Antibody-containing preparations

Abstract

In one non-limiting embodiment, the present disclosure relates to a lyophilized formulation comprising an IL-31 antagonist (e.g., an anti-IL-31RA antibody) as an active ingredient, the lyophilized formulation further containing 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 further containing arginine and / or a salt thereof. In other non-limiting embodiments, the present disclosure relates to a method for stabilizing an antibody (e.g., an anti-IL-31RA antibody) in an antibody-containing formulation, a method for inhibiting antibody aggregation (aggregate formation) in an antibody-containing formulation, and a method for reducing components with charge heterogeneity in an antibody-containing formulation, the method being characterized in that the formulation is prepared to contain arginine and / or a salt thereof, and / or sucrose and / or trehalose.

Description

Technical Field

[0001] The present invention relates to a stable formulation comprising an interleukin-31 (IL-31) antagonist (eg, 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 Art

[0002] Monoclonal antibodies (PTL1-3) that have the function of binding to interleukin 31 (IL-31) receptor A (IL-31RA) and inhibiting the binding of IL-31 to IL-31RA have been identified. Nemolizumab (CIM331), an anti-IL-31RA antibody, is a humanized IgG2 antibody that acts as an IL-31 antagonist to inhibit the function of IL-31, which is known as an itch-inducing cytokine; therefore, clinical trials for patients with atopic dermatitis are currently underway.

[0003] To improve stability, many lyophilized preparations for therapeutic proteins (e.g., antibodies) have been developed so far (NPL 1). As additives for lyophilized preparations of non-antibody therapeutic proteins, sugars such as sucrose and trehalose are commonly used (NPL 2), and there are also reports on the use of arginine as a stabilizer (PTLs 4 and 5).

[0004] However, for formulations containing an anti-IL31RA antibody (CIM331) as an IL-31 antagonist, there are no reports on stable formulations in which aggregate formation and / or components having charge heterogeneity, which have a great influence on antibody stability, are suppressed.

[0005] Reference List

[0006] Patent Literature

[0007] [PTL 1] WO2007 / 142325

[0008] [PTL 2] WO2009 / 072604

[0009] [PTL 3] WO2010 / 064697

[0010] [PTL 4]US6887852B1

[0011] [PTL 5] WO2010 / 148253

[0012] Non-patent literature

[0013] [NPL 1]Pharm Res.1997;14(8):969-975.

[0014] [NPL 2]J Pharm Sci.1998;87(11):1412-1420. Summary of the invention

[0015] Technical issues

[0016] An object of the present invention is to provide a stable formulation comprising an IL-31 antagonist anti-IL-31RA antibody (CIM331) as an active ingredient.

[0017] Solutions to the problem

[0018] To achieve the above purpose, the present inventors conducted a special study and found that the addition of arginine or a salt thereof to a formulation containing the above-mentioned IL-31 antagonist (particularly an anti-IL-31RA antibody (CIM331)) increases the stability of the formulation containing the IL-31 antagonist, regardless of whether there is a lyophilization step. It was also found that when the formulation is in a lyophilized state, the addition of sucrose or trehalose to the formulation increases the stability of the formulation containing the IL-31 antagonist. It was further found that when the formulation is in a solution state, the addition of a nonionic surfactant to the formulation increases the stability of the formulation containing the IL-31 antagonist.

[0019] In non-limiting embodiments, the present disclosure relates to the following.

[0020] [1] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, wherein the preparation comprises arginine and / or a salt thereof, sucrose and / or trehalose.

[0021] [2] The lyophilized preparation of [1], wherein the arginine and / or its salt is arginine hydrochloride, arginine aspartate or arginine glutamate.

[0022] [3] The lyophilized preparation of [1] or [2], wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl).

[0023] [4] The lyophilized preparation according to any one of [1] to [3], further comprising a Tris buffer as a buffer.

[0024] [5] The lyophilized preparation of [4], wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.

[0025] [6] The lyophilized preparation of [5], wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate.

[0026] [7] The lyophilized preparation of [5] or [6], wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl).

[0027] [8] The lyophilized preparation according to any one of [1] to [7], further comprising poloxamer 188 or polysorbate as a nonionic surfactant.

[0028] [9] The lyophilized preparation of [8], wherein the polysorbate is polysorbate 20 or polysorbate 80.

[0029]

[10] The lyophilized preparation of any one of [1] to [9], wherein the pH of the preparation is 6 to 8 when reconstituted in water.

[0030]

[11] The lyophilized preparation of any one of [1] to

[10] , wherein the pH of the preparation when reconstituted in water is 6.5 to 7.5.

[0031]

[12] The lyophilized preparation of any one of [1] to

[11] , wherein the pH of the preparation is 7 when reconstituted in water.

[0032]

[13] A solution preparation comprising an IL-31 antagonist as an active ingredient, wherein the solution preparation comprises arginine and / or a salt thereof.

[0033]

[14] The solution preparation described in

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

[0034]

[15] The solution preparation of

[13] or

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

[0035]

[16] The solution preparation according to any one of

[13] to

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

[0036]

[17] The solution preparation described in

[16] , wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.

[0037]

[18] The solution preparation described in

[17] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate.

[0038]

[19] The solution preparation of

[17] or

[18] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl).

[0039]

[20] The solution preparation according to any one of

[13] to

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

[0040]

[21] The solution preparation of

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

[0041]

[22] The solution preparation of any one of

[13] to

[21] , wherein the pH is 6 to 8.

[0042]

[23] The solution preparation of any one of

[13] to

[22] , wherein the pH is 6.5 to 7.5.

[0043]

[24] The solution preparation of any one of

[13] to

[23] , wherein the pH is 7.

[0044]

[25] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, which is a composition produced by lyophilizing a solution, the solution comprising:

[0045] -1 to 200 mg / mL IL-31 antagonist;

[0046] -1 to 200 mmol / L Tris buffer;

[0047] -4.5 to 1500 mmol / L arginine or its salt;

[0048] -7.5 to 2500 mmol / L sucrose or trehalose; and

[0049] -0.01 to 5 mg / mL poloxamer 188 or polysorbate 20,

[0050] wherein the pH of the formulation when reconstituted in water is 6 to 8:

[0051]

[26] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, which is a composition produced by lyophilizing a solution, the solution comprising:

[0052] -6 to 100 mg / mL IL-31 antagonist;

[0053] -6 to 20 mmol / L Tris buffer;

[0054] -45 to 150 mmol / L arginine or its salt;

[0055] -75 to 250 mmol / L sucrose or trehalose; and

[0056] -0.15 to 0.50 mg / mL poloxamer 188 or polysorbate 20,

[0057] wherein the pH of the formulation when reconstituted in water is 6 to 8:

[0058]

[27] A lyophilized formulation comprising an IL-31 antagonist as an active ingredient, comprising, per vial, cartridge or syringe:

[0059] - 1 to 800 mg IL-31 antagonist;

[0060] - 0.1 to 40 mg tris(hydroxymethyl)aminomethane;

[0061] - 0.8 to 400 mg arginine;

[0062] - 3 to 1100 mg sucrose or trehalose; and

[0063] -0.01 to 7 mg poloxamer 188 or polysorbate 20,

[0064] wherein the pH of the formulation when reconstituted in water is between 6 and 8.

[0065]

[28] A lyophilized formulation comprising an IL-31 antagonist as an active ingredient, comprising, per vial, cartridge or syringe:

[0066] - 10 to 80 mg IL-31 antagonist;

[0067] - 0.8 to 4 mg tris(hydroxymethyl)aminomethane;

[0068] -8 to 40 mg arginine;

[0069] - 30 to 110 mg sucrose or trehalose; and

[0070] - 0.1 to 0.7 mg poloxamer 188 or polysorbate 20,

[0071] wherein the pH of the formulation when reconstituted in water is between 6 and 8.

[0072]

[29] The preparation of any one of [1] to

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

[0073]

[30] The lyophilized preparation of any one of [1] to

[12] and

[25] to

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

[0074]

[31] The lyophilized preparation of any one of

[25] to

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

[0075]

[32] The lyophilized preparation of any one of

[25] to

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

[0076]

[33] The lyophilized preparation of

[32] , wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.

[0077]

[34] The lyophilized preparation of

[33] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate.

[0078]

[35] The lyophilized preparation of

[33] or

[34] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl).

[0079]

[36] The agent of any one of [1] to

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

[0080]

[37] The preparation described in

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

[0081]

[38] The preparation of

[37] , wherein the anti-IL-31RA neutralizing antibody is:

[0082] (1) an anti-IL-31RA antibody comprising an H chain variable region comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and an L chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6;

[0083] (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

[0084] (3) An anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10.

[0085]

[39] The preparation of

[37] or

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

[0086]

[40] The agent of any one of

[37] to

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

[0087]

[41] The lyophilized preparation of any one of

[37] to

[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 68 mg / mL.

[0088]

[42] The lyophilized preparation of any one of

[37] to

[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 50 mg / mL.

[0089]

[43] The lyophilized preparation of any one of

[37] to

[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 15 mg / mL.

[0090]

[44] The lyophilized preparation of any one of

[37] to

[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 7.5 mg / mL.

[0091]

[45] The lyophilized preparation according to any one of

[37] to

[41] , which is a composition produced by lyophilizing a solution in which the concentration of Tris-HCl is 13.6 mmol / L.

[0092]

[46] The lyophilized preparation of any one of

[37] to

[40] and

[42] , which is a composition produced by lyophilizing a solution in which the concentration of Tris-HCl is 10 mmol / L.

[0093]

[47] The lyophilized preparation of any one of

[37] to

[40] and

[43] to

[44] , which is a composition produced by lyophilizing a solution in which the concentration of Tris-HCl is 6 mmol / L.

[0094]

[48] ​​The lyophilized preparation of any one of

[37] to

[41] and

[45] , which is a composition produced by lyophilizing a solution in which the concentration of Arg-HCl is 102 mmol / L.

[0095]

[49] The lyophilized preparation of any one of

[37] to

[40] ,

[42] and

[46] , which is a composition produced by lyophilizing a solution in which the concentration of Arg-HCl is 75 mmol / L.

[0096]

[50] The lyophilized preparation of any one of

[37] to

[40] ,

[43] to

[44] and

[47] , which is a composition produced by lyophilizing a solution in which the Arg-HCl concentration is 45 mmol / L.

[0097]

[51] The lyophilized preparation of any one of

[37] to

[41] ,

[45] and

[48] , which is a composition produced by lyophilizing a solution in which the concentration of sucrose or trehalose is 170 mmol / L.

[0098]

[52] The lyophilized preparation of any one of

[37] to

[40] ,

[42] ,

[46] and

[49] , which is a composition produced by lyophilizing a solution containing sucrose or trehalose at a concentration of 125 mmol / L.

[0099]

[53] The lyophilized preparation of any one of

[37] to

[40] ,

[43] to

[44] ,

[47] and

[50] , which is a composition produced by lyophilizing a solution in which the concentration of sucrose or trehalose is 75 mmol / L.

[0100]

[54] The lyophilized preparation of any one of

[37] to

[41] ,

[45] ,

[48] and

[51] , which is a composition produced by lyophilizing a solution in which the concentration of poloxamer 188 or polysorbate 20 is 0.34 mg / mL.

[0101]

[55] The lyophilized preparation of any one of

[37] to

[40] ,

[42] ,

[46] ,

[49] and

[52] , which is a composition produced by lyophilizing a solution in which the concentration of poloxamer 188 or polysorbate 20 is 0.25 mg / mL.

[0102]

[56] The lyophilized preparation of any one of

[37] to

[40] ,

[43] to

[44] ,

[47] ,

[50] and

[53] , which is a composition produced by lyophilizing a solution in which the concentration of poloxamer 188 or polysorbate 20 is 0.15 mg / mL.

[0103]

[57] The lyophilized preparation of any one of

[37] to

[42] ,

[45] to

[46] ,

[48] to

[49] ,

[51] to

[52] and

[54] to

[55] , which is a composition produced by lyophilizing a solution in which the molar ratio between arginine and the anti-IL-31RA neutralizing antibody is 220:1 and / or the weight ratio is 0.3:1.

[0104]

[58] The lyophilized preparation of any one of

[37] to

[40] ,

[43] ,

[47] ,

[50] ,

[53] and

[56] , which is a composition produced by lyophilizing a solution in which the molar ratio between arginine and the anti-IL-31RA neutralizing antibody is 440:1 and / or the weight ratio is 0.5:1.

[0105]

[59] The lyophilized preparation of any one of

[37] to

[40] ,

[44] ,

[47] ,

[50] ,

[53] and

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

[0106]

[60] The lyophilized preparation of any one of

[37] to

[42] ,

[45] to

[46] ,

[48] to

[49] ,

[51] to

[52] ,

[54] to

[55] and

[57] , which is a composition produced by lyophilizing a solution in which the molar ratio between sucrose and the anti-IL-31RA neutralizing antibody is 370:1 and / or the weight ratio is 0.8:1 to 0.9:1.

[0107]

[61] The lyophilized preparation of any one of

[37] to

[40] ,

[43] ,

[47] ,

[50] ,

[53] ,

[56] and

[58] , which is a composition produced by lyophilizing a solution in which the molar ratio between sucrose and the anti-IL-3IRA neutralizing antibody is 740:1 and / or the weight ratio is 1.7:1.

[0108]

[62] The lyophilized preparation of any one of

[37] to

[40] ,

[44] ,

[47] ,

[50] ,

[53] ,

[56] and

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

[0109]

[63] The lyophilized preparation of any one of

[25] to

[62] , wherein the pH of the preparation when reconstituted in water is 6.5 to 7.5.

[0110]

[64] The lyophilized preparation of any one of

[25] to

[63] , wherein the pH of the preparation when reconstituted in water is 7.

[0111]

[65] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a syringe:

[0112] -75 mg of anti-IL-31RA neutralizing antibody;

[0113] -1.8 mg tris(hydroxymethyl)aminomethane;

[0114] - 19 mg arginine;

[0115] - 64 mg sucrose;

[0116] -0.4mg Poloxamer 188.

[0117]

[66] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a syringe:

[0118] -75 mg of anti-IL-31RA neutralizing antibody;

[0119] -0.24 mg tris(hydroxymethyl)aminomethane;

[0120] - 23.6 mg L-arginine hydrochloride;

[0121] - 63.9 mg sucrose;

[0122] - 0.37 mg poloxamer 188; and

[0123] -Tris(hydroxymethyl)aminomethane-hydrochloride as a pH adjuster.

[0124]

[67] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a syringe:

[0125] - 39 mg anti-IL-3IRA neutralizing antibody;

[0126] -0.9 mg tris(hydroxymethyl)aminomethane;

[0127] -10 mg arginine;

[0128] - 33 mg sucrose; and

[0129] -0.2mg Poloxamer 188.

[0130]

[68] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a cartridge:

[0131] -36mg anti-IL-31RA neutralizing antibody;

[0132] -0.9 mg tris(hydroxymethyl)aminomethane;

[0133] - 9 mg arginine;

[0134] - 31 mg sucrose; and

[0135] -0.2mg Poloxamer 188.

[0136]

[69] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a vial:

[0137] -51mg anti-IL-31RA neutralizing antibody;

[0138] -2.5 mg tris(hydroxymethyl)aminomethane;

[0139] - 27 mg arginine;

[0140] - 88 mg sucrose; and

[0141] -0.5mg Poloxamer 188.

[0142]

[70] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a vial:

[0143] -30 mg of anti-IL-31RA neutralizing antibody;

[0144] -3.0 mg tris(hydroxymethyl)aminomethane;

[0145] - 32 mg arginine;

[0146] - 104 mg sucrose; and

[0147] -0.6mg Poloxamer 188.

[0148]

[71] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a vial:

[0149] -19 mg of anti-IL-31RA neutralizing antibody;

[0150] -1.9 mg tris(hydroxymethyl)aminomethane;

[0151] - 20 mg arginine;

[0152] - 66 mg sucrose; and

[0153] -0.4mg Poloxamer 188.

[0154]

[72] The lyophilized preparation of any one of

[25] to

[40] , comprising, per container such as a vial:

[0155] -14 mg anti-IL-3IRA neutralizing antibody;

[0156] -1.3 mg tris(hydroxymethyl)aminomethane;

[0157] -15 mg arginine;

[0158] - 47 mg sucrose; and

[0159] -0.3mg Poloxamer 188.

[0160]

[73] The lyophilized preparation of any one of

[25] to

[40] , which is a composition produced by lyophilizing a solution, the solution comprising:

[0161] - 68 mg / mL anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;

[0162] -13.6mmol / L Tris-HCl buffer;

[0163] -102mmol / L arginine hydrochloride (Arg-HCl);

[0164] -170mmol / L sucrose; and

[0165] -0.34mg / mL Poloxamer 188,

[0166] The pH of the formulation is 7 when reconstituted in water.

[0167]

[74] The lyophilized preparation of any one of

[25] to

[40] , which is a composition produced by lyophilizing a solution, the solution comprising:

[0168] - 50 mg / mL anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;

[0169] -10mmol / L Tris-HCl buffer;

[0170] -75mmol / L arginine hydrochloride (Arg-HCl);

[0171] -125mmol / L sucrose; and

[0172] -0.25mg / mL Poloxamer 188,

[0173] The pH of the formulation is 7 when reconstituted in water.

[0174]

[75] The lyophilized preparation of any one of

[25] to

[40] , which is a composition produced by lyophilizing a solution, the solution comprising:

[0175] - 15 mg / mL anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;

[0176] -6mmol / L Tris-HCl buffer;

[0177] -45mmol / L arginine hydrochloride (Arg-HCl);

[0178] -75mmol / L sucrose; and

[0179] -0.15mg / mL Poloxamer 188,

[0180] The pH of the formulation is 7 when reconstituted in water.

[0181]

[76] The lyophilized preparation of any one of

[25] to

[40] , which is a composition produced by lyophilizing a solution, the solution comprising:

[0182] - 7.5 mg / mL anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;

[0183] -6mmol / L Tris-HCl buffer;

[0184] -45mmol / L arginine hydrochloride (Arg-HCl);

[0185] -75mmol / L sucrose; and

[0186] -0.15mg / mL Poloxamer 188,

[0187] The pH of the formulation is 7 when reconstituted in water.

[0188]

[77] A lyophilized formulation comprising an IL-31 antagonist as an active ingredient, the lyophilized formulation further comprising Tris buffer, arginine, sucrose or trehalose, and poloxamer 188 or polysorbate 20, wherein when the formulation is reconstituted in water, comprises:

[0189] -1 to 200 mg / mL IL-31 antagonist;

[0190] -1 to 200 mmol / L Tris buffer;

[0191] -4.5 to 1500 mmol / L arginine or its salt;

[0192] -7.5 to 2500 mmol / L sucrose or trehalose; and

[0193] -0.01 to 5 mg / mL poloxamer 188 or polysorbate 20,

[0194] and a pH of 6 to 8.

[0195]

[78] A lyophilized formulation comprising an IL-31 antagonist as an active ingredient, the lyophilized formulation further comprising a Tris buffer, arginine, sucrose or trehalose, and poloxamer 188 or polysorbate 20, wherein when the formulation is reconstituted in water, comprises:

[0196] -20 to 100 mg / mL IL-31 antagonist;

[0197] -10 to 20 mmol / L Tris buffer;

[0198] -75 to 150 mmol / L arginine or its salt;

[0199] -125 to 250 mmol / L sucrose or trehalose; and

[0200] -0.25 to 0.50 mg / mL poloxamer 188 or polysorbate 20,

[0201] and a pH of 6 to 8.

[0202]

[79] The lyophilized preparation of

[77] or

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

[0203]

[80] The lyophilized preparation of any one of

[77] to

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

[0204]

[81] The lyophilized preparation of any one of

[77] to

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

[0205]

[82] The lyophilized preparation of any one of

[77] to

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

[0206]

[83] The lyophilized preparation of any one of

[77] to

[82] , wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or a salt thereof.

[0207]

[84] The lyophilized preparation described in

[83] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate.

[0208]

[85] The lyophilized preparation of

[83] or

[84] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl).

[0209]

[86] The lyophilized preparation of any one of

[77] to

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

[0210]

[87] The lyophilized preparation of

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

[0211]

[88] The lyophilized preparation of

[87] , wherein the anti-IL-31RA neutralizing antibody is:

[0212] (1) an anti-IL-31RA antibody comprising an H chain variable region comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and an L chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6;

[0213] (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

[0214] (3) An anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10.

[0215]

[89] The lyophilized preparation of

[87] or

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

[0216]

[90] The lyophilized preparation of any one of

[87] to

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

[0217]

[91] The lyophilized formulation of any one of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody when the formulation is reconstituted in water is 100 mg / mL.

[0218]

[92] The lyophilized formulation of any one of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody is 61.5 mg / mL when the formulation is reconstituted in water.

[0219]

[93] The lyophilized formulation of any one of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody is 50 mg / mL when the formulation is reconstituted in water.

[0220]

[94] The lyophilized formulation of any one of

[87] to

[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody is 25 mg / mL when the formulation is reconstituted in water.

[0221]

[95] The lyophilized preparation of any one of

[87] to

[91] , wherein the concentration of Tris-HCl is 20 mmol / L when the preparation is reconstituted in water.

[0222]

[96] The lyophilized formulation of any one of

[87] to

[90] and

[92] , wherein the concentration of Tris-HCl is 12.3 mmol / L when the formulation is reconstituted in water.

[0223]

[97] The lyophilized formulation of any one of

[87] to

[90] and

[93] to

[94] , wherein the concentration of Tris-HCl is 20 mmol / L when the formulation is reconstituted in water.

[0224]

[98] The lyophilized formulation of any one of

[87] to

[91] and

[95] , wherein the concentration of Arg-HCl is 150 mmol / L when the formulation is reconstituted in water.

[0225]

[99] The lyophilized formulation of any one of

[87] to

[90] ,

[92] and

[96] , wherein the concentration of Arg-HCl is 92 mmol / L when the formulation is reconstituted in water.

[0226]

[100] The lyophilized formulation of any one of

[87] to

[90] ,

[93] to

[94] and

[97] , wherein the concentration of Arg-HCl when the formulation is reconstituted in water is 150 mmol / L.

[0227]

[101] The lyophilized formulation of any one of

[87] to

[91] ,

[95] and

[98] , wherein the concentration of sucrose or trehalose is 250 mmol / L when the formulation is reconstituted in water.

[0228]

[102] The lyophilized formulation of any one of

[87] to

[90] ,

[92] ,

[96] and

[99] , wherein the concentration of sucrose or trehalose when the formulation is reconstituted in water is 154 mmol / L.

[0229]

[103] The lyophilized formulation of any one of

[87] to

[90] ,

[93] to

[94] ,

[97] and

[100] , wherein the concentration of sucrose or trehalose is 250 mmol / L when the formulation is reconstituted in water.

[0230]

[104] The lyophilized formulation of any one of

[87] to

[91] ,

[95] ,

[98] and

[101] , wherein the concentration of poloxamer 188 or polysorbate 20 is 0.50 mg / mL when the formulation is reconstituted in water.

[0231]

[105] The lyophilized formulation of any one of

[87] to

[90] ,

[92] ,

[96] ,

[99] and

[102] , wherein the concentration of poloxamer 188 or polysorbate 20 is 0.31 mg / mL when the formulation is reconstituted in water.

[0232]

[106] The lyophilized formulation of any one of

[87] to

[90] ,

[93] to

[94] ,

[97] ,

[100] and

[103] , wherein the concentration of poloxamer 188 or polysorbate 20 is 0.50 mg / mL when the formulation is reconstituted in water.

[0233]

[107] The lyophilized preparation of any one of

[87] to

[91] ,

[95] ,

[98] ,

[101] and

[104] to

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

[0234]

[108] The lyophilized preparation of any one of

[87] to

[90] ,

[93] ,

[97] ,

[100] ,

[103] and

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

[0235]

[109] The lyophilized preparation of any one of

[87] to

[90] ,

[94] ,

[97] ,

[100] ,

[103] and

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

[0236]

[110] The lyophilized preparation of any one of

[87] to

[91] ,

[95] ,

[98] ,

[101] ,

[104] to

[105] and

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

[0237]

[111] The lyophilized preparation of any one of

[87] to

[90] ,

[93] ,

[97] ,

[100] ,

[103] ,

[106] and

[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.

[0238]

[112] The lyophilized preparation of any one of

[87] to

[90] ,

[94] ,

[97] ,

[100] ,

[103] and

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

[0239]

[113] The lyophilized formulation of any one of

[77] to

[112] , wherein the pH of the formulation when reconstituted in water is 6.5 to 7.5.

[0240]

[114] The lyophilized formulation of any one of

[77] to

[113] , wherein the pH of the formulation when reconstituted in water is 6.7 to 7.3.

[0241]

[115] The lyophilized preparation of any one of

[77] to

[114] , wherein the pH of the preparation when reconstituted in water is 7.

[0242]

[116] The lyophilized preparation of any one of

[87] to

[91] ,

[95] ,

[98] ,

[101] ,

[104] ,

[107] and

[110] , wherein the lyophilized preparation is 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, and is prepared by freeze-drying a solution comprising a buffer, a stabilizer, an excipient and a nonionic surfactant, and wherein the following concentrations are produced when the lyophilized preparation is reconstituted in water:

[0243] -100 mg / mL of anti-IL-31RA neutralizing antibody;

[0244] -20mmol / L Tris-HCl buffer;

[0245] -150mmol / L arginine hydrochloride (Arg-HCl);

[0246] -250mmol / L sucrose; and

[0247] -0.50 mg / mL of Poloxamer 188.

[0248]

[117] The lyophilized preparation of any one of

[87] to

[90] ,

[92] ,

[96] ,

[99] ,

[102] ,

[105] ,

[107] and

[110] , wherein the lyophilized preparation is a pharmaceutical composition comprising an anti-IL-31RA antibody comprising an H chain of SEQ ID NO: 9 and an L chain of SEQ ID NO: 10 as an active ingredient, and is prepared by freeze-drying a solution comprising a buffer, a stabilizer, an excipient and a nonionic surfactant, and when the lyophilized preparation is reconstituted in water, the following concentrations are produced:

[0249] -61.5 mg / mL of anti-IL-31RA neutralizing antibody;

[0250] -12.3mmol / L Tris-HCl buffer;

[0251] -92mmol / L arginine hydrochloride (Arg-HCl);

[0252] -154mmol / L sucrose; and

[0253] -0.31 mg / mL of Poloxamer 188.

[0254]

[118] The lyophilized preparation of any one of

[87] to

[90] ,

[93] ,

[97] ,

[100] ,

[103] ,

[106] ,

[108] and

[111] , wherein the lyophilized preparation is 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, and is prepared by freeze-drying a solution comprising a buffer, a stabilizer, an excipient and a nonionic surfactant, and wherein the following concentrations are produced when the lyophilized preparation is reconstituted in water:

[0255] -50 mg / mL of anti-IL-31RA neutralizing antibody;

[0256] -20mmol / L Tris-HCl buffer;

[0257] -150mmol / L arginine hydrochloride (Arg-HCl);

[0258] -250mmol / L sucrose; and

[0259] -0.50 mg / mL of Poloxamer 188.

[0260]

[119] The lyophilized preparation of any one of

[87] to

[90] ,

[94] ,

[97] ,

[100] ,

[103] ,

[109] and

[112] , wherein the lyophilized preparation is 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, and is prepared by freeze-drying a solution comprising a buffer, a stabilizer, an excipient and a nonionic surfactant, and wherein the following concentrations are produced when the lyophilized preparation is reconstituted in water:

[0261] -25 mg / mL of anti-IL-31RA neutralizing antibody;

[0262] -20mmol / L Tris-HCl buffer;

[0263] -150mmol / L arginine hydrochloride (Arg-HCl);

[0264] -250mmol / L sucrose; and

[0265] -0.50 mg / mL of Poloxamer 188.

[0266]

[120] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, which is a composition produced by lyophilizing a solution, the solution comprising:

[0267] -1 to 200 mg / mL IL-31 antagonist;

[0268] -1 to 200 mmol / L Tris buffer;

[0269] -4.5 to 1500 mmol / L arginine or its salt;

[0270] -7.5 to 2500 mmol / L sucrose or trehalose; and

[0271] -0.01 to 5 mg / mL poloxamer 188 or polysorbate 20,

[0272] Wherein, when the preparation is reconstituted in water, it comprises:

[0273] -1 to 200 mg / mL IL-31 antagonist;

[0274] -1 to 200 mmol / L Tris buffer;

[0275] -4.5 to 1500 mmol / L arginine or its salt;

[0276] -7.5 to 2500 mmol / L sucrose or trehalose; and

[0277] -0.01 to 5 mg / mL poloxamer 188 or polysorbate 20,

[0278] and a pH of 6 to 8.

[0279]

[121] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, which is a composition produced by lyophilizing a solution, the solution comprising:

[0280] -6 to 100 mg / mL IL-31 antagonist;

[0281] -6 to 20 mmol / L Tris buffer;

[0282] -45 to 150 mmol / L arginine or its salt;

[0283] -75 to 250 mmol / L sucrose or trehalose; and

[0284] -0.15 to 0.50 mg / mL poloxamer 188 or polysorbate 20,

[0285] Wherein, when the preparation is reconstituted in water, it comprises:

[0286] -20 to 100 mg / mL IL-31 antagonist;

[0287] -10 to 20 mmol / L Tris buffer;

[0288] -75 to 150 mmol / L arginine or its salt;

[0289] -125 to 250 mmol / L sucrose or trehalose; and

[0290] - 0.25 to 0.50 mg / mL poloxamer 188 or polysorbate 20, and pH 6 to 8.

[0291]

[122] The lyophilized preparation of

[120] or

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

[0292]

[123] The lyophilized preparation of any one of

[120] to

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

[0293]

[124] The lyophilized preparation of any one of

[120] to

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

[0294]

[125] The lyophilized preparation of any one of

[120] to

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

[0295]

[126] The lyophilized preparation of any one of

[120] to

[125] , wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.

[0296]

[127] The lyophilized preparation of any one of

[120] to

[126] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate.

[0297]

[128] The lyophilized preparation of any one of

[120] or

[127] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl).

[0298]

[129] The lyophilized preparation of any one of

[120] to

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

[0299]

[130] The lyophilized preparation of

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

[0300]

[131]

[130] The lyophilized preparation, wherein the anti-IL-31RA neutralizing antibody is:

[0301] (1) an anti-IL-31RA antibody comprising an H chain variable region comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and an L chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6;

[0302] (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

[0303] (3) An anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10.

[0304]

[132] The lyophilized preparation of

[130] or

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

[0305]

[133] The lyophilized preparation of any one of

[130] to

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

[0306]

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

[133] , which is used for preventing and / or treating an IL-31-related disorder or symptoms associated with the disorder.

[0307]

[135] The preparation of

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

[0308]

[136] The preparation of

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

[0309]

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

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

[0310]

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

[0311]

[139] The method of

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

[0312]

[140] The method of

[138] or

[139] further comprises preparing a lyophilized preparation containing the antibody by freeze-drying the antibody-containing solution.

[0313]

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

[0314]

[142] The use described in

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

[0315]

[143] The use described in

[141] or

[142] further comprises preparing a lyophilized preparation containing an antibody by freeze-drying the antibody-containing solution.

[0316]

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

[0317]

[145]

[144] The method according to claim 1, wherein the antibody-containing solution further comprises 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.

[0318]

[146] The method of

[144] or

[145] further comprises preparing a lyophilized preparation containing the antibody by freeze-drying the antibody-containing solution.

[0319]

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

[0320]

[148] The use described in

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

[0321]

[149] The use described in

[147] or

[148] further comprises preparing a lyophilized preparation containing an antibody by freeze-drying the antibody-containing solution.

[0322]

[150] A method for reducing components with charge heterogeneity in an antibody-containing preparation, comprising preparing an antibody-containing solution containing arginine and / or its salt, and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of arginine and / or its salt to the antibody is 220:1 to 1100:1, and the molar ratio of sucrose or trehalose to the antibody is 370:1 to 1840:1.

[0323]

[151]

[150] The method according to claim 1, wherein the antibody-containing solution further comprises 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.

[0324]

[152] The method of

[150] or

[151] further comprises preparing a lyophilized preparation containing the antibody by freeze-drying the antibody-containing solution.

[0325]

[153] Use of arginine and / or its salt, and / or sucrose and / or trehalose in reducing components with charge heterogeneity in antibody-containing preparations, comprising preparing an antibody-containing solution comprising arginine and / or its salt and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is 370:1 to 1840:1.

[0326]

[154] The use described in

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

[0327]

[155] The use described in

[153] or

[154] further comprises preparing a lyophilized preparation containing an antibody by freeze-drying the antibody-containing solution.

[0328]

[156] A method for preventing and / or treating an IL-31-related disorder, comprising administering an IL-31 antagonist to a subject suffering from an IL-31-related disorder or at risk of suffering from an IL-31-related disorder, the method comprising:

[0329] A lyophilized formulation is prepared by 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; a reconstituted solution is prepared by reconstituting the lyophilized formulation in water; and the reconstituted solution is administered to a subject.

[0330]

[157] Use of an IL-31 antagonist in the preparation of a medicament for preventing and / or treating an IL-31-related disorder, characterized in that the lyophilized preparation is prepared by freeze-drying a solution comprising 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.

[0331]

[158] An IL-31 antagonist for use in preventing and / or treating IL-31-related disorders, characterized in that a lyophilized preparation produced by lyophilizing a solution containing 6 to 100 mg / mL IL-31 antagonist, 45 to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 to 250 mmol / L sucrose or trehalose is reconstituted in water before use.

[0332]

[159] The method described in

[156] , the use described in

[157] or the IL-31 antagonist described in

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

[0333]

[160] An injection formulation or kit comprising (i) a container, (ii) the lyophilized formulation of any one of [1] to

[12] and

[25] to

[137] , and (iii) water for injection for reconstituting the lyophilized formulation.

[0334]

[161] A formulation for injection, comprising (i) a container, (ii) a lyophilized preparation in the container, the lyophilized preparation being produced by lyophilizing 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 (iii) optionally, water for injection for reconstituting the lyophilized preparation.

[0335]

[162] The injectable preparation described in

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

[0336]

[163] A formulation for injection, comprising (i) a container, (ii) a lyophilized formulation in the container, the lyophilized formulation being produced by lyophilizing a solution comprising an effective amount of an anti-IL-31RA neutralizing antibody and 220 to 1100 moles of arginine hydrochloride (Arg-HCl) and 370 to 1840 moles of sucrose or trehalose per 1 mole of the antibody, and (iii) optionally, water for injection for reconstituting the lyophilized formulation.

[0337]

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

[160] to

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

[0338]

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

[160] to

[164] , wherein the lyophilized preparation is reconstituted with water for injection in the container upon use. DETAILED DESCRIPTION

[0339] Preferred non-limiting embodiments of the present disclosure will be described below.

[0340] The description of all embodiments set forth in the following examples is intended to be interpreted as being equivalently described in the "Description of Embodiments" of this specification in the countries where protection of this patent application is sought, without being limited in a limiting manner by any patent practice, convention or law that may interpret the contents of the embodiments.

[0341] For the description of numerical values ​​in the present disclosure, the numerical value of the smallest digit (e.g., the ones digit) may include a rounded value that is one digit less than the smallest digit (e.g., one decimal place when the smallest digit is the ones digit). For example, the numerical value "5" is intended to include numerical values ​​within the range of 4.5 to 5.4.

[0342] In a non-limiting embodiment, the present disclosure relates to a lyophilized formulation comprising an IL-31 antagonist as an active ingredient, the lyophilized 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 comprising an IL-31 antagonist as an active ingredient, the solution formulation comprising arginine and / or a salt thereof. Arginine is preferably L-arginine. In one embodiment, arginine and / or its salt is arginine hydrochloride, L-arginine hydrochloride, arginine-aspartate, L-arginine-aspartate, arginine-glutamate or L-arginine-glutamate. It will be understood by those skilled in the art that when referring to the weight (e.g., mg) of arginine, the weight may be the weight of free arginine 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 free arginine 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 tris(hydroxymethyl)aminomethane and / or a salt thereof, such as tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate, or tris(hydroxymethyl)aminomethane-acetate. In one embodiment, the formulation of the present disclosure further comprises poloxamer 188 or polysorbate as a nonionic surfactant. Poloxamer 188 can be referred to as "polyoxyethylene (160) polyoxypropylene (30) glycol" in the Japanese Pharmacopoeia standard. In one embodiment, the polysorbate is polysorbate 20 or polysorbate 80. In one embodiment, the pH of the reconstituted solution after reconstitution of the lyophilized formulation of the present disclosure in water is 6 to 8, such as 6.5 to 7.5, such as 6.7 to 7.3, and for example 7. In one embodiment, the pH of the solution formulation of the present disclosure is 6 to 8, such as 6.5 to 7.5, such as 7. Meanwhile, tris(hydroxymethyl)aminomethane is referred to as "tromethamine" in the Japanese Pharmacopoeia Standard. Those skilled in the art will understand that when the weight (e.g., mg) of tris(hydroxymethyl)aminomethane is mentioned, the weight may be the weight of free tris(hydroxymethyl)aminomethane or the weight of tris(hydroxymethyl)aminomethane contained in a salt containing tris(hydroxymethyl)aminomethane. Furthermore, in the present disclosure, the weight or concentration of tris(hydroxymethyl)aminomethane may be the sum of the weight or concentration of free tris(hydroxymethyl)aminomethane and the weight or concentration of tris(hydroxymethyl)aminomethane contained in a salt containing tris(hydroxymethyl)aminomethane.

[0343] The amount and concentration of the IL-31 antagonist contained in the formulation of the present invention are not particularly limited and can be appropriately adjusted according to the subject to be administered, such as whether the formulation is for adults or children, or whether the formulation is for prevention or treatment, or depending on the type, severity, etc. of the disorder or symptom to be prevented or treated. Therefore, the molar ratio and weight ratio of the IL-31 antagonist to another component contained in the formulation of the present invention can be different values. In a non-limiting embodiment, the molar ratio of arginine and / or its salt to the IL-31 antagonist is 3: 1 to 220500: 1, such as 22: 1 to 6600: 1, 33: 1 to 5500: 1, 44: 1 to 4400: 1, 55: 1 to 3300: 1, 110: 1 to 2200: 1, 220: 1 to 1100: 1, 220: 1 to 880: 1, 220: 1 to 440: 1 or 440: 1 to 880: 1. In non-limiting embodiments, the weight ratio of arginine to IL-31 antagonist is 0.004:1 to 261:1, e.g., 0.03:1 to 9.6:1, 0.1:1 to 4.8:1, 0.2:1 to 3.2:1, 0.3:1 to 1.6:1, 0.3:1 to 1.3:1, 0.3:1 to 1.1:1, 0.5:1 to 1.1:1, or 0.3:1 to 0.5:1. In non-limiting embodiments, the molar ratio of sucrose or trehalose to IL-31 antagonist is 6:1 to 367500:1, e.g., 75:1 to 7360:1, 100:1 to 5520:1, 150:1 to 3680:1, 300:1 to 1840:1, 370:1 to 1840:1, 370:1 to 1470:1, 740:1 to 1470:1 or 370:1 to 740:1. In a non-limiting embodiment, the weight ratio of sucrose or trehalose to the IL-31 antagonist is 0.013: 1 to 856: 1, for example, 0.18: 1 to 16.8: 1, 0.23: 1 to 12.6: 1, 0.35: 1 to 8.4: 1, 0.7: 1 to 4.2: 1, 0.8: 1 to 4.3: 1, 0.8: 1 to 3.5: 1, 1.7: 1 to 3.5: 1 or 0.8: 1 to 1.7: 1. Meanwhile, in the Japanese Pharmacopoeia standard, sucrose is referred to as "Seisei Hakutou (purified sucrose)".

[0344] In a non-limiting embodiment, the concentration of the IL-31 antagonist contained in the formulation of the present disclosure in a solution state (i.e., the concentration in the solution formulation, the concentration in the solution before lyophilization of the lyophilized solution, or the concentration in the solution after the lyophilized formulation is reconstituted) is 1 mg / mL to 200 mg / mL, such as 2 mg / mL to 200 mg / mL, 3 mg / mL to 200 mg / mL, 3 mg / mL to 150 mg / mL, 6 mg / mL to 100 mg / mL, 10 mg / mL to 100 mg / mL, 15 mg / mL to 100 mg / mL, 30 mg / mL to 100 mg / mL, 50 mg / mL to 100 mg / mL, 6 mg / mL to 70 mg / mL, 10 mg / mL to 70 mg / mL, 15 mg / mL to 70 mg / mL, 30 mg / mL to 70 mg / mL, 50 mg / mL to 70 mg / mL, 6 mg / mL to 50 mg / mL, 10 mg / mL to 50 mg / mL, 30 mg / mL to 50 mg / mL or 6 mg / mL to 30 mg / mL.

[0345] In one embodiment, the concentration of arginine and / or its salt contained in the formulation of the present disclosure in a solution state is 4.5 mmol / L to 1500 mmol / L, e.g., 9 mmol / L to 750 mmol / L, 15 mmol / L to 450 mmol / L, 22.5 mmol / L to 300 mmol / L, 45 mmol / L to 150 mmol / L, 75 mmol / L to 150 mmol / L or 45 mmol / L to 75 mmol / L.

[0346] In one embodiment, the concentration of sucrose and / or trehalose contained in the formulation of the present disclosure in a solution state is 7.5 mmol / L to 2500 mmol / L, for example 15 mmol / L to 1250 mmol / L, 25 mmol / L to 750 mmol / L, 37.5 mmol / L to 500 mmol / L, 75 mmol / L to 250 mmol / L, 125 mmol / L to 250 mmol / L, 75 mmol / L to 170 mmol / L, 125 mmol / L to 170 mmol / L, or 75 mmol / L to 125 mmol / L.

[0347] In one embodiment, the concentration of the Tris buffer contained in the formulation of the present disclosure in a solution state is 1 mmol / L to 200 mmol / L, for example 1 mmol / L to 100 mmol / L, 2 mmol / L to 60 mmol / L, 3 mmol / L to 40 mmol / L, 6 mmol / L to 20 mmol / L, 3 mmol / L to 15 mmol / L, 10 mmol / L to 20 mmol / L, 10 mmol / L to 15 mmol / L, 6 mmol / L to 15 mmol / L, or 6 mmol / L to 10 mmol / L.

[0348] In one embodiment, the concentration of poloxamer 188 or polysorbate contained in the formulation of the present disclosure in a solution state is 0.015 mg / mL to 5 mg / mL, such as 0.03 mg / mL to 2.5 mg / mL, 0.05 mg / mL to 1.5 mg / mL, 0.075 mg / mL to 1 mg / mL, 0.15 mg / mL to 0.5 mg / mL, 0.15 mg / mL to 0.4 mg / mL, 0.25 mg / mL to 0.5 mg / mL or 0.15 mg / mL to 0.25 mg / mL.

[0349] In one embodiment, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:

[0350] 1 mg / mL to 200 mg / mL IL-31 antagonist;

[0351] 1mmol / L to 200mmol / L Tris buffer;

[0352] 4.5 mmol / L to 1500 mmol / L arginine or its salt;

[0353] 7.5mmol / L to 2500mmol / L sucrose or trehalose; and

[0354] 0.01 mg / mL to 5 mg / mL Poloxamer 188 or Polysorbate 20,

[0355] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0356] In certain embodiments, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:

[0357] 6 mg / mL to 100 mg / mL IL-31 antagonist;

[0358] 6mmol / L to 20mmol / L Tris buffer;

[0359] 45 mmol / L to 150 mmol / L arginine or its salt;

[0360] 75mmol / L to 250mmol / L sucrose or trehalose; and

[0361] 0.15mg / mL to 0.50mg / mL poloxamer 188 or polysorbate 20,

[0362] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0363] In certain embodiments, the lyophilized formulations of the present disclosure are compositions produced by lyophilizing a solution comprising, per vial, cartridge or syringe:

[0364] 1 mg to 800 mg IL-31 antagonist;

[0365] 0.1mg to 40mg tris(hydroxymethyl)aminomethane;

[0366] 0.8mg to 400mg arginine;

[0367] 3 mg to 1100 mg sucrose or trehalose; and

[0368] 0.01mg to 7mg poloxamer 188 or polysorbate 20,

[0369] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0370] In certain embodiments, the lyophilized formulations of the present disclosure are compositions produced by lyophilizing a solution comprising, per vial, cartridge or syringe:

[0371] 10 mg to 80 mg IL-31 antagonist;

[0372] 0.8 mg to 4 mg tris(hydroxymethyl)aminomethane;

[0373] 8mg to 40mg arginine;

[0374] 30 mg to 110 mg sucrose or trehalose; and

[0375] 0.1mg to 0.7mg poloxamer 188 or polysorbate 20,

[0376] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0377] In one embodiment, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:

[0378] 61 mg / mL to 75 mg / mL, for example 68 mg / mL anti-IL-31RA neutralizing antibody;

[0379] 11 mmol / L to 16 mmol / L, for example 13.6 mmol / L Tris-HCl;

[0380] 82mmol / L to 122mmol / L, for example 102mmol / L Arg-HCl;

[0381] 153 mmol / L to 187 mmol / L, for example 170 mmol / L sucrose or trehalose; and

[0382] 0.17 mg / mL to 0.51 mg / mL, such as 0.34 mg / mL poloxamer 188 or polysorbate 20,

[0383] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0384] In another embodiment, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:

[0385] 45 mg / mL to 55 mg / mL, for example, 50 mg / mL anti-IL-31RA neutralizing antibody:

[0386] 8mmol / L to 12mmol / L, for example 10mmol / L Tris-HCl;

[0387] 60mmol / L to 90mmol / L, for example 75mmol / L Arg-HCl;

[0388] 113 mmol / L to 138 mmol / L, for example 125 mmol / L sucrose or trehalose; and

[0389] 0.13 mg / mL to 0.38 mg / mL, such as 0.25 mg / mL poloxamer 188 or polysorbate 20,

[0390] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0391] In yet another embodiment, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:

[0392] 14 mg / mL to 17 mg / mL, for example 15 mg / mL of anti-IL-31RA neutralizing antibody;

[0393] 5mmol / L to 7mmol / L, for example 6mmol / L Tris-HCl;

[0394] 36mmol / L to 54mmol / L, for example 45mmol / L Arg-HCl;

[0395] 68 mmol / L to 83 mmol / L, for example 75 mmol / L sucrose or trehalose; and

[0396] 0.08 mg / mL to 0.23 mg / mL, such as 0.15 mg / mL poloxamer 188 or polysorbate 20,

[0397] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0398] In a further embodiment, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:

[0399] 7 mg / mL to 8 mg / mL, for example 7.5 mg / mL of anti-IL-31RA neutralizing antibody;

[0400] 5mmol / L to 7mmol / L, for example 6mmol / L Tris-HCl;

[0401] 36mmol / L to 54mmol / L, for example 45mmol / L Arg-HCl;

[0402] 68 mmol / L to 83 mmol / L, for example 75 mmol / L sucrose or trehalose; and

[0403] 0.08 mg / mL to 0.23 mg / mL, such as 0.15 mg / mL poloxamer 188 or polysorbate 20,

[0404] Wherein, when the formulation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.

[0405] The amount of each component contained in the lyophilized preparation of the present disclosure can also be expressed as the weight (mass) of each container such as a vial, a cartridge and a syringe. The container can contain a single dose or a multi-dose (e.g., two doses, three doses, four doses, etc.) preparation. For example, the container contains a single dose preparation. Multiple containers can also be used for a single dose. The dosage of each application can be appropriately determined according to the method of application (e.g., subcutaneous administration), target disease (e.g., atopic dermatitis), purpose of use (e.g., for prevention or treatment), patient type (e.g., adult or child), patient's situation (e.g., severity of itching), etc. Accordingly, the amount of a solvent such as water to be added to the container for reconstructing the lyophilized preparation can be appropriately determined. When the formulation is administered subcutaneously, the liquid volume of a single dose (in the case of a lyophilized formulation, the liquid volume to be administered after reconstitution with water) can be, for example, 0.1 mL to 10 mL, 0.2 mL to 5 mL, 0.2 mL to 1.6 mL, 0.5 mL to 2 mL, 0.8 mL to 1.2 mL or 0.9 mL to 1.1 mL, for example 1.0 mL, but not limited thereto. It should be noted that those skilled in the art will appreciate that the container may be filled with the formulation to ensure that a sufficient amount of IL-31 antagonist for administration of a single dose or multiple doses can be obtained from one container (e.g., a vial, cartridge, or syringe) taking into account the loss of the drug solution during administration.

[0406] In one embodiment, the lyophilized formulation of the present disclosure comprises, per container, e.g., syringe:

[0407] 68 mg to 83 mg, for example 75 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0408] 1.4 mg to 2.2 mg, for example 1.8 mg tris(hydroxymethyl)aminomethane;

[0409] 15mg to 23mg, for example 19mg arginine;

[0410] 58 mg to 70 mg, e.g. 64 mg sucrose; and

[0411] 0.2 mg to 0.6 mg, for example 0.4 mg poloxamer 188.

[0412] In the above embodiments, with respect to the description of numerical values, the numerical value intended to be the smallest digit (e.g., the unit digit) includes a rounded value that is one digit smaller than the smallest digit (e.g., when the smallest digit is the unit digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be referred to as comprising per container, such as a syringe:

[0413] 75 mg (74.5 mg to 75.4 mg) anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0414] 1.8 mg (1.75 mg to 1.84 mg) tris(hydroxymethyl)aminomethane;

[0415] 19 mg (18.5 mg to 19.4 mg) arginine;

[0416] 64 mg (63.5 mg to 64.4 mg) sucrose; and

[0417] 0.4 mg (0.35 mg to 0.44 mg) poloxamer 188.

[0418] In addition, in the above embodiment, the weight of the above tris(hydroxymethyl)aminomethane can be the sum of the weight of free tris(hydroxymethyl)aminomethane and the weight of tris(hydroxymethyl)aminomethane contained in tris(hydroxymethyl)aminomethane hydrochloride (which can be added as a pH adjuster). In addition, the above arginine can be added as a salt containing arginine (e.g., arginine hydrochloride). Those skilled in the art will understand that when adding a salt containing arginine, the weight of the above arginine is the weight of arginine contained in the salt.

[0419] Therefore, the lyophilized formulation of the present disclosure may also be referred to as comprising per container, such as a syringe:

[0420] 75 mg of anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0421] 0.24 mg tris(hydroxymethyl)aminomethane;

[0422] 23.6mg L-arginine hydrochloride;

[0423] 63.9mg sucrose;

[0424] 0.37 mg poloxamer 188; and

[0425] Tris(hydroxymethyl)aminomethane hydrochloride was used as a pH adjuster.

[0426] In another embodiment, the lyophilized formulation of the present disclosure comprises, per container, e.g., syringe:

[0427] 35 mg to 43 mg, for example 39 mg, of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0428] 0.7 mg to 1.1 mg, for example 0.9 mg tris(hydroxymethyl)aminomethane;

[0429] 8 mg to 12 mg, for example 10 mg arginine;

[0430] 30 mg to 36 mg, e.g. 33 mg sucrose; and

[0431] 0.1 mg to 0.3 mg, for example 0.2 mg poloxamer 188.

[0432] In the above embodiments, with respect to the description of numerical values, the numerical value intended to be the smallest digit (e.g., the unit digit) includes a rounded value that is one digit smaller than the smallest digit (e.g., when the smallest digit is the unit digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be referred to as comprising per container, such as a syringe:

[0433] 39 mg (38.5 mg to 39.4 mg) anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0434] 0.9 mg (0.85 mg to 0.94 mg) tris(hydroxymethyl)aminomethane;

[0435] 10 mg (9.5 mg to 10.4 mg) arginine;

[0436] 33 mg (32.5 mg to 33.4 mg) sucrose; and

[0437] 0.2 mg (0.15 mg to 0.24 mg) poloxamer 188.

[0438] In a further embodiment, the lyophilized formulation of the present disclosure comprises, per container, e.g., cartridge:

[0439] 32 mg to 40 mg, for example 36 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0440] 0.7 mg to 1.1 mg, for example 0.9 mg tris(hydroxymethyl)aminomethane;

[0441] 7mg to 11mg, for example 9mg arginine;

[0442] 28 mg to 34 mg, e.g. 31 mg sucrose; and

[0443] 0.1 mg to 0.3 mg, for example 0.2 mg poloxamer 188.

[0444] In the above embodiments, with respect to the description of numerical values, the numerical value intended to be the smallest digit (e.g., the unit digit) includes a rounded value that is one digit smaller than the smallest digit (e.g., when the smallest digit is the unit digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be referred to as comprising per container, such as a cartridge:

[0445] 36 mg (35.5 mg to 36.4 mg) anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0446] 0.9 mg (0.85 mg to 0.94 mg) tris(hydroxymethyl)aminomethane;

[0447] 9 mg (8.5 mg to 9.4 mg) arginine;

[0448] 31 mg (30.5 mg to 31.4 mg) sucrose; and

[0449] 0.2 mg (0.15 mg to 0.24 mg) poloxamer 188.

[0450] In yet another embodiment, the lyophilized formulation of the present disclosure comprises, per container, e.g., vial:

[0451] 46 mg to 56 mg, for example 51 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0452] 2.0 mg to 3.0 mg, for example 2.5 mg tris(hydroxymethyl)aminomethane;

[0453] 22 mg to 32 mg, for example 27 mg arginine;

[0454] 79 mg to 97 mg, e.g. 88 mg sucrose; and

[0455] 0.3 mg to 0.8 mg, for example 0.5 mg poloxamer 188.

[0456] In the above embodiments, with respect to the description of numerical values, it is intended that the numerical value of the smallest digit (e.g., the unit digit) includes a rounded value that is one digit smaller than the smallest digit (e.g., when the smallest digit is the unit digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be referred to as comprising per container, such as a vial:

[0457] 51 mg (50.5 mg to 51.4 mg) anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0458] 2.5 mg (2.45 mg to 2.54 mg) tris(hydroxymethyl)aminomethane;

[0459] 27 mg (26.5 mg to 27.4 mg) arginine;

[0460] 88 mg (87.5 mg to 88.4 mg) sucrose; and

[0461] 0.5 mg (0.45 mg to 0.54 mg) poloxamer 188.

[0462] Furthermore, in another embodiment, the lyophilized formulation of the present disclosure comprises, per container, e.g., vial:

[0463] 27 mg to 33 mg, for example 30 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0464] 2.4 mg to 3.6 mg, for example 3.0 mg tris(hydroxymethyl)aminomethane;

[0465] 26 mg to 38 mg, for example 32 mg arginine;

[0466] 94 mg to 114 mg, e.g. 104 mg sucrose; and

[0467] 0.3 mg to 0.9 mg, for example 0.6 mg poloxamer 188.

[0468] In the above embodiments, with respect to the description of numerical values, it is intended that the numerical value of the smallest digit (e.g., the unit digit) includes a rounded value that is one digit smaller than the smallest digit (e.g., when the smallest digit is the unit digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be referred to as comprising per container, such as a vial:

[0469] 30 mg (29.5 mg to 30.4 mg) anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0470] 3.0 mg (2.95 mg to 3.04 mg) tris(hydroxymethyl)aminomethane;

[0471] 32 mg (31.5 mg to 32.4 mg) arginine;

[0472] 104 mg (103.5 mg to 104.4 mg) sucrose; and

[0473] 0.6 mg (0.55 mg to 0.64 mg) poloxamer 188.

[0474] In yet another embodiment, the lyophilized formulation of the present disclosure comprises, per container, e.g., vial:

[0475] 17 mg to 21 mg, for example 19 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0476] 1.5 mg to 2.3 mg, for example 1.9 mg tris(hydroxymethyl)aminomethane;

[0477] 16 mg to 24 mg, for example 20 mg arginine;

[0478] 59 mg to 73 mg, e.g. 66 mg sucrose; and

[0479] 0.2 mg to 0.6 mg, for example 0.4 mg poloxamer 188.

[0480] In the above embodiments, with respect to the description of numerical values, it is intended that the numerical value of the smallest digit (e.g., the unit digit) includes a rounded value that is one digit smaller than the smallest digit (e.g., when the smallest digit is the unit digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be referred to as comprising per container, such as a vial:

[0481] 19 mg (18.5 mg to 19.4 mg) anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0482] 1.9 mg (1.85 mg to 1.94 mg) tris(hydroxymethyl)aminomethane;

[0483] 20 mg (19.5 mg to 20.4 mg) arginine;

[0484] 66 mg (65.5 mg to 66.4 mg) sucrose; and

[0485] 0.4 mg (0.35 mg to 0.44 mg) poloxamer 188.

[0486] In a further embodiment, the lyophilized formulation of the present disclosure comprises, per container, e.g., vial:

[0487] 13 mg to 15 mg, for example 14 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0488] 1.0 mg to 1.6 mg, for example 1.3 mg tris(hydroxymethyl)aminomethane;

[0489] 12 mg to 18 mg, for example 15 mg arginine;

[0490] 42 mg to 52 mg, e.g. 47 mg sucrose; and

[0491] 0.2 mg to 0.5 mg, for example 0.3 mg poloxamer 188.

[0492] In the above embodiments, with respect to the description of numerical values, it is intended that the numerical value of the smallest digit (e.g., the unit digit) includes a rounded value that is one digit smaller than the smallest digit (e.g., when the smallest digit is the unit digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be referred to as comprising per container, such as a vial:

[0493] 14 mg (13.5 mg to 14.4 mg) anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0494] 1.3 mg (1.25 mg to 1.34 mg) tris(hydroxymethyl)aminomethane;

[0495] 15 mg (14.5 mg to 15.4 mg) arginine;

[0496] 47 mg (46.5 mg to 47.4 mg) sucrose; and

[0497] 0.3 mg (0.25 mg to 0.34 mg) poloxamer 188.

[0498] In one embodiment, with respect to the lyophilized formulations of the present disclosure, when the formulation is reconstituted in water, the reconstituted solution comprises:

[0499] 90 mg / mL 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 of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0500] 16mmol / L to 24mmol / L, for example 20mmol / L Tris-HCl;

[0501] 120mmol / L to 180mmol / L, for example 150mmol / L Arg-HCl;

[0502] 225 mmol / L to 275 mmol / L, for example 250 mmol / L sucrose or trehalose; and

[0503] 0.25 mg / mL to 0.75 mg / mL, such as 0.50 mg / mL poloxamer 188 or polysorbate 20,

[0504] Wherein, the pH is 6 to 8, such as 6.7 to 7.3, such as 7.

[0505] In another embodiment, with respect to the lyophilized formulation of the present disclosure, when the formulation is reconstituted in water, the reconstituted solution comprises:

[0506] 55 mg / mL 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 of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0507] 10 mmol / L to 15 mmol / L, for example 12.3 mmol / L Tris-HCl;

[0508] 74mmol / L to 110mmol / L, for example 92mmol / L Arg-HCl;

[0509] 139 mmol / L to 169 mmol / L, for example 154 mmol / L sucrose or trehalose; and

[0510] 0.16 mg / mL to 0.47 mg / mL, such as 0.31 mg / mL poloxamer 188 or polysorbate 20,

[0511] Wherein, the pH is 6 to 8, such as 6.7 to 7.3, such as 7.

[0512] Furthermore, in another embodiment, with respect to the lyophilized formulation of the present disclosure, when the formulation is reconstituted in water, the reconstituted solution comprises:

[0513] 45 mg / mL 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 of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0514] 16mmol / L to 24mmol / L, for example 20mmol / L Tris-HCl;

[0515] 120mmol / L to 180mmol / L, for example 150mmol / L Arg-HCl;

[0516] 225 mmol / L to 275 mmol / L, for example 250 mmol / L sucrose or trehalose; and

[0517] 0.25 mg / mL to 0.75 mg / mL, such as 0.50 mg / mL poloxamer 188 or polysorbate 20,

[0518] Wherein, the pH is 6 to 8, such as 6.7 to 7.3, such as 7.

[0519] In yet another embodiment, with respect to the lyophilized formulation of the present disclosure, when the formulation is reconstituted in water, the reconstituted solution comprises:

[0520] 23 mg / mL 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 of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);

[0521] 16mmol / L to 24mmol / L, for example 20mmol / L Tris-HCl;

[0522] 120mmol / L to 180mmol / L, for example 150mmol / L Arg-HCl;

[0523] 225 mmol / L to 275 mmol / L, for example 250 mmol / L sucrose or trehalose; and

[0524] 0.25 mg / mL to 0.75 mg / mL, such as 0.50 mg / mL poloxamer 188 or polysorbate 20,

[0525] Wherein, the pH is 6 to 8, such as 6.7 to 7.3, such as 7.

[0526] Exemplary embodiments of the formulations disclosed herein include, but are not limited to, the following formulations:

[0527]

[0528]

[0529]

[0530] In non-limiting embodiments, the formulations disclosed herein can be used to prevent and / or treat IL-31-related disorders or their associated symptoms. In one embodiment, IL-31-related disorders are inflammatory disorders associated with IL-31 signaling. In a specific embodiment, IL-31-related disorders are atopic dermatitis, pruritus (e.g., dialysis pruritus or pruritus caused by atopic dermatitis) or nodular prurigo. In another specific embodiment, the treatment of IL-31-related disorders or their associated symptoms is to improve sleep disorders caused by pruritus (e.g., increase the time from falling asleep to waking up and / or reduce the latency to fall asleep (the time from going to bed to falling asleep)). In another embodiment, the treatment of IL-31-related disorders or their associated symptoms is to suppress at least one symptom caused by atopic dermatitis selected from the group consisting of redness, nodules, papules, edema, exfoliation and lichenification. In certain embodiments, the atopic dermatitis is moderate or severe atopic dermatitis for which topical treatment (e.g., treatment with a topical steroid or a topical calcineurin inhibitor) is insufficiently effective or is not tolerated. In one embodiment, the formulation of the present disclosure is a formulation for parenteral administration, e.g., for intravenous administration or for subcutaneous administration.

[0531] In a non-limiting embodiment, the present disclosure relates to a method for stabilizing an antibody in an antibody-containing formulation, the method 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: 1 to 1100: 1, and the molar ratio of sucrose or trehalose to the antibody is 370: 1 to 1840: 1. In another non-limiting embodiment, the present disclosure relates to a method for inhibiting aggregation (aggregate formation) of an antibody in an antibody-containing formulation, the method comprising preparing an antibody-containing lyophilized formulation by freeze-drying an antibody-containing solution, the antibody-containing solution comprising 45 mmol / L to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 mmol / L to 250 mmol / L sucrose or trehalose. In a further non-limiting embodiment, the present disclosure relates to a method for reducing components with charge heterogeneity in an antibody-containing lyophilized formulation, the method comprising preparing an antibody-containing lyophilized formulation by freeze drying an antibody-containing solution, the antibody-containing solution comprising 45 mmol / L to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 mmol / L to 250 mmol / L sucrose or trehalose. In one embodiment, the antibody-containing solution before lyophilization further comprises 6 mmol / L to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride and 0.15 mg / mL to 0.50 mg / mL poloxamer 188.

[0532] In a non-limiting embodiment, the present disclosure relates to a method for preventing and / or treating an IL-31-related disorder, comprising administering an IL-31 antagonist to a subject having an IL-31-related disorder or at risk of developing an IL-31-related disorder, the method comprising preparing a lyophilized formulation by freeze-drying a solution comprising 6 mg / mL to 100 mg / mL of an IL-31 antagonist, 45 mmol / L to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 mmol / L to 250 mmol / L of sucrose or trehalose; preparing a reconstituted solution by reconstituted the lyophilized formulation; and administering the reconstituted solution to the subject.

[0533] In a non-limiting embodiment, the present disclosure relates to the use of an IL-31 antagonist in the preparation of a medicament for preventing and / or treating an IL-31-related disorder, characterized in that the lyophilized preparation is prepared by freeze-drying a solution comprising 6 mg / mL to 100 mg / mL IL-31 antagonist, 45 mmol / L to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 mmol / L to 250 mmol / L sucrose or trehalose.

[0534] In a non-limiting embodiment, the present disclosure relates to an IL-31 antagonist for preventing and / or treating an IL-31-related disorder, characterized in that a lyophilized preparation produced by lyophilizing a solution comprising 6 mg / mL to 100 mg / mL of an IL-31 antagonist, 45 mmol / L to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 mmol / L to 250 mmol / L of sucrose or trehalose is reconstituted and used.

[0535] In one embodiment, the solution before lyophilization may further comprise 6 mmol / L to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride and 0.15 mg / mL to 0.50 mg / mL poloxamer 188.

[0536] In non-limiting embodiments, the present disclosure relates to an injection preparation or a test kit, which comprises (i) a container; (ii) a lyophilized preparation of the present disclosure; and (iii) optionally water for injection, for reconstructing the lyophilized preparation. In one embodiment, the container of the injection preparation of the present disclosure or the test kit is a glass syringe, a glass cartridge or a glass vial. In a specific embodiment, the container of the injection preparation of the present disclosure or the test kit is a double chamber syringe (DCS) or a double chamber cartridge (DCC), and the lyophilized preparation and the water for injection are packaged in a separate compartment in the container, that is, the lyophilized preparation of the present disclosure is filled into any one of the two chambers, and the water for injection is filled into the other chamber. Preferably, the water for injection is water, and optionally meets the standard of "water for injection" specified in the Japanese Pharmacopoeia.

[0537] IL-31 (interleukin-31) is a T cell cytokine that is known to be associated with itch, and in transgenic mice overexpressing IL-31, dermatitis-like symptoms similar to atopic dermatitis develop and persistent scratching behavior is observed.

[0538] The nucleic acid sequence and amino acid sequence of human IL-31 are also referred to as RefSeq Accession No. NM_001014336 and RefSeq Accession No. NP_001014358, respectively.

[0539] The IL-31 receptor is formed by a heterodimer of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR) (Nat Immunol (2004) 5, 752-60). IL-31RA, also known as NR10, is known to have multiple splice variants (WO 00 / 075314). Known splice variants are NR10.1 (652 amino acids), NR10.2 (252 amino acids), NR10.3 (662 amino acids, also known as IL-31RAv4), IL31RAv3 (764 amino acids), etc., and preferred examples of IL-31RA include NR10.3 (IL-31RAv4) and IL-31RAv3. The nucleic acid sequence and amino acid sequence 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 sequence and amino acid sequence 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 sequence and amino acid sequence of human OSMR are also known as RefSeq Accession No. NM_003999 and RefSeq Accession No. NP_003990, respectively.

[0540] The IL-31 antagonist of the present disclosure, in one embodiment, refers to a compound that inhibits or blocks intracellular signal transduction induced by IL-31. The compound can also be expressed as a compound that inhibits IL-31 signal transduction. This compound can be a naturally occurring compound or an artificially synthesized compound. In addition, such a compound can be a low molecular weight compound or a high molecular weight compound such as a protein.

[0541] It is known that IL-31 present outside the cell triggers intracellular signal transduction through the IL-31 receptor (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 includes the IL-31 binding domain, and IL-31 binds to it to cause conformational changes in the IL-31 receptor. Therefore, intracellular signal transduction starts from the intracellular domain of the IL-31 receptor.

[0542] In one method, it is possible to verify whether a certain compound inhibits IL-31 signaling by examining whether the compound inhibits the binding of IL-31 to the IL-31 receptor. Examples of methods for making such determinations include assays using ELISA or flow cytometry and assays using surface plasmon resonance. Taking ELISA as an example, a system for detecting the amount of IL-31 protein bound thereto by using a secondary antibody such as an enzyme-labeled anti-IL-31 antibody can be prepared by fixing the IL-31 receptor (or IL-31RA) protein on a plate, and determining whether the addition of the compound reduces the amount of IL-31 protein detected to assess whether the compound inhibits the binding of IL-31 to the IL-31 receptor.

[0543] In an alternative method, it is possible to verify whether the compound inhibits IL-31 signal transduction by checking whether the biological activity induced by the effect of IL-31 on cells is inhibited by a certain compound. Biological activity is not particularly limited, as long as any method can be used to determine quantitatively or qualitatively, and examples of such biological activity include cell proliferation activity, protein phosphorylation activity, and gene / protein expression induction activity. For example, whether the compound inhibits IL-31 signal transduction can be evaluated by preparing cells that express IL-31 receptors on the surface and whose proliferation activity is induced in response to external IL-31 stimulation, and determining whether the addition of the compound reduces the cell proliferation activity induced by IL-31. As such cells, naturally occurring cells that inherently express IL-31 receptors can be used, or recombinant cells that are artificially synthesized to express IL-31 receptors can be used. Suitable examples of recombinant cells include Ba / F3 cells expressing IL-31 receptors. As a further alternative, the method described in the document of Dillon et al. (Nat Immunol (2004) 5, 752-760) can be used.

[0544] In the present invention, the degree of inhibition of IL-31 signaling by an IL-31 antagonist may be, but is not limited to, 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, 95% or more, and 98% or more.

[0545] In the present disclosure, preferred embodiments of compounds that inhibit IL-31 signaling include proteins that inhibit IL-31 signaling. The protein used herein is not particularly limited as long as it has the property of specifically binding to IL-31 or IL-31 receptors. Examples of preferred proteins include antibodies and antibody-like molecules (Curr Opin Biotechnol (2006) 17, 653-658; Curt Opin Struct Biol (1997) 7, 463-469; and Protein Sci (2006) 15, 14-27). Antibodies include any antibodies, such as monoclonal antibodies (e.g., IgG, IgM, IgE, IgA and IgD), polyclonal antibodies, engineered antibodies (e.g., chimeric antibodies, humanized antibodies and glycoengineered antibodies (WO 99 / 54342 and WO 00 / 61739)), antibody fragments (e.g., Fab, F(ab')2, Fv and CDR), multispecific antibodies (e.g., bispecific antibodies) and conjugated antibodies (e.g., antibodies conjugated to polyethylene glycol (PEG), radioisotopes or drugs). On the other hand, examples of antibody-like molecules include DARPin (WO 2002 / 020565), Affibody (WO 1995 / 001937), Avimer (WO2004 / 044011) and Adnectin (WO2002 / 032925). More preferred are antibodies that inhibit IL-31 signaling. Examples of other preferred proteins that inhibit IL-31 signaling include proteins containing the extracellular domain of IL-31RA and proteins containing each extracellular domain of the IL-31 receptor (heterodimer of IL-31RA and OSMR).

[0546] In the present disclosure, preferred embodiments of antibodies that inhibit IL-31 signaling include antibodies that inhibit IL-31 signaling by binding to IL-31 (anti-IL-31 neutralizing antibodies) and antibodies that inhibit IL-31 signaling by binding to IL-31 receptors (anti-IL-31 receptor neutralizing antibodies). Anti-IL-31 receptor neutralizing antibodies include antibodies that inhibit IL-31 signaling by binding to IL-31RA (anti-IL-31RA neutralizing antibodies), antibodies that inhibit IL-31 signaling by binding to OSMR (anti-OSMR neutralizing antibodies), and antibodies that inhibit IL-31 signaling by binding to heterodimers of IL-31RA and OSMR (anti-IL-31RA / OSMR heterodimer neutralizing antibodies). Among these anti-IL-31 receptor neutralizing antibodies, anti-IL-31RA neutralizing antibodies or anti-IL-31RA / OSMR heterodimer neutralizing antibodies are preferred, and anti-IL-31RA neutralizing antibodies are more preferred.

[0547] The antibodies used in the present invention are not particularly limited as long as they bind to the desired antigen to inhibit IL-31 signal transduction, and they may be polyclonal antibodies or monoclonal antibodies. Monoclonal antibodies are preferred because they can stably produce homogeneous antibodies.

[0548] The amino acids contained in the amino acid sequences of the present invention may be post-translationally modified (for example, modification of N-terminal glutamine to pyroglutamic acid by pyroglutamylation is well known to those skilled in the art). Naturally, such post-translationally modified amino acids are included in the antibodies used in the present invention.

[0549] In a further embodiment or another embodiment, the antibody that inhibits IL-31 signaling of the present disclosure preferably comprises an amino acid variant of the H chain constant region sequence of IgG2, wherein the amino acid variant comprises glutamic acid at position 419 (EU numbering) in the H chain constant region sequence of wild-type IgG2 (SEQ ID NO: 12). Compared with a reference antibody comprising an H chain constant region sequence of wild-type IgG2 having the same amino acid sequence except for the amino acid change at position 419, the advantage of the engineered antibody is that it exhibits an increased plasma half-life. It is believed that this increased plasma half-life is caused by a decrease in the isoelectric point (pI) induced by replacing the amino acid with glutamic acid at position 419 (Example 2 of WO 2016 / 167263).

[0550] Therefore, in one embodiment, the lyophilized formulation and solution formulation of the present disclosure are advantageous because it relates to a lyophilized formulation and solution formulation for providing an increased plasma half-life relative to a (reference) lyophilized formulation and solution formulation comprising a reference antibody, wherein the reference antibody comprises an H chain constant region sequence of a wild-type IgG2 having the same amino acid sequence except for the amino acid change at position 419.

[0551] In this case, in a preferred embodiment, the antibody that inhibits IL-31 signaling of the present disclosure is any one of the following anti-IL-31RA neutralizing antibodies:

[0552] (1) an anti-IL-31RA antibody comprising an H chain variable region and an L chain variable region, wherein the H chain variable region comprises CDR1 shown in SEQ ID NO: 1, CDR2 shown in SEQ ID NO: 2, and CDR3 shown in SEQ ID NO: 3, and the L chain variable region comprises CDR1 shown in SEQ ID NO: 4, CDR2 shown in SEQ ID NO: 5, and CDR3 shown in SEQ ID NO: 6;

[0553] (2) an anti-IL-31RA antibody comprising the H chain variable region shown in SEQ ID NO: 7 and the L chain variable region shown in SEQ ID NO: 8; and

[0554] (3) An anti-IL-31RA antibody comprising the H chain represented by SEQ ID NO: 9 and the L chain represented by SEQ ID NO: 10.

[0555] It should be understood that the isoelectric point (pI), also referred to as "pI" for short, can be a theoretical isoelectric point or an experimentally measured isoelectric point, and is not explicitly described in this specification unless contradicted by the context.

[0556] For example, the value of the isoelectric point can be measured by isoelectric focusing known to those skilled in the art. The value of the theoretical isoelectric point can be calculated using gene and amino acid sequence analysis software (e.g., Genetyx). Alternatively, the value of the theoretical isoelectric point can be measured by using, for example, the plasma of mice, rats, rabbits, dogs, monkeys, people, etc. and in conjunction with methods known to those skilled in the art such as BIACORE, cell proliferation assays, ELISA, EIA (enzyme immunoassay), RIA (radioimmunoassay) or immunofluorescence to carry out pharmacokinetic studies of antibodies.

[0557] Whether the plasma half-life of an antibody changes before and after amino acid mutation (modification) can be verified by using methods known to those skilled in the art, for example, by conducting pharmacokinetic studies of the antibody using the plasma of mice, rats, rabbits, dogs, monkeys, humans, etc.

[0558] The antibody that inhibits IL-31 signaling of the present disclosure, in yet another embodiment or another embodiment, preferably does not (substantially) exhibit cross-reactivity with IL-31RA from any of mouse, rat and rabbit, although it has cross-reactivity with IL-31RA from human and cynomolgus monkey.

[0559] Methods for preparing antibodies are well known to those skilled in the art, for example, antibodies can be prepared using 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). Using IL-31 protein or IL-31 receptor protein as an immunogen, a large amount of anti-IL-31 antibodies or anti-IL-31 receptor antibodies can be obtained by these methods. In addition, screening these antibodies using any of the above methods for detecting compounds that inhibit IL-31 signaling allows the acquisition of anti-IL-31 neutralizing antibodies or anti-IL-31 receptor neutralizing antibodies. Proteins such as IL-31 or IL-31 receptor can also be prepared using genetic engineering techniques known to those skilled in the art. Specifically, such a protein can be prepared by inserting a gene encoding a target protein into an expression vector, introducing the vector into an appropriate host cell, and then purifying the target protein expressed in the host cell or the culture supernatant of the host cell.

[0560] Examples of preferred anti-IL-31 neutralizing antibodies include anti-IL-31 antibodies described in WO 2006 / 122079, WO 2008 / 028192, and WO 2009 / 071696.

[0561] Examples of preferred anti-IL-31RA neutralizing antibodies include, but are not limited to, anti-IL-31RA(NR10) antibodies described in WO 2007 / 142325, anti-IL-31RA(NR10) antibodies described in WO 2009 / 072604, and anti-IL-31RA(NR10) antibodies described in WO 2010 / 064697.

[0562] In addition, other preferred examples of anti-IL-31RA neutralizing antibodies include anti-human IL-31RA (neutralizing) antibodies, specifically anti-IL-31RA (neutralizing) antibodies that recognize human IL-31RA domain 1 and / or domain 2. As used herein, domain 1 of human IL-31RA refers to the region from amino acid 53 to amino acid 152 (LPAKP to LENIA) in the amino acid sequence shown in SEQ ID NO: 11. Domain 2 refers to the region from amino acid 153 to amino acid 259 (KTEPP to EEEAP) in the amino acid sequence shown in SEQ ID NO: 11.

[0563] Without any limitation, among the anti-IL-31RA neutralizing antibodies, more preferred are the anti-IL-31RA antibodies described in WO 2010 / 064697, which comprise an H chain (heavy chain) variable region comprising CDR1 as shown in SEQ ID NO: 1, CDR2 as shown in SEQ ID NO: 2, and CDR3 as shown in SEQ ID NO: 3, and an L chain variable region comprising CDR1 as shown in SEQ ID NO: 4, CDR2 as shown in SEQ ID NO: 5, and CDR3 as shown in SEQ ID NO: 6. Still more preferred are anti-IL-31RA antibodies comprising an H chain variable region as shown in SEQ ID NO: 7 and an L chain (light chain) variable region as shown in SEQ ID NO: 8. Particularly preferred is Nemolizumab (CIM331), which is an anti-IL-31RA antibody comprising an H chain as shown in SEQ ID NO: 9 and an L chain as shown in SEQ ID NO: 10.

[0564] Known methods for defining CDRs include the method according to Kabat et al. (Sequences of Proteins of Immunological Interest, 5th edition (1991), Bethesda, MD), the method according to Chothia et al. (Science (1986) 233, 755-758), and the method based on antigen-antibody contact regions (J Mol Biol (1996) 262, 732-745). Specifically, each method defines CDR as follows:

[0565]

[0566]

[0567] Examples of preferred anti-IL-31RA neutralizing antibodies of the present disclosure include anti-IL-31RA antibodies comprising CDR1, CDR2 and CDR3 contained in the H chain variable region shown in SEQ ID NO: 7, and CDR1, CDR2 and CDR3 contained in the L chain variable region shown in SEQ ID NO: 8, as H chain CDR1, CDR2 and CDR3 and L chain CDR1, CDR2 and CDR3, respectively. The CDRs in such antibodies can be defined according to any one of the method of Kabat et al., the method of Chothia et al., and the method based on antigen-antibody contact regions, or according to a combination of these methods.

[0568] Similarly, as anti-IL-31RA neutralizing antibodies, anti-IL-31RA antibodies that bind to the same epitope as the anti-IL-31RA antibodies defined by the CDR sequences of the H and L chains, the variable region sequences of the H and L chains, and the full-length H and L chain sequences are preferred. An epitope refers to a specific structural unit of an antigen that an antibody recognizes and binds to. When the antigen is a polypeptide, the epitope is generally composed of about 6 to 10 amino acids. Epitope identification can be performed using methods known to those skilled in the art, such as methods for synthesizing peptides by antigen fragmentation, methods for introducing site-directed mutagenesis into an antigen (e.g., arginine / glutamic acid scanning, J Biol Chem (1995) 270, 21619-21625; J Biol Chem (2006) 281, 20464-20473), and methods for crystallizing an antigen-antibody complex (Using Antibodies: A Laboratory Manual (1999), Cold Spring Harbor Laboratory Press, New York). In the present disclosure, the statement "binding to the same epitope" means that the epitopes bound by two antibodies at least partially overlap with each other. The degree of overlap is but not limited to 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%.

[0569] Similarly, as the anti-IL-31RA neutralizing antibody, an anti-IL-31RA antibody that competes for binding to IL-31RA with the anti-IL-31RA antibody defined by the above-mentioned H chain and L chain CDR sequences, H chain and L chain variable region sequences, and full-length H chain and L chain sequences is preferred. For example, whether the two antibodies compete with each other can be evaluated by using a competitive binding assay using ELISA. The specific method is as follows: One of the two antibodies is previously labeled with, for example, fluorescence. A system for detecting the binding of an antibody (labeled antibody) to an antigen is prepared. The case where the other unlabeled antibody (test antibody) coexists is compared with the case where the test antibody does not coexist in the system. If the binding level of the labeled antibody to the antigen is reduced in the presence of the test antibody, it can be judged that the test antibody and the labeled antibody compete with each other. In the present disclosure, the degree of competition is but is not particularly limited to 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, 95% or more, 98% or more (i.e., the binding level of other antibodies is reduced).

[0570] Atopic dermatitis in the present disclosure may preferably be atopic dermatitis caused by IL-31 signaling or induced by IL-31, or atopic dermatitis showing responsiveness to prevention and / or treatment with an IL-31 antagonist, but is not limited thereto.

[0571] The itch in the present disclosure may be itch caused by atopic dermatitis, preferably itch caused by atopic dermatitis caused by IL-31 signaling or induced by IL-31, but is not limited thereto. In addition, the itch may be itch caused by atopic dermatitis that is responsive to the prevention and / or treatment of an IL-31 antagonist.

[0572] For example, atopic dermatitis may be moderate to severe atopic dermatitis, and may preferably be moderate or severe atopic dermatitis for which topical treatment is insufficiently effective or intolerable, or standard topical treatment is insufficiently effective or intolerable, or standard topical treatment is prohibited (for reasons such as contraindications). More preferably, atopic dermatitis may be moderate or severe atopic dermatitis for which topical treatment is insufficiently effective or intolerable.

[0573] For topical treatment, for example, topical steroids (eg, glucocorticoids or derivatives thereof, such as prednisolone and hydrocortisone) and topical calcineurin inhibitors known as immunosuppressants (eg, tacrolimus and pimecrolimus) are known.

[0574] In addition to topical steroids and topical calcineurin inhibitors, for example, cyclosporine, methotrexate (MTX) or azathioprine (AZA) or antihistamines (various drugs are called antihistamines and are roughly divided into first-generation antihistamines and second-generation antihistamines) are known as therapeutic agents for atopic dermatitis.

[0575] More specifically, without any limitation, the following treatment methods are known for treating atopic dermatitis ("Therapeutic Guidelines for Atopic Dermatitis", Furue et al., the Japanese journal of dermatology: 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); and Saeki H et al., J Dermatol 2009, 36, pp. 563-77).

[0576] (1) Cyclosporine preparation (trade name: Neoral)

[0577] Generally, cyclosporine preparations are orally administered to adults at a dose of 3 mg / kg per day, calculated as cyclosporine, taken twice a day. The dose should not exceed 5 mg / kg per day, but will vary as appropriate depending on the symptoms.

[0578] (2) Oral administration of steroid preparations (trade name: prednisolone tablets)

[0579] Generally, steroid preparations are orally administered to adults at a dose of 5 to 60 mg per day, calculated as prednisolone (1 to 12 tablets in the case of tablets; 0.5 g to 6 g in the case of powder), taken once to four times. The dose will vary as appropriate depending on age or symptoms.

[0580] (3) Ultraviolet light therapy

[0581] While there are no set manuals or guidelines, it is generally said that patients need to visit the hospital once or twice a week.

[0582] (4) Antihistamine preparations (trade name: Allegra)

[0583] Typically, the antihistamine preparation is orally administered to adults in a single dose of 60 mg (calculated as fexofenadine hydrochloride), twice a day. Typically, the antihistamine preparation is orally administered to children aged 7 years or older and less than 12 years old in a single dose of 30 mg (calculated as fexofenadine hydrochloride), twice a day, and is orally administered to children aged 12 years or older in a single dose of 60 mg, calculated as fexofenadine hydrochloride, twice a day. The dosage will vary as appropriate depending on the symptoms.

[0584] (5) Topical steroid preparations (trade name: Fulmeta)

[0585] Typically, an appropriate amount of topical steroid preparation is applied to the affected area once to several times a day. The dosage will vary depending on the symptoms.

[0586] (6) Topical steroid preparations (trade name: Locoid)

[0587] Typically, an appropriate amount of topical steroid preparation is applied once to several times a day. The dosage will vary depending on the symptoms.

[0588] (7) Tacrolimus preparation (trade name: Protopic)

[0589] Generally, for adults, an appropriate amount of tacrolimus preparation is applied to the affected area once or twice a day. The amount used for each application should be up to 5 grams.

[0590] (8) Pimecrolimus preparation (trade name: Elidel)

[0591] Typically, an appropriate dose of pimecrolimus preparation is applied twice daily. The dosage will vary depending on the symptoms.

[0592] The severity of atopic dermatitis (e.g., mild, moderate, or severe) can be classified based on classification methods known to those skilled in the art for scoring the degree of rash or itching felt by a subject, such as Shiratori's severity criteria, the visual analog scale (VAS) described below, the Itch Verbal Rating Scale (VRS), the Scoring System for Atopic Dermatitis (SCORAD) established by the European Atopic Dermatitis Working Group, the Eczema Area and Severity Index (EASI) established in the United States, or, for example, the Static Investigator's Global Assessment (sIGA).

[0593] For example, the VAS consists of a straight line of 100 mm on which the subject (patient) indicates the intensity of the itch at the time of measurement by drawing a line between 0 and 100 mm, where 0 mm means no itch and 100 mm represents the worst itch imaginable. For example, a subject determined to have a VAS score of 40 mm or more may be identified as having moderate to severe atopic dermatitis, and in one embodiment, the VAS score may be 45 mm or more, or 50 mm or more. Similarly, in the case of VRS, for example, a subject classified as a "moderate itch" level or higher may be considered to have moderate to severe atopic dermatitis (Reich et al., 2012). Alternatively, for example, in the evaluation of the degree of itch during the day or night based on the Shirator severity criteria, a subject determined to have an EASI score of 10 or more, an sIGA score of 3 or more, or a total score of 4 or more may be considered to have moderate to severe atopic dermatitis. Alternatively, a subject with a rash with severe inflammation affecting, for example, 5% or more of the body surface area may be identified as having moderate to severe atopic dermatitis. Alternatively, a subject with a combination of one or more of the indicators mentioned herein may be considered to have moderate to severe atopic dermatitis, if appropriate.

[0594] As used herein, the "subject" may preferably be an animal, more preferably a mammal (mouse, rat, rabbit, dog, monkey (e.g., cynomolgus monkey), etc.), particularly preferably a human, but not limited thereto. The human may be an adult (18 years or older) or a child (0 to less than 18 years, e.g., 6 months to less than 18 years).

[0595] In one embodiment, the present disclosure relates to a lyophilized formulation and a solution formulation for preventing and / or treating atopic dermatitis, comprising an IL-31 antagonist as an active ingredient.

[0596] In this case, the IL-31 antagonist may be intended to be repeatedly administered in equal amounts at the same dosing intervals, using a predetermined dosing interval and a predetermined dose (dose) as will be described in detail below.

[0597] In one embodiment, the lyophilized formulation and solution formulation of the present disclosure can be used to prevent and / or treat itching caused by atopic dermatitis.

[0598] In yet another embodiment or another embodiment, the lyophilized formulation and solution formulation of the present disclosure can be used to improve sleep disorders caused by atopic dermatitis, wherein the sleep disorder may be caused by the pruritus caused by atopic dermatitis. The improvement of sleep disorders can be characterized by, for example, an increase in the time from falling asleep to waking up and / or a decrease in sleep latency (the time from going to bed to falling asleep).

[0599] In yet another or another embodiment, the lyophilized formulation and solution formulation of the present disclosure may be used to inhibit at least one symptom caused by atopic dermatitis selected from the group consisting of redness, induration, papules, edema, exfoliation, and lichenification.

[0600] In one embodiment of the present disclosure, the prevention and / or treatment of atopic dermatitis may refer to, but is not limited to, for example, administering a drug, etc., to a subject currently exhibiting atopic dermatitis or various symptoms caused by atopic dermatitis (e.g., itching, redness, nodules, papules, edema, exfoliation, lichenification, decreased quality of life, and lack of sleep), to suppress one or more of these symptoms, and / or administering a drug, etc., to a subject who has previously suffered from atopic dermatitis or various symptoms caused by atopic dermatitis, to eliminate the development of one or more of these symptoms or reduce their incidence. As long as it improves any of the various symptoms caused by atopic dermatitis, the prevention and / or treatment of atopic dermatitis can be judged or determined to be useful for prevention and / or treatment even if it cannot prevent and / or treat atopic dermatitis itself.

[0601] The subject who may have atopic dermatitis may be a subject who has had atopic dermatitis in the past and may have a risk of recurrence of symptoms, or may be a subject suspected of having atopic dermatitis before a doctor or the like makes a diagnosis or determines that the subject has atopic dermatitis, but is not limited thereto.

[0602] In one embodiment, in some cases, prevention and treatment of atopic dermatitis may be interpreted synonymously.

[0603] It is known that the IL-31 antagonist (CIM331) used in this example showed improvement in sleep efficiency in the IL-31 antagonist administration group in a single subcutaneous dose study of the IL-31 antagonist in patients with atopic dermatitis (WO 2016 / 167263).

[0604] Although atopic dermatitis is not necessarily a serious disease that threatens life, the symptoms associated with the disease can significantly affect daily life. In particular, pruritus, which is the most typical symptom, is an unpleasant sensation that significantly reduces the patient's quality of life (QOL) and is reported to hinder the patient's sleep (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, it is a great burden not only for the sick child but also for the parents. It is reported that parents of children with moderate or severe atopic dermatitis spend 3 hours a day on treatment and lose 1 to 2 hours of sleep a 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).

[0605] Therefore, in another embodiment, the present disclosure relates to a lyophilized formulation and a solution formulation for preventing and / or treating atopic dermatitis, which comprises an IL-31 antagonist as an active ingredient, which is further used to improve sleep disorders caused by atopic dermatitis. Alternatively, in a further embodiment or another embodiment, the present disclosure relates to a lyophilized formulation and a solution formulation for improving the reduced QOL caused by atopic dermatitis. The improvement of sleep disorders can be characterized by, for example, an increase in the time from falling asleep to waking up and / or a decrease in the latency to falling asleep (the time from going to bed to falling asleep).

[0606] As used herein, the description "repeated administration in equal amounts at the same dosing interval" means that the dose (initial dose) of the IL-31 antagonist of the present disclosure initially administered to the subject is equal to the subsequent continuous doses of the IL-31 antagonist (ie, the doses continuously administered after the initial dose), and the IL-31 antagonist is administered at equal dosing intervals (intervals between doses). Specifically, for example, the above description refers to the interval between the administration of the initial dose and the administration of the first continuous dose, or the interval between the administration of the nth (n is an integer greater than 1) continuous dose and the administration of the (n+1)th continuous dose is equal, and the doses are equal. Those skilled in the art will understand that for a determined dosing interval (e.g., every 4 weeks when the dosing interval is determined to be every 4 weeks), each dosing interval has a "tolerable range", and those skilled in the art can determine the tolerable range at their discretion.

[0607] In the present invention, the term "stable antibody-containing preparation" refers to a preparation in which aggregates and / or components with charge heterogeneity from proteins such as antibodies are difficult to produce, that is, a preparation in which deterioration reactions are difficult to occur in the preparation, wherein the deterioration reactions include the production of insoluble aggregates, soluble aggregates, and components with charge heterogeneity.

[0608] The "component having charge heterogeneity" refers to a component having a protein surface charge different from that of the main component due to deamidation, oxidation, hydrolysis, or the like.

[0609] 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 shielding automatic particle counter (HIAC), flow imaging, analytical ultracentrifuge (AUC), etc., and preferably by size exclusion chromatography (SEC) in the present invention. It is considered that as a measurement condition, a chromatographic column (TOSOH, TSKgel G3000SWXL) is used, 50mmol / L phosphate buffer (pH7.0), 300mmol / L sodium chloride, 0.05% sodium azide are used as mobile phases, and the flow rate is 0.5mL / min to measure the sample, but the conditions are not limited thereto. In one embodiment, the amount of aggregates is measured by the method described in the examples herein.

[0610] The component with charge heterogeneity can be measured by ion exchange chromatography (IEC), specifically cation exchange chromatography or anion exchange chromatography, isoelectric focusing, etc. In the present invention, it is preferably measured by anion exchange chromatography. The amount of the component with charge heterogeneity in the sample can be measured by ion exchange chromatography (IEC) using a chromatographic column (TOSOH, TSKgel DEAE-NPR), using 25mmol / L Tris-HCl buffer (pH 7.5) as mobile phase A and 25mmol / L Tris-HCl buffer (pH 7.5), 250mmol / L sodium chloride as mobile phase B, and a flow rate of 1.0mL / min, but the method is not limited thereto. In one embodiment, the component with charge heterogeneity is measured by the method described in the examples herein.

[0611] In the present invention, "polypeptide" generally refers to peptides and proteins with a length of about 10 amino acids or longer. Usually, they are polypeptides of biological origin, but are not particularly limited thereto, and for example, they may be polypeptides containing artificially designed sequences. In addition, they may be any naturally occurring polypeptide, synthetic polypeptide, recombinant polypeptide, etc. In addition, fragments of the above polypeptides are also included in the polypeptides of the present invention.

[0612] The term "antibody" is used in the broadest sense, including monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), antibody derivatives and modified antibodies (Miller K et al. J Immunol. 2003, 170 (9), 4854-61), as long as they show the desired biological activity. The antibody can be a mouse antibody, a human antibody, a humanized antibody, a chimeric antibody or an antibody from another species, or an artificially synthesized antibody. The antibodies disclosed herein can be any type (e.g., IgG, IgE, IgM, IgD and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or industry class of immunoglobulin molecules. Immunoglobulins can be derived from any species (e.g., human, mouse or rabbit). The terms "antibody", "immune globulin" and "immunoglobulin" are used interchangeably in a broad sense.

[0613] Recombinant antibodies produced by using genetic engineering techniques can be used as antibodies. Recombinant antibodies can be obtained by cloning DNA encoding the antibody from a hybridoma or an antibody-producing cell such as an antibody-producing sensitized lymphocyte; inserting it into a vector; and then introducing it into a host (host cell) to produce the antibody.

[0614] The antibodies of the present invention can be produced by methods known to those skilled in the art. Specifically, the DNA encoding the target antibody is inserted into an expression vector. Insertion into the expression vector is performed so that expression will be carried out under the control of expression regulatory regions such as enhancers and promoters. Next, the expression vector is used to transform a host cell to express the antibody. In this case, an appropriate combination of a host and an expression vector can be used.

[0615] The antibody of the present invention thus obtained can be separated from the host cell interior or the cell exterior (culture medium, etc.), and purified into substantially pure, homogeneous antibodies. The antibody can be separated and purified by methods commonly used for separation and purification of antibodies, and these methods are not subject to any restriction. For example, by appropriately selecting and combining column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, etc., separation and purification of antibodies.

[0616] The present inventors studied the effects of various additives by heat acceleration tests to evaluate the stability of samples containing the above-mentioned anti-IL-31RA antibody (CIM331) during storage. As a result, the present inventors found that by preparing a lyophilized preparation from a solution to which arginine hydrochloride and sucrose or trehalose were added, aggregate formation was suppressed compared to when they did not contain a stabilizer or filler (filler), when sodium chloride was added as a stabilizer, or when other sugars were added as fillers. The present inventors also found that subvisible particle formation and aggregate formation were suppressed by adding poloxamer 188 and / or polysorbate 20 as nonionic surfactants to the antibody-containing solution. In addition, the present inventors found that in an antibody-containing solution containing arginine hydrochloride, sucrose or trehalose and a nonionic surfactant, aggregate formation and components with charge heterogeneity were suppressed at pH 6 to pH 8.

[0617] The concentration (amount) of arginine in the preparation of the present invention is preferably 45 mM to 150 mM. Examples of the concentration (amount) of arginine include 45 mM, 75 mM, 92 mM, 102 mM and 150 mM.

[0618] The solution pH of the formulation of the present invention is preferably 6 to 8, more preferably 6.5 to 7.5, even more preferably 7.

[0619] The preparation of the present invention may include, for example, Tris buffer as a buffer. Tris buffer includes, for example, tris (hydroxymethyl) aminomethane and / or its salt, for example, tris (hydroxymethyl) aminomethane-hydrochloride, tris (hydroxymethyl) aminomethane-aspartate, tris (hydroxymethyl) aminomethane-glutamate or tris (hydroxymethyl) aminomethane-acetate. The amount of the Tris buffer added to the preparation of the present invention is preferably 6mM to 20mM, for example, 6mM, 10mM, 12.3mM, 13.6mM or 20mM.

[0620] Surfactants included in the preparation of the present invention are, for example, polysorbate 20 (PS20) and Pluronic F-68 (Poloxamer 188: polyoxyethylene (160) polyoxypropylene (30) glycol), particularly preferably Poloxamer 188. The amount of Poloxamer 188 (or PX188) added to the preparation of the present invention is preferably 0.15 mg / mL to 0.5 mg / mL. Examples of the amount of Poloxamer 188 added to the preparation include 0.15 mg / mL, 0.25 mg / mL, 0.31 mg / mL, 0.34 mg / mL, and 0.50 mg / mL.

[0621] The preparation of the present invention may further contain sugar. Preferred sugars used in the present invention are sucrose, trehalose, mannitol and lactose, with sucrose and trehalose being particularly preferred.

[0622] The amount of sugar added to the formulation of the invention is typically 1 mM to 1000 mM, preferably 5 mM to 500 mM, more preferably 10 mM to 300 mM, such as 75 mM to 250 mM, and for example 75 mM, 125 mM, 154 mM, 170 mM or 250 mM.

[0623] If necessary, the preparation of the present invention may additionally contain suitable cryoprotectants, suspending agents, solubilizers, tonicity agents, preservatives, adsorption inhibitors, diluents, excipients, pH adjusters, analgesics, sulfur-containing reducing agents, antioxidants, and the like.

[0624] Cryoprotectants include, for example, sugars such as trehalose, sucrose, and sorbitol.

[0625] The solubilizing agent includes, for example, polyoxyethylene hardened castor oil, polysorbate 80, niacinamide, polyoxyethylene sorbitan monolaurate, polyethylene glycol and castor oil fatty acid ethyl ester.

[0626] Tonicity agents include, for example, sodium chloride, potassium chloride, and calcium chloride.

[0627] Preservatives include, for example, methyl hydroxybenzoate, ethyl hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

[0628] Adsorption inhibitors include, for example, human serum albumin, lecithin, dextran, ethylene oxide / propylene oxide copolymers, hydroxypropylcellulose, methylcellulose, polyoxyethylene hardened castor oil, and polyethylene glycol.

[0629] Sulfur-containing reducing agents include, for example, those containing a sulfhydryl group, such as N-acetylcysteine, N-acetylhomocysteine, lipoic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and thioalkanoic acids having one to seven carbon atoms.

[0630] Antioxidants include, for example, isoascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, α-tocopherol, tocopheryl acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, tripentyl gallate, propyl gallate, and chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.

[0631] The antibody-containing formulations of the invention can be administered to a patient by any suitable route, for example by rapid bolus injection or continuous infusion over a period of time, intravenously, intramuscularly or subcutaneously. Intravenous administration or subcutaneous administration is preferred.

[0632] The dosage of Nemolizumab (CIM331) is, for example, 0.001 mg / kg to 1000 mg / kg, and the administration interval is at least one day or longer.

[0633] More specifically, for example, Nemolizumab (CIM331) is administered to a subject suffering from atopic dermatitis or at risk of atopic dermatitis in equal amounts and at the same dosing interval at 0.1 mg to 1000 mg / subject / 2 weeks, 0.1 mg to 1000 mg / subject / 4 weeks, or 0.1 mg to 1000 mg / subject / 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 / subject / 4 weeks. Alternatively, Nemolizumab (CIM331) is administered at the same dose and the same dosing interval at 60 mg / subject / 4 weeks. Alternatively, Nemolizumab (CIM331) is administered at a dosing interval of 4 weeks and is administered repeatedly at 60 mg / subject as an initial dose and 30 mg / subject as a continuous dose. Those skilled in the art will understand that when a lyophilized formulation containing a dose of Nemolizumab (CIM331) is packaged in a container (vial, cartridge or syringe), taking into account the loss of the reconstituted drug solution during administration, an excess of the lyophilized formulation will be filled to ensure an amount sufficient to administer a dose of Nemolizumab (CIM331) from one container (vial, cartridge or syringe).

[0634] Another embodiment of the present invention is a method for stabilizing an antibody in an antibody-containing formulation. For example, the embodiment is a method for stabilizing an antibody in an antibody-containing solution formulation, the method comprising adding arginine and / or a salt thereof, and sucrose and / or trehalose to the solution. In addition, for example, the embodiment is a method for stabilizing an antibody in an antibody-containing lyophilized formulation, the method comprising preparing an antibody-containing lyophilized formulation by freeze-drying an antibody-containing solution containing arginine and / or a salt thereof, and sucrose and / or trehalose.

[0635] In addition, another embodiment of the present invention is a method for suppressing antibody aggregation (aggregate formation) in an antibody-containing preparation. For example, the embodiment is a method for suppressing antibody aggregation (aggregate formation) in an antibody-containing solution preparation, the method comprising adding arginine and / or its salt, and sucrose and / or trehalose to the solution. In addition, for example, the embodiment is a method for suppressing antibody aggregation (aggregate formation) in an antibody-containing lyophilized preparation, the method comprising preparing an antibody-containing lyophilized preparation by freeze-drying an antibody-containing solution comprising arginine and / or its salt, and sucrose and / or trehalose.

[0636] Another embodiment of the present invention is a method for reducing components with charge heterogeneity in an antibody-containing formulation. For example, the embodiment is a method for reducing components with charge heterogeneity in an antibody-containing solution formulation, the method comprising adding arginine and / or its salt, and sucrose and / or trehalose to the solution. In addition, for example, the embodiment is a method for reducing components with charge heterogeneity in an antibody-containing lyophilized formulation, the method comprising preparing an antibody-containing lyophilized formulation by freeze-drying an antibody-containing solution containing arginine and / or its salt, and sucrose and / or trehalose.

[0637] In addition, in the above-mentioned method for stabilizing antibodies, the method for inhibiting antibody aggregation (aggregate formation), and the method for reducing components with charge heterogeneity, the concentration of arginine hydrochloride (Arg-HCl) in the solution is preferably 45 mmol / L to 150 mmol / L, and the concentration of sucrose or trehalose in the solution is preferably 75 mmol / L to 250 mmol / L.

[0638] In the above-mentioned method for stabilizing an antibody, method for inhibiting antibody aggregation (aggregate formation), and method for reducing components having charge heterogeneity, the antibody is preferably Nemolizumab (CIM331).

[0639] As used herein, aspects referred to by the expression "comprising" include those referred to by the expression "consisting essentially of, as well as those referred to by "consisting of.

[0640] The numerical values ​​listed here may vary within a certain range, for example, depending on the instruments or equipment, measurement conditions and procedures used by those skilled in the art, as long as they are within the range allowing the purpose of the present invention to be achieved, for example, they may contain a deviation of about 10%.

[0641] All patents and literature references explicitly cited herein are incorporated by reference in their entirety into this specification.

[0642] The present invention will be further illustrated by the following examples, but should not be construed as being limited thereto.

[0643] Example

[0644] definition

[0645] [Experimental methods]

[0646] To adjust the pH value, the formulation prepared in each example contained 6 mmol / L to 20 mmol / L Tris-HCl, which did not contribute to the stability of CIM331 (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10).

[0647] Thermal acceleration studies of solution formulations were conducted at 40°C / 75% RH. Meanwhile, since lyophilized formulations are generally more stable, thermal acceleration studies of lyophilized formulations were conducted at a higher temperature, 50°C 75% RH.

[0648] In Example 3, a vibration study was performed to verify the effect of the nonionic surfactant.

[0649] [Analysis method]

[0650] Regarding the measurement of the amount of CIM331 aggregates, considering the accuracy of the analytical method, it can be judged that there is a significant difference when the percentage of aggregates has a difference of 0.07% or more.

[0651] Regarding the measurement of components with charge heterogeneity of CIM331, considering the accuracy of the analytical method, it can be judged that there is a significant difference when the difference in the basic region is 1.3% or more, the difference in the main region is 1.4% or more, and the difference in the acidic region is 0.6% or more.

[0652] The results of the analytical methods cannot be interpreted similarly between solution formulations and lyophilized formulations due to the differences in stability between them.

[0653] [Example 1] Aggregation inhibition of humanized IgG2 antibody CIM331 by arginine during heat-accelerated storage

[0654] [1-1] Stability evaluation of lyophilized preparations

[0655] (1) Materials

[0656] CIM331 is a monoclonal antibody that binds to IL-31RA and is a humanized IgG2 antibody that is expected to treat atopic dermatitis, etc. by inhibiting the function of IL-31, which has been identified as an itch-inducing cytokine.

[0657] (2) Test samples

[0658] Various prepared solutions including 30 mg / mL CIM331, 6 mmol / L Tris-HCl, 75 mmol / L sucrose, 0.15 mg / mL poloxamer 188, and one of 45 mmol / L Arg-HCl or 45 mmol / L NaCl as stabilizers and prepared solutions without stabilizers were prepared and filled into glass vials (2 mL / vial). The filled drug solutions were lyophilized under the conditions shown below.

[0659]

[0660] After the thus prepared lyophilized preparation containing the humanized antibody was allowed to stand in a 50°C / 75%RH incubator for 8 weeks, a reconstituted solution prepared by adding ultrapure water so that the CIM331 concentration became 100 mg / mL was used as a test sample.

[0661] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates

[0662] The amount of aggregates of the sample was measured by size exclusion chromatography (SEC) at a flow rate of 0.5 mL / min using a chromatography column (TOSOH, TSKgel G3000SWXL) and 50 mmol / L phosphate buffer (pH 7.0), 300 mmol / L sodium chloride, 0.05% sodium azide as the mobile phase.

[0663] Among the detected peaks, the peak showing the largest area and height was defined as the monomer body, and the peaks detected before the monomer body were collectively referred to as aggregates (HMWS).

[0664] For all peaks, calculate the areas and determine the peak area ratio of the target peak according to the following equation.

[0665]

[0666] (4) Results

[0667] The obtained results are shown in Table 1.

[0668] [Table 1]

[0669]

[0670] *: The relative increase rate compared to the case where no stabilizer was added was calculated based on the increase in HMWS when no stabilizer was added and the increase in HMWS when each stabilizer was added.

[0671] As shown in Table 1, after 8 weeks of thermal acceleration at 50°C / 75%RH, the sample to which arginine hydrochloride was added showed a high aggregation inhibition effect compared with the sample without stabilizer addition and the sample to which sodium chloride was added.

[0672] [1-2] Stability evaluation of solution preparations

[0673] (1) Materials

[0674] The antibodies described in [1-1] were used.

[0675] (2) Test samples

[0676] Various prepared solutions including 100 mg / mL CIM331, 20 mmol / L Tris-HCl, 250 mmol / L sucrose, 0.5 mg / mL poloxamer 188, pH 7, and one of 150 mmol / L Arg-HCl or 150 mmol / L NaCl as stabilizers and prepared solutions without stabilizers were prepared and filled into glass vials (1 mL / vial). After the solution preparations containing humanized antibodies thus prepared were placed in an incubator at 40°C / 75%RH for 4 weeks, they were used as test samples.

[0677] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates These methods were performed according to the method described in [1-1].

[0678] (4) Results

[0679] The obtained results are shown in Table 2.

[0680] [Table 2]

[0681]

[0682] *: The relative increase rate compared to the case where no stabilizer was added was calculated based on the increase in HMWS when no stabilizer was added and the increase in HMWS when each stabilizer was added.

[0683] As shown in Table 2, after thermal acceleration at 40°C / 75%RH for 4 weeks, the sample to which arginine hydrochloride was added showed a high aggregation inhibition effect compared with the sample without stabilizer addition and the sample to which sodium chloride was added.

[0684] [Example 2] Aggregation inhibition of sucrose and trehalose on humanized IgG2 antibody CIM331 during heat-accelerated storage

[0685] (1) Materials

[0686] The antibodies described in Example 1 were used.

[0687] (2) Test samples

[0688] Various prepared solutions including 30 mg / mL CIM331, 6 mmol / L Tris-HCl, 45 mmol / L Arg-HCl, 0.15 mg / mL poloxamer 188, and any one of 75 mmol / L sucrose, 75 mmol / L mannitol, 75 mmol / L glucose, 75 mmol / L lactose or 75 mmol / L trehalose as fillers and prepared solutions without fillers were prepared and filled into glass vials (2 mL / vial). The filled drug solutions were lyophilized under the conditions shown below.

[0689]

[0690] After the thus prepared lyophilized preparation containing the humanized antibody was allowed to stand in a 50°C / 75%RH incubator for 8 weeks, a reconstituted solution prepared by adding ultrapure water so that the CIM331 concentration became 100 mg / mL was used as a test sample.

[0691] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates These methods were performed according to the methods described in Example 1.

[0692] (4) Results

[0693] The obtained results are shown in Table 3.

[0694] [Table 3]

[0695]

[0696] *: The relative increase rate compared to the case where no filler was added was calculated from the increase in HMWS when no filler was added and the increase in HMWS when each filler was added.

[0697] As can be seen from Table 3, after 8 weeks of thermal acceleration at 50°C / 75%RH, the samples with added sucrose or trehalose showed a relative increase rate in the range of 10% compared with the samples without added fillers and the samples with added other fillers, and showed a high aggregation inhibition effect.

[0698] [Example 3] Effect of nonionic surfactants on the inhibition of microscopic particle formation and solution stabilization of humanized IgG2 antibody CIM331 during vibration stress testing

[0699] (1) Materials

[0700] The antibodies described in Example 1 were used.

[0701] (2) Test samples

[0702] Various prepared solutions including 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 nonionic surfactant and prepared solutions without a nonionic surfactant were prepared and filled into glass vials (1 mL / vial). After the solution preparations containing humanized antibodies thus prepared were shaken at a speed of about 200 rpm at room temperature for three days, they were used as test samples.

[0703] (3)Method for measuring particles that can only be seen under a microscope

[0704] The number of particles visible under a microscope was counted using a liquid particle counter (Hach UltraAnalytics, Model 9703).

[0705] (4) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates These methods were performed according to the methods described in Example 1.

[0706] (5) Results

[0707] The obtained results are shown in Tables 4 and 5.

[0708] [Table 4]

[0709]

[0710] [Table 5]

[0711]

[0712] *: The relative increase rate compared to the case where no nonionic surfactant was added was calculated based on the increase in HMWS when no nonionic surfactant was added and the increase in HMWS when each nonionic surfactant was added.

[0713] As is apparent from Tables 4 and 5, the samples containing Poloxamer 188 or Polysorbate 20, which is a nonionic surfactant, showed a high microscopic particle formation inhibitory effect and a high aggregation inhibitory effect in the samples after being shaken at a speed of about 200 rpm at room temperature for 3 days.

[0714] [Example 4] Effect of pH on the stability of humanized IgG2 antibody CIM331 during heat-accelerated storage

[0715] (1) Materials

[0716] The antibodies described in Example 1 were used.

[0717] (2) Test samples

[0718] Various prepared solutions including 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, wherein the pH was any one of pH 6, pH 7 or pH 8, were prepared and filled into glass vials (1 mL / vial). After the solution preparations containing the humanized antibody thus prepared were allowed to stand in an incubator at 40°C / 75%RH for 4 weeks, they were used as test samples.

[0719] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates These methods were performed according to the methods described in Example 1.

[0720] (4) Measurement and calculation method of components with charge heterogeneity in CIM331

[0721] The amount of components with charge heterogeneity in the sample was measured by ion exchange chromatography (IEC) at a flow rate of 1.0 mL / min using a chromatographic column (TOSOH, TSKgel DEAE-NPR) and 25 mmol / L Tris-HCl buffer (pH 7.5) as mobile phase A and 25 mmol / L Tris-HCl buffer (pH 7.5), 250 mmol / L sodium chloride as mobile phase B.

[0722] Among the detected peaks, the peak showing the largest area and height is defined as the main region, the peaks detected before the main region are collectively referred to as the basic region, and the peaks detected after the main region are collectively referred to as the acidic region.

[0723] For all peaks, calculate the areas, and determine the peak area ratio of the target peak according to the following equation.

[0724]

[0725] (5) Results

[0726] The obtained results are shown in Table 6.

[0727] [Table 6]

[0728]

[0729] As can be seen from Table 6, the samples of pH 6 to pH 8 showed sufficient stability after thermal acceleration at 40°C / 75%RH for 4 weeks, and in particular, in the sample of pH 7, a high aggregation inhibition effect and an effect of inhibiting components with charge heterogeneity were achieved.

[0730] [Example 5] Effects of humanized IgG2 antibody CIM331 concentration and other formulation component concentrations on stability during heat-accelerated storage

[0731] (1) Materials

[0732] The antibodies described in Example 1 were used.

[0733] (2) Test samples

[0734] Prepare various prepared solutions including 100mg / mL or 50mg / mL CIM331, 20mmol / L or 10mmol / L Tris-HCl, 150mmol / L or 75mmol / L Arg-HCl as stabilizer, 250mmol / L or 125mmol / L sucrose as filler, and 0.5mg / mL or 0.25mg / mL poloxamer 188 as nonionic surfactant, and prepared solutions including 6mmol / L Tris-HCl, 45mmol / L Arg-HCl, 75mmol / L sucrose, 0.15mg / mL poloxamer 188 and 30mg / mL, 15mg / mL or 6mg / mL CIM331, and fill in glass vials (2mL / vial). Filled drug solution is lyophilized under the conditions shown below.

[0735]

[0736] After the thus prepared lyophilized preparation containing the humanized antibody was allowed to stand in a 50°C / 75%RH incubator for 8 weeks, a reconstituted solution prepared by adding ultrapure water so that the CIM331 concentration shown below was used as a test sample.

[0737]

[0738] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates These methods were performed according to the methods described in Example 1.

[0739] (4) Measurement and calculation method of components with charge heterogeneity in CIM331

[0740] These methods were carried out according to the methods described in Example 4.

[0741] (5) Results

[0742] The obtained results are shown in Table 7.

[0743] [Table 7]

[0744]

[0745] As is apparent from Table 7, samples containing the tested concentrations of each ingredient (i.e., samples containing 6 to 100 mg / mL CIM331, 6 to 20 mmol / L Tris-HCl, 45 to 150 mmol / L Arg-HCl, 75 to 250 mmol / L sucrose, and 0.15 to 0.5 mg / mL Poloxamer 188) had sufficient stability after 8 weeks of thermal acceleration at 50°C / 75% RH. With regard to HMWS, when the concentrations of formulation ingredients other than antibodies were the same, samples containing lower concentrations of antibodies exhibited more excellent stability.

[0746] [Example 6] Effect of arginine in inhibiting aggregates and components with charge heterogeneity of humanized IgG2 antibody CIM331 during heat-accelerated storage

[0747] [6-1] Stability evaluation of lyophilized preparations

[0748] (1) Materials

[0749] The antibodies described in Example 1 were used.

[0750] (2) Test samples

[0751] Prepare various prepared solutions containing 30 mg / mL CIM331, 6 mmol / L Tris-HCl, pH 7, 75 mmol / L sucrose, 0.15 mg / mL poloxamer 188, and any one of 45 mmol / L Arg-HCl, 45 mmol / L histidine, 45 mmol / L lysine-HCl and 45 mmol / L glycine as stabilizers, and fill in glass vials (2 mL / vial). The filled drug solution is lyophilized under the conditions shown below.

[0752]

[0753] After the thus prepared lyophilized preparation containing the humanized antibody was allowed to stand in a 50°C / 75%RH incubator for 8 weeks, a reconstituted solution prepared by adding ultrapure water so that the CIM331 concentration became 100 mg / mL was used as a test sample.

[0754] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates These methods were performed according to the methods described in Example 1.

[0755] (4) Methods of measuring and calculating components having charge heterogeneity in CIM331 These methods were performed according to the methods described in Example 4.

[0756] (5) Results

[0757] The obtained results are shown in Table 8.

[0758] [Table 8]

[0759]

[0760] As shown in Table 8, after 8 weeks of thermal acceleration at 50°C / 75%RH, the sample to which arginine hydrochloride was added showed the highest aggregation inhibition effect and effect of inhibiting components with charge heterogeneity compared with the samples to which histidine, lysine hydrochloride, or glycine was added.

[0761] [6-2] Stability evaluation of solution preparations

[0762] (1) Materials

[0763] The antibodies described in Example 1 were used.

[0764] (2) Test samples

[0765] Prepare various solutions containing 100 mg / mL CIM331, 20 mmol / L Tris-HCl, pH 7, 250 mmol / L sucrose, 0.50 mg / mL poloxamer 188, and any one of 150 mmol / L Arg-HCl, 150 mmol / L histidine, 150 mmol / L lysine-HCl and 150 mmol / L glycine as stabilizers, and fill in glass vials (1 mL / vial). After the solution preparations containing humanized antibodies thus prepared are placed in an incubator at 40°C / 75%RH for 4 weeks, they are used as test samples.

[0766] (3) Methods of measuring and calculating components having charge heterogeneity in CIM331 These methods were performed according to the methods described in Example 4.

[0767] (4) Results

[0768] The obtained results are shown in Table 9.

[0769] [Table 9]

[0770]

[0771] As shown in Table 9, after thermal acceleration at 40°C / 75%RH for 4 weeks, the sample to which arginine hydrochloride was added showed the highest effect of suppressing components having charge heterogeneity compared with the sample to which histidine, lysine hydrochloride, or glycine was added.

[0772] Industrial Applicability

[0773] The preparation of the present invention is a preparation having excellent stability in both the lyophilized state and the solution state, characterized in that the aggregate formation of proteins such as antibody molecules is suppressed after storage in the solution state and after storage in the lyophilized state and reconstitution with water. The preparation of the present invention itself is difficult to deteriorate, and can be used, for example, to treat atopic dermatitis by subcutaneous administration.

Claims

1. A solution preparation comprising: 6 to 100 mg / mL of an IL-31 antagonist as an active ingredient, wherein the IL-31 antagonist is an anti-IL-31 receptor A (anti-IL-31RA) antibody, comprising: (1) an H chain variable region and an L chain variable region, wherein the H chain variable region comprises CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and the L chain variable region comprises CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6; (2) the H chain variable region of SEQ ID NO: 7 and the L chain variable region of SEQ ID NO: 8; or (3) H chain of SEQ ID NO: 9 and L chain of SEQ ID NO: 10; 6 to 20 mmol / L Tris buffer; 45 to 150 mmol / L arginine and / or its salts; 75 to 250 mmol / L sucrose or trehalose; and 0.15 to 0.50 mg / mL poloxamer 188 or polysorbate 20, The pH of the solution preparation is 6 to 8.

2. The preparation of claim 1, wherein the arginine and / or its salt is arginine hydrochloride, arginine aspartate or arginine glutamate.

3. The formulation of claim 1 or 2, wherein the molar ratio of the arginine and / or its salt to the IL-31 antagonist is 220:1 to 1100:1, and / or the weight ratio of the arginine to the IL-31 antagonist is 0.3:1 to 1.3:

1.

4. The preparation according to claim 1 or 2, wherein The molar ratio between the sucrose or trehalose and the IL-31 antagonist is 370:1 to 1840:1 and / or the weight ratio is 0.8:1 to 4.3:

1.

5. A lyophilized preparation obtained by lyophilizing the solution preparation according to any one of claims 1 to 4.

6. The freeze-dried preparation according to claim 5, wherein When the lyophilized formulation is reconstituted in water, it comprises, 20 to 100 mg / mL IL-31 antagonist; 10 to 20 mmol / L Tris buffer; 75 to 150 mmol / L arginine and / or its salts; 125 to 250 mmol / L sucrose or trehalose; and 0.25 to 0.5 mg / mL poloxamer 188 or polysorbate 20, and a pH of 6 to 8.

7. A solution preparation comprising: 20 to 100 mg / mL of an IL-31 antagonist as an active ingredient, wherein the IL-31 antagonist is (1) an anti-IL-31RA antibody comprising an H chain variable region comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and an L chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of 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) an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10; 10 to 20 mmol / L Tris buffer; 75 to 150 mmol / L arginine and / or its salts; 125 to 250 mmol / L sucrose or trehalose; and 0.25 to 0.50 mg / mL poloxamer 188 or polysorbate 20, The pH of the solution formulation is 6 to 8.

8. The formulation of claim 1, 5 or 7, wherein the IL-31 antagonist is an antibody that inhibits IL-31 signaling.

9. A method for stabilizing an anti-IL-31RA antibody in an antibody-containing formulation, comprising preparing the antibody-containing formulation according to any one of claims 1 to 8.

10. A method for inhibiting aggregation (aggregate formation) of an anti-IL-31RA antibody in an antibody-containing formulation, comprising preparing the antibody-containing formulation according to any one of claims 1 to 8.

11. A method for reducing components having charge heterogeneity in an anti-IL-31RA antibody-containing preparation, comprising preparing the antibody-containing preparation according to any one of claims 1 to 8.

12. An injection preparation or kit comprising: (i) container; (ii) a lyophilized preparation contained in the container, the lyophilized preparation being a composition produced by lyophilizing the solution preparation according to claim 1, wherein the pH of the lyophilized formulation is 6 to 8 when reconstituted in water.

13. The injection preparation or kit according to claim 12, further comprising: (iii) water for injection for reconstitution of the lyophilized formulation.

14. An injection preparation or kit comprising: (i) container; (ii) a lyophilized formulation contained in the container, the lyophilized formulation comprising: - 10 to 80 mg of an anti-IL-31RA antibody comprising: (1) an H chain variable region and an L chain variable region, wherein the H chain variable region comprises CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and the L chain variable region comprises CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6; (2) the H chain variable region of SEQ ID NO: 7 and the L chain variable region of SEQ ID NO: 8; or (3) H chain of SEQ ID NO: 9 and L chain of SEQ ID NO: 10; - 0.8 to 4 mg tris(hydroxymethyl)aminomethane; - 8 to 40 mg arginine hydrochloride; - 30 to 110 mg sucrose; and - 0.1 to 0.7 mg poloxamer 188, wherein the pH of the lyophilized formulation is 6 to 8 when reconstituted in water.

15. The injection preparation or kit according to claim 14, further comprising: (iii) water for injection for reconstitution of the lyophilized formulation.

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