Etanercept formulations stabilized with amino acids
View Patent ↗The invention provides stabilized aqueous pharmaceutical etanercept compositions stabilized with an amino acid and 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 comprising about 50 mg/ml etanercept, and 100-120 mM glutamate, wherein the composition has a pH of about 6.0 to 6.6, 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 2 wherein the formulation comprises less than 6 wt. % sucrose; optionally up to about 100 mM NaCl; and about 1 to about 30 mM sodium phosphate buffer.
4. The composition of claim 1 eliciting 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 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 3 wt. %.
5. The composition of claim 1 having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μm.
6. The composition of claim 1 further comprising about 0 to 3 wt. % sucrose.
7. The composition of claim 1 further comprising less than 4 wt. % sucrose, and about 10 to 30 mM sodium phosphate buffer; and having a pH of about 6.3 to 6.5.
8. The composition of claim 1 further comprising 100 mM glutamate; less than 2 wt. % sucrose, about 100 mM NaCl; about 10-30 mM sodium phosphate buffer; and having a pH of about 6.3 to 6.5.
9. The composition of claim 1 , wherein the composition elicits long term storage stability as characterized by an HIC chromatogram, at M 3 or T 2 or T 4 , in which (i) peak 3 is absent, or essentially absent and (ii) peak 2 represents greater than 95 weight % of the composition; and peak 1 represents less than 3 wt. %.
10. The composition of claim 1 , wherein the composition elicits long term storage stability as characterized by an SEC chromatogram, at M 3 or T 2 or T 4 , containing essentially no peak corresponding to aggregate(s) and a monomer content of at least 95 wt % of the composition and fragment 3 content less than 5 wt. % of the composition.
11. The 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 90%; aggregates content of less than 3 wt %; and fragment 3 content less than 5 wt %.
12. The 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 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. %.
13. The composition of claim 6 , having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μm.
14. The composition of claim 7 , having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μm.
15. The composition of claim 8 , having no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μm.