Etanercept formulations stabilized with amino acids

• US 10,293,049 B2
• Filed: 10/18/2012
• Issued: 05/21/2019
• Est. Priority Date: 10/18/2011
• Status: Expired due to Fees

• Current Assignee: Coherus BioSciences Inc.
• Original Assignee: Coherus BioSciences Inc.
• Inventors: Manning, Mark, Murphy, Brian
• Primary Examiner(s): Ford, Vanessa L.
• Assistant Examiner(s): Dillahunt, Sandra E
• Application Number:
  US13/654,735
• Publication Number:
  US 20130108632A1
• Time in Patent Office: 2,406 Days
• Field of Search: None
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• 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 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• 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 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• 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 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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: C07K 14/705 : Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/7151 : for tumor necrosis factor [TNF], for lymphotoxin [LT]
• 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

The invention provides stabilized aqueous pharmaceutical etanercept compositions stabilized with an amino acid and suitable for long-term storage of etanercept, methods of manufacture of these compositions, methods of administration, and kits containing same.

Claims

1. A stable aqueous pharmaceutical composition comprising about 50 mg/ml etanercept, and 100-120 mM glutamate, wherein the composition has a pH of about 6.0 to 6.6, and wherein the composition is free or essentially free of arginine.

2. The composition of claim 1, further comprising one or more additional components selected from:

a buffer;

a tonicity modifier, and an excipient.

3. The composition of claim 2 wherein the formulation comprises less than 6 wt. % sucrose;

optionally up to about 100 mM NaCl; and

about 1 to about 30 mM sodium phosphate buffer.

4. The composition of claim 1 eliciting long term storage stability as characterized by:

an HIC analysis at M₃ or T₂ or T₄ wherein the amount of the composition represented by peak 2 of the HIC chromatogram is greater than or equal to 95 wt. %; and

wherein, if peak 3 is present on the HIC chromatogram, the amount of the composition represented by peak 3 is less than or equal to 3 wt. %.

5. The composition of claim 1 having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μ

m.

6. The composition of claim 1 further comprising about 0 to 3 wt. % sucrose.

7. The composition of claim 1 further comprising less than 4 wt. % sucrose, and about 10 to 30 mM sodium phosphate buffer;

and having a pH of about 6.3 to 6.5.

8. The composition of claim 1 further comprising 100 mM glutamate;

less than 2 wt. % sucrose, about 100 mM NaCl;

about 10-30 mM sodium phosphate buffer; and

having a pH of about 6.3 to 6.5.

9. The composition of claim 1, wherein the composition elicits long term storage stability as characterized by an HIC chromatogram, at M₃ or T₂ or T₄, in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than 95 weight % of the composition;

and peak 1 represents less than 3 wt. %.

10. The composition of claim 1, wherein the composition elicits long term storage stability as characterized by an SEC chromatogram, at M₃ or T₂ or T₄, containing essentially no peak corresponding to aggregate(s) and a monomer content of at least 95 wt % of the composition and fragment 3 content less than 5 wt. % of the composition.

11. The composition of claim 1, wherein the composition elicits long term storage stability as characterized by SEC analysis at M₃ or T₂ or T₄ of:

monomer content greater than 90%;

aggregates content of less than 3 wt %; and

fragment 3 content less than 5 wt %.

12. The composition of claim 1, wherein the composition elicits long term storage stability as characterized by HIC analysis at M₃ or T₂ or T₄, wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt. %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt. %; and

the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt. %.

13. The composition of claim 6, having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μ

m.

14. The composition of claim 7, having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μ

m.

15. The composition of claim 8, having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μ

m.