Etanercept formulations stabilized with metal ions
View Patent ↗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.
1. A stable aqueous pharmaceutical composition containing no arginine or essentially free of arginine comprising about 50 mg/mL etanercept and 5 to 10 mM magnesium, wherein the composition has a pH of about 6.0 to 6.6.
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 stabilized etanercept composition of claim 2 wherein magnesium is in the form of magnesium chloride.
4. The stabilized etanercept composition of claim 2 wherein magnesium is in the form of magnesium chloride and wherein the composition comprises: optionally up to about 6 wt. % sucrose; about 25 to 150 mM NaCl; and about 1 to about 30 mM sodium phosphate.
5. The magnesium chloride stabilized etanercept composition of claim 4 eliciting long term storage stability as characterized by:
SEC analysis at M 3 or T 2 , or T 4 of greater than about 90 wt. % monomer content; less than about 3 wt. % aggregate(s) content; and less than about 5 wt % fragment 3; or HIC analysis at M 3 or T 2 or T 4 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. %.
6. The magnesium chloride stabilized etanercept composition of claim 5 which elicits long term storage stability as characterized by: an HIC analysis at M 3 or T 2 or T 4 wherein the amount of the composition represented by peak 2 of the HIC chromatogram is greater than or equal to about 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. %.
7. The magnesium chloride stabilized etanercept composition of claim 5 having, on average, no more than about 10,000 subvisible particles per mL having a size greater than 5 μm.
8. The magnesium chloride stabilized etanercept composition of claim 5 comprising about 50 mg/ml of etanercept; about 10 mM magnesium chloride; about 10-30 mM sodium phosphate; less than about 150 mM sodium chloride; and less than about 3 wt. % sucrose, wherein the composition has a pH from about 6.3 to 6.5.
9. The magnesium chloride etanercept stabilized composition of claim 5 comprising about 50 mg/ml of etanercept; about 5 mM magnesium chloride; less than about 30 mM sodium phosphate; less than about 100 mM sodium chloride; and less than about 4 wt. % sucrose, wherein the composition has a pH from about 6.3 to 6.5.
10. The magnesium chloride stabilized etanercept composition of claim 5 comprising about 50 mg/ml of etanercept; about 10 mM magnesium chloride; less than about 30 mM sodium phosphate; less than about 100 mM sodium chloride; and less than about 5 wt. % sucrose, wherein the composition has a pH from about 6.3 to 6.5.
11. A stabilized etanercept composition containing no arginine, or essentially free of arginine, comprising about 50 mg/mL etanercept, 5 to 10 mM magnesium chloride, optionally up to about 6 wt. % sucrose, about 25 to 150 mM NaCl, and about 1 to about 30 mM sodium phosphate, wherein the composition has a pH from about 6.0 to 6.6.
12. The stabilized etanercept composition of claim 1 , wherein magnesium is in the form of magnesium chloride.
13. The stabilized etanercept composition of claim 1 , wherein the composition elicits long term storage stability as characterized by SEC analysis at M 3 or T 2 or T 4 of: monomer content greater than about 90%, aggregates content of less than about 3 wt %, and fragment 3 content less than about 5 wt %.
14. The stabilized etanercept composition of claim 1 , wherein the composition elicits long term storage stability as characterized by HIC analysis at M 3 or T 2 or T 4 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. %.
15. The stabilized etanercept composition of claim 1 having, on average, no more than about 10,000 subvisible particles per mL having a size greater than 5 μm.
16. The stabilized etanercept composition of claim 1 , wherein the composition, at M 3 or T 2 or T 4 , elicits long term storage stability that meets the following criteria: an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition.
17. The stabilized etanercept composition of claim 1 , wherein the composition, at M 3 or T 2 or T 4 , elicits long term storage stability that meets the following criteria: an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.
18. The stabilized etanercept composition of claim 1 , wherein the composition, at M 3 or T 2 or T 4 , elicits long term storage stability that meets the following criteria:
(A) an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition; and
(B) an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.
19. The stabilized etanercept composition of claim 11 , wherein the composition elicits long term storage stability as characterized by SEC analysis at M 3 or T 2 or T 4 of: monomer content greater than about 90%, aggregates content of less than about 3 wt %, and fragment 3 content less than about 5 wt %.
20. The stabilized etanercept composition of claim 11 , wherein the composition elicits long term storage stability as characterized by HIC analysis at M 3 or T 2 or T 4 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. %.
21. The stabilized etanercept composition of claim 11 having, on average, no more than about 10,000 subvisible particles per mL having a size greater than 5 μm.
22. The stabilized etanercept composition of claim 11 , wherein the composition, at M 3 or T 2 or T 4 , elicits long term storage stability that meets the following criteria: an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition.
23. The stabilized etanercept composition of claim 11 , wherein the composition, at M 3 or T 2 or T 4 , elicits long term storage stability that meets the following criteria: an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.
24. The stabilized etanercept composition of claim 11 , wherein the composition, at M 3 or T 2 or T 4 , elicits long term storage stability that meets the following criteria:
(A) an HIC chromatogram in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than about 95 wt % of the composition; and
(B) an SEC chromatogram in which (i) essentially no peak corresponds to aggregate(s) and (ii) the monomer content represents at least about 95 wt % of the composition.