Stabilized antibody-containing liquid formulations

Patent metadata

Field	Value
Publication number	US-10022319-B2
Application number	US-201113522848-A
Country	US
Kind code	B2
Filing date	Jan 20, 2011
Priority date	Jan 20, 2010
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

The present inventors discovered that a significant stabilization effect was achieved by using an acidic amino acid, aspartic acid or glutamic acid as a counter ion species in histidine buffer or tris(hydroxymethyl)aminomethane, specifically by using histidine-aspartate buffer or histidine-glutamate buffer, or tris(hydroxymethyl)aminomethane-aspartate or tris(hydroxymethyl)aminomethane-glutamate as a buffer. The present inventors also discovered that a significant stabilization effect was achieved by using an acidic amino acid, aspartic acid or glutamic acid, as a counter ion species to a basic amino acid such as arginine, specifically by using arginine-aspartate or arginine-glutamate.

First claim

The invention claimed is:

1. A stable antibody-comprising formulation comprising a histidine-aspartate buffer or histidine glutamate-buffer, and arginine-aspartate or arginine-glutamate, wherein the pH of the formulation is 5.5 to 6.5 and wherein (a) the formulation does not substantially comprise a chloride ion and an acetate ion; (b) the concentration of the antibody in the formulation is 50 mg/mL or more; and (c) the antibody has been modified to have an isoelectric point (pI) of between 5.0 to 8.0, wherein the formulation is a liquid formulation.

2. The formulation of claim 1 comprising histidine aspartate buffer and arginine aspartate.

3. The formulation of claim 1 comprising a histidine glutamate buffer and arginine glutamate.

4. A stable antibody-comprising an anti-IL-6 receptor antibody, histidine-aspartate buffer or histidine-glutamate buffer, and arginine-aspartate or arginine-glutamate, wherein (a) the formulation does not substantially comprise a chloride ion and an acetate ion; (b) the concentration of the antibody in the formulation is 50 mg/mL or greater; and (c) the antibody has been modified to have an isoelectric point (pI) of between 5.0 to 8.0, wherein the formulation is a liquid formulation.

5. The formulation according to any one of claims 1 - 4 , which additionally comprises a sugar.

6. The formulation according to any one of claims 1 - 4 , wherein the antibody is a humanized antibody or a human antibody.

7. The formulation according to any one of claims 1 - 4 , wherein the antibody concentration is 50 to 250 mg/ml.

8. The formulation according to any one of claims 1 to 4 , wherein the viscosity of the liquid formulation is 30 mPa·s or less.

9. The formulation according to any one of claims 1 to 4 , wherein the liquid formulation is stable at 2° C. to 8° C. for at least six months.

10. The formulation according to any one of claims 1 to 4 , which has not been subjected to lyophilization during preparation of the formulation.

11. The formulation according to any one of claims 1 to 4 , which is frozen stored at −30° C. to −10° C.

12. The formulation according to claim 1 or 4 , wherein the buffer concentration is 5 to 100 mM.

13. The formulation according to claim 3 , wherein the arginine concentration is 5 to 300 mM.

14. The formulation according to any one of claims 1 to 3 , wherein the antibody is an anti-IL-6 receptor antibody.

15. The formulation according to any one of claims 1 to 4 , which is for subcutaneous administration.

16. A method for suppressing aggregation formation during frozen storage of an antibody-comprising formulation by using aspartic acid or glutamic acid as a counter ion species to a histidine buffer in the formulation, wherein the pH of the formulation is 5.5 to 6.5, and wherein the concentration of the antibody in the formulation is 50 mg/mL or more.

17. A method for suppressing aggregation formation during liquid storage of an antibody-comprising formulation by using aspartic acid or glutamic acid as a counter ion species to a histidine buffer in the formulation, wherein the pH of the formulation is 5.5 to 6.5, and wherein the concentration of the antibody in the formulation is 50 mg/mL or more.

Assignees

• Igawa Tomoyuki
• Moriyama Chifumi
• Chugai Pharmaceutical Co Ltd

Inventors

• Igawa Tomoyuki
• Moriyama Chifumi

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K39/39591 Primary

  Stabilisation, fragmentation · CPC title