Stabilized Formulations Containing Anti-Interleukin-4 Receptor (IL-4R) Antibodies

Patent metadata

Field	Value
Publication number	US-2016102147-A1
Application number	US-201514963712-A
Country	US
Kind code	A1
Filing date	Dec 9, 2015
Priority date	Oct 6, 2010
Publication date	Apr 14, 2016
Grant date	—

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

1 - 29 . (canceled)

30 . A stable pharmaceutical formulation comprising:
(i) a human antibody that specifically binds to human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5; (ii) acetate at a concentration of from 10 mM to 15 mM; (iii) histidine at a concentration of from 15 mM to 25 mM; (iv) sucrose at a concentration of from 2.5% w/v to 10% w/v; (v) polysorbate at a concentration of from 0.1% w/v to 0.3% w/v; and (vi) arginine at a concentration of from 20 mM to 100 mM, wherein the formulation has a pH of from 5.6 to 6.2.

31 . The pharmaceutical formulation of claim 30 , wherein the acetate is present at a concentration of 12.5 mM±1.85 mM and the histidine is present at a concentration of 20 mM±0.3 mM.

32 . The pharmaceutical formulation of claim 30 , wherein the polysorbate is polysorbate 20, or polysorbate 80.

33 . The pharmaceutical formulation of claim 32 , wherein the polysorbate is polysorbate 20 at a concentration of 0.2%±0.03% w/v.

34 . The pharmaceutical formulation of claim 32 , wherein the polysorbate is polysorbate 80 at a concentration of 0.2%±0.03% w/v.

35 . The pharmaceutical formulation of claim 30 , wherein the sucrose is present at a concentration of 5%±0.75% w/v.

36 . The pharmaceutical formulation of claim 30 , wherein the arginine is present at a concentration of 25 mM±3.75 mM.

37 . The pharmaceutical formulation of claim 30 , wherein the arginine is present at a concentration of 50 mM±7.5 mM.

38 . The pharmaceutical formulation of claim 30 , wherein the viscosity of the liquid is 11±1.1 cPoise or 8.5±0.85 cPoise.

39 . The pharmaceutical formulation of claim 30 , wherein the osmolality of the liquid is 290±20 mOsm/kg.

40 . The pharmaceutical formulation of claim 30 , wherein:
(a) at least about 98% of the native form of the antibody is recovered after about six months of storage at about 5° C., as determined by size exclusion chromatography; (b) at least about 90% of the native form of the antibody is recovered after about eight weeks of storage at about 45° C., as determined by size exclusion chromatography; (c) less than about 45% of the antibody recovered after about eight weeks of storage at about 45° C. is an acidic form, as determined by cation exchange chromatography; or (d) less than about 4% of the antibody recovered after six months of storage at 25° C. is aggregated, as determined by size exclusion exchange chromatography.

41 . The pharmaceutical formulation of claim 30 , wherein the pharmaceutical formulation is contained in a glass vial.

42 . The pharmaceutical formulation of claim 30 , wherein the pharmaceutical formulation is contained in a syringe.

43 . The pharmaceutical composition of claim 30 , wherein the pharmaceutical composition is contained in a prefilled syringe.

44 . The pharmaceutical composition of claim 30 , wherein the pharmaceutical composition is contained in an autoinjector.

45 . The pharmaceutical formulation of claim 30 , wherein the pharmaceutical formulation is contained in a microinfusor.

46 . The pharmaceutical formulation of claim 42 , wherein the syringe comprises a fluorocarbon-coated plunger.

47 . The pharmaceutical formulation of claim 42 , wherein the syringe is a low tungsten syringe.

48 . A stable pharmaceutical formulation comprising:
(i) a human antibody that specifically binds to hIL-4Rα, wherein the antibody comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs:1/5; (ii) 12.5 mM±2 mM acetate; (iii) 20 mM±3 mM histidine; (iv) 5%±0.75% sucrose; (v) 0.2%±0.03% polysorbate 20; and (vi) 25 mM±3.75 mM arginine, at a pH of 5.9±0.5.

49 . The pharmaceutical formulation of claim 48 , wherein the viscosity of the liquid is 11±1.1 cPoise or 8.5±0.85 cPoise, and the osmolality of the liquid is 290±20 mOsm/kg.

50 . The pharmaceutical formulation of claim 48 , wherein:
(a) at least about 98% of the native form of the antibody is recovered after six months of storage at 5° C., as determined by size exclusion chromatography; (b) at least about 90% of the native form of the antibody is recovered after eight weeks of storage at 45° C., as determined by size exclusion chromatography; (c) less than about 45% of the antibody recovered after eight weeks of storage at 45° C. is an acidic form, as determined by cation exchange chromatography; or (d) less than about 4% of the antibody recovered after six months of storage at 25° C. is aggregated, as determined by size exclusion exchange chromatography.

51 . A stable pharmaceutical formulation comprising:
(i) a human antibody that specifically binds to hIL-4Rα, wherein the antibody comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs:1/5; (ii) 12.5 mM±2 mM acetate; (iii) 20 mM±3 mM histidine; (iv) 5%±0.75% sucrose; (v) 0.2%±0.03% polysorbate 80; and (vi) 50 mM±3.75 mM arginine, at 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

• A61P11/06

  Antiasthmatics · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title