Claims for Patent: 9,801,942

Summary for Patent: 9,801,942

Title:	Etanercept formulations stabilized with metal ions
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 City, CA)
Application Number:	13/654,770
Patent Claims:	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.sub.3 or T.sub.2, or T.sub.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.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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 .mu.m. 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.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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 .mu.m. 16. The stabilized etanercept composition of claim 1, wherein the composition, at M.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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 .mu.m. 22. The stabilized etanercept composition of claim 11, wherein the composition, at M.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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.sub.3 or T.sub.2 or T.sub.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.

Details for Patent 9,801,942

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