Antibody-containing formulations

Abstract

A stable formulation containing, as an active ingredient, an anti-IL-31RA antibody (CIM331), which is an IL-31 antagonist, is provided. The present invention provides a freeze-dried preparation containing an IL-31 antagonist as an active ingredient, the freeze-dried preparation comprising arginine and / or a salt thereof, and sucrose and / or trehalose.

Description

[Technical field]

[0001] The present invention relates to a stable formulation containing an interleukin-31 (IL-31) antagonist (for example, a monoclonal antibody having the function of binding to IL-31 receptor A (IL-31RA) and inhibiting the binding of IL-31 to IL-31RA). [Background technology]

[0002] Monoclonal antibodies have been found that bind to interleukin-31 (IL-31) receptor A (IL-31RA) and inhibit the binding of IL-31 to IL-31RA (Patent Documents 1 to 3). The anti-IL-31RA antibody Nemolizumab (CIM331) is a humanized IgG2 antibody that acts as an IL-31 antagonist and inhibits the function of IL-31, which is considered to be an itching-inducing cytokine, and is therefore undergoing clinical trials in patients with atopic dermatitis. Aiming to improve stability, many freeze-dried preparations of therapeutic proteins, including antibodies, have been developed so far (Non-Patent Document 1). Sugars such as sucrose and trehalose are commonly used as additives for freeze-dried preparations of therapeutic proteins other than antibodies (Non-Patent Document 2), and there have also been reports of the use of arginine as a stabilizer (Patent Documents 4 and 5). However, no stable formulation containing the anti-IL-31RA antibody (CIM331), which is an IL-31 antagonist, has yet been reported in which aggregate formation and / or charged heterogeneity components, which significantly affect the stability of the antibody, are suppressed. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] WO2007 / 142325 [Patent Document 2] WO2009 / 072604 [Patent Document 3] WO2010 / 064697 [Patent Document 4] US6887852B1 [Patent Document 5] WO2010 / 148253 [Non-patent literature]

[0004] [Non-Patent Document 1] Pharm Res. 1997; 14(8): 969-975. [Non-Patent Document 2] J Pharm Sci. 1998; 87(11): 1412-1420. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a stable preparation containing, as an active ingredient, an anti-IL-31RA antibody (CIM331), which is an IL-31 antagonist. [Means for solving the problem]

[0006] As a result of intensive research to achieve the above object, the present inventors have found that by adding arginine or a salt thereof to a formulation containing the IL-31 antagonist (particularly an anti-IL-31RA antibody (CIM331)), the stability of the formulation containing the IL-31 antagonist is improved regardless of whether a freeze-drying process is performed or not. In addition, they have found that by adding sucrose or trehalose to the formulation, the stability of the formulation containing the IL-31 antagonist in the freeze-dried state is improved. Furthermore, they have found that by adding a nonionic surfactant to the formulation, the stability of the formulation containing the IL-31 antagonist in the solution state is improved.

[0007] In one non-limiting embodiment, the present disclosure relates to: [1] A freeze-dried formulation comprising an IL-31 antagonist as an active ingredient, the formulation comprising arginine and / or a salt thereof, sucrose and / or trehalose. [2] The freeze-dried formulation according to [1], wherein the arginine and / or a salt thereof is arginine hydrochloride, arginine aspartate, or arginine glutamate. [3] The freeze-dried formulation according to [1] or [2], wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl). [4] The freeze-dried preparation according to any one of [1] to [3], further comprising a Tris buffer as a buffer. [5] The freeze-dried formulation according to [4], wherein the Tris buffer is trishydroxymethylaminomethane and / or a salt thereof. [6] The freeze-dried formulation according to [5], wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl), trishydroxymethylaminomethane aspartate, trishydroxymethylaminomethane glutamate, or trishydroxymethylaminomethane acetate. [7] The freeze-dried formulation according to [5] or [6], wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl). [8] The freeze-dried preparation according to any one of [1] to [7], further comprising poloxamer 188 or polysorbate as a nonionic surfactant. [9] The freeze-dried formulation according to [8], wherein the polysorbate is polysorbate 20 or polysorbate 80.

[10] The freeze-dried preparation according to any one of [1] to [9], which has a pH of 6 to 8 after reconstitution in water.

[11] The freeze-dried preparation according to any one of [1] to

[10] , which has a pH of 6.5 to 7.5 after reconstitution with water.

[12] The freeze-dried preparation according to any one of [1] to

[11] , which has a pH of 7 after reconstitution with water.

[0008]

[13] A liquid preparation containing an IL-31 antagonist as an active ingredient, the liquid preparation including arginine and / or a salt thereof.

[14] The solution formulation according to

[13] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl), arginine aspartate, or arginine glutamate.

[15] The solution formulation according to

[13] or

[14] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl).

[16] The solution formulation according to any one of

[13] to

[15] , further comprising a Tris buffer as a buffer.

[17] The solution formulation according to

[16] , wherein the Tris buffer is trishydroxymethylaminomethane and / or a salt thereof.

[18] The solution formulation according to

[17] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl), trishydroxymethylaminomethane aspartate, trishydroxymethylaminomethane glutamate, or trishydroxymethylaminomethane acetate.

[19] The solution formulation according to

[17] or

[18] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl).

[20] The solution formulation according to any one of

[13] to

[19] , further comprising a nonionic surfactant, wherein the nonionic surfactant is poloxamer 188 or polysorbate.

[21] The solution formulation according to

[20] , wherein the polysorbate is polysorbate 20 or polysorbate 80.

[22] The solution preparation according to any one of

[13] to

[21] , having a pH of 6 to 8.

[23] The solution preparation according to any one of

[13] to

[22] , having a pH of 6.5 to 7.5.

[24] The solution preparation according to any one of

[13] to

[23] , which has a pH of 7.

[0009]

[25] A freeze-dried preparation comprising an IL-31 antagonist as an active ingredient, 1–200 mg / mL of an IL-31 antagonist, 1 to 200 mmol / L Tris buffer, 4.5 to 1500 mmol / L of arginine or its salts, 7.5–2500 mmol / L of sucrose or trehalose, and 0.01-5 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising the compound is a freeze-dried composition, and has a pH of 6 to 8 after reconstitution in water.

[26] A freeze-dried preparation comprising an IL-31 antagonist as an active ingredient, 6–100 mg / mL of an IL-31 antagonist, 6 to 20 mmol / L Tris buffer, 45-150 mmol / L arginine or its salts, 75–250 mmol / L sucrose or trehalose, and 0.15-0.50 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising the compound is a freeze-dried composition, and has a pH of 6 to 8 after reconstitution in water.

[27] A freeze-dried preparation containing an IL-31 antagonist as an active ingredient, the freeze-dried preparation being packed in a vial, cartridge, or syringe. 1–800 mg of an IL-31 antagonist, 0.1-40 mg of tris(hydroxymethyl)aminomethane, 0.8-400 mg arginine, 3–1100 mg of sucrose or trehalose, and 0.01–7 mg of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8 after reconstitution with water.

[28] A freeze-dried preparation containing an IL-31 antagonist as an active ingredient, the freeze-dried preparation being packed in a vial, cartridge, or syringe. 10–80 mg of an IL-31 antagonist, 0.8-4 mg of tris(hydroxymethyl)aminomethane, 8-40 mg arginine, 30–110 mg of sucrose or trehalose, and 0.1-0.7 mg of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8 after reconstitution with water.

[29] The formulation according to any one of [1] to

[28] , wherein the molar ratio of the arginine and / or its salt to the IL-31 antagonist is 220 to 1100:1, and / or the weight ratio of the arginine to the IL-31 antagonist is 0.3 to 1.3:1.

[30] The freeze-dried preparation according to any one of [1] to

[12] and

[25] to

[28] , wherein the molar ratio of the sucrose or trehalose to the IL-31 antagonist is 370 to 1840:1 and / or the weight ratio is 0.8 to 4.3:1.

[31] The freeze-dried preparation according to any one of

[25] to

[30] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl), arginine aspartate, or arginine glutamate.

[32] The freeze-dried preparation according to any one of

[25] to

[31] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl).

[33] The freeze-dried formulation according to

[32] , wherein the Tris buffer is trishydroxymethylaminomethane and / or a salt thereof.

[34] The freeze-dried formulation according to

[33] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl), trishydroxymethylaminomethane aspartate, trishydroxymethylaminomethane glutamate, or trishydroxymethylaminomethane acetate.

[35] The freeze-dried formulation according to

[33] or

[34] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl).

[0010]

[36] The formulation according to any one of [1] to

[35] , wherein the IL-31 antagonist is an antibody that inhibits IL-31 signaling.

[37] The formulation according to

[36] , wherein the antibody that inhibits IL-31 signaling is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.

[38] The anti-IL-31RA neutralizing antibody, (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising the heavy chain variable region set forth in SEQ ID NO: 7 and the light chain variable region set forth in SEQ ID NO: 8; or (3) The formulation of

[37] , which is an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10.

[39] The formulation according to

[37] or

[38] , wherein the anti-IL-31RA neutralizing antibody is an IgG antibody, preferably an IgG2 antibody.

[40] The formulation according to any one of

[37] to

[39] , wherein the anti-IL-31RA neutralizing antibody is nemolizumab.

[0011]

[41] The freeze-dried preparation according to any one of

[37] to

[40] , wherein the composition is a freeze-dried solution having an anti-IL-31RA neutralizing antibody concentration of 68 mg / mL.

[42] The freeze-dried preparation according to any one of

[37] to

[40] , wherein the composition is a freeze-dried solution having an anti-IL-31RA neutralizing antibody concentration of 50 mg / mL.

[43] The freeze-dried preparation according to any one of

[37] to

[40] , wherein the composition is a freeze-dried solution having an anti-IL-31RA neutralizing antibody concentration of 15 mg / mL.

[44] The freeze-dried preparation according to any one of

[37] to

[40] , wherein the composition is a freeze-dried solution having an anti-IL-31RA neutralizing antibody concentration of 7.5 mg / mL.

[0012]

[45] The freeze-dried preparation according to any one of

[37] to

[41] , wherein the composition is a freeze-dried solution having a Tris-HCl concentration of 13.6 mmol / L.

[46] The freeze-dried preparation according to any one of

[37] to

[40] and

[42] , wherein the solution having a Tris-HCl concentration of 10 mmol / L is a freeze-dried composition.

[47] The freeze-dried preparation according to any one of

[37] to

[40] and

[43] to

[44] , wherein the solution having a Tris-HCl concentration of 6 mmol / L is a freeze-dried composition.

[0013]

[48] ​​The freeze-dried preparation according to any one of

[37] to

[41] and

[45] , wherein the solution having an Arg-HCl concentration of 102 mmol / L is freeze-dried.

[49] The freeze-dried preparation according to any one of

[37] to

[40] ,

[42] , and

[46] , wherein the solution having an Arg-HCl concentration of 75 mmol / L is a freeze-dried composition.

[50] The freeze-dried preparation according to any one of

[37] to

[40] ,

[43] to

[44] , and

[47] , wherein the solution having an Arg-HCl concentration of 45 mmol / L is a freeze-dried composition.

[0014]

[51] The freeze-dried preparation according to any one of

[37] to

[41] ,

[45] , and

[48] , wherein the solution having a concentration of sucrose or trehalose of 170 mmol / L is a freeze-dried composition.

[52] The freeze-dried preparation according to any one of

[37] to

[40] ,

[42] ,

[46] , and

[49] , wherein the solution having a concentration of sucrose or trehalose of 125 mmol / L is a freeze-dried composition.

[53] The freeze-dried preparation according to any one of

[37] to

[40] ,

[43] to

[44] ,

[47] , and

[50] , wherein the solution having a concentration of sucrose or trehalose of 75 mmol / L is a freeze-dried composition.

[0015]

[54] The freeze-dried preparation according to any one of

[37] to

[41] ,

[45] ,

[48] , and

[51] , wherein the solution having a concentration of poloxamer 188 or polysorbate 20 of 0.34 mg / mL is a freeze-dried composition.

[55] The freeze-dried preparation according to any one of

[37] to

[40] ,

[42] ,

[46] ,

[49] , and

[52] , wherein the solution having a concentration of poloxamer 188 or polysorbate 20 of 0.25 mg / mL is a freeze-dried composition.

[56] The freeze-dried preparation according to any one of

[37] to

[40] ,

[43] to

[44] ,

[47] ,

[50] , and

[53] , wherein the solution having a concentration of poloxamer 188 or polysorbate 20 of 0.15 mg / mL is a freeze-dried composition.

[0016]

[57] The freeze-dried preparation according to any one of

[37] to

[42] ,

[45] to

[46] ,

[48] to

[49] ,

[51] to

[52] , and

[54] to

[55] , wherein the solution in which the molar ratio of arginine to the anti-IL-31RA neutralizing antibody is 220:1 and / or the weight ratio is 0.3:1 is a freeze-dried composition.

[58] The freeze-dried preparation according to any one of

[37] to

[40] ,

[43] ,

[47] ,

[50] ,

[53] , and

[56] , wherein the solution in which the molar ratio of arginine to the anti-IL-31RA neutralizing antibody is 440:1 and / or the weight ratio is 0.5:1 is a freeze-dried composition.

[59] The freeze-dried preparation according to any one of

[37] to

[40] ,

[44] ,

[47] ,

[50] ,

[53] , and

[56] , wherein the solution in which the molar ratio of arginine to the anti-IL-31RA neutralizing antibody is 880:1 and / or the weight ratio is 1.0 to 1.1:1 is a freeze-dried composition.

[0017]

[60] The freeze-dried preparation according to any one of

[37] to

[42] ,

[45] to

[46] ,

[48] to

[49] ,

[51] to

[52] ,

[54] to

[55] , and

[57] , wherein the solution in which the molar ratio of the sucrose to the anti-IL-31RA neutralizing antibody is 370:1 and / or the weight ratio is 0.8 to 0.9:1 is freeze-dried.

[61] The freeze-dried preparation according to any one of

[37] to

[40] ,

[43] ,

[47] ,

[50] ,

[53] ,

[56] , and

[58] , wherein the solution in which the molar ratio of the sucrose to the anti-IL-31RA neutralizing antibody is 740:1 and / or the weight ratio is 1.7:1 is a freeze-dried composition.

[62] The freeze-dried preparation according to any one of

[37] to

[40] ,

[44] ,

[47] ,

[50] ,

[53] ,

[56] , and

[59] , wherein the solution in which the molar ratio of the sucrose to the anti-IL-31RA neutralizing antibody is 1470:1 and / or the weight ratio is 3.4 to 3.5:1 is a freeze-dried composition.

[0018]

[63] The freeze-dried preparation according to any one of

[25] to

[62] , which has a pH of 6.5 to 7.5 after reconstitution with water.

[64] The freeze-dried preparation according to any one of

[25] to

[63] , which has a pH of 7 after redissolution in water.

[0019]

[65] For syringes and other containers 75 mg of anti-IL-31RA neutralizing antibody, 1.8 mg trishydroxymethylaminomethane, 19 mg arginine, 64 mg sucrose 0.4 mg Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] ,

[66] For containers such as syringes, 75 mg of anti-IL-31RA neutralizing antibody, 0.24 mg trishydroxymethylaminomethane, 23.6 mg L-arginine hydrochloride, 63.9 mg sucrose, 0.37 mg of poloxamer 188, and Tris(hydroxymethyl)aminomethane hydrochloride as a pH adjuster The freeze-dried preparation according to any one of

[25] to

[40] ,

[67] For syringes and other containers 39 mg of anti-IL-31RA neutralizing antibody, 0.9 mg trishydroxymethylaminomethane, 10 mg arginine, 33 mg of sucrose, and 0.2 mg Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] ,

[68] For cartridges and other containers 36 mg of anti-IL-31RA neutralizing antibody, 0.9 mg trishydroxymethylaminomethane, 9 mg arginine, 31 mg of sucrose, and 0.2 mg Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] ,

[69] Per vial or other container 51 mg of anti-IL-31RA neutralizing antibody, 2.5 mg of trishydroxymethylaminomethane, 27 mg arginine, 88 mg of sucrose, and 0.5 mg Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] ,

[70] Per vial or other container 30 mg of anti-IL-31RA neutralizing antibody, 3.0 mg trishydroxymethylaminomethane, 32 mg arginine, 104 mg of sucrose, and 0.6 mg Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] ,

[71] Per vial or other container 19 mg of anti-IL-31RA neutralizing antibody, 1.9 mg trishydroxymethylaminomethane, 20 mg arginine, 66 mg of sucrose, and 0.4 mg Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] ,

[72] Per vial or other container 14 mg of anti-IL-31RA neutralizing antibody, 1.3 mg trishydroxymethylaminomethane, 15 mg arginine, 47 mg of sucrose, and 0.3 mg Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] ,

[0020]

[73] 68 mg / mL of an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10. 13.6 mmol / L trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer, 102 mmol / L arginine hydrochloride (Arg-HCl), 170 mmol / L sucrose, and 0.34 mg / mL Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] , wherein the solution comprising the compound is a freeze-dried composition, and has a pH of 7 after redissolution in water.

[74] 50 mg / mL of an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10. 10 mmol / L trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer, 75 mmol / L arginine hydrochloride (Arg-HCl), 125 mmol / L sucrose, and 0.25 mg / mL Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] , wherein the solution comprising the compound is a freeze-dried composition, and has a pH of 7 after redissolution in water.

[75] 15 mg / mL of an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10. 6 mmol / L trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer, 45 mmol / L arginine hydrochloride (Arg-HCl), 75 mmol / L sucrose, and 0.15 mg / mL Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] , wherein the solution comprising the compound is a freeze-dried composition, and has a pH of 7 after redissolution in water.

[76] 7.5 mg / mL of an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10. 6 mmol / L trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer, 45 mmol / L arginine hydrochloride (Arg-HCl), 75 mmol / L sucrose, and 0.15 mg / mL Poloxamer 188 The freeze-dried preparation according to any one of

[25] to

[40] , wherein the solution comprising the compound is a freeze-dried composition, and has a pH of 7 after redissolution in water.

[0021]

[77] A freeze-dried preparation comprising an IL-31 antagonist as an active ingredient, and further comprising a Tris buffer, arginine, sucrose or trehalose, poloxamer 188, or polysorbate 20, wherein the preparation, after being reconstituted in water, 1–200 mg / mL of an IL-31 antagonist, 1 to 200 mmol / L Tris buffer, 4.5 to 1500 mmol / L of arginine or its salts, 7.5–2500 mmol / L of sucrose or trehalose, and 0.01-5 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8.

[78] A freeze-dried preparation comprising an IL-31 antagonist as an active ingredient, and further comprising a Tris buffer, arginine, sucrose or trehalose, poloxamer 188, or polysorbate 20, wherein the preparation, after being reconstituted in water, 20-100 mg / mL of IL-31 antagonist, 10-20 mmol / L Tris buffer, 75-150 mmol / L arginine or its salts, 125–250 mmol / L sucrose or trehalose, and 0.25-0.50 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8.

[79] The freeze-dried formulation according to

[77] or

[78] , wherein the molar ratio of the arginine and / or a salt thereof to the IL-31 antagonist is 220 to 1100:1, and / or the weight ratio of the arginine to the IL-31 antagonist is 0.3 to 1.3:1.

[80] The freeze-dried preparation according to any one of

[77] to

[79] , wherein the molar ratio of the sucrose or trehalose to the IL-31 antagonist is 370 to 1840:1 and / or the weight ratio is 0.8 to 4.3:1.

[81] The freeze-dried preparation according to any one of

[77] to

[80] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl), arginine aspartate, or arginine glutamate.

[82] The freeze-dried preparation according to any one of

[77] to

[81] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl).

[83] The freeze-dried preparation according to any one of

[77] to

[82] , wherein the Tris buffer is trishydroxymethylaminomethane and / or a salt thereof.

[84] The freeze-dried formulation according to

[83] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl), trishydroxymethylaminomethane aspartate, trishydroxymethylaminomethane glutamate, or trishydroxymethylaminomethane acetate.

[85] The freeze-dried formulation according to

[83] or

[84] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl).

[0022]

[86] The freeze-dried preparation according to any of

[77] to

[85] , wherein the IL-31 antagonist is an antibody that inhibits IL-31 signaling.

[87] The freeze-dried formulation according to

[86] , wherein the antibody that inhibits IL-31 signaling is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.

[0023]

[88] The anti-IL-31RA neutralizing antibody, (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising the heavy chain variable region set forth in SEQ ID NO: 7 and the light chain variable region set forth in SEQ ID NO: 8; or (3) The lyophilized preparation according to

[87] , which is an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10.

[89] The freeze-dried formulation according to

[87] or

[88] , wherein the anti-IL-31RA neutralizing antibody is an IgG antibody, preferably an IgG2 antibody.

[90] The freeze-dried preparation according to any one of

[87] to

[89] , wherein the anti-IL-31RA neutralizing antibody is nemolizumab.

[0024]

[91] The freeze-dried preparation according to any one of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody after reconstitution with water is 100 mg / mL.

[92] The freeze-dried preparation according to any of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody after reconstitution with water is 61.5 mg / mL.

[93] The freeze-dried preparation according to any one of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody after reconstitution with water is 50 mg / mL.

[94] The freeze-dried preparation according to any one of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody after reconstitution with water is 25 mg / mL.

[0025]

[95] The freeze-dried preparation according to any one of

[87] to

[91] , wherein the concentration of the Tris-HCl after reconstitution with water is 20 mmol / L.

[96] The freeze-dried preparation according to any one of

[87] to

[90] and

[92] , wherein the concentration of the Tris-HCl after reconstitution with water is 12.3 mmol / L.

[97] The freeze-dried preparation according to any one of

[87] to

[90] and

[93] to

[94] , wherein the concentration of the Tris-HCl after reconstitution with water is 20 mmol / L.

[0026]

[98] The freeze-dried preparation according to any one of

[87] to

[91] and

[95] , wherein the concentration of the Arg-HCl after reconstitution with water is 150 mmol / L.

[99] The freeze-dried preparation according to any one of

[87] to

[90] ,

[92] , and

[96] , wherein the concentration of the Arg-HCl after reconstitution with water is 92 mmol / L.

[100] The freeze-dried preparation according to any one of

[87] to

[90] ,

[93] to

[94] , and

[97] , wherein the concentration of the Arg-HCl after reconstitution with water is 150 mmol / L.

[0027]

[101] The freeze-dried preparation according to any one of

[87] to

[91] ,

[95] , or

[98] , wherein the concentration of the sucrose or trehalose after reconstitution with water is 250 mmol / L.

[102] The freeze-dried preparation according to any one of

[87] to

[90] ,

[92] ,

[96] , or

[99] , wherein the concentration of the sucrose or trehalose after reconstitution with water is 154 mmol / L.

[103] The freeze-dried preparation according to any one of

[87] to

[90] ,

[93] to

[94] ,

[97] , and

[100] , wherein the concentration of the sucrose or trehalose after reconstitution with water is 250 mmol / L.

[0028]

[104] The freeze-dried preparation according to any one of

[87] to

[91] ,

[95] ,

[98] , or

[101] , wherein the concentration of the poloxamer 188 or polysorbate 20 after reconstitution with water is 0.50 mg / mL.

[105] The freeze-dried formulation according to any one of

[87] to

[90] ,

[92] ,

[96] ,

[99] , or

[102] , wherein the concentration of the poloxamer 188 or polysorbate 20 after reconstitution with water is 0.31 mg / mL.

[106] The freeze-dried preparation according to any one of

[87] to

[90] ,

[93] to

[94] ,

[97] ,

[100] , and

[103] , wherein the concentration of the poloxamer 188 or polysorbate 20 after reconstitution with water is 0.50 mg / mL.

[0029]

[107] The freeze-dried preparation according to any one of

[87] to

[91] ,

[95] ,

[98] ,

[101] , and

[104] to

[105] , wherein the molar ratio of the arginine to the anti-IL-31RA neutralizing antibody is 220:1 and / or the weight ratio is 0.3:1.

[108] The freeze-dried preparation of any one of

[87] to

[90] ,

[93] ,

[97] ,

[100] ,

[103] , or

[106] , wherein the molar ratio of the arginine to the anti-IL-31RA neutralizing antibody is 440:1 and / or the weight ratio is 0.5:1.

[109] The freeze-dried preparation according to any one of

[87] to

[90] ,

[94] ,

[97] ,

[100] ,

[103] , or

[106] , wherein the molar ratio of the arginine to the anti-IL-31RA neutralizing antibody is 880:1 and / or the weight ratio is 1.0 to 1.1:1.

[0030]

[110] The freeze-dried preparation according to any one of

[87] to

[91] ,

[95] ,

[98] ,

[101] ,

[104] to

[105] , and

[107] , wherein the molar ratio of the sucrose to the anti-IL-31RA neutralizing antibody is 370:1 and / or the weight ratio is 0.8 to 0.9:1.

[111] The freeze-dried formulation according to any one of

[87] to

[90] ,

[93] ,

[97] ,

[100] ,

[103] ,

[106] , or

[108] , wherein the molar ratio of the sucrose to the anti-IL-31RA neutralizing antibody is 740:1 and / or the weight ratio is 1.7:1.

[112] The freeze-dried preparation according to any one of

[87] to

[90] ,

[94] ,

[97] ,

[100] ,

[103] , or

[109] , wherein the molar ratio of the sucrose to the anti-IL-31RA neutralizing antibody is 1470:1 and / or the weight ratio is 3.4 to 3.5:1.

[0031]

[113] The freeze-dried preparation according to any one of

[77] to

[112] , wherein the pH after reconstitution with water is 6.5 to 7.5.

[114] The freeze-dried preparation according to any one of

[77] to

[113] , wherein the pH after reconstitution with water is 6.7 to 7.3.

[115] The freeze-dried preparation according to any one of

[77] to

[114] , which has a pH of 7 after reconstitution with water.

[0032]

[116] A pharmaceutical composition comprising, as an active ingredient, an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10, wherein the lyophilized preparation is prepared by lyophilizing a solution containing a buffer, a stabilizer, an excipient, and a nonionic surfactant, and the concentration after reconstitution with water is Anti-IL-31RA neutralizing antibody at 100 mg / mL Tris-hydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer at 20 mmol / L Arginine hydrochloride (Arg-HCl) 150 mmol / L Sucrose 250 mmol / L Poloxamer 188 at 0.50 mg / mL The freeze-dried preparation according to any one of

[87] to

[91] ,

[95] ,

[98] ,

[101] ,

[104] ,

[107] , and

[110] ,

[117] A pharmaceutical composition comprising an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10 as an active ingredient, the composition being a lyophilized preparation prepared by lyophilizing a solution comprising a buffer, a stabilizer, an excipient, and a nonionic surfactant, the concentration of which after reconstitution with water is Anti-IL-31RA neutralizing antibody at 61.5 mg / mL Tris-hydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer at 12.3 mmol / L Arginine hydrochloride (Arg-HCl) 92 mmol / L Sucrose 154 mmol / L Poloxamer 188 at 0.31 mg / mL The freeze-dried preparation according to any one of

[87] to

[90] ,

[92] ,

[96] ,

[99] ,

[102] ,

[105] ,

[107] , and

[110] ,

[118] A pharmaceutical composition comprising an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10 as an active ingredient, the composition being a lyophilized preparation prepared by lyophilizing a solution containing a buffer, a stabilizer, an excipient, and a nonionic surfactant, the concentration of which after reconstitution with water is Anti-IL-31RA neutralizing antibody at 50 mg / mL Tris-hydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer at 20 mmol / L Arginine hydrochloride (Arg-HCl) 150 mmol / L Sucrose 250 mmol / L Poloxamer 188 at 0.50 mg / mL The freeze-dried preparation according to any one of

[87] to

[90] ,

[93] ,

[97] ,

[100] ,

[103] ,

[106] ,

[108] , and

[111] ,

[119] A pharmaceutical composition comprising, as an active ingredient, an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10, wherein the lyophilized preparation is prepared by lyophilizing a solution containing a buffer, a stabilizer, an excipient, and a nonionic surfactant, and the concentration after reconstitution with water is Anti-IL-31RA neutralizing antibody at 25 mg / mL Tris-hydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer at 20 mmol / L Arginine hydrochloride (Arg-HCl) 150 mmol / L Sucrose 250 mmol / L Poloxamer 188 at 0.50 mg / mL The freeze-dried preparation according to any one of

[87] to

[90] ,

[94] ,

[97] ,

[100] ,

[103] ,

[109] , and

[112] ,

[0033]

[120] A freeze-dried preparation comprising an IL-31 antagonist as an active ingredient, comprising: 1–200 mg / mL of an IL-31 antagonist, 1 to 200 mmol / L Tris buffer, 4.5 to 1500 mmol / L of arginine or its salts, 7.5–2500 mmol / L of sucrose or trehalose, and 0.01-5 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising the above is a lyophilized composition, which upon reconstitution with water comprises 1–200 mg / mL of an IL-31 antagonist, 1 to 200 mmol / L Tris buffer, 4.5 to 1500 mmol / L of arginine or its salts, 7.5–2500 mmol / L of sucrose or trehalose, and 0.01-5 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8.

[121] A freeze-dried preparation comprising an IL-31 antagonist as an active ingredient, comprising: 6–100 mg / mL of an IL-31 antagonist, 6 to 20 mmol / L Tris buffer, 45-150 mmol / L arginine or its salts, 75–250 mmol / L sucrose or trehalose, and 0.15-0.50 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising the above is a lyophilized composition, which upon reconstitution with water comprises 20-100 mg / mL of IL-31 antagonist, 10-20 mmol / L Tris buffer, 75-150 mmol / L arginine or its salts, 125–250 mmol / L sucrose or trehalose, and 0.25-0.50 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8.

[122] The freeze-dried formulation according to

[120] or

[121] , wherein the molar ratio of the arginine and / or a salt thereof to the IL-31 antagonist is 220 to 1100:1.

[123] The freeze-dried preparation according to any one of

[120] to

[122] , wherein the molar ratio of the sucrose or trehalose to the IL-31 antagonist is 370 to 1840:1.

[124] The freeze-dried preparation according to any one of

[120] to

[123] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl), arginine aspartate, or arginine glutamate.

[125] The freeze-dried preparation according to any one of

[120] to

[124] , wherein the arginine and / or a salt thereof is arginine hydrochloride (Arg-HCl).

[126] The freeze-dried preparation according to any one of

[120] to

[125] , wherein the Tris buffer is trishydroxymethylaminomethane and / or a salt thereof.

[127] The freeze-dried preparation according to any one of

[120] to

[126] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl), trishydroxymethylaminomethane aspartate, trishydroxymethylaminomethane glutamate, or trishydroxymethylaminomethane acetate.

[128] The freeze-dried preparation according to any one of

[120] to

[127] , wherein the trishydroxymethylaminomethane and / or a salt thereof is trishydroxymethylaminomethane hydrochloride (Tris-HCl).

[0034]

[129] The freeze-dried preparation according to any of

[120] to

[128] , wherein the IL-31 antagonist is an antibody that inhibits IL-31 signaling.

[130] The freeze-dried formulation according to

[129] , wherein the antibody that inhibits IL-31 signaling is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.

[0035]

[131] The anti-IL-31RA neutralizing antibody, (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising the heavy chain variable region set forth in SEQ ID NO: 7 and the light chain variable region set forth in SEQ ID NO: 8; or (3) The lyophilized preparation according to

[130] , which is an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10.

[132] The freeze-dried formulation according to

[130] or

[131] , wherein the anti-IL-31RA neutralizing antibody is an IgG antibody, preferably an IgG2 antibody.

[133] The freeze-dried preparation according to any one of

[130] to

[132] , wherein the anti-IL-31RA neutralizing antibody is nemolizumab.

[0036]

[134] The formulation according to any one of [1] to

[133] above, for use in the prevention and / or treatment of an IL-31-related disease or a symptom associated therewith.

[135] The formulation according to

[134] , wherein the IL-31-associated disease is an inflammatory disease associated with IL-31 signaling.

[136] The formulation according to

[135] , wherein the inflammatory disease is selected from the group consisting of atopic dermatitis, dialysis pruritus, and prurigo nodularis.

[137] The formulation according to any one of [1] to

[136] , wherein the IL-31 antagonist is administered subcutaneously.

[0037]

[138] A method for stabilizing an antibody in an antibody-containing formulation, comprising preparing an antibody-containing solution containing arginine and / or a salt thereof, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or a salt thereof to the antibody in the solution is 220-1100:1, and the molar ratio of sucrose or trehalose to the antibody is 370-1840:1.

[139] The method according to

[138] , wherein the antibody-containing solution further contains 6 to 20 mmol / L of trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.

[140] The method according to

[138] or

[139] , further comprising lyophilizing the antibody-containing solution to prepare an antibody-containing lyophilized formulation.

[141] Use of arginine and / or a salt thereof, and / or sucrose and / or trehalose for stabilizing an antibody in an antibody-containing formulation, comprising preparing an antibody-containing solution containing arginine and / or a salt thereof, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or a salt thereof to the antibody in the solution is 220-1100:1, and the molar ratio of sucrose or trehalose to the antibody is 370-1840:1.

[142] The use according to

[141] , wherein the antibody-containing solution further contains 6 to 20 mmol / L of trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.

[143] The use according to

[141] or

[142] , further comprising lyophilizing the antibody-containing solution to prepare an antibody-containing lyophilized formulation.

[0038]

[144] A method for suppressing antibody aggregation (aggregate formation) in an antibody-containing formulation, comprising preparing an antibody-containing solution containing arginine and / or a salt thereof, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or a salt thereof to the antibody in the solution is 220-1100:1, and the molar ratio of sucrose or trehalose to the antibody is 370-1840:1.

[145] The method according to

[144] , wherein the antibody-containing solution further contains 6 to 20 mmol / L of trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.

[146] The method according to

[144] or

[145] , further comprising lyophilizing the antibody-containing solution to prepare an antibody-containing lyophilized formulation.

[147] Use of arginine and / or a salt thereof, and / or sucrose and / or trehalose for suppressing antibody aggregation (aggregate formation) in an antibody-containing formulation, comprising preparing an antibody-containing solution containing arginine and / or a salt thereof, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or a salt thereof to the antibody in the solution is 220-1100:1, and the molar ratio of sucrose or trehalose to the antibody is 370-1840:1.

[148] The use according to

[147] , wherein the antibody-containing solution further contains 6 to 20 mmol / L of trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.

[149] The use according to

[147] or

[148] , further comprising lyophilizing the antibody-containing solution to prepare an antibody-containing lyophilized formulation.

[0039]

[150] A method for reducing charged hetero components in an antibody-containing formulation, comprising preparing an antibody-containing solution containing arginine and / or a salt thereof, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or a salt thereof to the antibody in the solution is 220 to 1100:1, and the molar ratio of sucrose or trehalose to the antibody is 370 to 1840:1.

[151] The method according to

[150] , wherein the antibody-containing solution further contains 6 to 20 mmol / L of trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.

[152] The method according to

[150] or

[151] , further comprising lyophilizing the antibody-containing solution to prepare an antibody-containing lyophilized formulation.

[153] Use of arginine and / or a salt thereof, and / or sucrose and / or trehalose for reducing charged hetero components in an antibody-containing formulation, comprising preparing an antibody-containing solution containing arginine and / or a salt thereof, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or a salt thereof to the antibody in the solution is 220-1100:1, and the molar ratio of sucrose or trehalose to the antibody is 370-1840:1.

[154] The use according to

[153] , wherein the antibody-containing solution further contains 6 to 20 mmol / L of trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.

[155] The use according to

[153] or

[154] , further comprising lyophilizing the antibody-containing solution to prepare an antibody-containing lyophilized formulation.

[0040]

[156] A method for preventing and / or treating an IL-31-associated disease, comprising administering an IL-31 antagonist to a subject suffering from or at risk of suffering from an IL-31-associated disease, preparing a lyophilized formulation by lyophilizing a solution containing 6-100 mg / mL of an IL-31 antagonist, 45-150 mmol / L of arginine hydrochloride (Arg-HCl), and 75-250 mmol / L of sucrose or trehalose; redissolving the freeze-dried formulation in water to prepare a reconstituted solution; and administering said reconstituted solution to said subject. The method comprising:

[157] Use of an IL-31 antagonist in the manufacture of a medicament for the prevention and / or treatment of an IL-31-associated disease, the use comprising freeze-drying a solution containing 6 to 100 mg / mL of an IL-31 antagonist, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose to prepare a freeze-dried preparation.

[158] An IL-31 antagonist for use in the prevention and / or treatment of an IL-31-associated disease, characterized in that the IL-31 antagonist is used after being reconstituted in water to obtain a lyophilized preparation obtained by lyophilizing a solution containing 6 to 100 mg / mL of the IL-31 antagonist, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose.

[159] The method according to

[156] , the use according to

[157] , or the IL-31 antagonist according to

[158] , wherein the solution before lyophilization further comprises 6 to 20 mmol / L trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.

[0041]

[160] An injectable preparation or kit comprising: (i) a container; (ii) a lyophilized preparation according to any one of [1] to

[12] and

[25] to

[137] ; and (iii) water for injection for reconstituting the lyophilized preparation.

[161] An injectable formulation comprising: (i) a container; (ii) a lyophilized formulation in the container, the lyophilized formulation comprising a solution comprising 6 to 100 mg / mL of an anti-IL-31RA neutralizing antibody, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose; and, optionally, (iii) water for injection for reconstituting the lyophilized formulation.

[162] The injectable formulation according to

[161] , wherein the solution before lyophilization further contains 6 to 20 mmol / L of trishydroxymethylaminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.

[163] (i) a container; (ii) a lyophilized preparation in the container, obtained by lyophilizing a solution containing an effective amount of an anti-IL-31RA neutralizing antibody and 220 to 1,100 moles of arginine hydrochloride (Arg-HCl) and 370 to 1,840 moles of sucrose or trehalose per mole of the antibody; and (iii) optionally, water for injection for reconstituting the lyophilized preparation.

[164] The injectable preparation or kit according to any one of

[160] to

[163] , wherein the lyophilized preparation and the water for injection are sealed in separate compartments within a container.

[165] The injectable preparation or kit according to any one of

[160] to

[164] , wherein the lyophilized preparation is reconstituted in the container with the water for injection at the time of use. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Preferred, non-limiting aspects of the present disclosure are described below.

[0043] All embodiments described in the following examples are intended to be considered as being equivalently described in this "Form for Carrying Out the Invention" without being bound by any patent practice, custom, laws, regulations, etc. that may attempt to interpret the contents of the examples in a restrictive manner in the country in which this patent application is intended to be granted.

[0044] In the present disclosure, the description of numerical values ​​may include numerical values ​​rounded to the nearest digit (e.g., the 1st digit) to the next lower digit (e.g., the 1st decimal place when the 1st digit is the minimum digit). For example, the numerical value 5 is intended to include numerical values ​​in the range of 4.5 to 5.4.

[0045] In one non-limiting embodiment, the present disclosure relates to a freeze-dried formulation containing an IL-31 antagonist as an active ingredient, the freeze-dried formulation comprising arginine and / or a salt thereof, and sucrose and / or trehalose. In another non-limiting embodiment, the present disclosure relates to a solution formulation containing an IL-31 antagonist as an active ingredient, the solution formulation comprising arginine and / or a salt thereof. The arginine is preferably L-arginine. In one embodiment, the arginine and / or a salt thereof is arginine hydrochloride, L-arginine hydrochloride, arginine aspartate, L-arginine aspartate, arginine glutamate, or L-arginine glutamate. It is to be understood by those skilled in the art that when arginine is expressed by weight (e.g., mg), the weight may be the weight of arginine alone or the weight of arginine contained in a salt containing arginine. In addition, in the present disclosure, the weight or concentration of arginine may be the sum of the weight or concentration of arginine alone and the weight or concentration of arginine contained in a salt containing arginine. In one embodiment, the formulation of the present disclosure further comprises a Tris buffer as a buffer. In one embodiment, the Tris buffer is trishydroxymethylaminomethane and / or a salt thereof, for example, trishydroxymethylaminomethane-hydrochloride (Tris-HCl), trishydroxymethylaminomethane-aspartate, trishydroxymethylaminomethane-glutamate, or trishydroxymethylaminomethane-acetate. In one embodiment, the formulation of the present disclosure further comprises poloxamer 188 or polysorbate as a nonionic surfactant. Note that poloxamer 188 is sometimes referred to as "polyoxyethylene (160) polyoxypropylene (30) glycol" in the standards of the Japanese Pharmacopoeia. In one embodiment, the polysorbate is polysorbate 20 or polysorbate 80. In one embodiment, the pH of the reconstituted solution after reconstituting the lyophilized formulation of the present disclosure with water is 6 to 8, for example, 6.5 to 7.5, for example, 6.7 to 7.3, for example, 7. In one embodiment, the pH of the solution formulation of the present disclosure is 6 to 8, for example, 6.5 to 7.5, for example, 7.In addition, trishydroxymethylaminomethane is sometimes referred to as "trometamol" in the standards of the Japanese Pharmacopoeia. When trishydroxymethylaminomethane is expressed by weight (e.g., mg), it will be understood by those skilled in the art that the weight may be the weight of trishydroxymethylaminomethane alone or the weight of trishydroxymethylaminomethane contained in a salt containing trishydroxymethylaminomethane. In addition, in the present disclosure, the weight or concentration of trishydroxymethylaminomethane may be the sum of the weight or concentration of trishydroxymethylaminomethane alone and the weight or concentration of trishydroxymethylaminomethane contained in a salt containing trishydroxymethylaminomethane.

[0046] The amount and concentration of the IL-31 antagonist contained in the formulation of the present disclosure are not particularly limited, and can be appropriately adjusted depending on the subject to which it is administered, for example, whether it is for adults or children, whether it is for prevention or treatment, or the type or severity of the disease or symptom to be prevented or treated. Therefore, the molar ratio and weight ratio of the IL-31 antagonist to other components contained in the formulation of the present disclosure can take various values. In a non-limiting embodiment, the molar ratio of arginine and / or its salt to the IL-31 antagonist is 3 to 220500:1, for example, 22 to 6600:1, 33 to 5500:1, 44 to 4400:1, 55 to 3300:1, 110 to 2200:1, 220 to 1100:1, 220 to 880:1, 220 to 440:1, or 440 to 880:1. In a non-limiting embodiment, the weight ratio of arginine to IL-31 antagonist is 0.004 to 261:1, for example, 0.03 to 9.6:1, 0.1 to 4.8:1, 0.2 to 3.2:1, 0.3 to 1.6:1, 0.3 to 1.3:1, 0.3 to 1.1:1, 0.5 to 1.1:1, or 0.3 to 0.5:1. In a non-limiting embodiment, the molar ratio of sucrose or trehalose to the IL-31 antagonist is 6 to 367500:1, for example, 75 to 7360:1, 100 to 5520:1, 150 to 3680:1, 300 to 1840:1, 370 to 1840:1, 370 to 1470:1, 740 to 1470:1, or 370 to 740:1. In a non-limiting embodiment, the weight ratio of sucrose or trehalose to the IL-31 antagonist is 0.013 to 856:1, for example, 0.18 to 16.8:1, 0.23 to 12.6:1, 0.35 to 8.4:1, 0.7 to 4.2:1, 0.8 to 4.3:1, 0.8 to 3.5:1, 1.7 to 3.5:1, or 0.8 to 1.7:1. Sucrose is sometimes referred to as "refined white sugar" in the standards of the Japanese Pharmacopoeia.

[0047] In a non-limiting embodiment, the concentration of the IL-31 antagonist in a solution state contained in the formulation of the present disclosure (i.e., the concentration in a solution formulation, the concentration in a solution before lyophilization of a lyophilized formulation, or the concentration in a solution after reconstitution of a lyophilized formulation) is 1 to 200 mg / mL, for example, 2 to 200 mg / mL, 3 to 200 mg / mL, 3 to 150 mg / mL, 6 to 100 mg / mL, 10 to 100 mg / mL, 15 to 100 mg / mL, 30 to 100 mg / mL, 50 to 100 mg / mL, 6 to 70 mg / mL, 10 to 70 mg / mL, 15 to 70 mg / mL, 30 to 70 mg / mL, 50 to 70 mg / mL, 6 to 50 mg / mL, 10 to 50 mg / mL, 30 to 50 mg / mL, or 6 to 30 mg / mL.

[0048] In one embodiment, the concentration of arginine and / or a salt thereof in a solution state contained in a formulation of the present disclosure is 4.5 to 1500 mmol / L, for example, 9 to 750 mmol / L, 15 to 450 mmol / L, 22.5 to 300 mmol / L, 45 to 150 mmol / L, 75 to 150 mmol / L, or 45 to 75 mmol / L. In one embodiment, the concentration of sucrose and / or trehalose in a solution state contained in a formulation of the present disclosure is 7.5 to 2500 mmol / L, for example, 15 to 1250 mmol / L, 25 to 750 mmol / L, 37.5 to 500 mmol / L, 75 to 250 mmol / L, 125 to 250 mmol / L, 75 to 170 mmol / L, 125 to 170 mmol / L, or 75 to 125 mmol / L.

[0049] In one embodiment, the concentration of the Tris buffer in a solution state contained in the formulation of the present disclosure is 1 to 200 mmol / L, e.g., 1 to 100 mmol / L, 2 to 60 mmol / L, 3 to 40 mmol / L, 6 to 20 mmol / L, 3 to 15 mmol / L, 10 to 20 mmol / L, 10 to 15 mmol / L, 6 to 15 mmol / L, or 6 to 10 mmol / L. In one embodiment, the concentration of poloxamer 188 or polysorbate in a solution state contained in a formulation of the present disclosure is 0.015 to 5 mg / mL, e.g., 0.03 to 2.5 mg / mL, 0.05 to 1.5 mg / mL, 0.075 to 1 mg / mL, 0.15 to 0.5 mg / mL, 0.15 to 0.4 mg / mL, 0.25 to 0.5 mg / mL, or 0.15 to 0.25 mg / mL.

[0050] In one aspect, the lyophilized formulation of the present disclosure comprises: 1-200 mg / mL of an IL-31 antagonist; 1 to 200 mmol / L Tris buffer, 4.5 to 1500 mmol / L of arginine or a salt thereof, 7.5–2500 mmol / L sucrose or trehalose, and 0.01-5 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water. In certain embodiments, the lyophilized formulation of the present disclosure comprises: 6-100 mg / mL of an IL-31 antagonist; 6 to 20 mmol / L Tris buffer, 45 to 150 mmol / L of arginine or a salt thereof, 75–250 mmol / L sucrose or trehalose, and 0.15-0.50 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water. In certain embodiments, the lyophilized formulation of the present disclosure is 1 to 800 mg of an IL-31 antagonist, 0.1-40 mg of tris(hydroxymethyl)aminomethane, 0.8 to 400 mg of arginine, 3–1100 mg of sucrose or trehalose, and 0.01-7 mg of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water. In certain embodiments, the lyophilized formulation of the present disclosure is 10-80 mg of IL-31 antagonist, 0.8-4 mg of trishydroxymethylaminomethane, 8-40 mg of arginine, 30-110 mg of sucrose or trehalose, and 0.1-0.7 mg of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water.

[0051] In one aspect, the lyophilized formulation of the present disclosure comprises: 61 to 75 mg / mL, for example 68 mg / mL, of an anti-IL-31RA neutralizing antibody; 11-16 mmol / L, e.g., 13.6 mmol / L Tris-HCl; 82-122 mmol / L, e.g., 102 mmol / L Arg-HCl; 153 to 187 mmol / L, for example 170 mmol / L, of sucrose or trehalose, and 0.17 to 0.51 mg / mL, e.g., 0.34 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water. In another embodiment, the lyophilized formulation of the present disclosure comprises: 45 to 55 mg / mL, for example 50 mg / mL, of an anti-IL-31RA neutralizing antibody; 8-12 mmol / L, e.g. 10 mmol / L Tris-HCl, 60-90 mmol / L, e.g. 75 mmol / L Arg-HCl; 113 to 138 mmol / L, for example 125 mmol / L, of sucrose or trehalose, and 0.13 to 0.38 mg / mL, e.g., 0.25 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water. In yet another aspect, the lyophilized formulation of the present disclosure comprises: 14 to 17 mg / mL, for example 15 mg / mL, of an anti-IL-31RA neutralizing antibody; 5-7 mmol / L, e.g. 6 mmol / L Tris-HCl; 36-54 mmol / L, e.g., 45 mmol / L Arg-HCl; 68-83 mmol / L, e.g., 75 mmol / L, of sucrose or trehalose, and 0.08 to 0.23 mg / mL, e.g., 0.15 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water. In yet another aspect, the lyophilized formulation of the present disclosure comprises: 7 to 8 mg / mL, for example 7.5 mg / mL, of an anti-IL-31RA neutralizing antibody; 5-7 mmol / L, e.g. 6 mmol / L Tris-HCl; 36-54 mmol / L, e.g., 45 mmol / L Arg-HCl; 68-83 mmol / L, e.g., 75 mmol / L, of sucrose or trehalose, and 0.08 to 0.23 mg / mL, e.g., 0.15 mg / mL of poloxamer 188 or polysorbate 20 The solution comprising is a lyophilized composition, which has a pH of 6-8, such as 6.5-7.5, for example 7, after reconstitution in water.

[0052] The amount of each component contained in the lyophilized formulation of the present disclosure can also be described by weight (mass) per container such as a vial, cartridge, or syringe. The amount of the formulation contained in the container may be for a single administration or for multiple administrations (e.g., 2, 3, 4, etc.), for example, for a single administration. In addition, multiple containers may be used for a single administration. The dosage per administration can be appropriately set according to the administration method (e.g., subcutaneous administration), the target disease (e.g., atopic dermatitis), the purpose of use (e.g., for prevention or treatment), the type of patient (e.g., adult or child), the condition of the patient (e.g., the severity of pruritus), etc., and the amount of a solvent such as water added to the container to redissolve the lyophilized formulation can also be appropriately set accordingly. When the formulation is administered subcutaneously, the amount of liquid for one administration (in the case of a lyophilized formulation, the amount of liquid to be administered after reconstitution with water) may be, for example, but is not limited to, 0.1 to 10 mL, 0.2 to 5 mL, 0.2 to 1.6 mL, 0.5 to 2 mL, 0.8 to 1.2 mL, 0.9 to 1.1 mL, e.g., 1.0 mL. Note that, taking into consideration losses during administration of the drug solution, it will be naturally understood by those skilled in the art that the formulation may be overfilled into a container (e.g., vial, cartridge, or syringe) to ensure a sufficient amount for administering one or multiple doses of the IL-31 antagonist from one container. In one aspect, the lyophilized formulation of the present disclosure is 68 to 83 mg, for example 75 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 1.4-2.2 mg, e.g. 1.8 mg, of tris(hydroxymethylaminomethane); 15-23 mg, e.g. 19 mg arginine, 58-70 mg, e.g., 64 mg, of sucrose, and 0.2-0.6 mg, e.g. 0.4 mg of poloxamer 188 Includes. In the above embodiment, the description of the numerical value is intended to include a numerical value rounded off to the next lower digit (e.g., the first decimal place when the minimum digit is the first decimal place) when the numerical value is stated at the lowest digit (e.g., the first decimal place when the minimum digit is the first decimal place). That is, the lyophilized formulation of the present disclosure is 75 mg (74.5 mg to 75.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 1.8 mg (1.75 mg~1.84 mg) of tris(hydroxymethylaminomethane), 19 mg (18.5 mg-19.4 mg) arginine, 64 mg (63.5 mg to 64.4 mg) of sucrose, and 0.4 mg (0.35 mg~ 0.44 mg) of Poloxamer 188 It can also be expressed as including. Furthermore, in the above embodiment, the weight of the trishydroxymethylaminomethane may be the sum of the weight of trishydroxymethylaminomethane alone and the weight of trishydroxymethylaminomethane contained in trishydroxymethylaminomethane hydrochloride (which may be added as a pH adjuster). The arginine may also be added as a salt containing arginine (e.g., arginine hydrochloride). When a salt containing arginine is added, it is understood by those skilled in the art that the weight of the arginine is the weight of arginine contained in the salt. Therefore, the freeze-dried formulation of the present disclosure contains: 75 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 0.24 mg of trishydroxymethylaminomethane, 23.6 mg L-arginine hydrochloride, 63.9 mg sucrose, 0.37 mg of poloxamer 188, and As a pH adjuster, tris(hydroxymethyl)aminomethane hydrochloride It can also be expressed as including.

[0053] In another embodiment, the lyophilized formulation of the present disclosure is 35 to 43 mg, for example 39 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 0.7-1.1 mg, e.g. 0.9 mg, of tris(hydroxymethylaminomethane); 8-12 mg, e.g. 10 mg arginine, 30-36 mg, e.g., 33 mg, of sucrose, and 0.1-0.3 mg, e.g. 0.2 mg of poloxamer 188 Includes. In the above embodiment, the description of the numerical value is intended to include a numerical value rounded off to the next lower digit (e.g., the first decimal place when the minimum digit is the first decimal place) when the numerical value is stated at the lowest digit (e.g., the first decimal place when the minimum digit is the first decimal place). That is, the lyophilized formulation of the present disclosure is 39 mg (38.5 mg to 39.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 0.9 mg (0.85 mg~0.94 mg) of tris(hydroxymethyl)aminomethane, 10 mg (9.5 mg-10.4 mg) arginine, 33 mg (32.5 mg–33.4 mg) of sucrose, and 0.2 mg (0.15 mg to 0.24 mg) of Poloxamer 188 It can also be expressed as including.

[0054] In another aspect, the lyophilized formulation of the present disclosure is a container such as a cartridge. 32 to 40 mg, for example 36 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 0.7-1.1 mg, e.g. 0.9 mg, of tris(hydroxymethylaminomethane); 7-11 mg, e.g. 9 mg arginine, 28-34 mg, e.g., 31 mg, of sucrose, and 0.1-0.3 mg, e.g. 0.2 mg of poloxamer 188 Includes. In the above-mentioned embodiment, the description of the numerical value is intended to include a numerical value in the lowest digit (e.g., the 1st digit) rounded to the next lower digit (e.g., the 1st decimal place when the lowest digit is the 1st digit). That is, the lyophilized formulation of the present disclosure is 36 mg (35.5 mg to 36.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 0.9 mg (0.85 mg~0.94 mg) of tris(hydroxymethyl)aminomethane, 9 mg (8.5 mg-9.4 mg) arginine, 31 mg (30.5 mg–31.4 mg) of sucrose, and 0.2 mg (0.15 mg~0.24 mg) of Poloxamer 188 It can also be expressed as including.

[0055] In yet another aspect, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 46 to 56 mg, for example 51 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 2.0-3.0 mg, e.g., 2.5 mg, of tris(hydroxymethylaminomethane); 22-32 mg, e.g. 27 mg arginine, 79-97 mg, e.g., 88 mg sucrose, and 0.3-0.8 mg, e.g. 0.5 mg of poloxamer 188 Includes. In the above embodiment, the description of the numerical value is intended to include a numerical value rounded off to the next lower digit (e.g., the first decimal place when the minimum digit is the first decimal place) when the numerical value is stated at the lowest digit (e.g., the first decimal place when the minimum digit is the first decimal place). That is, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 51 mg (50.5 mg to 51.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 2.5 mg (2.45 mg~2.54 mg) of tris(hydroxymethyl)aminomethane, 27 mg (26.5 mg-27.4 mg) arginine, 88 mg (87.5 mg–88.4 mg) of sucrose, and 0.5 mg (0.45 mg - 0.54 mg) of Poloxamer 188 It can also be expressed as including.

[0056] In yet another aspect, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 27 to 33 mg, for example 30 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 2.4-3.6 mg, e.g. 3.0 mg of tris(hydroxymethylaminomethane); 26-38 mg, e.g. 32 mg arginine, 94-114 mg, e.g., 104 mg, of sucrose, and 0.3-0.9 mg, e.g. 0.6 mg of poloxamer 188 Includes. In the above embodiment, the description of the numerical value is intended to include a numerical value rounded off to the next lower digit (e.g., the first decimal place when the minimum digit is the first decimal place) when the numerical value is stated at the lowest digit (e.g., the first decimal place when the minimum digit is the first decimal place). That is, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 30 mg (29.5 mg to 30.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 3.0 mg (2.95 mg~3.04 mg) of trishydroxymethylaminomethane, 32 mg (31.5 mg-32.4 mg) of arginine, 104 mg (103.5 mg to 104.4 mg) of sucrose, and 0.6 mg (0.55 mg - 0.64 mg) of Poloxamer 188 It can also be expressed as including.

[0057] In yet another aspect, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 17 to 21 mg, for example 19 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 1.5-2.3 mg, e.g. 1.9 mg, of tris(hydroxymethylaminomethane); 16-24 mg, e.g. 20 mg arginine, 59-73 mg, e.g., 66 mg of sucrose, and 0.2-0.6 mg, e.g. 0.4 mg of poloxamer 188 Includes. In the above embodiment, the description of the numerical value is intended to include a numerical value rounded off to the next lower digit (e.g., the first decimal place when the minimum digit is the first decimal place) when the numerical value is stated at the lowest digit (e.g., the first decimal place when the minimum digit is the first decimal place). That is, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 19 mg (18.5 mg to 19.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 1.9 mg (1.85 mg~1.94 mg) of tris(hydroxymethyl)aminomethane, 20 mg (19.5 mg-20.4 mg) arginine, 66 mg (65.5 mg–66.4 mg) of sucrose, and 0.4 mg (0.35 mg - 0.44 mg) of Poloxamer 188 It can also be expressed as including.

[0058] In yet another aspect, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 13 to 15 mg, for example 14 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 1.0-1.6 mg, e.g. 1.3 mg, of tris(hydroxymethylaminomethane); 12-18 mg, e.g. 15 mg arginine, 42-52 mg, e.g., 47 mg of sucrose, and 0.2-0.5 mg, e.g. 0.3 mg of poloxamer 188 Includes. In the above embodiment, the description of the numerical value is intended to include a numerical value rounded off to the next lower digit (e.g., the first decimal place when the minimum digit is the first decimal place) when the numerical value is stated at the lowest digit (e.g., the first decimal place when the minimum digit is the first decimal place). That is, the lyophilized formulation of the present disclosure is contained in a container such as a vial. 14 mg (13.5 mg to 14.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10), 1.3 mg (1.25 mg~1.34 mg) of tris(hydroxymethylaminomethane), 15 mg (14.5 mg-15.4 mg) arginine, 47 mg (46.5 mg–47.4 mg) of sucrose, and 0.3 mg (0.25 mg to 0.34 mg) of Poloxamer 188 It can also be expressed as including.

[0059] In one embodiment, the lyophilized formulation of the present disclosure has a solution after reconstitution with water. 90 to 110 mg / mL, for example, 100 mg / mL of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 16-24 mmol / L, e.g. 20 mmol / L Tris-HCl; 120-180 mmol / L, e.g. 150 mmol / L Arg-HCl; 225-275 mmol / L, for example 250 mmol / L, of sucrose or trehalose, and 0.25 to 0.75 mg / mL, e.g., 0.50 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8, for example a pH of 6.7 to 7.3, for example 7. In another embodiment, the lyophilized formulation of the present disclosure has a solution after reconstitution with water. 55 to 68 mg / mL, for example 61.5 mg / mL, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 10-15 mmol / L, e.g. 12.3 mmol / L Tris-HCl; 74-110 mmol / L, e.g., 92 mmol / L Arg-HCl; 139 to 169 mmol / L, for example 154 mmol / L, of sucrose or trehalose, and 0.16 to 0.47 mg / mL, e.g., 0.31 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8, for example a pH of 6.7 to 7.3, for example 7. In another embodiment, the lyophilized formulation of the present disclosure has a solution after reconstitution with water. 45 to 55 mg / mL, for example 50 mg / mL, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 16-24 mmol / L, e.g. 20 mmol / L Tris-HCl; 120-180 mmol / L, e.g. 150 mmol / L Arg-HCl; 225-275 mmol / L, for example 250 mmol / L, of sucrose or trehalose, and 0.25 to 0.75 mg / mL, e.g., 0.50 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8, for example a pH of 6.7 to 7.3, for example 7. In yet another embodiment, the lyophilized formulation of the present disclosure has a solution after reconstitution with water. 23 to 28 mg / mL, for example, 25 mg / mL, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10); 16-24 mmol / L, e.g. 20 mmol / L Tris-HCl; 120-180 mmol / L, e.g. 150 mmol / L Arg-HCl; 225-275 mmol / L, for example 250 mmol / L, of sucrose or trehalose, and 0.25 to 0.75 mg / mL, e.g., 0.50 mg / mL of poloxamer 188 or polysorbate 20 and having a pH of 6 to 8, for example a pH of 6.7 to 7.3, for example 7.

[0060] Exemplary embodiments of formulations of the present disclosure include, but are not limited to, the following formulations: TIFF0007675049000001.tif22899TIFF0007675049000002.tif21594TIFF0007675049000003.tif23194

[0061] In a non-limiting embodiment, the formulation of the present disclosure can be used to prevent and / or treat an IL-31-related disease or a symptom associated therewith. In one embodiment, the IL-31-related disease is an inflammatory disease associated with IL-31 signaling. In a particular embodiment, the IL-31-related disease is atopic dermatitis, pruritus (e.g., dialysis pruritus or pruritus caused by atopic dermatitis), or prurigo nodularis. In another particular embodiment, the treatment of an IL-31-related disease or a symptom associated therewith is an improvement in sleep disturbance caused by pruritus (e.g., an increase in the time from sleep onset to awakening, and / or a decrease in sleep latency (time from implantation to sleep)). In another embodiment, the treatment of an IL-31-related disease or a symptom associated therewith is the suppression of at least one symptom selected from the group consisting of redness, induration, papules, edema, scratch marks, and lichenification caused by atopic dermatitis. In certain embodiments, the atopic dermatitis is moderate or severe atopic dermatitis that is ineffective or intolerant to topical treatment (e.g., topical steroids or topical calcineurin inhibitors). In one embodiment, the formulations of the present disclosure are for parenteral administration, e.g., for intravenous or subcutaneous administration.

[0062] In one non-limiting embodiment, the present disclosure relates to a method for stabilizing an antibody in an antibody-containing formulation, comprising preparing an antibody-containing solution comprising arginine and / or a salt thereof, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or a salt thereof to the antibody in the solution is 220 to 1100: 1, and the molar ratio of sucrose or trehalose to the antibody is 370 to 1840: 1. In another non-limiting embodiment, the present disclosure relates to a method for suppressing antibody aggregation (aggregate formation) in an antibody-containing formulation, comprising lyophilizing an antibody-containing solution comprising 45 to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 to 250 mmol / L sucrose or trehalose to prepare an antibody-containing lyophilized formulation. In yet another non-limiting embodiment, the present disclosure relates to a method for reducing charged heterogeneous components in an antibody-containing lyophilized formulation, the method comprising freeze-drying an antibody-containing solution containing 45 to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 to 250 mmol / L sucrose or trehalose to prepare an antibody-containing lyophilized formulation. In one embodiment, the antibody-containing solution before lyophilization further contains 6 to 20 mmol / L trishydroxymethylaminomethane hydrochloride and 0.15 to 0.50 mg / mL poloxamer 188.

[0063] In one non-limiting embodiment, the present disclosure relates to a method for preventing and / or treating an IL-31-associated disease, comprising administering an IL-31 antagonist to a subject suffering from or at risk of suffering from an IL-31-associated disease, the method comprising: freeze-drying a solution containing 6 to 100 mg / mL of an IL-31 antagonist, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose to prepare a freeze-dried preparation; redissolving the freeze-dried preparation to prepare a reconstituted solution; and administering the reconstituted solution to the subject. In one non-limiting embodiment, the present disclosure relates to use of an IL-31 antagonist in the manufacture of a medicament for the prevention and / or treatment of an IL-31-associated disease, the use comprising freeze-drying a solution containing 6 to 100 mg / mL of an IL-31 antagonist, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose to prepare a lyophilized formulation. In one non-limiting embodiment, the present disclosure relates to an IL-31 antagonist for use in the prevention and / or treatment of an IL-31-associated disease, characterized in that the IL-31 antagonist is used by redissolving a lyophilized preparation obtained by lyophilizing a solution comprising 6 to 100 mg / mL of the IL-31 antagonist, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose. In one embodiment, the solution before lyophilization may further comprise 6-20 mmol / L of trishydroxymethylaminomethane hydrochloride, and 0.15-0.50 mg / mL of poloxamer 188.

[0064] In a non-limiting embodiment, the present disclosure relates to an injection formulation or kit, comprising: (i) a container; (ii) a lyophilized formulation of the present disclosure; and (iii) optionally, water for injection to reconstitute said lyophilized formulation. In one embodiment, the container of the injection formulation or kit of the present disclosure is a glass syringe, cartridge, or vial. In a particular embodiment, the container of the injection formulation or kit of the present disclosure is a dual chamber syringe (DCS) or dual chamber cartridge (DCC), in which the lyophilized formulation and water for injection are enclosed in separate compartments in the container, i.e., one of the two chambers is filled with the lyophilized formulation of the present disclosure, and the other is filled with water for injection. Preferably, the water for injection is water, and optionally meets the standard of "water for injection" as defined in the Japanese Pharmacopoeia.

[0065] Interleukin-31 (IL-31) is a T cell cytokine, and transgenic mice overexpressing IL-31 develop dermatitis-like symptoms similar to atopic dermatitis and exhibit persistent scratching behavior, indicating that IL-31 is involved in pruritus.

[0066] The nucleic acid and amino acid sequences of human IL-31 are also known as RefSeq Accession No. NM_001014336 and RefSeq Accession No. NP_001014358, respectively.

[0067] The IL-31 receptor is formed from a heterodimer of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR) (Nat Immunol (2004) 5, 752-60). IL-31RA is also called NR10, and is known to have multiple splicing variants (WO00 / 075314). Known splicing variants include NR10.1 (652 amino acids), NR10.2 (252 amino acids), NR10.3 (662 amino acids, also called IL-31RAv4), and IL31RAv3 (764 amino acids). Preferred examples of IL-31RA include NR10.3 (IL-31RAv4) and IL-31RAv3. The nucleic acid and amino acid sequences of human IL-31RA (IL-31RAv4) are also known as RefSeq Accession No. NM_001242638 and RefSeq Accession No. NP_001229567, respectively. The nucleic acid and amino acid sequences of human IL-31RA (IL-31RAv3) are also known as RefSeq Accession No. NM_139017 and RefSeq Accession No. NP_620586, respectively. The nucleic acid and amino acid sequences of human OSMR are also known as RefSeq Accession No. NM_003999 and RefSeq Accession No. NP_003990, respectively.

[0068] In one embodiment, the IL-31 antagonist in the present disclosure means a compound that suppresses or blocks intracellular signal transduction induced by IL-31, which can also be said to be a compound that inhibits IL-31 signaling. Such a compound may be a naturally occurring compound or an artificially synthesized compound. In addition, it may be a low molecular weight compound or a high molecular weight compound such as a protein.

[0069] It is known that extracellular IL-31 induces intracellular signal transduction via the IL-31 receptor (a heterodimer of IL-31RA and OSMR) present on the cell surface (Nat Immunol (2004) 5, 752-760). The extracellular domain of the IL-31 receptor contains an IL-31-binding domain, and when IL-31 binds to this domain, the three-dimensional structure of the IL-31 receptor changes, resulting in the initiation of intracellular signal transduction from the intracellular domain of the IL-31 receptor.

[0070] As one method for determining whether a compound inhibits IL-31 signaling, it is possible to confirm whether the compound inhibits the binding between IL-31 and the IL-31 receptor. Examples of methods for performing such measurements include ELISA, an assay using flow cytometry, and an assay using surface plasmon resonance. For example, in the case of ELISA, a system is prepared in which IL-31 receptor (or IL-31RA) protein is immobilized on a plate, and the amount of IL-31 protein bound thereto is detected with a secondary antibody such as an enzyme-labeled anti-IL-31 antibody. When a compound is added thereto, it is possible to evaluate whether the compound inhibits the binding between IL-31 and the IL-31 receptor by measuring whether the amount of the detected IL-31 protein decreases. Alternatively, whether a compound inhibits IL-31 signaling can be confirmed by examining whether the compound inhibits physiological activity caused by the action of IL-31 on cells. The physiological activity is not particularly limited as long as it can be quantitatively or qualitatively measured by some method, and examples thereof include cell proliferation activity, protein phosphorylation activity, and gene / protein expression induction activity. For example, cells expressing IL-31 receptor on the surface and whose proliferation activity is induced in response to external IL-31 stimulation are prepared, and a compound is added thereto to measure whether the cell proliferation activity induced by IL-31 is reduced, thereby evaluating whether the compound inhibits IL-31 signaling. As such cells, natural cells that naturally express IL-31 receptors may be used, or genetically modified cells in which IL-31 receptors are artificially expressed may be used. A suitable example of a genetically modified cell is Ba / F3 cell in which IL-31 receptors are expressed. As a further alternative method, the method described in Dillon et al. (Nat Immunol (2004) 5, 752-760) can also be used.

[0071] In the present disclosure, the degree to which an IL-31 antagonist inhibits IL-31 signaling is not limited, but may inhibit IL-31 signaling by at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, and particularly preferably 90% or more, 95% or more, or 98% or more.

[0072] In the present disclosure, a preferred embodiment of a compound that inhibits IL-31 signaling can include a protein that inhibits IL-31 signaling. The protein is not particularly limited as long as it has the property of specifically binding to IL-31 or an IL-31 receptor. Preferred examples include antibodies and antibody-like molecules (Curr Opin Biotechnol (2006) 17, 653-658, Curr Opin Struct Biol (1997) 7, 463-469, Protein Sci (2006) 15, 14-27). The antibody includes any antibody, such as a monoclonal antibody (e.g., IgG, IgM, IgE, IgA, IgD, etc.), a polyclonal antibody, a modified antibody (e.g., a chimeric antibody, a humanized antibody, a glycosylated antibody (WO99 / 54342, WO00 / 61739), etc.), an antibody fragment (e.g., Fab, F(ab')2, Fv, CDR, etc.), a multispecific antibody (e.g., a bispecific antibody), a conjugated antibody (e.g., an antibody to which polyethylene glycol (PEG), a radioisotope, or a drug is attached, etc.). On the other hand, examples of antibody-like molecules include DARPin (WO2002 / 020565), Affibody (WO1995 / 001937), Avimer (WO2004 / 044011), Adnectin (WO2002 / 032925), etc. More preferred are antibodies that inhibit IL-31 signals. Other preferred examples of proteins that inhibit IL-31 signaling include proteins containing the extracellular domain of IL-31RA, or proteins containing each extracellular domain of the IL-31 receptor (a heterodimer of IL-31RA and OSMR).

[0073] In the present disclosure, preferred embodiments of the antibody that inhibits IL-31 signaling include an antibody that inhibits IL-31 signaling by binding to IL-31 (anti-IL-31 neutralizing antibody), or an antibody that inhibits IL-31 signaling by binding to the IL-31 receptor (anti-IL-31 receptor neutralizing antibody). Anti-IL-31 receptor neutralizing antibodies include an antibody that inhibits IL-31 signaling by binding to IL-31RA (anti-IL-31RA neutralizing antibody), an antibody that inhibits IL-31 signaling by binding to OSMR (anti-OSMR neutralizing antibody), or an antibody that inhibits IL-31 signaling by binding to the heterodimer of IL-31RA and OSMR (anti-IL-31RA / OSMR heterodimer neutralizing antibody). Among these anti-IL-31 receptor neutralizing antibodies, preferred are anti-IL-31RA neutralizing antibodies or anti-IL-31RA / OSMR heterodimer neutralizing antibodies, more preferred are anti-IL-31RA neutralizing antibodies.

[0074] The antibody used in the present invention is not particularly limited as long as it binds to the desired antigen and inhibits IL-31 signaling, and may be a polyclonal or monoclonal antibody, with monoclonal antibodies being preferred in that homogeneous antibodies can be stably produced.

[0075] In addition, the amino acids contained in the amino acid sequences described in the present invention may be modified after translation (for example, modification of N-terminal glutamine to pyroglutamic acid by pyroglutamylation is a modification well known to those skilled in the art), and even if the amino acids are post-translationally modified in this way, they are naturally included in the antibodies used in the present invention.

[0076] In a further or alternative embodiment, the antibody of the present disclosure that inhibits IL-31 signaling comprises an amino acid mutant of an IgG2 H-chain constant region sequence, and the amino acid mutant preferably comprises glutamic acid (EU numbering) at position 419 in the native IgG2 H-chain constant region sequence (SEQ ID NO: 12). Such modified antibodies are advantageous because they exhibit an increased plasma half-life compared to a reference antibody comprising a native IgG2 H-chain constant region sequence that has the same amino acid sequence except for the amino acid mutation at position 419. Such an increased plasma half-life is believed to be brought about by a decrease in isoelectric point (pI) due to the amino acid substitution at position 419 to glutamic acid (Example 2 of WO2016 / 167263). Thus, in one embodiment, the lyophilized and solution formulations of the present disclosure are advantageous in that they provide increased plasma half-life compared to (reference) lyophilized and solution formulations comprising a reference antibody comprising the H-chain constant region sequence of a native IgG2 that is identical except for the amino acid mutation at position 419. In this case, the antibody that inhibits IL-31 signaling according to the present disclosure in a preferred embodiment is any of the following anti-IL-31RA neutralizing antibodies. (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising the heavy chain variable region set forth in SEQ ID NO: 7 and the light chain variable region set forth in SEQ ID NO: 8; or (3) An anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10.

[0077] Unless expressly stated in this specification and unless contrary to the context, it is understood that the isoelectric point (pI) may be either the theoretical isoelectric point or the experimentally measured isoelectric point, and is also referred to simply as "pI". For example, the isoelectric point value can be measured by isoelectric focusing known to those skilled in the art. In addition, the theoretical isoelectric point value can be calculated using gene and amino acid sequence analysis software (Genetyx, etc.). Alternatively, the isoelectric point value can be measured by performing a pharmacokinetic test of the antibody using plasma, etc., of mice, rats, rabbits, dogs, monkeys, humans, etc., in combination with a method known to those skilled in the art, such as BIACORE, cell proliferation assay, ELISA, EIA (enzyme immunoassay), RIA (radioimmunoassay), or fluorescent immunoassay.

[0078] Whether or not the plasma half-life of the antibody has increased or decreased before and after the amino acid mutation (modification) may be confirmed by conducting a pharmacokinetic test of the antibody using plasma from mice, rats, rabbits, dogs, monkeys, humans, etc., by a method known to those skilled in the art.

[0079] In yet a further or alternative embodiment, the antibody that inhibits IL-31 signaling of the present disclosure has cross-reactivity with human and cynomolgus monkey IL-31RA, but preferably has no (substantially) cross-reactivity with mouse, rat, or rabbit IL-31RA.

[0080] Methods for producing antibodies are well known to those skilled in the art, and can be produced, for example, by the hybridoma method (Nature (1975) 256, 495) or the phage antibody library method (Nature (1991) 352, 624-628, J Mol Biol (1991) 222, 581-597). By using IL-31 protein, IL-31 receptor protein, or the like as an immunogen, a large number of anti-IL-31 antibodies or anti-IL-31 receptor antibodies can be obtained by these methods. Furthermore, by screening from these antibodies using the above-mentioned method for detecting compounds that inhibit IL-31 signaling, anti-IL-31 neutralizing antibodies or anti-IL-31 receptor neutralizing antibodies can be obtained. Proteins such as IL-31 and IL-31 receptor may be prepared by genetic engineering techniques known to those skilled in the art. Specifically, the desired protein can be prepared by inserting a gene encoding the desired protein into an expression vector, introducing the vector into a suitable host cell, and then purifying the desired protein expressed in the host cell or in the culture supernatant of the host cell.

[0081] Preferred examples of anti-IL-31 neutralizing antibodies include the anti-IL-31 antibodies described in WO2006 / 122079, WO2008 / 028192, and WO2009 / 071696.

[0082] Preferred examples of anti-IL-31RA neutralizing antibodies include, but are not limited to, the anti-IL-31RA (NR10) antibody described in WO2007 / 142325, the anti-IL-31RA (NR10) antibody described in WO2009 / 072604, and the anti-IL-31RA (NR10) antibody described in WO2010 / 064697. Another preferred example is an anti-human IL-31RA (neutralizing) antibody, specifically an anti-IL-31RA (neutralizing) antibody that recognizes domain 1 and / or domain 2 of human IL-31RA. Here, domain 1 of human IL-31RA refers to the region from amino acid 53 to amino acid 152 (LPAKP-LENIA) in the amino acid sequence of SEQ ID NO: 11. Furthermore, domain 2 refers to the region from amino acid 153 to amino acid 259 (KTEPP-EEEAP) in the amino acid sequence of SEQ ID NO: 11. Among anti-IL-31RA neutralizing antibodies, more preferred are, but not limited to, anti-IL-31RA antibodies comprising an H-chain (heavy chain) variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6, which are also described in WO2010 / 064697, more preferred are anti-IL-31RA antibodies comprising an H-chain variable region set forth in SEQ ID NO: 7 and an L-chain (light chain) variable region set forth in SEQ ID NO: 8, and particularly preferred is Nemolizumab (CIM331), an anti-IL-31RA antibody comprising an H-chain set forth in SEQ ID NO: 9 and an L-chain set forth in SEQ ID NO: 10.

[0083] Known methods for defining CDRs include the method of Kabat et al. (Sequences of Proteins of Immunological Interest, 5th Ed (1991), Bethesda, MD), the method of Chothia et al. (Science (1986) 233, 755-758), and a method based on antigen-antibody contact regions (J Mol Biol (1996) 262, 732-745). Specifically, CDRs according to each method are defined as follows: CDR Kabat Chothia Contact L1 L24-L34 L24-L34 L30-L36 L2 L50-L56 L50-L56 L46-L55 L3 L89-L97 L89-L97 L89-L96 H1 H31-H35B H26-H32 / 34 H30-H35B (Kabat numbering) H1 H31-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H52-H56 H47-H58 H3 H95-H102 H95-H102 H93-H101

[0084] A preferred example of the anti-IL-31RA neutralizing antibody in the present disclosure is an anti-IL-31RA antibody that contains, as H chain CDR1, CDR2, and CDR3, CDR1, CDR2, and CDR3, respectively, the CDR1, CDR2, and CDR3 contained in the H chain variable region set forth in SEQ ID NO: 7, and the CDR1, CDR2, and CDR3 contained in the L chain variable region set forth in SEQ ID NO: 8. The method for defining the CDRs in such an antibody may follow any of the methods of Kabat et al., Chothia et al., or a method based on antigen-antibody contact regions, or a combination of these methods.

[0085] Anti-IL-31RA antibodies that bind to the same epitope as the anti-IL-31RA antibodies specified by the above-mentioned sequences of the CDRs of each of the H and L chains, the sequences of the variable regions of the H and L chains, and the sequences of the full-length H and L chains are also preferred as anti-IL-31RA neutralizing antibodies. An epitope is a specific structural unit of an antigen that an antibody recognizes and binds to, and when the antigen is a polypeptide, it usually consists of about 6 to 10 amino acids. Epitopes can be identified by methods known to those skilled in the art, such as a method of synthesizing a peptide fragmented from an antigen, a method of introducing site-specific mutations into an antigen (e.g., arginine / glutamic acid scanning, J Biol Chem (1995) 270, 21619-21625, J Biol Chem (2006) 281, 20464-20473), or a method of crystallizing an antigen-antibody complex (Using Antibodies: A Laboratory Manual (1999), Cold Spring Harbor Laboratory Press, New York). In the present disclosure, "binding to the same epitope" means that the epitopes bound by two types of antibodies overlap at least partially. The degree of overlap is not limited, but is at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, particularly preferably 90% or more, and most preferably 100%.

[0086] Similarly, anti-IL-31RA antibodies whose binding to IL-31RA compete with anti-IL-31RA antibodies specified by the above-mentioned sequences of the CDRs of the H and L chains, the sequences of the variable regions of the H and L chains, and the sequences of the full-length H and L chains are also preferred as anti-IL-31RA neutralizing antibodies. Whether two types of antibodies compete with each other can be evaluated by a competitive binding assay using ELISA or the like. Specifically, one of two types of antibodies is labeled in advance with fluorescence or the like, and a system is prepared to detect the binding of the antibody (labeled antibody) to an antigen, and a comparison is made between the case where the other unlabeled antibody (test antibody) is coexistent and the case where it is not coexistent. If the amount of binding of the labeled antibody to the antigen is reduced when the test antibody is coexistent, it can be determined that the test antibody and the labeled antibody compete with each other. In the present disclosure, the degree of competition is not particularly limited, but it should compete by at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, and particularly preferably 90% or more, 95% or more, or 98% or more (i.e., it reduces the amount of binding of the other antibody).

[0087] The atopic dermatitis in the present disclosure is not limited to, but may be preferably atopic dermatitis caused by IL-31 signaling or caused by IL-31, or may be atopic dermatitis that is responsive to prevention and / or treatment with an IL-31 antagonist. Furthermore, the itch in the present disclosure may be itch caused by atopic dermatitis, and may be, but is not limited to, preferably itch caused by atopic dermatitis caused by IL-31 signaling or induced by IL-31. It may also be itch caused by atopic dermatitis that is responsive to prevention and / or treatment with an IL-31 antagonist.

[0088] The atopic dermatitis may be, for example, moderate to severe atopic dermatitis, preferably moderate or severe atopic dermatitis for which topical treatment is insufficiently effective or intolerable, for which standard topical treatment is insufficiently effective or intolerable, or for which standard topical treatment cannot be performed (due to contraindications, etc.), and more preferably moderate or severe atopic dermatitis for which topical treatment is insufficiently effective or intolerable. For example, topical treatments include topical steroids (eg, glucocorticoids or derivatives thereof, such as prednisolone or hydrocortisone) and topical calcineurin inhibitors known as immunosuppressants (eg, tacrolimus, pimecrolimus).

[0089] Known therapeutic agents for atopic dermatitis include topical steroids and topical calcineurin inhibitors, as well as cyclosporine, methotrexate (MTX), azathioprine (AZA), and antihistamines (a variety of antihistamine preparations are known, which can be broadly divided into first-generation antihistamines and second-generation antihistamines). More specifically, the following treatments are known for treating atopic dermatitis, but are not limited to these ("Guidelines for the Treatment of Atopic Dermatitis" Furue et al., J Dermatological Journal: 119(8), pp.1515-1534, 2009; "Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents." Sidbury R et al. J Am Acad Dermatol. (2014), pp. 327-337); Saeki H, et al. J Dermatol 2009, 36, pp.563-77). (1) Cyclosporine preparations (product name: Neoral) The usual adult dosage is 3 mg / kg of cyclosporine administered orally twice a day. This can be increased or decreased depending on symptoms, but should not exceed 5 mg / kg per day. (2) Oral steroid preparation (product name: prednisolone tablets) The usual dosage for adults is 5-60 mg of prednisolone (1-12 tablets, 0.5-6 g for powder) administered orally in 1-4 divided doses per day. The dosage may be increased or decreased depending on age and symptoms. (3) Ultraviolet light therapy It is generally said that patients need to visit the hospital once or twice a week, but there are no definitive guidelines. (4) Antihistamine preparations (product name: Allegra) The usual dosage for adults is 60 mg of fexofenadine hydrochloride, given orally twice daily. The usual dosage for children aged 7 to 12 years is 30 mg of fexofenadine hydrochloride, given orally twice daily, and for children aged 12 years or older, 60 mg of fexofenadine hydrochloride, given orally twice daily. The dosage may be increased or decreased depending on symptoms. (5) Topical steroid (product name: Fulmeta) In general, apply an appropriate amount to the affected area once or several times a day. The dosage may be increased or decreased depending on symptoms. (6) Topical steroids (product name: Locoid) In general, apply an appropriate amount once or several times a day. The dosage may be increased or decreased depending on symptoms. (7) Tacrolimus preparation (product name: Protopic) In general, for adults, apply an appropriate amount to the affected area 1 to 2 times a day, up to 5g per application. (8) Pimecrolimus preparations (product name: Elidel) In general, apply an appropriate amount twice a day. The dosage may be increased or decreased depending on symptoms.

[0090] The severity of atopic dermatitis (mild, moderate, severe, etc.) may be classified based on a classification method for scoring the degree of skin rash or itch felt by a subject, known to those skilled in the art, such as, for example, Shiratori's severity criteria, the visual analogue scale (VAS) described below, the itch verbal rating scale (VRS), SCORing Atopic Dermatitis (SCORAD) by the European Task Force on Atopic Dermatitis, the Eczema Area and Severity Index (EASI) in the United States, or the static Investigator's Global Assessment (sIGA). For example, the VAS is a straight line of 100 mm, with 0 mm being no itching and 100 mm being the worst itching imaginable, and the subject (patient) indicates the intensity of itching at the time of measurement with a line between 0 and 100 mm. For example, a subject whose VAS is judged to be 40 mm or more may be recognized as suffering from moderate to severe atopic dermatitis, and in one embodiment, the VAS may be 45 mm or more, or 50 mm or more. Similarly, for example, in the case of VRS, a subject classified as having "moderate itching" or more may be recognized as suffering from moderate to severe atopic dermatitis (Reich et al. 2012), or, for example, a subject whose EASI is 10 or more, or whose sIGA score is 3 or more, or whose total evaluation of the degree of daytime and nighttime itching based on Shiratori's severity classification is 4 or more may be recognized as suffering from moderate to severe atopic dermatitis. Alternatively, a subject with a skin rash accompanied by strong inflammation covering, for example, 5% or more of the body surface area may be identified as suffering from moderate to severe atopic dermatitis. Alternatively, a subject who satisfies one or a combination of the multiple indicators listed here may be identified as suffering from moderate to severe atopic dermatitis.

[0091] The term "subject" as used herein is not limited to, but is preferably an animal, more preferably a mammal (mouse, rat, rabbit, dog, monkey (e.g., cynomolgus monkey), etc.), and particularly preferably a human, and the human may be an adult (18 years of age or older) or a child (0 to under 18 years of age, for example, 6 months to under 18 years of age).

[0092] In one aspect, the present disclosure relates to lyophilized and solution formulations for the prevention and / or treatment of atopic dermatitis, comprising an IL-31 antagonist as an active ingredient. In such cases, the IL-31 antagonist may be intended to be administered repeatedly at predetermined dosing intervals, in equal amounts and at the same dosing intervals, at predetermined doses (dosage amounts), as detailed below.

[0093] In one embodiment, the lyophilized and solution formulations of the present disclosure may be used for the prevention and / or treatment of pruritus caused by atopic dermatitis.

[0094] In a further or alternative embodiment, the lyophilized formulation and solution formulation of the present disclosure may be used to improve sleep disorders caused by atopic dermatitis, where the sleep disorders may be caused by pruritus caused by atopic dermatitis. The improvement of the sleep disorders may be characterized, for example, by an increase in the time from sleep onset to awakening and / or a decrease in sleep latency (the time from implantation to sleep).

[0095] In yet a further or alternative embodiment, the lyophilized and solution formulations of the present disclosure may be used to suppress at least one symptom caused by atopic dermatitis selected from the group consisting of redness, induration, papules, edema, scarring, and lichenification.

[0096] In one embodiment of the present disclosure, the prevention and / or treatment of atopic dermatitis may refer to, but is not limited to, administering a drug or the like to a subject currently exhibiting atopic dermatitis or various symptoms associated therewith (e.g., itching, redness, induration, papules, edema, scratch marks, lichenification, decreased QOL, or lack of sleep, etc.) to suppress one or more of these symptoms, and / or administering a drug or the like to a subject who has exhibited atopic dermatitis or various symptoms associated therewith to prevent the onset of one or more of these symptoms or reduce the incidence rate. The prevention and / or treatment of atopic dermatitis may be judged or determined to be useful for prevention and / or treatment even if atopic dermatitis itself cannot be prevented and / or treated, as long as any one of the various symptoms associated with atopic dermatitis is improved.

[0097] Without being limited thereto, a subject who may be suffering from atopic dermatitis may be a subject who has previously suffered from atopic dermatitis and is at risk of experiencing a relapse of symptoms, or a subject who is suspected of having atopic dermatitis before a doctor or other such person has diagnosed or determined that the subject is suffering from atopic dermatitis. In one embodiment, prevention and treatment of atopic dermatitis may be interpreted as synonymous in some cases.

[0098] The IL-31 antagonist (CIM331) used in this example is known to have shown improved sleep efficiency in the IL-31 antagonist-administered group in a single subcutaneous administration study of the IL-31 antagonist in patients with atopic dermatitis (WO2016 / 167263). Although atopic dermatitis is not necessarily a life-threatening disease, the symptoms associated with the disease have a significant impact on daily life. Itching is the most characteristic symptom, and is an unpleasant sensation that significantly reduces the quality of life (QOL) of patients, and patients have been reported to have sleep disturbance due to itching (Zuberbier T, Orlow SJ, Paller AS, Taieb A, Allen R, Hernanz-Hermosa JM, Ocampo-Candiani J, Cox M, Langeraar J, Simon JC. Patient perspective on the management of atopic dermatitis. J Allergy Clin Immunol 2006;118:226-32.). In addition, when the patient is a child, the burden is great not only on the patient but also on the parents, and it has been reported that parents of moderate to severely ill children spend three hours per day on treatment, losing one to two hours of sleep each day (Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family and financial cost. Arch Dis Chil 1997;76:159-62.). Therefore, in another aspect, the present disclosure relates to a freeze-dried formulation and a solution formulation for preventing and / or treating atopic dermatitis, comprising an IL-31 antagonist as an active ingredient, and further for improving sleep disorders caused by atopic dermatitis. Alternatively, in a further or alternative aspect, the present disclosure relates to a freeze-dried formulation and a solution formulation for improving QOL caused by atopic dermatitis. The improvement of sleep disorders may be characterized, for example, by an increase in the time from falling asleep to waking up and / or a decrease in sleep latency (the time from implantation to falling asleep).

[0099] In the present specification, repeated administration at equal doses and the same administration intervals is intended to mean that the dose (initial dose) of the IL-31 antagonist of the present disclosure administered to a subject for the first time and the subsequent doses (i.e., doses administered continuously after the administration of the initial dose) are equal in amount and are administered at equal administration intervals (intervals between each administration). That is, for example, it means that the interval between the administration of the initial dose and the administration of the first subsequent dose, the interval between the administration of the nth (n is an integer of 1 or more) subsequent dose and the administration of the n+1th subsequent dose are all equal, and the doses are equal. It is naturally understood by those skilled in the art that there may be a "tolerance range" for each administration interval in the determined administration interval (for example, every 4 weeks when the administration interval is determined to be every 4 weeks), and those skilled in the art can appropriately determine the tolerance range.

[0100] In the present invention, a "stable antibody-containing formulation" refers to a formulation in which protein aggregates such as antibodies and / or charged heterogeneous components are not easily formed in the formulation, i.e., a formulation in which deterioration reactions such as the formation of insoluble aggregates, soluble aggregates, charged heterogeneous components, etc. are not easily caused in the formulation.

[0101] The term "heterocharged component" refers to a component whose surface charge differs from that of the main component of a protein due to deamidation, oxidation, hydrolysis, or the like.

[0102] The amount of aggregates can be measured by size exclusion chromatography (SEC), SDS polyacrylamide gel electrophoresis (SDS-PAGE), capillary SDS gel electrophoresis (CE-SDS), dynamic light scattering (DLS), light-obscured automated particle counter (HIAC), flow imaging, analytical ultracentrifugation (AUC), and the like. In the present invention, the measurement is preferably performed by size exclusion chromatography (SEC). The measurement conditions include, but are not limited to, using a column (Tosoh, TSKgel G3000SWXL) for the sample, using 50 mmol / L phosphate buffer (pH 7.0), 300 mmol / L sodium chloride, and 0.05% sodium azide as the mobile phase, and performing the measurement at a flow rate of 0.5 mL / min. In one embodiment, the amount of aggregates is measured by the method described in the Examples of this specification.

[0103] The charge-heterogeneous component can be measured by ion exchange chromatography (IEC), specifically, cation exchange chromatography, anion exchange chromatography, isoelectric focusing, etc., but in the present invention, the measurement is preferably by anion exchange chromatography. The sample can be measured by ion exchange chromatography (IEC) performed at a flow rate of 1.0 mL / min using a column (Tosoh, TSKgel DEAE-NPR) with 25 mmol / L Tris-HCl buffer (pH 7.5) as mobile phase A, 25 mmol / L Tris-HCl buffer (pH 7.5), and 250 mmol / L sodium chloride as mobile phase B, but is not limited thereto. In one embodiment, the charge-heterogeneous component is measured by the method described in the Examples of this specification.

[0104] The polypeptide of the present invention generally refers to a peptide or protein having a length of about 10 amino acids or more. Generally, the polypeptide is derived from an organism, but is not particularly limited thereto, and may be, for example, a polypeptide consisting of an artificially designed sequence. The polypeptide may be any of a natural polypeptide, a synthetic polypeptide, a recombinant polypeptide, and the like. Furthermore, fragments of the above polypeptides are also included in the polypeptide of the present invention.

[0105] The term "antibody" is used in the broadest sense and may be a monoclonal antibody, a polyclonal antibody, a dimer, a multimer, a multispecific antibody (e.g., a bispecific antibody), an antibody derivative, and an antibody modification, so long as it exhibits the desired biological activity (Miller K et al. J Immunol. 2003, 170(9), 4854-61). The antibody may be murine, human, humanized, chimeric, or derived from other species or may be artificially synthesized. The antibody disclosed herein may be any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecule. The immunoglobulin may be derived from any species (e.g., human, mouse, or rabbit). The terms "antibody," "immunoglobulin," and "immunoglobulin" are used interchangeably and in a broad sense.

[0106] The antibody may be a recombinant antibody produced using gene recombination technology. A recombinant antibody can be obtained by cloning the DNA encoding it from an antibody-producing cell, such as a hybridoma or an antibody-producing sensitized lymphocyte, incorporating it into a vector, and introducing this into a host (host cell) to produce the antibody.

[0107] The antibody of the present invention can be produced by a method known to those skilled in the art. Specifically, DNA encoding the antibody of interest is incorporated into an expression vector. In this case, the DNA is incorporated into the expression vector so that it is expressed under the control of an expression control region, such as an enhancer or promoter. Next, a host cell is transformed with this expression vector to express the antibody. In this case, a suitable combination of a host and an expression vector can be used.

[0108] The antibody of the present invention thus obtained can be isolated from inside or outside the host cell (such as the medium) and purified as a substantially pure and homogeneous antibody. Separation and purification of the antibody can be performed using any separation and purification method that is commonly used in the purification of antibodies, and is not limited in any way. For example, the antibody can be separated and purified by appropriately selecting and combining a chromatography column, a filter, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, and the like.

[0109] The present inventors investigated the effects of various additives by a thermal acceleration test in order to evaluate the storage stability of a sample containing the anti-IL-31RA antibody (CIM331). As a result, it was found that by preparing a lyophilized preparation with a solution containing arginine hydrochloride and sucrose or trehalose, the formation of aggregates was suppressed compared to when the solution did not contain a stabilizer or bulking agent (bulking agent), when sodium chloride was added as a stabilizer, and when other sugars were added as bulking agents. In addition, it was found that the formation of highly insoluble fine particles and the formation of aggregates were suppressed by adding nonionic surfactants, such as poloxamer 188 and polysorbate 20, to an antibody-containing solution. Furthermore, it was found that the formation of aggregates and charged heterogeneous components were suppressed at pH 6 to 8 in an antibody-containing solution containing arginine hydrochloride, sucrose or trehalose, and a nonionic surfactant.

[0110] The concentration (amount) of arginine in the formulation of the present invention is preferably 45 mM to 150 mM, and the concentration (amount) of arginine is, for example, 45 mM, 75 mM, 92 mM, 102 mM, or 150 mM.

[0111] The formulation of the present invention has a solution pH of preferably 6-8, more preferably 6.5-7.5, and even more preferably 7.

[0112] The preparation of the present invention may contain, for example, a Tris buffer as a buffer. Examples of the Tris buffer include trishydroxymethylaminomethane and / or a salt thereof, such as trishydroxymethylaminomethane-hydrochloride, trishydroxymethylaminomethane-aspartate, trishydroxymethylaminomethane-glutamate, or trishydroxymethylaminomethane-acetate. The amount of Tris buffer added to the preparation of the present invention is preferably 6 to 20 mM, for example, 6 mM, 10 mM, 12.3 mM, or 13.6 mM, 20 mM.

[0113] The surfactant contained in the formulation of the present invention is, for example, polysorbate 20 (PS20) or Pluronic F-68 (Poloxamer 188: polyoxyethylene (160) polyoxypropylene (30) glycol), with poloxamer 188 being particularly preferred. The amount of poloxamer 188 (Poloxamer 188 or PX188) added to the formulation of the present invention is preferably 0.15 mg / mL to 0.5 mg / mL. The amount of poloxamer 188 added to the formulation is, for example, 0.15 mg / mL, 0.25 mg / mL, 0.31 mg / mL, 0.34 mg / mL, or 0.50 mg / mL.

[0114] The formulation of the present invention may further contain a sugar. Preferred sugars for use in the present invention are sucrose, trehalose, mannitol, and lactose, with sucrose and trehalose being particularly preferred.

[0115] The amount of saccharide added to the formulation of the present invention is generally 1 mM to 1000 mM, preferably 5 mM to 500 mM, and more preferably 10 mM to 300 mM, for example, 75 mM to 250 mM, for example, 75 mM, 125 mM, 154 mM, 170 mM, or 250 mM.

[0116] Furthermore, cryoprotectants, suspending agents, solubilizing agents, isotonicity agents, preservatives, adsorption inhibitors, diluents, excipients, pH adjusters, soothing agents, sulfur-containing reducing agents, antioxidants and the like can be appropriately added to the formulations of the present invention, as necessary.

[0117] Examples of cryoprotectants include sugars such as trehalose, sucrose (cane sugar), and sorbitol.

[0118] Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, castor oil fatty acid ethyl ester, and the like.

[0119] Examples of the isotonic agent include sodium chloride, potassium chloride, calcium chloride, and the like.

[0120] Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

[0121] Examples of anti-adsorption agents include human serum albumin, lecithin, dextran, ethylene oxide-propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, polyoxyethylene hydrogenated castor oil, and polyethylene glycol.

[0122] Examples of sulfur-containing reducing agents include those having a sulfhydryl group, such as N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and thioalkanoic acids having 1 to 7 carbon atoms.

[0123] Examples of antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbyl stearate, sodium hydrogen sulfite, sodium sulfite, triamyl gallate, propyl gallate, and chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.

[0124] The antibody-containing formulations of the present invention can be administered to a patient via any suitable route, for example, intravenously, intramuscularly, subcutaneously, as a bolus or by continuous infusion over a period of time, with intravenous or subcutaneous administration being preferred.

[0125] The dose of Nemolizumab (CIM331) is, for example, 0.001 to 1000 mg / kg, and the administration interval is at least one day or more. More specifically, for example, Nemolizumab (CIM331) is repeatedly administered at the same dose and at the same administration interval to a subject suffering from or likely to suffer from atopic dermatitis at 0.1 mg to 1000 mg / body / 2 weeks, 0.1 mg to 1000 mg / body / 4 weeks, or 0.1 mg to 1000 mg / body / 8 weeks, or 0.01 mg to 10 mg / kg / 2 weeks, 0.01 mg to 10 mg / kg / 4 weeks, or 0.01 mg to 10 mg / kg / 8 weeks, preferably 0.5 mg / kg / 4 weeks, or 50 mg to 75 mg / body / 4 weeks. Alternatively, Nemolizumab (CIM331) is repeatedly administered at the same dose and at the same administration interval at 60 mg / body / 4 weeks. Alternatively, Nemolizumab (CIM331) is administered at a 4-week interval, with an initial dose of 60 mg / body and a subsequent dose of 30 mg / body being repeatedly administered. Note that, when a freeze-dried preparation containing a single dose of Nemolizumab (CIM331) is sealed in a container (vial, cartridge, or syringe), it is naturally understood by those skilled in the art that the freeze-dried preparation may be overfilled in order to ensure a sufficient amount of Nemolizumab (CIM331) to be administered from one container (vial, cartridge, or syringe) in consideration of the loss of the reconstituted drug solution during administration.

[0126] Another embodiment of the present invention is a method for stabilizing an antibody in an antibody-containing formulation. For example, the method for stabilizing an antibody in an antibody-containing solution formulation comprises adding arginine and / or a salt thereof, and sucrose and / or trehalose to the solution. Also, for example, the method for stabilizing an antibody in an antibody-containing freeze-dried formulation comprises freeze-drying an antibody-containing solution containing arginine and / or a salt thereof, and sucrose and / or trehalose to prepare an antibody-containing freeze-dried formulation.

[0127] Another embodiment of the present invention is a method for suppressing antibody aggregation (aggregate formation) in an antibody-containing formulation. For example, the method for suppressing antibody aggregation (aggregate formation) in an antibody-containing solution formulation comprises adding arginine and / or a salt thereof, and sucrose and / or trehalose to a solution. Also, for example, the method for suppressing antibody aggregation (aggregate formation) in an antibody-containing freeze-dried formulation comprises freeze-drying an antibody-containing solution containing arginine and / or a salt thereof, and sucrose and / or trehalose to prepare an antibody-containing freeze-dried formulation.

[0128] Another embodiment of the present invention is a method for reducing charge heterogeneous components in an antibody-containing formulation. For example, the method for reducing charge heterogeneous components in an antibody-containing solution formulation comprises adding arginine and / or a salt thereof, and sucrose and / or trehalose to a solution. Also, for example, the method for reducing charge heterogeneous components in an antibody-containing freeze-dried formulation comprises freeze-drying an antibody-containing solution containing arginine and / or a salt thereof, and sucrose and / or trehalose to prepare an antibody-containing freeze-dried formulation.

[0129] In the above-mentioned methods for stabilizing an antibody, for suppressing antibody aggregation (aggregate formation), and for reducing charged heterogeneous components, the concentration of arginine hydrochloride (Arg-HCl) in the solution is preferably 45 to 150 mmol / L, and the concentration of sucrose or trehalose is preferably 75 to 250 mmol / L.

[0130] In the above-mentioned methods for stabilizing an antibody, for suppressing antibody aggregation (aggregate formation), and for reducing charge heterogeneity components, the antibody is preferably Nemolizumab (CIM331).

[0131] As used in this specification, an embodiment expressed by the expression "comprising" includes an embodiment expressed by the expression "essentially consisting of," as well as an embodiment expressed by the expression "consisting of."

[0132] The numerical values ​​described in this specification may vary within a certain range due to, for example, the equipment, measurement conditions, and the technique of a person skilled in the art, and may vary, for example, by about 10% as long as the objective of the present invention is achieved.

[0133] The contents of all patents and literature references expressly cited herein are hereby incorporated by reference in their entirety. The present invention is further illustrated by, but not limited to, the following examples. EXAMPLES

[0134] definition [Experimental Method] To adjust the pH, the formulations prepared in each Example contained 6 to 20 mmol / L Tris-HCl, which does not contribute to the stability of CIM331 (an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10).

[0135] The thermal acceleration test for the solution formulation was performed at 40°C / 75% RH, but because lyophilized formulations are generally more stable, the thermal acceleration test for the lyophilized formulation was performed at a higher temperature of 50°C / 75% RH.

[0136] In Example 3, a shaking test was carried out to verify the effect of the nonionic surfactant.

[0137] [Analysis method] Regarding the measurement of the amount of aggregates of CIM331, taking into consideration the accuracy of the analytical method, a difference in the proportion of aggregates of 0.07% or more can be determined to be significant.

[0138] Regarding the measurement of the charge heterogeneity of CIM331, taking into consideration the accuracy of the analytical method, it can be judged that there is a significant difference when there is a difference of 1.3% or more in the basic region, when there is a difference of 1.4% or more in the main region, and when there is a difference of 0.6% or more in the acidic region.

[0139] Because the stability of solution and lyophilized formulations differ, the results of analytical methods cannot be interpreted the same for solution and lyophilized formulations.

[0140] Example 1: Aggregation-suppressing effect of arginine on humanized IgG2 antibody CIM331 during accelerated heat storage [1-1] Stability evaluation of freeze-dried formulations (1) Material CIM331 is a monoclonal antibody that binds to IL-31RA, and is a humanized IgG2 antibody that is expected to be useful in the treatment of atopic dermatitis and other conditions by inhibiting the function of IL-31, which is known to be a pruritus-inducing cytokine.

[0141] (2) Test sample Preparations containing 30 mg / mL CIM331, 6 mmol / L Tris-HCl, 75 mmol / L Sucrose, 0.15 mg / mL Poloxamer 188, and either 45 mmol / L Arg-HCl or 45 mmol / L NaCl as a stabilizer, as well as a stabilizer-free preparation were prepared and filled into glass vials at 2 mL each. The filled drug solutions were freeze-dried under the following conditions. TIFF0007675049000004.tif41170The thus-prepared freeze-dried formulation containing the humanized antibody was left to stand in a thermostatic chamber at 50°C / 75% RH for 8 weeks, after which ultrapure water was added to reconstitute the formulation so that the CIM331 concentration was adjusted to 100 mg / mL. This was used as the test sample.

[0142] (3) Method for measuring and calculating the amount of aggregates of CIM331 The amount of aggregates was measured by size exclusion chromatography (SEC) using a column (Tosoh Corporation, TSKgel G3000SWXL) and a mobile phase of 50 mmol / L phosphate buffer (pH 7.0), 300 mmol / L sodium chloride, and 0.05% sodium azide at a flow rate of 0.5 mL / min. Among the detected peaks, the one with the largest area and height was designated as the monomer, and the peaks detected before the monomer were collectively designated as the aggregate (HMWS). The areas of all peaks were calculated, and the peak area ratio of the target peak was calculated according to the following formula. TIFF0007675049000005.tif15131

[0143] (4) Results The results obtained are shown in Table 1.

[0144] [Table 1] *: The relative increase rate compared to when no stabilizer was added was calculated from the amount of HMWS increase when no stabilizer was added and the amount of HMWS increase when each stabilizer was added.

[0145] As is clear from Table 1, the sample to which arginine hydrochloride was added showed a higher aggregation inhibition effect after 8 weeks of thermal acceleration at 50°C / 75% RH compared to the sample to which no stabilizer was added and the sample to which sodium chloride was added.

[0146] [1-2] Stability evaluation of solution formulations (1) Material The antibodies described in [1-1] were used.

[0147] (2) Test sample Each formulation containing 100 mg / mL CIM331, 20 mmol / L Tris-HCl, 250 mmol / L Sucrose, 0.5 mg / mL Poloxamer 188, pH 7, and either 150 mmol / L Arg-HCl or 150 mmol / L NaCl as a stabilizer, as well as a stabilizer-free formulation, was prepared and filled into a glass vial at 1 mL each. The humanized antibody-containing solution formulation thus prepared was left to stand in a thermostatic chamber at 40°C / 75% RH for 4 weeks, and then used as a test sample.

[0148] (3) Method for measuring and calculating the amount of aggregates of CIM331 The method described in [1-1] was followed.

[0149] (4) Results The results obtained are shown in Table 2.

[0150] [Table 2] *: The relative increase rate compared to when no stabilizer was added was calculated from the amount of HMWS increase when no stabilizer was added and the amount of HMWS increase when each stabilizer was added.

[0151] As is clear from Table 2, the sample to which arginine hydrochloride was added showed a higher aggregation inhibition effect after 4 weeks of thermal acceleration at 40°C / 75% RH compared to the sample to which no stabilizer was added and the sample to which sodium chloride was added.

[0152] Example 2: Aggregation-suppressing effect of sucrose and trehalose on humanized IgG2 antibody CIM331 during accelerated heat storage (1) Material The antibody described in Example 1 was used.

[0153] (2) Test sample Preparations containing 30 mg / mL CIM331, 6 mmol / L Tris-HCl, 45 mmol / L Arg-HCl, 0.15 mg / mL poloxamer 188, and either 75 mmol / L sucrose, 75 mmol / L mannitol, 75 mmol / L glucose, 75 mmol / L lactose, or 75 mmol / L trehalose as bulking agents were prepared, as well as preparations without bulking agents, and 2 mL of each was filled into glass vials. The filled drug solutions were freeze-dried under the following conditions. TIFF0007675049000008.tif41170The freeze-dried formulation containing the humanized antibody prepared in this manner was allowed to stand in a constant temperature bath at 50°C / 75% RH for 8 weeks, after which ultrapure water was added to reconstitute the solution so that the CIM331 concentration became 100 mg / mL, and the reconstituted solution was used as the test sample.

[0154] (3) Method for measuring and calculating the amount of aggregates of CIM331 The method described in Example 1 was followed.

[0155] (4) Results The results obtained are shown in Table 3.

[0156] [Table 3] *: The relative increase rate compared to when no bulking agent was added was calculated from the amount of HMWS increase when no bulking agent was added and the amount of HMWS increase when each bulking agent was added.

[0157] As is clear from Table 3, the relative increase rate for both samples with added sucrose or trehalose was in the 10% range, and a high aggregation inhibition effect was obtained after 8 weeks of thermal acceleration at 50°C / 75% RH, compared to samples with no added bulking agent and samples with added other bulking agents.

[0158] Example 3: Effects of non-ionic surfactants on suppressing the formation of insoluble particles and stabilizing the solution state during shaking stress testing of humanized IgG2 antibody CIM331 (1) Material The antibody described in Example 1 was used.

[0159] (2) Test sample Preparations containing 100 mg / mL CIM331, 20 mmol / L Tris-HCl, pH 7, 150 mmol / L Arg-HCl, 250 mmol / L Sucrose, and either 0.5 mg / mL poloxamer 188 or 0.5 mg / mL polysorbate 20 as a non-ionic surfactant, as well as preparations without a non-ionic surfactant, were prepared and filled in glass vials at 1 mL each. The humanized antibody-containing solution formulations thus prepared were shaken at room temperature at a speed of about 200 rpm for 3 days and then used as test samples.

[0160] (3) Insoluble particle measurement method The number of insoluble particles in the liquid was measured using a liquid particle counter (Hach Ultra Analytics, Model 9703). (4) Method for measuring and calculating the amount of aggregates of CIM331 The method described in Example 1 was followed.

[0161] (5) Results The results obtained are shown in Tables 4 and 5.

[0162] [Table 4]

[0163] [Table 5] *: The relative increase rate compared to when no nonionic surfactant was added was calculated from the increase in HMWS when no nonionic surfactant was added and the increase in HMWS when each nonionic surfactant was added.

[0164] As is clear from Tables 4 and 5, the samples containing the nonionic surfactants poloxamer 188 and polysorbate 20 exhibited high inhibitory effects on the formation of insoluble fine particles and high inhibitory effects on aggregation in the samples after shaking at a speed of about 200 rpm at room temperature for 3 days.

[0165] Example 4: Effect of pH on the stability of humanized IgG2 antibody CIM331 during heat-accelerated storage (1) Material The antibody described in Example 1 was used.

[0166] (2) Test sample Each formulation was prepared containing 100 mg / mL CIM331, 20 mmol / L Tris-HCl, 150 mmol / L Arg-HCl, 250 mmol / L Sucrose, and 0.5 mg / mL poloxamer 188, and either pH 6, pH 7, or pH 8, and filled into a glass vial at 1 mL each. The humanized antibody-containing solution formulation thus prepared was left to stand in a thermostatic chamber at 40°C / 75% RH for 4 weeks, and then used as a test sample.

[0167] (3) Method for measuring and calculating the amount of aggregates of CIM331 The method described in Example 1 was followed.

[0168] (4) Measurement and calculation methods for charge heterogeneity of CIM331 The sample was subjected to ion exchange chromatography (IEC) using a column (Tosoh, TSKgel DEAE-NPR) with 25 mmol / L Tris-HCl buffer (pH 7.5) as mobile phase A, 25 mmol / L Tris-HCl buffer (pH 7.5) and 250 mmol / L sodium chloride as mobile phase B at a flow rate of 1.0 mL / min to measure the amount of charged heterogeneous components. Among the detected peaks, the one with the largest area and height was called the Main region, the peaks detected before the Main region were collectively called the Basic region, and the peaks detected after the Main region were collectively called the Acidic region. The areas of all peaks were calculated, and the peak area ratio of the target peak was calculated according to the following formula. TIFF0007675049000012.tif15131

[0169] (5) Results The results obtained are shown in Table 6.

[0170] [Table 6]

[0171] As is clear from Table 6, the samples with pH 6 to pH 8 showed sufficient stability after 4 weeks of thermal acceleration at 40°C / 75% RH, and the sample with pH 7 in particular showed high aggregation suppression effects and charge heterogeneity suppression effects.

[0172] Example 5: Effect of concentration of humanized IgG2 antibody CIM331 and concentrations of other formulation components on stability during heat-accelerated storage (1) Material The antibody described in Example 1 was used.

[0173] (2) Test sample Preparations containing 100 mg / mL or 50 mg / mL CIM331, 20 mmol / L or 10 mmol / L Tris-HCl, 150 mmol / L or 75 mmol / L Arg-HCl as a stabilizer, 250 mmol / L or 125 mmol / L Sucrose as a bulking agent, and 0.5 mg / mL or 0.25 mg / mL poloxamer 188 as a non-ionic surfactant, as well as preparations containing 6 mmol / L Tris-HCl, 45 mmol / L Arg-HCl, 75 mmol / L Sucrose, 0.15 mg / mL poloxamer 188, and 30 mg / mL, 15 mg / mL, or 6 mg / mL CIM331 were prepared and filled into glass vials at 2 mL each. The filled drug solutions were freeze-dried under the following conditions. TIFF0007675049000014.tif41170The freeze-dried formulation containing the humanized antibody prepared in this manner was allowed to stand in a constant temperature bath at 50°C / 75% RH for 8 weeks, and then ultrapure water was added to reconstitute the solution so that the CIM331 concentration was adjusted to the values ​​shown below, and this was used as the test sample. TIFF0007675049000015.tif17170

[0174] (3) Method for measuring and calculating the amount of aggregates of CIM331 The method described in Example 1 was followed.

[0175] (4) Measurement and calculation methods for charge heterogeneity of CIM331 The method described in Example 4 was followed.

[0176] (5) Results The results obtained are shown in Table 7.

[0177] [Table 7]

[0178] As is clear from Table 7, samples containing each component at the tested concentrations, i.e., 6-100 mg / mL CIM331, 6-20 mmol / L Tris-HCl, 45-150 mmol / L Arg-HCl, 75-250 mmol / L Sucrose, and 0.15-0.5 mg / mL poloxamer 188, had sufficient stability after 8 weeks of accelerated thermal treatment at 50°C / 75% RH. For HMWS, when the formulation components other than the antibody were at the same concentration, a dilute antibody concentration showed better stability.

[0179] Example 6: Effect of arginine on aggregation and charge heterogeneity suppression of humanized IgG2 antibody CIM331 during accelerated heat storage [6-1] Stability evaluation of freeze-dried formulations (1) Material The antibody described in Example 1 was used.

[0180] (2) Test sample Each formulation was prepared containing 30 mg / mL CIM331, 6 mmol / L Tris-HCl, pH 7, 75 mmol / L Sucrose, 0.15 mg / mL Poloxamer 188, and either 45 mmol / L Arg-HCl, 45 mmol / L Histidine, 45 mmol / L Lysine-HCl, or 45 mmol / L Glycine as a stabilizer, and 2 mL of each was filled into a glass vial. The filled drug solution was freeze-dried under the following conditions. TIFF0007675049000017.tif39170The thus-prepared freeze-dried formulation containing the humanized antibody was left to stand in a thermostatic chamber at 50°C / 75% RH for 8 weeks, after which ultrapure water was added to reconstitute the formulation so that the CIM331 concentration was adjusted to 100 mg / mL. This was used as the test sample.

[0181] (3) Method for measuring and calculating the amount of aggregates of CIM331 The method described in Example 1 was followed.

[0182] (4) Measurement and calculation methods for charge heterogeneity of CIM331 The method described in Example 4 was followed.

[0183] (5) Results The results obtained are shown in Table 8.

[0184] [Table 8]

[0185] As is clear from Table 8, the sample to which arginine hydrochloride was added exhibited the highest aggregation inhibition effect and charge heterogeneity inhibition effect after 8 weeks of thermal acceleration at 50°C / 75% RH compared to the samples to which histidine, lysine hydrochloride, or glycine was added.

[0186] [6-2] Stability evaluation of solution formulations (1) Material The antibody described in Example 1 was used.

[0187] (2) Test sample Each formulation was prepared containing 100 mg / mL CIM331, 20 mmol / L Tris-HCl, pH 7, 250 mmol / L Sucrose, 0.50 mg / mL Poloxamer 188, and either 150 mmol / L Arg-HCl, 150 mmol / L Histidine, 150 mmol / L Lysine-HCl, or 150 mmol / L Glycine as a stabilizer, and filled into a glass vial at 1 mL each. The humanized antibody-containing solution formulation thus prepared was left to stand in a thermostatic chamber at 40°C / 75% RH for 4 weeks, and then used as a test sample.

[0188] (3) Measurement and calculation methods for charge heterogeneity of CIM331 The method described in Example 4 was followed.

[0189] (4) Results The results obtained are shown in Table 9.

[0190] [Table 9]

[0191] As is clear from Table 9, the sample to which arginine hydrochloride was added exhibited the highest suppression effect on charged heterogeneous components after 4 weeks of thermal acceleration at 40°C / 75% RH compared to the samples to which histidine, lysine hydrochloride, or glycine were added. [Industrial Applicability]

[0192] The preparation of the present invention is a preparation that has excellent stability both in a lyophilized state and in a solution state, and is characterized by suppressing the formation of protein aggregates of antibody molecules and other proteins after storage in a solution state, storage in a lyophilized state, and reconstitution with water. The preparation of the present invention, which is thus resistant to deterioration reactions, can be used, for example, for the treatment of atopic dermatitis by subcutaneous administration.

Claims

1. A freeze-dried preparation containing an IL-31 antagonist as an active ingredient, wherein the lyophilized preparation is a composition obtained by lyophilizing a solution containing an IL-31 antagonist, arginine and / or a salt thereof, sucrose and / or trehalose, and poloxamer 188 or polysorbate 20 or polysorbate 80, and has a pH of 6 to 8 after reconstitution with water; Further herein, the IL-31 antagonist is (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising the heavy chain variable region of SEQ ID NO: 7 and the light chain variable region of SEQ ID NO: 8; or (3) An anti-IL-31RA antibody comprising an H chain set forth in SEQ ID NO: 9 and an L chain set forth in SEQ ID NO: 10, Further, after the freeze-dried preparation is redissolved in water, 1-200 mg / mL of an IL-31 antagonist; 4.5 to 1500 mmol / L of arginine or a salt thereof, 7.5–2500 mmol / L sucrose or trehalose, and 0.01-5 mg / mL of poloxamer 188 or polysorbate 20 or polysorbate 80 and having a pH of 6 to 8.

2. A freeze-dried preparation containing an IL-31 antagonist as an active ingredient, wherein the lyophilized preparation is a composition obtained by lyophilizing a solution containing an IL-31 antagonist, arginine and / or a salt thereof, sucrose and / or trehalose, and poloxamer 188 or polysorbate 20 or polysorbate 80, and has a pH of 6 to 8 after reconstitution with water; Further herein, the IL-31 antagonist is (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising the heavy chain variable region of SEQ ID NO: 7 and the light chain variable region of SEQ ID NO: 8; or (3) A lyophilized preparation of any one of anti-IL-31RA antibodies comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO: 10, wherein the lyophilized preparation is a vial, cartridge, or syringe containing 1–800 mg of an IL-31 antagonist, 0.8 to 400 mg of arginine or a salt thereof, 3-1100 mg of sucrose or trehalose, and 0.01-7 mg of poloxamer 188 or polysorbate 20 or polysorbate 80 and having a pH of 6 to 8 after reconstitution with water.

3. A freeze-dried preparation containing an IL-31 antagonist as an active ingredient, - 6-100 mg / mL of an IL-31 antagonist; 45 to 150 mmol / L arginine or a salt thereof, 75–250 mmol / L sucrose or trehalose, and 0.15-0.50 mg / mL of poloxamer 188, polysorbate 20, or polysorbate 80 a lyophilized composition having a pH of 6 to 8 after reconstitution with water; wherein the IL-31 antagonist is (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising the H chain variable region of SEQ ID NO: 7 and the L chain variable region of SEQ ID NO: 8; or (3) A lyophilized preparation of an anti-IL-31RA antibody comprising the H chain set forth in SEQ ID NO: 9 and the L chain set forth in SEQ ID NO:

10.

4. (i) Container; (ii) in the container, a lyophilized formulation according to any one of claims 1 to 3; and (iii) optionally, water for injection to reconstitute the lyophilized formulation; 13. An injectable formulation comprising:

Images