Etanercept Formulations Stabilized with Sodium Chloride

• US 20190314499A1
• Filed: 06/26/2019
• Published: 10/17/2019
• Est. Priority Date: 10/18/2011
• Status: Abandoned Application

• Current Assignee: Coherus BioSciences Inc.
• Original Assignee: Coherus BioSciences Inc.
• Inventors: MANNING, Mark, Murphy, Brian
• Application Number:
  US16/453,154
• Publication Number:
  US 20190314499A1
• Time in Patent Office: 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 method of reducing formation of etanercept aggregates or fragments in a composition containing 25 to 75 mg/ml etanercept, the method comprising combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially free of arginine, thereby preparing a stable aqueous etanercept composition.

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

a buffer;

a tonicity modifier, and an excipient to the aqueous pharmaceutical composition.

3. The method of claim 2, wherein the aqueous pharmaceutical composition has a pH of about 6.0 to about 6.6.

4. The method of claim 1, wherein the stable aqueous etanercept composition elicits long term storage stability as characterized by:

an HIC analysis at M₃ or T₂ or T₄ wherein the amount of the stable aqueous etanercept 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 about 3 wt. %.

5. The method of claim 1, wherein the stable aqueous etanercept composition has no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μ

m.

6. The method of claim 1, wherein the stable aqueous etanercept composition elicits 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. %.

7. The method of claim 1, wherein etanercept is at a concentration of 50 mg/ml and wherein sodium chloride is at a concentration of 75 mM.

8. The method of claim 1, wherein the stable aqueous etanercept composition comprises 10 mM or 25 mM sodium phosphate.

9. The method of claim 1, wherein the stable aqueous etanercept composition comprises 25 to 75 mg/ml of etanercept, up to 150 mM sodium chloride, 10 to 25 mM sodium phosphate, and 3 to 5 wt. % trehalose, and is free of arginine.

10. The method of claim 1, wherein the stable aqueous etanercept composition comprises 50 mg/ml etanercept, 75 mM sodium chloride, and 25 mM sodium phosphate.

11. The method of claim 1, wherein the stable aqueous etanercept composition elicits long term storage stability as characterized by at least one of:

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. %.

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

(A) an SEC analysis 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

(B) an HIC analysis 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. %.

13. A method of treating a subject in need of treatment by injection of etanercept comprising administering to the subject a stable aqueous etanercept composition comprising 25 to 75 mg/ml etanercept, the method comprising combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially free of arginine.

14. The method of claim 13, comprising administering 25-100 mg etanercept per dose to the subject.

15. The method of claim 13, comprising injecting the stable aqueous etanercept composition subcutaneously or intramuscularly.

16. A method of treating a subject in need of treatment for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Wegener'"'"'s disease (granulomatosis), Crohn'"'"'s disease (or inflammatory bowel disease), chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, or atopic dermatitis comprising administering to the subject a stable aqueous etanercept composition comprising 25 to 75 mg/ml etanercept, the method comprising combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially free of arginine.

17. The method of claim 16, comprising administering 25-100 mg etanercept per dose to the subject.

18. The method of claim 16, wherein the administering comprises injecting the stable aqueous etanercept composition subcutaneously or intramuscularly.

19. A vial, syringe, or injector pen containing a stable aqueous etanercept composition comprising 25 to 75 mg/ml etanercept, the method comprising combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially free of arginine.

20. The vial, syringe, or injector pen of claim 19, wherein the stable aqueous pharmaceutical composition has a pH of about 6.0 to about 6.6.