Stable liquid formulations of dimer VEGF antagonists

• US 9,416,167 B2
• Filed: 11/21/2014
• Issued: 08/16/2016
• Est. Priority Date: 03/25/2005
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Dix, Daniel, Frye, Kelly, Kautz, Susan
• Primary Examiner(s): STOICA, ELLY GERALD
• Application Number:
  US14/550,385
• Publication Number:
  US 20150079087A1
• Time in Patent Office: 634 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4172 Imidazole-alkanecarboxylic acids, e.g. histidine
• CPC Class Codes: A61K 31/7012 Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid gluconic acid A61K31/191; ascorbic acid A61K31/375
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 9/08 Solutions composition of solutions A61K47/00
• 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: 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2318/20 : Antigen-binding scaffold molecules wherein the scaffold is not an immunoglobulin variable region or antibody mimetics
• 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
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Formulations of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist are provided including a pre-lyophilized formulation, a reconstituted lyophilized formulation, and a stable liquid formulation. Preferably, the fusion protein has the sequence of SEQ ID NO:4.

Claims

1. A stable pharmaceutical formulation comprising:

(a) 50-100 mg/mL of a vascular endothelial growth factor (VEGF) antagonist fusion protein dimer consisting of two identical fusion polypeptides consisting essentially of (i) the immunoglobulin-like domain 2 of the human Flt1 VEGF receptor, (ii) the immunoglobulin-like domain 3 of the human Flk1 or the human Flt4 VEGF receptor, and (iii) an immunoglobulin Fc domain;

(b) 5-50 mM histidine;

(c) 0.1-3.0% polyethylene glycol (PEG) 3350;

(d) 0.24-3.0% glycine; and

(e) 0.5-6.0% sucrose, pH 6.3-6.5.

2. The stable pharmaceutical formulation of claim 1, wherein the two identical fusion polypeptides consist of amino acids 27-457 of SEQ ID NO:

4.

3. The stable pharmaceutical formulation of claim 2, wherein the VEGF antagonist fusion protein dimer is at a concentration of 50 mg/mL.

4. The stable pharmaceutical formulation of claim 3, wherein the histidine is at a concentration of 10 mM.

5. The stable pharmaceutical formulation of claim 4, wherein the PEG 3350 is at a concentration of 1.5%.

6. The stable pharmaceutical formulation of claim 5, wherein the glycine is at a concentration of 0.75%.

7. The stable pharmaceutical formulation of claim 6, wherein the sucrose is at a concentration of 2.5%.

8. The stable pharmaceutical formulation of claim 2, wherein (a) the VEGF antagonist fusion protein dimer is at a concentration of 50 mg/mL;

(b) the histidine is at a concentration of 10 mM;

(c) the PEG 3350 is at a concentration of 1.5%;

(d) the glycine is at a concentration of 0.75%; and

(e) the sucrose is at a concentration of 2.5%.