Claims for Patent: 9,700,595

Summary for Patent: 9,700,595

Title:	Liquid formulation of a fusion protein comprising TNFR and Fc region
Abstract:	The present invention relates to a liquid formulation comprising a TNFR-Fc fusion protein and a stabilizer, in which the fusion protein comprises TNFR (tumor necrosis factor receptor) or a fragment thereof and an immunoglobulin Fc region, and the stabilizer comprises one or more amino acids selected from the group consisting of proline and histidine, a buffer solution, and an isotonic agent containing sodium chloride (NaCl) and sucrose, and a preparation method of the liquid formulation. The liquid formulation according to the present invention provides excellent storage stability because long-term storage of TNFR-Fc fusion protein (etanercept) is possible and particular storage conditions are not needed. Since the liquid formulation of the present invention shows excellent storage stability even though the formulation is simple, it is more economical than other stabilizers or lyophilized formulations, and thus the formulation can be effectively applied for uses wherein treatment of TNFR-Fc fusion protein (etanercept) is beneficial.
Inventor(s):	Lee; Jung Tae (Yuseong-gu, KR), Kim; In Hyuk (Daejeon, KR), Yu; Jae Keun (Incheon, KR), Yim; Jung Yim (Daejeon, KR), Jeong; Myeong Hyeon (Daejeon, KR), Ahn; Yong Ho (Daejeon, KR)
Assignee:	ARES TRADING SA (Aubonne, CH)
Application Number:	15/038,953
Patent Claims:	1. A liquid formulation comprising a TNFR-Fc fusion protein, one or more amino acids, a buffer solution, and an isotonic agent, wherein the fusion protein has the amino acid sequence of SEQ ID NO. 1, the concentration of the fusion protein is in the range from 20 to 55 mg/mL, and the formulation comprises a mixture of proline at a concentration of 1 mM to 9 mM and histidine at a concentration of 0.01 to 0.09 mM. 2. The liquid formulation according to claim 1, wherein the fusion protein is etanercept. 3. The liquid formulation of claim 1, wherein the isotonic agent allows the liquid formulation to maintain an osmotic pressure of 280 to 350 mOsm. 4. The liquid formulation of claim 1, wherein the isotonic agent contains sodium chloride (NaCl) and sucrose. 5. The liquid formulation of claim 4, wherein sodium chloride is present at a concentration of 1 to 1000 mM and sucrose is present in an amount of 0.01 to 3% by weight of the formulation. 6. The liquid formulation of claim 5, wherein sodium chloride is present at a concentration of 105 mM to 150 mM, and sucrose is present in an amount of 0.01 to 1.5% by weight of the formulation. 7. The liquid formulation of claim 1, wherein the buffer solution is a citrate-phosphate or phosphate buffer solution. 8. The liquid formulation of claim 7, wherein the concentration of the buffer solution is in the range from 10 to 35 mM. 9. The liquid formulation according to claim 8, wherein pH of the liquid formulation is in the range from 6.0 to 6.6. 10. The liquid formulation of claim 1, wherein the formulation comprises proline at a concentration of less than 10 mM or histidine at a concentration of less than 5 mM. 11. The liquid formulation of claim 10, wherein the formulation comprises proline at a concentration of less than 9 mM or histidine at a concentration of less than 0.1 mM. 12. The liquid formulation according to claim 1, wherein proline is present at a concentration of 6 mM and histidine is present at a concentration of 0.09 mM. 13. The liquid formulation of claim 1, further comprising glutamic acid at a concentration of 1 mM to 20 mM. 14. The liquid formulation of claim 13, wherein glutamic acid is present at a concentration of 10 to 15 mM. 15. A method for preparing a liquid formulation comprising a TNFR-Fc fusion protein of claim 1, comprising: a) preparing the TNFR-Fc fusion protein; and b) mixing the TNFR-Fc fusion protein prepared in step a) with a stabilizer comprising one or more amino acids selected from the group consisting of proline and histidine, a buffer solution, and an isotonic agent containing sodium chloride (NaCl) and sucrose. 16. The method according to claim 15, wherein the mixing in step b) comprises i) preparing a solution comprising the stabilizer, the buffer solution, and the isotonic agent and ii) exchanging the solution in which the TNFR-Fc fusion protein is prepared in step a) with the solution in step i). 17. A liquid formulation comprising TNFR-Fc fusion protein in a pharmaceutically effective amount, a citrate-phosphate buffer solution, sodium chloride, sucrose, and a mixture of amino acids comprising proline and histidine, wherein the TNFR-Fc fusion protein is a p75 sTNFR-Fc fusion protein. 18. The liquid formulation of claim 17, wherein the liquid formulation comprises 30 to 55 mg/mL of the TNFR-Fc fusion protein, and 10 to 35 mM citrate-phosphate buffer solution, 105 to 120 mM NaCl, 0.5 to 1.5% sucrose, 1 to 9 mM proline and 0.01 to 0.1 mM histidine and has a pH of 6.3. 19. The liquid formulation of claim 18, wherein the liquid formulation comprises 50 mg/mL of the TNFR-Fc fusion protein, 25 mM citrate-phosphate buffer, 115 mM NaCl, 1% of sucrose, 6 mM proline, and 0.09 mM histidine and has a pH of 6.3. 20. The liquid formulation according to claim 17, wherein the liquid formulation comprises 30 to 55 mg/mL of TNFR-Fc fusion protein, and 10 to 35 mM citrate-phosphate buffer solution, 120 to 150 mM NaCl, 0.01 to 0.5% sucrose, 1 to 9 mM proline and 0.01 to 0.1 mM histidine and has a pH of 6.3. 21. The liquid formulation according to claim 20, wherein the liquid formulation comprises 50 mg/mL of the TNFR-Fc fusion protein, 25 mM citrate-phosphate buffer, 130 mM NaCl, 0.1% of sucrose, 6 mM proline, and 0.09 mM histidine as the stabilizer and has a pH of 6.3. 22. The liquid formulation according to claim 17, further comprising glutamic acid, wherein the liquid formulation comprises 30 to 55 mg/mL of the TNFR-Fc fusion protein, 10 to 35 mM citrate-phosphate buffer, 100-150 mM NaCl, 0.1 to 1.5% of sucrose, 5 to 15 mM glutamate, 1 to 10 mM proline, and 1 to 10 mM histidine and has a pH of 6.3. 23. The liquid formulation according to claim 22, wherein the liquid formulation comprises 50 mg/mL of the TNFR-Fc fusion protein, 25 mM citrate-phosphate buffer, 100 mM NaCl, 1% of sucrose, 10 mM glutamate, 10 mM proline, and 5 mM histidine and has a pH of 6.3. 24. A liquid formulation comprising a TNFR-Fc fusion protein, one or more amino acids, a buffer solution, and an isotonic agent, wherein the fusion protein has the amino acid sequence of SEQ ID NO. 1 and the concentration of the protein is in the range from 20 to 55 mg/mL, and wherein the amino acids comprise proline at a concentration of 1 mM to 9 mM; histidine at a concentration of 0.01 to 0.09 mM; or a combination thereof.

Details for Patent 9,700,595

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2033-11-29
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2033-11-29
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2033-11-29
Immunex Corporation	ENBREL	etanercept	Injection	103795	02/01/2007		2033-11-29
Immunex Corporation	ENBREL MINI	etanercept	Injection	103795	09/14/2017		2033-11-29