Mixed buffer system for stabilizing polypeptide formulations

• US 6,734,162 B2
• Filed: 12/08/2000
• Issued: 05/11/2004
• 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
• Primary Examiner(s): Wax, Robert A.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US09/733,738
• Publication Number:
  US 20010031726A1
• Time in Patent Office: 1,250 Days
• Field of Search: 514/2-4, 530/303, 530/304
• US Class Current: 530/303
• 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 polypeptide 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 method of inhibiting aggregation of a polypeptide comprising combining the polypeptide with a buffer comprising tris(hydroxymethyl)aminomethane (TRIS) mixed with a buffering molecule that does not contain a free amine group and which mitigates the change in pH that results from the formation of carbonic acid;

zinc; and

a phenolic preservative for a time and under conditions effective to inhibit aggregation.

2. The method of claim 1, wherein the buffering molecule is selected from the group consisting of acetate, phosphate and citrate.

3. The method of claim 1, wherein the buffer further comprises an isotonicity agent.

4. The method of claim 1, wherein the polypeptide is a monomeric insulin analog selected from the group consisting of LysB28ProB29-human insulin and AspB28 human insulin.

5. The method of claim 4, 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.

6. The method of claim 5, 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.

7. A method of inhibiting aggregation of a polypeptide consisting essentially of combining the polypeptide with a buffer comprising tris(hydroxymethyl)aminomethane (TRIS) mixed with a buffering molecule selected so that it does not contain a free amine group and which mitigates the change in pH that results from the formation of carbonic acid;

zinc; and

a phenolic preservative for a time and under conditions effective to inhibit aggregation.