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Last Updated: March 29, 2024

Claims for Patent: 9,770,510


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Summary for Patent: 9,770,510
Title:Etanercept formulations stabilized with xylitol
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.
Inventor(s): Manning; Mark (Johnstown, CO), Murphy; Brian (Fort Collins, CO)
Assignee: Coherus Biosciences, Inc. (Redwood, CA)
Application Number:15/209,484
Patent 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 .mu.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.

Details for Patent 9,770,510

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Immunex Corporation ENBREL etanercept For Injection 103795 11/02/1998 ⤷  Try a Trial 2039-02-26
Immunex Corporation ENBREL etanercept For Injection 103795 05/27/1999 ⤷  Try a Trial 2039-02-26
Immunex Corporation ENBREL etanercept Injection 103795 09/27/2004 ⤷  Try a Trial 2039-02-26
Immunex Corporation ENBREL etanercept Injection 103795 02/01/2007 ⤷  Try a Trial 2039-02-26
Immunex Corporation ENBREL MINI etanercept Injection 103795 09/14/2017 ⤷  Try a Trial 2039-02-26
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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