Stabilized formulations containing anti-interleukin-4 receptor (IL-4R) antibodies

Patent metadata

Field	Value
Publication number	US-9238692-B2
Application number	US-201414578179-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Oct 6, 2010
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-4 receptor (hIL-4R). The formulations may contain, in addition to an anti-hIL-4R antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.

First claim

What is claimed is:

1. A pre-filled syringe composition comprising a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation comprises:
(a) 100±10 mg/mL to 200±20 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human interleukin-4 receptor alpha (hIL-4Rα), wherein the antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:5;
(b) 10 mM to 15 mM acetate;
(c) 15 mM to 25 mM histidine;
(d) 2.5% w/v to 10% w/v sucrose;
(e) 0.1% w/v to 0.3% w/v polysorbate; and
(f) 20 mM to 100 mM arginine;
wherein said liquid pharmaceutical formulation has a pH of from 5.6 to 6.2 and is contained within a syringe.

2. The pre-filled syringe composition of claim 1 , wherein the syringe is a normal tungsten syringe.

3. The pre-filled syringe composition of claim 1 , wherein the syringe is a low tungsten syringe.

4. The pre-filled syringe composition of claim 1 , wherein the syringe comprises a coated plunger.

5. The pre-filled syringe composition of claim 4 , wherein the coated plunger is coated with a fluorocarbon film.

6. The pre-filled syringe composition of claim 1 , wherein the syringe is a low tungsten syringe, and wherein the syringe comprises a coated plunger.

7. The pre-filled syringe composition of claim 1 , wherein at least 90% of the antibody has native conformation after eight weeks of storage at 45° C.

8. The pre-filled syringe composition of claim 1 , wherein less than 45% of the antibody is an acidic form of the antibody after eight weeks of storage at 45° C.

9. The pre-filled syringe composition of claim 1 , wherein at least 98% of the antibody has native conformation after six months of storage at 5° C.

10. The pre-filled syringe composition of claim 1 , wherein less than 4% of the antibody recovered after six months of storage at 25° C. is aggregated.

11. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 175 mg/mL of the antibody.

12. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 150 mg/mL of the antibody.

13. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 100 mg/mL of the antibody.

14. The pre-filled syringe composition of claim 1 , wherein the polysorbate is polysorbate 20.

15. The pre-filled syringe composition of claim 1 , wherein the polysorbate is polysorbate 80.

16. The pre-filled syringe composition of claim 1 , wherein the polysorbate is present at a concentration of 0.2%±0.03% w/v.

17. The pre-filled syringe composition of claim 1 , wherein the arginine is present at a concentration of 25 mM±3.75 mM.

18. The pre-filled syringe composition of claim 1 , wherein the arginine is present at a concentration of 50 mM±7.5 mM.

19. The pre-filled syringe composition of claim 1 , wherein the formulation comprises:
(a) 150±50.0 mg/mL of the antibody;
(b) 12.5 mM±2 mM acetate;
(c) 20 mM±3 mM histidine;
(d) 5%±0.75% w/v sucrose;
(e) 0.2% w/v±0.03% w/v polysorbate 20; and
(f) 25 mM±3.75 mM arginine;
wherein said liquid pharmaceutical formulation has a pH of 5.9±0.5.

20. The pre-filled syringe composition of claim 1 , wherein the formulation comprises:
(a) 150±50.0 mg/mL of the antibody;
(b) 12.5 mM±2 mM acetate;
(c) 20 mM±3 mM histidine;
(d) 5%±0.75% w/v sucrose;
(e) 0.2% w/v±0.03% w/v polysorbate 80; and
(f) 25 mM±3.75 mM arginine;
wherein said liquid pharmaceutical formulation has a pH of 5.9±0.5.

21. The pre-filled syringe composition of claim 1 , wherein the formulation comprises:
(a) 175 mg/mL of the antibody;
(b) 12.5 mM±2 mM acetate;
(c) 20 mM±3 mM histidine;
(d) 5%±0.75% w/v sucrose;
(e) 0.2% w/v±0.03% w/v polysorbate 20; and
(f) 50 mM±7.5 mM arginine;
wherein said liquid pharmaceutical formulation has a pH of 5.9±0.5.

22. The pre-filled syringe composition of claim 1 , wherein the formulation comprises:
(a) 175 mg/mL of the antibody;
(b) 12.5 mM±2 mM acetate;
(c) 20 mM±3 mM histidine;
(d) 5%±0.75% w/v sucrose;
(e) 0.2% w/v±0.03% w/v polysorbate 80; and
(f) 50 mM±7.5 mM arginine;
wherein said liquid pharmaceutical formulation has a pH of 5.9±0.5.

Assignees

• Regeneron Pharma

Inventors

• Dix Daniel B
• Tang Xiaolin

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P27/14

  Decongestants or antiallergics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P17/04

  Antipruritics · CPC title