Etanercept Formulations Stabilized with Xylitol

• US 20180028668A1
• Filed: 09/26/2017
• Published: 02/01/2018
• Est. Priority Date: 10/18/2011
• Status: Active Grant

• Current Assignee: Coherus BioSciences Inc.
• Original Assignee: Coherus BioSciences Inc.
• Inventors: Manning, Mark, Murphy, Brian
• Granted Patent: US 10,213,508 B2
• 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 stabilized aqueous pharmaceutical composition comprising

a) etanercept,

b) buffer, and

c) stabilizer comprising xylitol,

wherein the composition has a pH of about 6.0 to about 6.6 and is free or essentially free of arginine.

2. The composition of claim 1, wherein the pH is about 6.3.

3. The composition of claim 1 having, at T₂ no more than, on average, 10,000 subvisible particles per mL having a size greater than 5 μ

m.

4. The composition of claim 1, comprising 25 to 75 mg/mL of etanercept.

5. The composition of claim 1, comprising xylitol in an amount constituting up to 10 wt. % of the composition.

6. The composition of claim 1, comprising 25 to 75 mg/mL of etanercept, and xylitol in an amount constituting up to 10 wt. % of the composition.

7. The composition of claim 6, comprising about 50 mg/mL of etanercept.

8. The composition of claim 7, comprising about 10 wt. % xylitol.

9. The composition of claim 7, comprising about 6 wt. % xylitol.

10. The composition of claim 6 having, at T₂ no more than, on average, 10,000 subvisible particles per mL having a size greater than 5 μ

m.

11. The composition of claim 1, further comprising one or more additional components selected from a tonicity modifier and an excipient.

12. The composition of claim 11, comprising up to 100 mM NaCl.

13. The composition of claim 11, comprising up to 5 wt. % sucrose.

14. The composition of claim 4, further comprising up to 100 mM NaCl and up to 5 wt. % sucrose.

15. The composition of claim 14 having, at T₂ no more than, on average, 10,000 subvisible particles per mL having a size greater than 5 μ

m.

16. The composition of claim 6, further comprising up to 100 mM NaCl and up to 5 wt. % sucrose.

17. The composition of claim 16 having, at T₂ no more than, on average, 10,000 subvisible particles per mL having a size greater than 5 μ

m.

18. A stabilized aqueous pharmaceutical composition comprising

a) 25 to 75 mg/mL of etanercept,

b) buffer, and

c) stabilizer comprising xylitol in an amount up to 10 wt. % of the composition,

wherein the composition has a pH of about 6.3 and is free or essentially free of arginine.

19. The composition of claim 18 having, at T₂ no more than, on average, 10,000 subvisible particles per mL having a size greater than 5 μ

m.

20. The composition of claim 18, comprising about 50 mg/mL of etanercept.

21. The composition of claim 18, comprising about 6 wt. % xylitol.

22. The composition of claim 18, comprising about 50 mg/mL of etanercept and about 10 wt. % xylitol.

23. The composition of claim 22 having, at T₂ no more than, on average, 10,000 subvisible particles per mL having a size greater than 5 μ

m.

24. The composition of claim 18, comprising about 50 mg/mL of etanercept and about 6 wt. % xylitol.

25. The composition of claim 18, further comprising one or more additional components selected from a tonicity modifier and an excipient.

26. The composition of claim 25, comprising up to 100 mM NaCl.

27. The composition of claim 25, comprising up to 5 wt. % sucrose.

28. The composition of claim 18, further comprising up to 100 mM NaCl and up to 5 wt. % sucrose.

29. The composition of claim 20, further comprising up to 100 mM NaCl and up to 5 wt. % sucrose.

30. The composition of claim 28, wherein the composition has osmolality of about 180 to 420 mOsM;

the composition is suitable for administration to a subject as a single dose; and

the dose contains about 40 mg of adalimumab.