Etanercept formulations stabilized with sodium chloride

• US 11,000,588 B2
• Filed: 06/28/2019
• Issued: 05/11/2021
• 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 E
• Application Number:
  US16/456,267
• Publication Number:
  US 20190343955A1
• Time in Patent Office: 683 Days
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• 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 syringe or injector pen containing a single dose of an aqueous pharmaceutical composition comprising about 25 to about 75 mg/ml etanercept and a stabilizing composition comprising about 3 to 5 wt. % of sucrose, sodium chloride, and an aqueous buffer, wherein the aqueous etanercept composition is free of arginine, wherein the single dose is 1 mL, wherein the aqueous pharmaceutical 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 90%;

aggregates content of less than 3 wt. %; and

fragment 3 content less than 5 wt. %,

wherein the aqueous pharmaceutical composition has no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μ

m.

2. The syringe or injector pen of claim 1, wherein the aqueous pharmaceutical composition has a pH of about 6.0 to about 6.6.

3. The syringe or injector pen of claim 1, wherein etanercept is at a concentration of 50 mg/ml.

4. The syringe or injector pen of claim 1, wherein the aqueous buffer is a citrate buffer.

5. The syringe or injector pen of claim 1, wherein the aqueous pharmaceutical composition elicits long term storage stability as characterized by:

an HIC analysis at M₃ or T₂ or T₄ wherein the amount of the aqueous pharmaceutical 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 3 wt. % or equal to about 3 wt. %.

6. The syringe or injector pen of claim 1, wherein the aqueous 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 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. %.

7. The syringe or injector pen of claim 1, wherein the aqueous composition is free of cysteine.

12. A method of treating a subject suffering from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, a psoriasis, or atopic dermatitis comprising injecting the subject with the syringe or injector pen of claim 1.

13. The method of claim 12, wherein the etanercept-containing protein mixture contains less than 5 wt. % incorrectly folded etanercept.

14. The method of claim 12, wherein the aqueous pharmaceutical composition has aggregates content of less than 3 wt. %.

15. The method of claim 12, wherein 25-100 mg etanercept is administered to the subject.

16. The method of claim 12, wherein the injecting is subcutaneous.

8. A syringe or injector pen containing a single dose of an aqueous composition consisting of about 50 mg/ml of etanercept stabilized by about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, an aqueous buffer, and glycine or lysine.

9. The syringe or injector pen of claim 8, wherein the aqueous pharmaceutical 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 90%;

aggregates content of less than 3 wt. %; and

fragment 3 content less than 5 wt. %.

17. A method of treating a subject suffering from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, a psoriasis, or atopic dermatitis comprising injecting the subject with the syringe or injector pen of claim 8.

10. A syringe or injector pen containing a single dose of an aqueous composition consisting of about 50 mg/ml of etanercept stabilized by about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, an aqueous citrate buffer, and glycine or lysine.

11. The syringe or injector pen of claim 10, wherein the aqueous composition consists of about 50 mg/ml of etanercept stabilized by about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, an aqueous citrate buffer, and lysine.

18. A method of treating a subject suffering from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, a psoriasis, or atopic dermatitis comprising injecting the subject with the syringe or injector pen of claim 10.

19. A method of treating a subject suffering from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, a psoriasis, or atopic dermatitis comprising injecting the subject with the syringe or injector pen of claim 11.