VEGF antagonist formulations for intravitreal administration

• US 9,340,594 B2
• Filed: 07/14/2014
• Issued: 05/17/2016
• Est. Priority Date: 06/16/2006
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Furfine, Eric, Dix, Daniel, Graham, Kenneth, Frye, Kelly
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): LOCKARD, JON MCCLELLAND
• Application Number:
  US14/330,096
• Publication Number:
  US 20140323983A1
• Time in Patent Office: 673 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/26 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 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: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61M 5/178 Syringes
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/4705 stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

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 an amino acid sequence of SEQ ID NO:4.

Claims

1. A pre-filled syringe suitable for intravitreal administration comprising a 1 mL luer glass syringe fitted with a plunger and a stable ophthalmic formulation of a vascular endothelial growth factor (VEGF) trap, which consists of (i) a receptor component consisting essentially of an immunoglobulin-like domain 2 of a first VEGF receptor and an immunoglobulin-like domain 3 of a second VEGF receptor, and (ii) a multimerizing component, wherein the stable ophthalmic formulation comprises:

(a) 1-100 mg/ml a VEGF antagonist;

(b) 0.01-5% of one or more organic co-solvent;

(c) 5-40 mM of buffer; and

(d) optionally comprising 1.0-7.5% of a stabilizing agent.

2. The pre-filled syringe of claim 1, wherein the first VEGF receptor is Flt1, and the second VEGF receptor is Flk1 or Flt4.

3. The pre-filled syringe according to claim 2, wherein the VEGF trap is stable for at least 4 months.

4. The pre-filled syringe according to claim 3, wherein the VEGF trap consists of amino acids 27-457 of SEQ ID NO:

4.

5. The pre-filled syringe according to claim 4, wherein the stable ophthalmic formulation comprises 40 mg/mL of the VEGF trap, 10 mM phosphate, 40 mM NaCI, 0.03% polysorbate 20, 5% sucrose, at pH 6.2-6.4.

6. The pre-filled syringe of claim 3, wherein the VEGF trap consists of the amino acid sequence of SEQ ID NO:

2.

7. The pre-filled syringe of claim 3, wherein the VEGF trap consists of the amino acid sequence of SEQ ID NO:

4.

8. The pre-filled syringe according to claim 2 wherein the VEGF trap is stable for at least 5 months.

9. The pre-filled syringe according to claim 8, wherein the VEGF trap consists of amino acids 27-457 of SEQ ID NO:

4.

10. The pre-filled syringe according to claim 9, wherein the stable ophthalmic formulation comprises 40 mg/mL of the VEGF trap, 10 mM phosphate, 135 mM NaCI, and 0.03% polysorbate 20, at pH 6.2-6.4.

11. The pre-filled syringe of claim 8, wherein the VEGF trap consists of the amino acid sequence of SEQ ID NO:

2.

12. The pre-filled syringe of claim 8, wherein the VEGF trap consists of the amino acid sequence of SEQ ID NO:

4.