Stabilized insulin preparations and method for their production

• US 4,472,385 A
• Filed: 03/09/1982
• Issued: 09/18/1984
• Est. Priority Date: 03/10/1981
• Status: Expired due to Term

• Current Assignee: NOVO Industri A/S Bagsvaerd
• Original Assignee: Novo Industri A/S (Novo Nordisk A/S)
• Inventors: Havelund, Svend, Brange, Jens J. V.
• Primary Examiner(s): WADDELL, FREDERICK
• Application Number:
  US06/356,343
• Time in Patent Office: 924 Days
• Field of Search: 260/112.7, 424/178, 424/153, 424/154
• US Class Current: 514/6.4
• CPC Class Codes: A61K 38/28 Insulins

Abstract

Novel pharmaceutical preparations of dissolved insulin having improved physical stability particularly adapted for use in continuous insulin delivery equipment prepared by incorporating therein a calcium or magnesium salt so as to provide a solution containing essentially ionized calcium or magnesium in insulin stabilizing concentrations.

The magnesium or calcium ions concentrations are with the range of about 0.4×10^-3 to 10^-2 molar.

Claims

1. An insulin preparation adapted to use in continuous insulin infusion systems consisting essentially of zinc insulin in solution, a preserving agent and, optionally, a non-ionizing osmotic pressure regulating agent and/or a buffering agent which does not form complex or slightly soluble compounds with calcium or magnesium ions, which preparation contains calcium or magnesium ions at a concentration within the range of about 0.4×

10^-3 molar to about 10^-2 molar but insufficient to induce precipitation therein under normal conditions, the calcium or magnesium imparting physical stability to said solution, the pH of said preparation being within the range of 7 to 8.

2. The insulin preparation according to claim 1, wherein the calcium or magnesium ions are furnished as salts of hydrochloric, sulfuric or nitric acid.

3. The insulin preparation according to claim 1, wherein the ion is calcium.

4. The insulin preparation according to claim 1, wherein the insulin concentration is in the range of from 5 to 1500 international insulin units per ml.

5. The insulin preparation according to claim 4 wherein the insulin is in the range of from 40-1000 international insulin units per ml.

6. A method of stabilizing zinc insulin for use in continuous insulin infusion systems comprising bringing insulin into solution together with an essentially ionizable calcium or magnesium salt to impart stability to the insulin solution, in concentration within the range of about 0.4×

10^-3 to 10^-2 molar but insufficient to induce insulin precipitation therein under normal conditions;

further adding a preserving agent and, optionally, a non-ionizing osmotic pressure regulating agent and/or a buffering agent which does not form complex or slightly soluble compounds with calcium or magnesium ions.

7. The method of claim 6, wherein the insulin and preserving agent, the latter optionally in the presence of osmotic pressure regulating agent and/or buffering agent, are dissolved separately and then admixed before the calcium or magnesium salt is added.