Stabilized antibody-containing liquid formulations
An objective of the present invention is to provide stable antibody-containing formulations which are suitable for subcutaneous administration and in which aggregation formation is suppressed during long-term storage. 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.
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.