Etanercept formulations stabilized with xylitol

• US 9,770,510 B2
• Filed: 07/13/2016
• Issued: 09/26/2017
• 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): HOWARD, ZACHARY C
• Application Number:
  US15/209,484
• Publication Number:
  US 20160317667A1
• Time in Patent Office: 440 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 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 etanercept and a stabilizer to inhibit instability, misfolding, aggregation and/or fragmentation of the etanercept, wherein the stabilizer comprises xylitol and meglumine, 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 1, eliciting long term storage stability as characterized by at least one of:

(a) SEC (Size Exclusion Chromatography) analysis at T2 of;

monomer content greater than 80 or 90%;

aggregates content of less than 3 wt. %; and

fragment 3 content less than 5 or 6 wt. %;

or

(b) HIC (Hydrophobic Interaction Chromatography) analysis at T2 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. %.

4. The composition of claim 3 having an HIC analysis at T2 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 1 wt. %;

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

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

5. The composition of claim 3 comprising 25 to 75 mg/ml of etanercept;

1-10 wt. % xylitol;

up to 5 wt. % meglumine;

1 to 30 mM sodium phosphate;

optionally up to 100 mM NaCl; and

optionally up to 5 wt. % sucrose.

6. The composition of claim 5 comprising 1-100 mM NaCl;

and 1 to 5 wt. % sucrose.

7. The composition of claim 5 comprising 50 mg/ml of etanercept;

10 wt. % xylitol; and

10 to 30 mM sodium phosphate.

8. The composition of claim 5 comprising 50 mg/ml of etanercept;

1-3 wt. % xylitol; and

1-3 wt. % meglumine.

9. The composition of claim 5 comprising 50 mg/ml of etanercept;

10-30 mM sodium phosphate;

1-3 wt. % xylitol;

1-3 wt. % meglumine;

1-100 mM sodium chloride; and

1-4 wt. % sucrose.

10. The composition of claim 5 comprising 50 mg/ml of etanercept;

6 wt. % xylitol; and

10-30 mM sodium phosphate.

11. The composition of claim 5 comprising 50 mg/ml of etanercept;

10-30 mM sodium phosphate;

2-3 wt. % xylitol; and

5% sucrose.

12. The composition of claim 3 eliciting long term storage stability as characterized by an HIC analysis at T2 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 1 wt. %.

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

m.

14. 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, wherein the composition has a pH of 6.0 to 6.6, and is characterized by an SEC (Size Exclusion Chromatography) analysis at T2 of:

greater than 80 wt. % monomer content;

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

less than 6 wt. % fragment 3 content.

15. The composition of claim 14, comprising up to 5 wt. % meglumine.

16. The composition of claim 14 eliciting long term storage stability characterized by:

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

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

(b) an HIC (Hydrophobic Interaction Chromatography) analysis at T2 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 4 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. %.

17. The composition of claim 1, containing no arginine, or essentially free of arginine, wherein the composition, at T2, elicits long term storage stability that meets one or both of the following criteria:

(a) stability comparable to or better than commercially available etanercept as measured by (i) SEC (Size Exclusion Chromatography) analysis of the amounts of aggregate(s), monomer and fragment(s) in the composition and (ii) HIC analysis of amounts of material in the composition corresponding to peaks 1, 2 and 3 of the HIC chromatogram; and

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

an SEC chromatogram containing essentially no peak corresponding to aggregate(s); and

an SEC chromatogram in which the monomer content represents at least 95 wt. % of the composition.

18. A stabilized aqueous pharmaceutical composition comprising etanercept and a stabilizer to inhibit instability, misfolding, aggregation and/or fragmentation of the etanercept, wherein the stabilizer comprises xylitol and a compound selected from the group consisting of mannosylglycerate, mannosyllactate, mannosylglycolate, or diglycerolphosphate, and wherein the composition is free or essentially free of arginine.