Etanercept formulations stabilized with metal ions

• US 9,801,942 B2
• Filed: 10/18/2012
• Issued: 10/31/2017
• 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): Ford, Vanessa L
• Assistant Examiner(s): Dillahunt, Sandra
• Application Number:
  US13/654,770
• Publication Number:
  US 20130108633A1
• Time in Patent Office: 1,839 Days
• 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 containing no arginine or essentially free of arginine comprising about 50 mg/mL etanercept and 5 to 10 mM magnesium, wherein the composition has a pH of about 6.0 to 6.6.

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 stabilized etanercept composition of claim 2 wherein magnesium is in the form of magnesium chloride.

4. The stabilized etanercept composition of claim 2 wherein magnesium is in the form of magnesium chloride and wherein the composition comprises:

optionally up to about 6 wt. % sucrose;

about 25 to 150 mM NaCl; and

about 1 to about 30 mM sodium phosphate.

5. The magnesium chloride stabilized etanercept composition of claim 4 eliciting long term storage stability as characterized by:

SEC analysis at M₃ or T₂, or T₄ of greater than about 90 wt. % monomer content;

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

less than about 5 wt % fragment 3;

or 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. %.

6. The magnesium chloride stabilized etanercept composition of claim 5 which elicits 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. %.

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

m.

8. The magnesium chloride stabilized etanercept composition of claim 5 comprising about 50 mg/ml of etanercept;

about 10 mM magnesium chloride;

about 10-30 mM sodium phosphate;

less than about 150 mM sodium chloride; and

less than about 3 wt. % sucrose, wherein the composition has a pH from about 6.3 to 6.5.

9. The magnesium chloride etanercept stabilized composition of claim 5 comprising about 50 mg/ml of etanercept;

about 5 mM magnesium chloride;

less than about 30 mM sodium phosphate;

less than about 100 mM sodium chloride; and

less than about 4 wt. % sucrose, wherein the composition has a pH from about 6.3 to 6.5.

10. The magnesium chloride stabilized etanercept composition of claim 5 comprising about 50 mg/ml of etanercept;

about 10 mM magnesium chloride;

less than about 30 mM sodium phosphate;

less than about 100 mM sodium chloride; and

less than about 5 wt. % sucrose, wherein the composition has a pH from about 6.3 to 6.5.

12. The stabilized etanercept composition of claim 1, wherein magnesium is in the form of magnesium chloride.

13. The stabilized etanercept 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 about 90%, aggregates content of less than about 3 wt %, and fragment 3 content less than about 5 wt %.

14. The stabilized etanercept 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 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. %.

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

m.

16. The stabilized etanercept composition of claim 1, wherein the composition, at M₃ or T₂ or T₄, elicits long term storage stability that meets the following criteria:

an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition.

17. The stabilized etanercept composition of claim 1, wherein the composition, at M₃ or T₂ or T₄, elicits long term storage stability that meets the following criteria:

an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.

18. The stabilized etanercept composition of claim 1, wherein the composition, at M₃ or T₂ or T₄, elicits long term storage stability that meets the following criteria:

(A) an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition; and

(B) an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.

11. A stabilized etanercept composition containing no arginine, or essentially free of arginine, comprising about 50 mg/mL etanercept, 5 to 10 mM magnesium chloride, optionally up to about 6 wt. % sucrose, about 25 to 150 mM NaCl, and about 1 to about 30 mM sodium phosphate, wherein the composition has a pH from about 6.0 to 6.6.

19. The stabilized etanercept composition of claim 11, wherein the composition elicits long term storage stability as characterized by 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 %.

20. The stabilized etanercept composition of claim 11, 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 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. %.

21. The stabilized etanercept composition of claim 11 having, on average, no more than about 10,000 subvisible particles per mL having a size greater than 5 μ

m.

22. The stabilized etanercept composition of claim 11, wherein the composition, at M₃ or T₂ or T₄, elicits long term storage stability that meets the following criteria:

an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition.

23. The stabilized etanercept composition of claim 11, wherein the composition, at M₃ or T₂ or T₄, elicits long term storage stability that meets the following criteria:

an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.

24. The stabilized etanercept composition of claim 11, wherein the composition, at M₃ or T₂ or T₄, elicits long term storage stability that meets the following criteria:

(A) an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition; and

(B) an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.