Mixed buffer system for stabilizing polypeptide formulations

• US 20010031726A1
• Filed: 12/08/2000
• Published: 10/18/2001
• Est. Priority Date: 01/24/2000
• Status: Active Grant

• Current Assignee: Minimed, Inc. (Medtronic Plc)
• Original Assignee: Minimed, Inc. (Medtronic Plc)
• Inventors: Gulati, Poonam S., Van Antwerp, William Peter
• Granted Patent: US 6,734,162 B2
• Time in Patent Office: Days
• US Class Current: 514/4
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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 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 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention is a pharmaceutical composition for polypeptdes which are not stably soluble. A preferred polypeptide is monomeric insulin and a preferred formulation consists of a TRIS-phosphate combination buffer, zinc; a phenolic preservative and an isotonicity agent such as glycerol.

Claims

1. A solution formulation comprising:

(a) a physiologically tolerated mixed buffer system comprising TRIS combined with a buffering molecule which;

(i) absorbs carbon dioxide; and

(ii) does not contain a free amine group; and

(b) a polypeptide.

2. The formulation of

claim 1

, wherein the polypeptide is prone to aggregation.

3. The formulation of

claim 1

, further comprising zinc, wherein the zinc forms a stabilizing complex with the polypeptide.

4. The formulation of

claim 1

, further comprising a phenolic preservative.

5. The formulation of

claim 1

, wherein the buffering molecule is selected from the group consisting of acetate, phosphate and citrate.

6. The formulation of

claim 5

, wherein the buffering molecule is phosphate.

7. The formulation of

claim 4

further comprising an isotonicity agent.

8. The formulation of

claim 7

, wherein the polypeptide is insulin.

9. The formulation of

claim 8

, wherein the insulin is a monomeric insulin analog selected from the group consisting of LysB28ProB29-human insulin and AspB28 human insulin.

10. The formulation of

claim 8

, wherein TRIS is present at a concentration of about 1.5 mg/ml to about 4.5 mg/ml;

phosphate is present at a concentration of about 0.2 mg/ml to about 2.5 mg/ml, insulin is present at a concentration of about 250 to about 1000 U/ml, zinc is present at a concentration of about 0.07 μ

g/ml to about 0.09 μ

g/ml, m-cresol is present at a concentration of about 2.2 mg/ml, phenol is present at a concentration of about 0.9 mg/nl and glycerol is the isotonicity agent and is present at a concentration of about 16 mg/ml.

11. The formulation of

claim 10

, wherein TRIS is present at a concentration of about 2 mg/ml to about 3 mg/ml and phosphate is present at a concentration of about 0.5 mg/ml to about 1.5 mg/ml.

13. A method for treating diabetes comprising administering an effective dose of the formulation of

claim 8

to a patient in need thereof.

14. A method for treating diabetes comprising administering an effective dose of the formulation of

claim 8

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

15. A method for treating hyperglycemia comprising administering an effective dose of the formulation of

claim 8

to a patient in need thereof.

16. The method of

claim 15

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

18. A process for preparing the monomeric insulin analog formulation of

claim 9

comprising the steps of combining a physiologically-tolerated mixed buffer system comprising TRIS combined with a buffer selected from the group consisting of phosphate buffer, acetate buffer and citrate buffer;

with the monomeric insulin analog;

zinc; and

a phenolic preservative.

12. The formulation of 8 for use in a continuous infusion system.

17. A stable, soluble formulation of insulin for use in a continuous infusion system, comprising:

an isotonicity agent;

a mixed buffer system comprising TRIS combined with a buffer selected from the group consisting of phosphate buffer, acetate buffer and citrate buffer;

insulin;

zinc; and

a phenolic preservative.

19. A method of stabilizing a polypeptide prone to aggregation comprising combining the peptide with a physiologically-tolerated mixed buffer system comprising TRIS mixed with a buffering molecule that does not contain a free amine group and which counteracts carbon dioxide;

zinc; and

a phenolic preservative.

20. The method of

claim 19

, wherein the buffering molecule is selected from the group consisting of acetate, phosphate and citrate.

21. The method of

claim 19

, wherein the mixed buffer system further comprises an isotonicity agent.

22. The method of

claim 19

, wherein the polypeptide is a monomeric insulin analog selected from the group consisting of LysB28ProB29-human insulin and AspB28 human insulin.

23. The method of

claim 22

, wherein TRIS is present at a concentration of about 1.5 mg/ml to about 4.5 mg/ml;

phosphate is present at a concentration of about 0.2 mg/ml to about 2.5 mg/ml, the monomeric insulin analog is present at a concentration of about 250 to about 1000 U/ml, zinc is present at a concentration of about 0.07 μ

g/ml to about 0.09 μ

g/ml, m-cresol is present at a concentration of about 2.2 mg/ml, phenol is present at a concentration of about 0.9 mg/ml and glycerol is the isotonicity agent and is present at a concentration of about 16 mg/ml.

24. The method of

claim 23

, wherein TRIS is present at a concentration of about 2 mg/ml to about 3 mg/ml and phosphate is present at a concentration of about 0.5 mg/ml to about 1.5 mg/ml.