounded PZI products met all USP specifications in all vials tested. Use of compounded PZI insulin products could potentially lead to serious problems with glycemic control in veterinary patients.

Assessment of the mixing efficiency of neutral protamine Hagedorn cartridges.

Reliable 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 (20x 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 high-pressure 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.