Etanercept formulations stabilized with combinations of sugars and polyols

• US 9,302,002 B2
• Filed: 10/18/2012
• Issued: 04/05/2016
• Est. Priority Date: 10/18/2011
• Status: Active Grant

• Current Assignee: Coherus BioSciences Inc.
• Original Assignee: Coherus BioSciences Inc.
• Inventors: Manning, Mark, Murphy, Brian
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Al-Awadi, Danah
• Application Number:
  US13/654,950
• Publication Number:
  US 20130101640A1
• Time in Patent Office: 1,265 Days
• Field of Search: None
• US Class Current: 1/1
• 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 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 25 to about 75 mg/ml etanercept in combination with a stabilizer to reduce instability, aggregation misfolding and/or fragmentation of the etanercept during storage of the formulation;

said stabilizer consisting of about 1 to about 10 wt. % sugar, about 1 mM to about 30 mM sodium phosphate and up to about 10 wt. % polyol, wherein said sugar and said polyol are different from each other, and wherein said formulation is free or essentially free of arginine.

2. The composition of claim 1 eliciting long term storage stability as characterized by at least one of:

SEC analysis at M₃ or T₂ or T₄ of;

monomer content greater than about 90%;

aggregates content of less than about 3 wt %; and

fragment 3 content less than about 5 wt %; and

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 about 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 about 20 wt. %.

3. The composition of claim 1, comprising about 1 to about 10 wt. % sucrose, trehalose or dextrose;

up to about 10 wt. % mannitol or sorbitol said composition having pH about 6.0 to 6.6; and

wherein the composition is characterized by SEC analysis at M₃ or T₂ or T₄ in which;

the monomer content is greater than about 80 wt. %;

aggregates content is less than about 3 wt. %, and fragment 3 content less than about 10 wt. %.

4. The composition of claim 3 eliciting long term storage stability characterized by:

(a) an SEC analysis at M₃ or T₂ or T₄ of greater than about 90 wt. % monomer content; and

less than about 3 wt. % aggregate(s) content; and

(b) an 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 about 4 wt. %;

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

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

5. The composition of claim 2 having an 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 about 1 wt. %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than about 95 wt. %; and

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

6. The composition of claim 2 comprising:

about 50 mg/ml of etanercept;

about 1 to 5 wt. % sucrose, trehalose or dextrose;

about 1-2 wt. % mannitol or sorbitol, about 10-30 mM sodium phosphate, said composition having pH of about 6.3 to 6.5.

7. The composition of claim 2 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 about 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 about 3 wt. %.

8. The composition of claim 2 having, at M₃ or T₂ or T₄ no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μ

m.