VEGF antagonist formulations for intravitreal administration
Ophthalmic formulations of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist are provided suitable for intravitreal administration to the eye. The ophthalmic formulations include a stable liquid formulation and a lyophilizable formulation. Preferably, the protein antagonist has the amino acid sequence of residues 27-457 of SEQ ID NO:4.
1. A method of producing a lyophilized formulation of a VEGF antagonist, comprising the step of subjecting to lyophilization a prelyophilization formulation, which comprises
(a) 5-50 mg/ml of a vascular endothelial growth factor (VEGF) antagonist, comprising amino acids 27-457 of SEQ ID NO:4;
(b) 5-25 mM of sodium phosphate buffer, pH about 5.8-7.0;
(c) 0.01-0.15% of an organic co-solvent, selected from the group consisting of polysorbate, polyethylene glycol (PEG), propylene glycol, and a combination thereof; and,
(d) 1-10% of a stabilizing agent selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol, to generate a lyophilized formulation.
2. The method of claim 1 , wherein the prelyophilization formulation comprises about 20 mg/ml of the VEGF antagonist, about 10 mM sodium phosphate buffer, about 0.03% polysorbate, about 0.1% PEG, and about 2.5% sucrose, wherein the pH is about 6.2-6.3.
3. The method of claim 1 , wherein the prelyophilization formulation comprises about 20 mg/ml of the VEGF antagonist, about 5 mM sodium phosphate buffer, about 0.015% polysorbate, about 2.5% sucrose, and further comprising sodium chloride at about 20 mM, pH about 6.2-6.3.
4. The method of claim 1 , wherein the prelyophilization formulation comprises about 20 mg/ml of the VEGF antagonist, about 5 mM sodium phosphate buffer, about 0.015% polysorbate, and further comprising sodium chloride at about 67.5 mM, pH about 6.2-6.3.
5. A method of producing a lyophilized formulation of a VEGF antagonist, comprising the step of subjecting to lyophilization a prelyophilization formulation, which comprises
(a) 5-50 mg/ml of a vascular endothelial growth factor (VEGF) antagonist, comprising amino acids 27-457 of SEQ ID NO:4;
(b) 5-25 mM of a phosphate buffer, pH about 5.8-7.0;
(c) 0.01-0.15% of an organic co-solvent, selected from the group consisting of polysorbate, polyethylene glycol (PEG), propylene glycol, and a combination thereof; and
(d) 20-150 mM of a tonicity agent, to generate a lyophilized formulation.
6. The method of claim 5 , wherein the tonicity agent is sodium chloride at a concentration selected from the group consisting of 20 mM and 67.5 mM.
7. The method of claim 5 , wherein the organic co-solvent is polysorbate at 0.015%.
8. The method of claim 5 , wherein the VEGF antagonist is at a concentration selected from the group consisting of 5 mg/ml, 10 mg/ml, 20 mg/ml, and 40 mg/ml.
9. The method of claim 5 , wherein the sodium phosphate buffer is at 5 mM.