Stable insulin formulations

• US 6,034,054 A
• Filed: 06/11/1998
• Issued: 03/07/2000
• 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, Dobbins, Michael Allen, Frank, Bruce Hill, Rebhun, Dawn Marie
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/096,247
• Time in Patent Office: 635 Days
• Field of Search: 530/303, 530/304, 530/305, 514/3.4
• US Class Current: 514/6.5
• 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 solution formulation comprising:

a physiologically tolerated buffer selected from the group consisting of TRIS and arginine;

a monomeric insulin analog wherein the insulin analog is Lys^B28 Pro^B29 -human insulin;

zinc; and

a phenolic preservative.

2. The formulation of claim 1, wherein the buffer is TRIS.

3. The formulation of claim 2, further comprising an isotonicity agent and wherein the pH of the formulation is between pH 7.0 and pH 8.0 when measured at a temperature of 22°

C.

4. The formulation of claim 3, wherein the concentration of Lys^B28 Pro^B29 -human insulin is between about 1.2 mg/mL and about 50 mg/mL.

5. The formulation of claim 4, wherein the concentration of Lys^B28 Pro^B29 -human insulin is between about 3.0 mg/mL and about 35 mg/mL.

6. The formulation of claim 5, wherein the concentration of Lys^B28 Pro^B29 -human insulin is between about 3.5 mg/mL and about 35 mg/mL.

7. The formulation of claim 6, wherein the concentration of Lys^B28 Pro^B29 -human insulin is between about 7 mg/mL and about 35 mg/mL.

8. The formulation of claim 7, wherein the concentration of Lys^B28 Pro^B29 -human insulin is between about 14 mg/mL and about 35 mg/mL.

9. The formulation of claim 8, wherein the concentration of Lys^B28 Pro^B29 -human insulin is between about 17.5 mg/mL and about 35 mg/mL.

10. The formulation of claim 6, wherein the phenolic preservative is a mixture of m-cresol and phenol.

11. The formulation of claim 10, wherein TRIS is present at a concentration of about 2 mg/mL;

glycerol is the isotonicity agent and is present at a concentration of about 16 mg/mL; and

wherein m-cresol is present at a concentration of about 1.76 mg/mL and phenol is present at a concentration of about 0.715 mg/mL.

13. The formulation of claim 1, which further comprises protamine.

14. A method for treating diabetes comprising administering an effective dose of the formulation of claim 1 to a patient in need thereof.

15. The method of claim 14, wherein the formulation is administered using a continuous infusion system.

16. A method for treating hyperglycemia comprising administering an effective dose of the formulation of claim 1 to a patient in need thereof.

17. The method of claim 16, wherein the formulation is administered using a continuous infusion system.

18. A method for treating diabetes comprising administering an effective dose of the formulation of claim 13 to a patient in need thereof.

19. A method for treating hyperglycemia comprising administering an effective dose of the formulation of claim 13 to a patient in need thereof.

12. A stable, soluble formulation of a monomeric insulin analog, for use in a continuous infusion system, consisting essentially of:

an isotonicity agent;

a buffer selected from the group consisting of TRIS and arginine;

Lys^B28 Pro^B29 -human insulin;

zinc; and

a phenolic preservative.