Stable protein formulations comprising a molar excess of sorbitol
A stable pharmaceutical formulation comprising a protein of interest, sorbitol and polyethylene glycol (PEG). The sorbitol and protein is present in a molar ratio of 550 to 700 mole of sorbitol:1 mole of protein and the PEG to protein is present in the molar ratio of 2-50:1. The formulation optionally comprising buffer. The formulation in lyophilised form is stable for at least 4 years at 2-8° C. Also provided is a process for preparing the composition and a pharmaceutical kit comprising the same.
1. A stable pharmaceutical formulation comprising an anti-HER2 antibody in a molar concentration of 0.10 mM to 0.25 mM, a sugar alcohol consisting of sorbitol, a histidine buffer comprising from 1.0 mM to 3.0 mM L-histidine and from 1.5 mM to 3.0 mM L-histidine hydrochloride and polyethylene glycol (PEG), wherein the PEG has a molecular weight from 2000 g/mol to 5000 g/mol and wherein the sorbitol and the anti-HER2 antibody is present in a molar ratio of 550 to 700 mole of sorbitol:1 mole of the anti-HER2 antibody; wherein the PEG is present in a molar ratio of 5 to 15 mole PEG:1 mole of the anti-HER2 antibody, wherein the stable pharmaceutical formulation has a pH of 5.0-7.5.
2. The formulation as claimed in claim 1 , wherein the anti-HER2 antibody and sorbitol are present in a molar ratio of 660 mole of sorbitol:1 mole of antibody.
3. The formulation as claimed in claim 1 wherein PEG is PEG 3350.
4. The formulation as claimed in claim 1 , wherein the molar concentration of sorbitol is about 90 mM to about 120 mM.
5. The formulation as claimed in claim 1 , which is lyophilized or liquid formulation.
6. The formulation as claimed in claim 3 comprising the sorbitol, PEG 3350, the anti-HER2 antibody and histidine buffer, wherein the sorbitol to the anti-HER2 antibody is in molar ratio of 631:1 and PEG 3350 to the anti-HER2 antibody is in molar ratio of 10:1.
7. The formulation as claimed in claim 6 in a lyophilized form which is stable at 2-8° C. for at least 4 years.
8. The formulation as claimed in claim 1 , wherein the formulation does not include either of sucrose or trehalose.
9. The formulation as claimed in claim 1 , wherein the formulation further comprises L-methionine.
10. A process for preparing a stable formulation, comprising the steps of:
a) mixing an anti-HER2 antibody in a molar concentration of 0.10 mM to 0.25 mM and a sugar alcohol consisting of sorbitol in the molar ratio of 550-700 mole sorbitol:1 mole of the anti-HER2 antibody, a histidine buffer comprising from 1.0 mM to 3.0 mM L-histidine and from 1.5 mM to 3.0 mM L-histidine hydrochloride and polyethylene glycol PEG in the molar ratio of 5 to 15 mole PEG:1 mole of the anti-HER2 antibody, wherein the PEG has a molecular weight from 2000 g/mol to 5000 g/mol and wherein the stable formulation has a pH of 5.0-7.5;
b) lyophilizing the mixture; and optionally
c) reconstituting the lyophilized mixture of step (b) in a diluent such that the anti-HER2 antibody concentration is from 5 mg/ml to 50 mg/ml.
11. The process as claimed in claim 10 , wherein the lyophilized mixture further comprises a bulking agent.
12. A pharmaceutical kit comprising:
a) a container which holds a lyophilized mixture of an anti-HER2 antibody in a molar concentration of 0.10 mM to 0.25 mM, and a sugar alcohol consisting of sorbitol in a molar ratio of 550-700 mole sorbitol:1 mole of the anti-HER2 antibody, and polyethylene glycol PEG in a molar ratio of 5 to 15 mole PEG:1 mole of the anti-HER2 antibody, wherein the PEG has a molecular weight from 2000 g/ml to 5000 g/ml, wherein the mixture before lyophilization is buffered with a histidine buffer comprising from 1.0 mM to 3.0 mM L-histidine and from 1.5 mM to 3.0 mM L-histidine hydrochloride, wherein the mixture before lyophilization has a pH of 5.0-7.5; and
b) instruction for reconstituting the lyophilized mixture with a diluent.
13. The pharmaceutical kit as claimed in claim 12 , further comprising a second container which holds the diluent.
14. The pharmaceutical kit as claimed in claim 13 , wherein the diluent is selected from sterile water for injection and bacteriostatic water for injection (BWFI) comprising an aromatic alcohol.
15. The pharmaceutical kit as claimed in claim 12 , wherein the container is selected from multi-use vial and vial with stopper pierceable syringe.
16. The pharmaceutical kit as claimed in claim 12 , wherein the lyophilized formulation is stable upon storage at 2-8° C. for at least 4 years.
17. The pharmaceutical kit as claimed in claim 12 , wherein the anti-HER2 antibody is trastuzumab.