Stable insulin formulations

• US 6,906,028 B2
• Filed: 10/03/2002
• Issued: 06/14/2005
• Est. Priority Date: 06/13/1997
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Li, Shun, DeFelippis, Michael Rosario, Frank, Bruce Hill, Rebhun, Dawn Marie, Dobbins, Michael Allen
• Primary Examiner(s): Tate, Christopher
• Assistant Examiner(s): TELLER, ROY R
• Application Number:
  US10/264,176
• Publication Number:
  US 20030104983A1
• Time in Patent Office: 985 Days
• Field of Search: 514/3, 514/4, 514/12, 530/303, 530/304, 530/305
• US Class Current: 514/6.3
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention provides a monomeric insulin analog formulation stabilized against aggregation in which the buffering agent is either TRIS or arginine. The stable formulations of the present invention are useful for treating diabetes, and are particularly advantageous in treatment regimes requiring lengthy chemical and physical stability, such as, in continuous infusion systems.

Claims

1. A method for treating diabetes comprising administering an effective dose of a solution formulation, the solution formulation comprising

a physiologically tolerated buffer selected from the group consisting of 2-amino-2-hydroxymethyl-1,3-propanediol and arginine;

a monomeric insulin analog;

zinc;

a phenolic preservative; and

an isotonicity agent,

wherein the solution formulation is administered using a continuous infusion system.

2. The method of claim 1, wherein the solution formulation is a stable formulation.

3. The method of claim 1, wherein the buffer is 2-amino-2-hydroxymethyl-1,3-propanediol.

4. The method of claim 1, wherein the monomeric insulin analog is Asp^B28-human insulin.

5. The method of claim 1, wherein the monomeric insulin analog is Lys^B28Pro^B29-human insulin.

6. The method of claim 1, wherein the pH of the formulation is between pH 7.0 and pH 8.0 when measured at a temperature of 22°

C.

7. The method of claim 1, wherein the concentration of the monomeric insulin analog is between about 1.2 mg/mL and about 50 mg/mL.

8. The method of claim 7, wherein the concentration of the monomeric insulin analog is between about 3.0 mg/mL and about 35 mg/mL.

9. The method of claim 4, wherein the concentration of Asp^B28-human insulin is between about 1.2 mg/mL and about 50 mg/mL.

10. The method of claim 9, wherein the concentration of Asp^B28-human insulin is between about 3.0 mg/mL and about 35 mg/mL.

11. The method of claim 5, wherein the concentration of Lys^B28Pro^B29-human insulin is between about 1.2 mg/mL and about 50 mg/mL.

12. The method of claim 11, wherein the concentration of Lys^B28Pro^B29-human insulin is between about 3.0 mg/mL and about 35 mg/mL.

13. A method for treating hyperglycemia comprising administering an effective dose of a solution formulation, the solution formulation comprising

a physiologically tolerated buffer selected from the group consisting of 2-amino-2-hydroxymethyl-1,3-propanediol and arginine;

a monomeric insulin analog;

zinc;

a phenolic preservative; and

an isotonicity agent,

wherein the solution formulation is administered using a continuous infusion system.

14. The method of claim 13, wherein the solution formulation is a stable formulation.

15. The method of claim 13, wherein the buffer is 2-amino-2-hydroxymethyl-1,3-propanediol.

16. The method of claim 13, wherein the monomeric insulin analog is Asp^B28-human insulin.

17. The method of claim 13, wherein the monomeric insulin analog is Lys^B28Pro^B29-human insulin.

18. The method of claim 13, wherein the pH of the formulation is between pH 7.0 and pH 8.0 when measured at a temperature of 22°

C.

19. The method of claim 13, wherein the concentration of the monomeric insulin analog is between about 1.2 mg/mL and about 50 mg/mL.

20. The method of claim 19, wherein the concentration of the monomeric insulin analog is between about 3.0 mg/mL and about 35 mg/mL.

21. The method of claim 16, wherein the concentration of Asp^B28-human insulin is between about 1.2 mg/mL and about 50 mg/mL.

22. The method of claim 21, wherein the concentration of Asp^B28-human insulin is between about 3.0 mg/mL and about 35 mg/mL.

23. The method of claim 17, wherein the concentration of Lys^B28Pro^B29-human insulin is between about 1.2 mg/mL and about 50 mg/mL.

24. The method of claim 23, wherein the concentration of Lys^B28Pro^B29-human insulin is between about 3.0 mg/mL, and about 35 mg/mL.