Stabilized insulin preparations

• US 4,476,118 A
• Filed: 02/04/1983
• Issued: 10/09/1984
• Est. Priority Date: 02/05/1982
• 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 E.
• Application Number:
  US06/463,730
• Time in Patent Office: 613 Days
• Field of Search: 424/178
• US Class Current: 514/6.4
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: H05K 13/06 Wiring by machine

Abstract

Novel pharmaceutical solutions of dissolved insulin having improved physical stability prepared by incorporating therein an essentially ionized zinc salt in a concentration corresponding to a content of zinc ions at the disposal of the insulin of more than 4 Zn²⁺ /hexamer insulin preferably 4.2-4.5 Zn²⁺ /hexamer insulin. The solutions exhibit a stability factor exceeding 5.

The novel insulin solutions are particularly adapted for use in continuous insulin delivery equipment.

Claims

1. An insulin solution suitable for use in continuous insulin delivery characterized by being physically stable under conditions for such delivery optionally, comprising a preserving agent, an agent rendering the solution isotonic, and a pH-buffering agent, which solution contains essentially ionized zinc in a concentration corresponding to a content of zinc ions at the disposal of the insulin of more than 4 Zn²⁺ /hexamer insulin but below the limit for Zn insulin precipitation.

2. The insulin solution according to claim 1, containing zinc ions at the disposal of the insulin in proportions less than about 4.8 Zn²⁺ /hexamer insulin.

3. The insulin solution according to claim 1 wherein the content of zinc ions at the disposal of the insulin in said solution is in the range of from about 4.2 to about 4.5 Zn²⁺ /hexamer insulin.

4. The insulin solution according to claim 1 wherein the zinc salt is zinc acetate or zinc chloride.

5. The insulin solution according to claim 1 wherein the preserving agent contains phenol and the agent rendering the solution isotonic contains glycerol.

6. The insulin solution according to claim 1 wherein the pH is in the range of about 7 to 8.

7. The insulin solution according to claim 1 wherein the the insulin concentration is in the range of 40 to 500 international insulin units per ml.

8. The insulin solution according to claim 1 further comprising a complexing agent, and wherein the total zinc content would calculate out to be at least 5 Zn²⁺ /hexamer insulin provided that the content of zinc ions at the disposal of the insulin is at least more than 4 Zn²⁺ /hexamer of insulin as foresaid.

9. The insulin solution according to claim 8 wherein the total zinc content would calculate out to be at least 6 Zn²⁺ /hexamer insulin.

10. The insulin solution according to claim 8 wherein the zinc complexing agent comprises glycine or citric acid.

11. The insulin solution according to claim 1 wherein a weak complexing agent is present, and wherein the total zinc content would calculate out to be in the range of from about 5 to about 8 Zn²⁺ /hexamer insulin provided that the content of zinc ions at the disposal of the insulin is at least more than 4 Zn²⁺ /hexamer of insulin as foresaid.

12. The insulin solution according to claim 1 further characterized by a stability factor exceeding 5.

13. The insulin solution according to claim 8 wherein the amount of zinc ions present is from about 50 to about 90% of the amount of zinc ions that would cause precipitation of zinc insulin complex.

14. The insulin solution according to claim 13 wherein the amount of zinc ions present is from about 60 to about 90% of the amount of zinc ions that would cause precipitation of zinc insulin complex.

15. The insulin solution according to claim 13 wherein the amount of zinc ions present is from about 75 to about 90% of the amount of zinc ions that would cause precipitation of zinc insulin complex.

16. A method for producing an insulin solution suitable for use in continuous insulin delivery for being physically stable under delivery conditions, optionally, comprising a preserving agent, an agent rendering the solution isotonic, and a pH buffering agent, which method comprises incorporating into said insulin solution an essentially ionized zinc salt in concentration corresponding to a content of zinc ions at the disposal of the insulin of between 4 and 5 Zn²⁺ /hexamer insulin.