Stable saccharide-free liquid formulation of Anti-il-4rα antibody

Abstract

The present invention relates to: a liquid formulation which includes an anti-IL-4Rα antibody, a buffering agent, and an amino acid but does not include saccharides, and which has a pH of 4.5 to 6.5; a device comprising same; and a use thereof for treating conditions related to IL-4Rα thereof. The liquid formulation can improve viscosity while ensuring the stability of an antibody without including saccharides, and thus can be effectively used as a medicine for treating IL-4Rα-related conditions.

Description

Stable sugar-free liquid formulation of anti-IL-4Rα antibody

[0001] A stable, sugar-free liquid formulation of an anti-IL-4Rα antibody, a device comprising the same, and their use for treating an IL-4Rα-associated condition are disclosed.

[0002] Antibody drugs have larger molecular weights and complex secondary and higher-order structures compared to typical protein drugs, which can lead to physicochemical instability. For this reason, the development of optimal formulations that ensure quality and stability throughout the entire process of antibody drugs, from manufacturing and storage to administration to patients, is essential. Protein instability can be caused by various external factors, such as temperature, light, and chemicals, and can lead to decreased activity, reduced efficacy, or immunogenicity when administered to the human body. Therefore, improving the instability of antibody drugs and maintaining optimal quality until administration to patients is crucial. To achieve optimal quality, methods such as changing buffer solutions, assessing optimal pH, and adding stabilizers are used. Because the material properties of each antibody protein vary, and the optimal combination of buffer solution, pH, and stabilizer can vary, developing a formulation appropriate for the target substance is essential to address these issues.

[0003] For example, dupilumab, an anti-IL-4Rα antibody, is available from Dupixent. ®) is manufactured and sold under the trade name Dupixent. Dupixent 200 mg is a 1.14 mL liquid formulation consisting of 200 mg anti-IL4Rα IgG, 1.2 mg sodium acetate, 3.5 mg histidine, 12 mg arginine, 57 mg sucrose, and 2.3 mg polysorbate 80, and Dupixent 300 mg is a 2.00 mL liquid formulation consisting of 300 mg anti-IL4Rα IgG, 2.0 mg sodium acetate, 6.2 mg histidine, 10.5 mg arginine, 100 mg sucrose, and 4 mg polysorbate 80. To stabilize liquid formulations containing various antibody proteins, such as dupilumab, various conditions, such as the type and concentration of each component, are being reviewed and applied, such as adding sugars, amino acids, buffers, and surfactants, or applying a specific pH, as in the Dupixent product composition.

[0004] In addition to ensuring the stability described above, there is a need to develop high-concentration formulations that can reduce the number of administrations while increasing therapeutic activity through high-dose injections in small volumes to improve patient convenience during injection. When developing a formulation for a high-concentration formulation, there are limitations such as protein instability due to protein aggregation and decreased injectability due to increased viscosity as the protein concentration increases. Therefore, it is important to develop a formulation that can improve viscosity while ensuring protein stability. Typically, sugars are used as stabilizers for protein stabilization, but in the case of formulations containing such stabilizers, viscosity increases accelerate when the protein concentration increases, making it difficult to improve viscosity while ensuring protein stability. Therefore, the development of a formulation that can overcome these limitations is necessary.

[0005] The present disclosure relates to a stable, sugar-free liquid formulation of an anti-IL-4Rα antibody, such as dupilumab. The sugar-free liquid formulation exhibits improved stability and viscosity compared to commercially available formulations of anti-IL-4Rα antibodies, such as dupilumab (e.g., Dupixent), making it applicable to high-concentration formulations, thereby increasing patient convenience.

[0006] One aspect is to provide a liquid formulation comprising an anti-IL-4Rα antibody; a buffer; and an amino acid, wherein the formulation does not contain a sugar, and wherein the pH is from about 4.5 to about 6.5.

[0007] Another aspect is to provide a device comprising the liquid formulation.

[0008] Another aspect provides a method of treating an IL-4Rα associated condition, comprising administering the liquid formulation to a subject in need thereof.

[0009] Another aspect provides the use of the liquid formulation in the manufacture of a medicament for treating an IL-4Rα associated condition.

[0010] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art in the relevant field of the present invention. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Furthermore, numerical values ​​described herein are considered to include the meaning of "about," even if not explicitly stated. The contents of all publications cited as references herein are incorporated herein by reference in their entirety.

[0011] The terms "about" or "approximately" in this specification can generally be interpreted to mean a value or range that is within 10%, 5%, 4%, 3%, 2%, or 1% above or below a given value or range.

[0012] One aspect provides a stable, sugar-free liquid formulation of an anti-IL-4Rα antibody, specifically,

[0013] anti-IL-4Rα antibody;

[0014] buffer; and

[0015] Contains amino acids,

[0016] Does not contain sugar,

[0017] The pH is about 4.5 to about 6.5,

[0018] Provides liquid formulation.

[0019] (1) Antibodies

[0020] The term "antibody" as used herein may be interpreted to mean a full-length antibody or an antigen-binding fragment thereof. The antibody includes a monoclonal antibody, a polyclonal antibody, a humanized antibody, a human antibody, and a chimeric antibody.

[0021] The term "antigen-binding fragment" refers to a fragment comprising the antigen-binding site of an antibody. For example, an antigen-binding fragment includes, but is not limited to, a Fab fragment, an F(ab')2 fragment, an Fc fragment, or an scFv fragment.

[0022] In the present specification, the antibody may be an anti-IL-4Rα antibody. The anti-IL-4Rα antibody may refer to any antibody that binds to the interleukin-4 receptor alpha chain (IL-4Rα). The anti-IL-4Rα antibody may inhibit IL-4 and IL-13 signaling.

[0023] The above anti-IL-4Rα antibody may be dupilumab (CAS No. 1190264-60-8). Therefore, the above liquid formulation may be a stable liquid formulation of dupilumab. Dupilumab is a fully human monoclonal antibody that binds to IL-4Rα and belongs to IgG4. Dupilumab is Dupixent. ® ) is sold under the trade name Dupixent. After receiving approval from the U.S. Food and Drug Administration (FDA) for the treatment of atopic dermatitis, Dupixent is expanding its indications to various type 2 inflammatory diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and eosinophilic esophagitis (EoE). The sequence of dupilumab is known, and it can be produced by general methods known in the art. More detailed information on dupilumab can be easily obtained by those skilled in the art from known databases.

[0024] The term "dupilumab" herein may also be interpreted to mean dupilumab having a modified amino acid sequence (deletion, insertion, and / or substitution) and / or a modified glycosylation characteristic, as long as it does not affect the polypeptide function.

[0025] The above anti-IL-4Rα antibody may be included in a therapeutically effective amount in a liquid formulation.

[0026] The concentration of the anti-IL-4Rα antibody is about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 175 mg / mL, about 5 mg / mL to about 300 mg / mL, about 5 mg / mL to about 250 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 175 mg / mL, about 10 mg / mL to about 300 mg / mL, about 10 mg / mL to about 250 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 175 mg / mL, about 25 mg / mL to about 300 mg / mL, about 25 mg / mL to about 250 mg / mL, about 25 mg / mL to about 200 mg / mL, about 25 mg / mL to about 175 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 250 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 175 mg / mL, about 75 mg / mL to about 300 mg / mL, about 75 mg / mL to about 250 mg / mL, about 75 mg / mL to about 200 mg / mL, about 75 mg / mL to about 175 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 250 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 175 mg / mL, about 125 mg / mL to about 300 mg / mL, about 125 mg / mL to about 250 mg / mL, about 125 mg / mL to about 200 mg / mL, about 125 mg / mL to about 175 mg / mL, about 145 mg / mL to about 300 mg / mL, about 145 mg / mL to about 250 mg / mL, about 145 mg / mL to about 200 mg / mL, about 145 mg / mL to about 180 mg / mL,About 145 mg / mL to about 175 mg / mL, about 149 mg / mL to about 151 mg / mL, about 150 mg / mL to about 300 mg / mL, about 150 mg / mL to about 250 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 170 mg / mL to about 300 mg / mL, about 170 mg / mL to about 250 mg / mL, about 170 mg / mL to about 225 mg / mL, about 170 mg / mL to about 200 mg / mL, about 170 mg / mL to about 180 mg / mL, or about 174 mg / mL may be about 176 mg / mL.

[0027] In one specific example, the concentration of the anti-IL-4Rα antibody may be about 100 mg / mL to about 200 mg / mL.

[0028] In one specific example, the concentration of the anti-IL-4Rα antibody may be about 125 mg / mL to about 200 mg / mL.

[0029] In one specific example, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL to about 200 mg / mL.

[0030] In one specific example, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL to about 175 mg / mL.

[0031] In one specific example, the concentration of the anti-IL-4Rα antibody may be 135 mg / mL to 165 mg / mL.

[0032] In one specific example, the concentration of the anti-IL-4Rα antibody may be 158 mg / mL to 192 mg / mL.

[0033] In certain embodiments, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL.

[0034] In certain embodiments, the concentration of the anti-IL-4Rα antibody may be about 175 mg / mL.

[0035] The concentration of the anti-IL-4Rα antibody may be high. Accordingly, the liquid formulation may be a high-concentration liquid formulation of the anti-IL-4Rα antibody. The high concentration may mean, but is not limited to, 100 mg / mL or more or 150 mg / mL or more, for example, 100 mg / mL to 300 mg / mL or 150 mg / mL to 300 mg / mL.

[0036] (2) Buffer and pH

[0037] Liquid formulations according to one aspect include a buffer. The buffer can function to regulate the pH of the formulation. The buffer can maintain the pH of the liquid formulation at a certain value or within a certain range. Therefore, the buffer can serve to provide a pH of a certain value or within a certain range to the liquid formulation.

[0038] The above buffer may be used without limitation in its type as long as it is applicable to biopharmaceuticals.

[0039] The buffer may include at least one selected from acetate, phosphate, citrate, succinate, malate, tartarate, carbonate, salts thereof, and hydrates thereof.

[0040] The term "salt" may be a pharmaceutically acceptable salt. The salt may include an inorganic acid salt, an organic acid salt, a metal salt, etc. of the compound. The inorganic acid salt may be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfate. The organic acid salt may be a formate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a besylate, a camsylate, an edisyl salt, a trichloroacetic acid, a trifluoroacetate, a benzoate, a gluconate, a methanesulfonate, a glycolate, a succinate, a 4-toluenesulfonate, a galacturonate, an embonate, a glutamate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, or an aspartate. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.

[0041] The term "hydrate" refers to a substance containing water molecules within its molecules. The hydrate may be a monohydrate, a dihydrate, or a trihydrate.

[0042] The pH of the liquid formulation, depending on the aspect, may be from about 5.3 to about 6.5. The pH of the liquid formulation may be provided by a buffer. Alternatively, the pH of the liquid formulation may be adjusted by the addition of any acid (e.g., HCl) or base (e.g., NaOH).

[0043] Specifically, the pH of the formulation can be any range or any value selected from about 4.5 to about 6.5. For example, the pH may be from about 4.5 to about 6.5, from about 4.5 to about 6.0, from about 4.5 to about 5.5, from about 4.5 to about 5.3, from about 4.5 to about 5.2, from about 5.0 to about 6.5, from about 5.0 to about 6.0, from about 5.0 to about 5.5, from about 5.0 to about 5.3, from about 5.0 to about 5.2, from about 5.1 to about 6.5, from about 5.1 to about 6.0, from about 5.1 to about 5.5, from about 5.1 to about 5.3, from about 5.1 to about 5.2, from about 5.2 to about 6.5, from about 5.2 to about 6.0, from about 5.2 to about 5.5, from about 5.2 to about 5.3, from about 5.2 to about 5.2, about 5.3 to about 6.5, about 5.3 to about 6.4, about 5.3 to about 6.3, about 5.3 to about 6.2, about 5.3 to about 6.1, about 5.3 to about 6.0, about 5.4 to about 6.5, about 5.4 to about 6.4, about 5.4 to about 6.3, about 5.4 to about 6.2, about 5.4 to about 6.1, about 5.4 to about 6.0, about 5.5 to about 6.5, about 5.5 to about 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, or about 5.5 to about 6.0.

[0044] In one embodiment, the pH of the liquid formulation can be about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0045] In one embodiment, the buffer may include one or more selected from acetate, a salt thereof, and a hydrate thereof. In one embodiment, the buffer may include acetate. In one embodiment, the buffer may be acetate. In one embodiment, the buffer may include sodium acetate. In one embodiment, the buffer may be sodium acetate.

[0046] The concentration of the buffer may be any range or any value selected from about 0.1 mM to about 50 mM. For example, the concentration of the buffer may be about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 15 mM, about 0.1 mM to about 14 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 14 mM, about 3 mM to about 50 mM, about 3 mM to about 40 mM, about 3 mM to about 30 mM, about 3 mM to about 20 mM, about 3 mM to about 15 mM, about 3 mM to about 14 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 About 30 mM, about 5 mM to about 20 mM, about 5 mM to about 15 mM, about 5 mM to about 14 mM, about 6 mM to about 50 mM, about 6 mM to about 40 mM, about 6 mM to about 30 mM, about 6 mM to about 20 mM, about 6 mM to about 15 mM, about 6 mM to about 14 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 20 mM to about 50 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 25 mM to about 50 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, or about 25 mM to It could be about 30 mM.

[0047] The concentration of the acetate may be any range or any value selected from about 0.1 mM to about 50 mM. For example, the concentration of the acetate may be about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 15 mM, about 0.1 mM to about 14 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 14 mM, about 3 mM to about 50 mM, about 3 mM to about 40 mM, about 3 mM to about 30 mM, about 3 mM to about 20 mM, about 3 mM to about 15 mM, about 3 mM to about 14 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 20 mM, about 5 mM to about 15 mM, about 5 mM to about 14 mM, about 6 mM to about 50 mM, about 6 mM to about 40 mM, about 6 mM to about 30 mM, about 6 mM to about 20 mM, about 6 mM to about 15 mM, about 6 mM to about 14 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 20 mM to about 50 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 25 mM to about 50 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, or about 25 It can be from 1 mM to about 30 mM.

[0048] In one specific embodiment, the concentration of the acetate can be about 6 mM to about 14 mM, about 6 mM to about 12 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, about 8 mM to about 14 mM, about 8 mM to about 12 mM, about 8 mM to about 10 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, or about 12 mM to about 14 mM.

[0049] In one specific embodiment, the concentration of the acetate can be from about 10 mM to about 50 mM, from about 10 mM to about 40 mM, from about 10 mM to about 35 mM, from about 10 mM to about 30 mM, from about 20 mM to about 50 mM, from about 20 mM to about 40 mM, from about 20 mM to about 35 mM, from about 20 mM to about 30 mM, from about 25 mM to about 50 mM, from about 25 mM to about 40 mM, from about 25 mM to about 35 mM, or from about 25 mM to about 30 mM.

[0050] (3) Sugars

[0051] The liquid formulation according to the aspect does not contain saccharide (free of saccharide). Therefore, the liquid formulation may be a saccharide-free formulation.

[0052] The above liquid formulation may have improved stability and improved viscosity compared to commercialized formulations, despite being a saccharide-free formulation.

[0053] The term 'free of component A' or 'substantially free of A' may be interpreted to include cases where component A is not present at all, or where component A is present in trace amounts that do not substantially affect the properties of the formulation, or where it is present in undetectable amounts.

[0054] In this specification, the phrase "does not contain sugars" may be interpreted to mean that no sugar component is present in the formulation, or that the sugar component is present in an amount that cannot function as the intended stabilizer in the formulation.

[0055] The above-mentioned sugar may include sugar and sugar alcohol. Accordingly, the liquid formulation may not include either sugar or sugar alcohol.

[0056] The sugar may be a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide. The sugar may include one or more selected from sucrose, trehalose, galactose, mannose, maltose, lactose, fructose, and glucose.

[0057] The sugar alcohol described above is a general term for polyols having two or more hydroxyl groups, which are formed by reducing an aldehyde group or a ketone group of a sugar to an alcohol group. The sugar alcohol may include at least one selected from mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol. The sugar alcohol includes an anhydride or hydrate of the sugar alcohol. For example, trehalose may include not only trehalose but also trehalose dihydrate.

[0058] In one embodiment, the liquid formulation may not contain any of sucrose, trehalose, sorbitol, and mannitol.

[0059] (4) Amino acids

[0060] Liquid formulations according to the aspect of the invention contain amino acids.

[0061] The above amino acids may include one or more selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, and glutamic acid.

[0062] In one specific embodiment, the amino acid may include one or more selected from arginine, histidine, glycine, methionine, and lysine.

[0063] In one specific embodiment, the amino acid may be selected from:

[0064] 1) Arginine;

[0065] 2) Combination of arginine and lysine;

[0066] 3) Combination of arginine and methionine;

[0067] 4) Histidine;

[0068] 5) Combination of histidine and lysine;

[0069] 6) Combination of histidine and methionine;

[0070] 7) Glycine;

[0071] 8) Combination of glycine and lysine

[0072] 9) A combination of glycine and methionine; or

[0073] 10) A combination of histidine, arginine and methionine.

[0074] The concentration of the amino acid may be any range or any value selected from about 20 mM to about 355 mM.

[0075] In one specific embodiment, the concentration of arginine is about 75 mM to about 165 mM, about 75 mM to about 150 mM, about 75 mM to about 135 mM, about 75 mM to about 125 mM, about 75 mM to about 115 mM, about 75 mM to about 105 mM, about 75 mM to about 100 mM, about 90 mM to about 165 mM, about 90 mM to about 150 mM, about 90 mM to about 135 mM, about 90 mM to about 125 mM, about 90 mM to about 115 mM, about 90 mM to about 105 mM, about 90 mM to about 100 mM, about 95 mM to about 165 mM, about 95 mM to about 150 mM, about 95 mM to about 135 mM, about 95 mM to about 125 mM, about 95 mM to about 115 mM, about 95 mM to about 105 mM, about 95 mM to about 100 mM, about 100 mM to about 165 mM, about 100 mM to about 150 mM, about 100 mM to about 135 mM, about 100 mM to about 125 mM, about 100 mM to about 115 mM, about 100 mM to about 105 mM, about 105 mM to about 165 mM, about 105 mM to about 150 mM, about 105 mM to about 135 mM, about 105 mM to about 125 mM, about 115 mM to about 165 mM, about 115 mM to about 150 mM, about 115 mM to about 135 mM, or 115 mM to about 125 mM. In certain embodiments, the concentration of arginine may be about 100 mM or about 120 mM.

[0076] In one embodiment, the concentration of histidine can be about 85 mM to about 205 mM, about 85 mM to about 175 mM, about 85 mM to about 145 mM, about 85 mM to about 115 mM, about 115 mM to about 205 mM, about 115 mM to about 175 mM, about 115 mM to about 145 mM, about 145 mM to about 205 mM, about 145 mM to about 175 mM, or about 140 mM to about 150 mM. In a particular embodiment, the concentration of histidine can be about 145 mM.

[0077] In one embodiment, the concentration of histidine can be about 30 mM to about 70 mM, about 30 mM to about 60 mM, about 30 mM to about 55 mM, about 30 mM to about 50 mM, 40 mM to about 70 mM, about 40 mM to about 60 mM, about 40 mM to about 55 mM, about 40 mM to about 50 mM, 45 mM to about 70 mM, about 45 mM to about 60 mM, about 45 mM to about 55 mM, about 45 mM to about 50 mM, 50 mM to about 70 mM, about 50 mM to about 60 mM, or about 50 mM to about 55 mM. In a particular embodiment, the concentration of histidine can be about 50 mM.

[0078] The concentration of the glycine is about 125 mM to about 315 mM, about 125 mM to about 290 mM, about 125 mM to about 270 mM, about 125 mM to about 250 mM, about 125 mM to about 230 mM, about 150 mM to about 315 mM, about 150 mM to about 290 mM, about 150 mM to about 270 mM, about 150 mM to about 250 mM, about 150 mM to about 230 mM, about 170 mM to about 315 mM, about 170 mM to about 290 mM, about 170 mM to about 270 mM, about 170 mM to about 250 mM, about 170 mM to about 230 mM, about 190 mM to about 315 mM, about 190 mM to about 290 The concentration of glycine may be about 190 mM to about 270 mM, about 190 mM to about 250 mM, about 190 mM to about 230 mM, about 210 mM to about 315 mM, about 210 mM to about 290 mM, about 210 mM to about 270 mM, about 210 mM to about 250 mM, or about 210 mM to about 230 mM. In certain embodiments, the concentration of glycine may be about 220 mM.

[0079] The concentration of the methionine may be about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, or about 25 mM to about 30 mM. In certain embodiments, the concentration of the methionine may be about 25 mM or about 30 mM.

[0080] The concentration of the lysine may be about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, or about 25 mM to about 30 mM. In certain embodiments, the concentration of the lysine may be about 30 mM.

[0081] In one specific example, the amino acid may be a combination of histidine and methionine. In this case, the concentration of histidine may be about 85 mM to about 205 mM, and the concentration of methionine may be about 20 mM to about 40 mM.

[0082] In one specific example, the amino acid may be a combination of histidine, arginine, and methionine. In this case, the concentration of histidine may be about 30 mM to about 70 mM, the concentration of arginine may be about 80 mM to about 120 mM, and the concentration of methionine may be about 10 mM to about 40 mM.

[0083] The above amino acid may have at least one function of a viscosity reducing agent and a stabilizer. The above amino acid may have both the functions of a viscosity reducing agent and a stabilizer.

[0084] The term "viscosity reducing agent" or "viscosity reducer" refers to a substance that lowers the viscosity of a liquid substance.

[0085] The term "stabilizer" refers to a substance added to a substance during preservation to prevent changes in state or chemical change. The stabilizer may be a thermal stabilizer. The stabilizer may inhibit antibody aggregation.

[0086] The above liquid formulation may have improved viscosity compared to a liquid formulation of an anti-IL-4Rα antibody containing a sugar by including a specific type of amino acid or a specific combination of amino acids instead of containing a sugar.

[0087] The liquid formulation may reduce the high molecular weight species content (%HMW) of the antibody in the liquid formulation by including a specific type of amino acid or a specific combination of amino acids instead of including sugars.

[0088] The above liquid formulation may contain a specific type of amino acid or a specific combination of amino acids instead of a sugar, thereby reducing the %HMW of the antibody in the liquid formulation immediately after preparation or when stored under the same conditions (e.g., 4 weeks at 25°C) compared to a liquid formulation of anti-IL-4Rα antibody containing a sugar.

[0089] The above liquid formulation may have both improved viscosity and stability since it contains a specific type of amino acid or a specific combination of amino acids instead of sugar, thereby reducing both viscosity and %HMW compared to Dupixent containing sugar.

[0090] (5) Surfactant

[0091] Liquid formulations according to the aspect may additionally contain a surfactant.

[0092] Accordingly, the liquid formulation may be a liquid formulation comprising an anti-IL-4Rα antibody; a buffer; an amino acid; and a surfactant, and does not contain a sugar, and having a pH of about 5.3 to about 6.5.

[0093] The surfactant may be selected from any pharmaceutically acceptable surfactants capable of evenly dispersing a protein (e.g., antibody) in a liquid formulation medium.

[0094] The above surfactant may be a nonionic surfactant.

[0095] Specifically, the surfactant may be at least one selected from the group consisting of polysorbate, poloxamer, sorbitan ester of other fatty acids, polyethylene-polypropylene glycol, polyoxyethylene compound, and sodium dodecyl sulfate (SDS).

[0096] The above polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85.

[0097] The above poloxamer may include a PEO-PPO-PEO copolymer (PEO is poly(ethylene oxide) and PPO is poly(propylene oxide)).

[0098] The above sorbitan esters of other fatty acids may mean sorbitan esters of other fatty acids than polysorbates, and may include, for example, sorbitan polyethoxylates.

[0099] The above polyoxyethylene compound may include polyoxyethylene-stearate, polyoxyethylene alkyl ether (alkyl: C1-C30), polyoxyethylene monolyl ether, alkylphenyl polyoxyethylene copolymer (alkyl: C1-C30), etc.

[0100] In one specific example, the surfactant may be a polysorbate.

[0101] In one embodiment, the surfactant may include one or more selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85.

[0102] In one embodiment, the surfactant may include polysorbate 20, polysorbate 80, or a combination thereof.

[0103] In certain embodiments, the surfactant may comprise polysorbate 80. In certain embodiments, the surfactant may be polysorbate 80.

[0104] The concentration of the surfactant may be any range or any value selected from about 0.01% (w / v) to about 0.9% (w / v). For example, the concentration of the surfactant may be from about 0.01% (w / v) to about 0.9% (w / v), from about 0.01% (w / v) to about 0.5% (w / v), from about 0.1% (w / v) to about 0.9% (w / v), from about 0.1% (w / v) to about 0.5% (w / v), from about 0.1% (w / v) to about 0.4% (w / v), from about 0.1% (w / v) to about 0.3% (w / v), from about 0.15% (w / v) to about 0.9% (w / v), from about 0.15% (w / v) to about 0.5% (w / v), from about 0.15% (w / v) to about 0.4% (w / v), from about 0.15% (w / v) to about 0.3% (w / v), or about 0.15% (w / v) to about 0.25% (w / v).

[0105] In certain embodiments, the concentration of the surfactant may be about 0.2% (w / v).

[0106] (6) Diluent

[0107] Liquid formulations according to the aspect may additionally contain a diluent.

[0108] The diluent may be an aqueous carrier. The aqueous carrier may be a pharmaceutically acceptable carrier that is safe and non-toxic when administered to humans, such as water, saline solution, Ringer's solution, dextrose, or a mixture thereof.

[0109] In one specific example, the diluent may be water. Accordingly, the liquid formulation may be an aqueous liquid formulation.

[0110] (7) Formulation

[0111] The term "liquid formulation" means a formulation in liquid form.

[0112] The liquid formulation according to the aspect is a stable liquid formulation of anti-IL-4Rα antibody.

[0113] The liquid formulation according to the aspect may be a pharmaceutical formulation of an anti-IL-4Rα antibody.

[0114] The term "pharmaceutical composition" or "pharmaceutical preparation" means a preparation that allows the biological activity of the active ingredient to be effectively carried out and does not contain additional components that are seriously toxic to the subject to which the preparation is administered.

[0115] The term "pharmaceutical formulation" refers to the product of a process that combines an active drug with chemicals to produce the final drug product.

[0116] The term "pharmaceutically acceptable" may refer to excipients, carriers, vehicles, diluents, additives, salts, etc. that are suitable for administration to a subject.

[0117] Liquid formulations according to the daily pattern are Dupixent ® ) may be a biosimilar. The liquid formulation according to the aspect has improved stability and improved viscosity compared to Dupixent.

[0118] The term "biosimilar," also known as "biogeneric," refers to a copy of an original biopharmaceutical. Because biopharmaceuticals are produced through cells, not synthetic chemicals, they cannot be perfectly identical to the original drug. Therefore, a biopharmaceutical copy is called a biosimilar, meaning it is similar, though not identical, to the original drug.

[0119] Liquid formulations according to the aspect of the work may be selected from the following items:

[0120] 1) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer; and an amino acid, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0121] 2) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer; an amino acid; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0122] 3) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; an amino acid comprising arginine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0123] 4) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; amino acids comprising arginine and lysine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0124] 5) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; amino acids comprising arginine and methionine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0125] 6) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; an amino acid comprising histidine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0126] 7) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; amino acids comprising histidine and lysine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0127] 8) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; amino acids comprising histidine and methionine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0128] 9) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; an amino acid comprising glycine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0129] 10) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; an amino acid comprising glycine and lysine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0130] 11) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer comprising acetate; amino acids comprising glycine and methionine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;

[0131] 12) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; about 6 mM to about 14 mM of acetate; about 20 mM to about 355 mM of an amino acid, wherein the amino acid comprises at least one selected from arginine, histidine, glycine, methionine, and lysine; and about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, wherein the formulation does not contain a sugar, and wherein the pH is about 4.5 to about 6.5;

[0132] 13) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; about 6 mM to about 14 mM of acetate; about 85 mM to about 205 mM of histidine; about 20 mM to about 40 mM of methionine; and about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, wherein the formulation does not contain a sugar, and has a pH of about 4.5 to about 6.5;

[0133] 14) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; 6 mM±1 mM of acetate, 145 mM±20 mM of histidine; 30 mM±2 mM of methionine; and 0.2%±0.1% (w / v) of polysorbate 80, free of sugars, and having a pH of 5.9±0.2;

[0134] 15) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; 8 mM±1 mM of acetate, 115 mM to 175 mM of histidine; 30 mM±2 mM of methionine; and 0.2%±0.1% (w / v) of polysorbate 80, free of sugars, and having a pH of 4.5 to 6.2;

[0135] 16) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; 10 mM±1 mM of acetate, 85 mM to 205 mM of histidine; 20 mM to 40 mM of methionine; and 0.2%±0.1% (w / v) of polysorbate 80, free of sugars, and having a pH of 4.5 to 6.5;

[0136] 17) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; 12 mM±1 mM of acetate, 115 mM to 175 mM of histidine; 25 mM to 35 mM of methionine; and 0.2%±0.1% (w / v) of polysorbate 80, free of sugars, and having a pH of 4.5 to 6.2;

[0137] 18) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; 14 mM±1 mM of acetate, 145 mM±20 mM of histidine; 30 mM±2 mM of methionine; and 0.2%±0.1% (w / v) of polysorbate 80, free of sugars, and having a pH of 5.9±0.2;

[0138] 19) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab, about 20 mM to about 40 mM of acetate, about 40 mM to about 60 mM of histidine, about 80 mM to about 120 mM of arginine, about 10 mM to about 40 mM of methionine, and about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, wherein the formulation does not contain sugars and has a pH of about 4.5 to about 5.9; or

[0139] 20) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab, 30 mM±5 mM of acetate, 50 mM±5 mM of histidine, 100 mM±5 mM of arginine, 25 mM±5 mM of methionine, and about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, free of sugars, and having a pH of 5.2±0.2.

[0140] (8) Stability and viscosity

[0141] Liquid formulations according to the aspect can have low viscosity while ensuring the stability of the antibody.

[0142] In the examples of this specification, two experiments were conducted. First, the viscosity and high molecular weight species content (%HMW) of sugar-free and sugar-containing formulations were compared and evaluated, confirming that the sugar-free formulation had improved viscosity and stability compared to the sugar-containing formulation. Second, through a comparative evaluation of viscosity and %HMW with the Dupixent formulation, it was confirmed that various sugar-free anti-IL-4Rα antibody liquid formulations with different buffer concentrations, amino acid concentrations, and pHs simultaneously improved stability and viscosity compared to commercialized formulations.

[0143] The above liquid formulation may have improved viscosity. The term "improvement" in viscosity may refer to a "reduction" in viscosity. Accordingly, the above liquid formulation may have reduced viscosity. The unit of viscosity may be expressed as cP (centiPoise).

[0144] The above sugar-free liquid formulation may have improved viscosity compared to a sugar-containing anti-IL-4Rα antibody liquid formulation.

[0145] The viscosity of the above sugar-free liquid formulation may be reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% compared to the viscosity of the anti-IL-4Rα antibody liquid formulation containing sugar.

[0146] The viscosity of the above sugar-free liquid formulation may be less than 17.0 cP, 16.8 cP or less, 16.0 cP or less, 15.0 cP or less, 14.0 cP or less, 13.0 cP or less, 12.0 cP or less, 11.0 cP or less, 10.0 cP or less, 9.0 cP or less, 8.0 cP or less, or 7.0 cP or less.

[0147] The liquid formulation according to one aspect may have a reduced viscosity compared to Dupixent. In one embodiment, the liquid formulation according to one aspect may have a reduced viscosity compared to the viscosity of 11.1 cP (centiPoise) of Dupixent 200 mg. In another embodiment, the liquid formulation according to one aspect may have a reduced viscosity compared to the viscosity of 300 mg of Dupixent.

[0148] In one embodiment, a sugar-free liquid formulation comprising an amino acid selected from the following can have a viscosity reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% relative to the viscosity of a Dupixent formulation:

[0149] 1) Arginine;

[0150] 2) Combination of arginine and lysine;

[0151] 3) Combination of arginine and methionine;

[0152] 4) Histidine;

[0153] 5) Combination of histidine and lysine;

[0154] 6) Combination of histidine and methionine;

[0155] 7) Glycine;

[0156] 8) Combination of glycine and lysine;

[0157] 9) A combination of glycine and methionine; or

[0158] 10) A combination of histidine, arginine and methionine.

[0159] In one embodiment, the sugar-free liquid formulation comprising the amino acid combination of histidine and methionine can have a viscosity that is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% relative to the viscosity of the Dupixent formulation.

[0160] Accordingly, the viscosity of the liquid formulation may be less than 11.1 cP. The viscosity of the liquid formulation may be less than 11.1 cP, 11.0 cP or less, 10.5 cP or less, 10.0 cP or less, 9.5 cP or less, 9.0 cP or less, 8.5 cP or less, 8.0 cP or less, 7.5 cP or less, 7.0 cP or less, or 6.5 cP or less. The viscosity of the above liquid formulation is 5.0 cP or more and less than 11.1 cP, 5.0 cP to 11.0 cP, 5.0 cP to 10.5 cP, 5.0 cP to 10.0 cP, 5.0 cP to 9.5 cP, 5.0 cP to 9.0 cP, 5.0 cP to 8.5 cP, 5.0 cP to 8.0 cP, 5.0 cP to 7.5 cP, 5.0 cP to 7.0 cP, 5.0 cP to 6.5 cP, 5.5 cP or more and less than 11.1 cP, 5.5 cP to 11.0 cP, 5.5 cP to 10.5 cP, 5.5 cP to 10.0 cP, 5.5 cP to 9.5 cP, 5.5 cP to 9.0 cP, 5.5 cP to 8.5 cP, 5.5 cP to 8.0 cP, 5.5 cP to 7.5 cP, 5.5 cP to 7.0 cP, 5.5 cP to 6.5 cP, 6.0 cP or more to less than 11.1 cP, 6.0 cP to 11.0 cP, 6.0 cP to 10.5 cP, 6.0 cP to 10.0 cP, 6.0 cP to 9.5 cP, 6.0 cP to 9.0 cP, 6.0 cP to 8.5 cP, 6.0 cP to 8.0 cP, 6.0 cP to 7.5 cP, 6.0 cP to 7.0 cP, 6.0 cP to 6.5 cP, 6.5 cP or more but less than 11.1 cP, 6.5 cP to 11.0 cP, 6.5 cP to 10.5 cP, 6.5 cP to 10.0 cP, 6.5 cP to 9.5 cP, 6.5 cP to 9.0 cP, 6.5 cP to 8.5 cP, 6.5 cP to 8.0 cP, 6.5 cP to 7.5 cP, 6.5 cP to 7.0 cP, 7.0 cP or more to less than 11.1 cP, 7.0 cP to 11.0 cP, 7.0 cP to 10.5 cP, 7.0 cP to 10.0 cP, 7.0 cP to 9.5 cP, 7.0 cP to 9.0 cP, 7.0 cP to 8.5 cP, 7.0 cP to 8.0 cP, 7.5 cP or more to less than 11.1 cP, 7.5 cP to 11.0 cP, 7.5 cP to 10.5 cP, 7.5 cP to 10.0 cP, 7.5 cP to 9.5 cP, 7.5 cP to 9.0 cP, 7.5 cP to 8.5 cP, 7.5 cP to It may be 8.0 cP, 8.0 cP or more and less than 11.1 cP, 8.0 cP to 11.0 cP, 8.0 cP to 10.5 cP, 8.0 cP to 10.0 cP, 8.0 cP to 9.5 cP, 8.0 cP to 9.0 cP, or 8.0 cP to 8.5 cP.

[0161] The term "stability" means that an antibody (e.g., dupilumab) contained in a formulation substantially retains its physical stability, chemical stability, and / or biological activity before and after administration, during further manufacturing processes, storage, or preservation. For example, it can be understood to mean that the degree of loss of stability, such as aggregation, degradation, denaturation (acidic or basic), oxidation, etc. of the antibody contained in the formulation is 20% or less, 15% or less, 10% or less, or 5% or less compared to the initial storage. Accordingly, "excellent stability" or "improved stability" can mean a low protein aggregation rate, a low protein degradation rate, a low protein denaturation rate, a low amino acid oxidation rate, etc. during storage. Physical stability, chemical stability, and / or biological activity can be evaluated by conventionally known methods.

[0162] The term "aggregate" may refer to high molecular weight (HMW) species formed by aggregation of antibody proteins. The term "protein aggregation rate" may be expressed as the percentage of high molecular weight species content (%HMW) of the antibody in the formulation at a given point in time. %HMW may be measured by, but is not limited to, size exclusion chromatography (SEC). For example, "improved stability" may mean that the %HMW of the antibody measured for the formulation is reduced by at least 0.01%, at least 0.1%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, or at least 20% compared to the original formulation. A decrease in %HMW may mean that the degree to which the antibody in the formulation undergoes aggregation is reduced, thereby improving stability.

[0163] The stability assessment may be performed immediately after manufacturing the formulation; or after a certain period of storage under accelerated stability conditions or stress stability conditions. The accelerated stability conditions may include conditions used in accelerated tests for pharmaceuticals, such as a temperature of 25±2°C and a relative humidity (RH) of 60±5%. The stress stability conditions may include conditions used in stress tests for pharmaceuticals, such as a temperature of 40±2°C and a relative humidity (RH) of 75+5%.

[0164] The above liquid formulation may have a reduced high molecular weight species content (%HMW).

[0165] The above sugar-free liquid formulation may have a reduced %HMW compared to a sugar-containing anti-IL-4Rα antibody liquid formulation.

[0166] The above sugar-free liquid formulation may have a %HMW of antibody measured after 4 weeks of storage at 25°C reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 12%, at least 15%, or at least 20% compared to the sugar-containing formulation.

[0167] The above sugar-free liquid formulation may have a %HMW of antibody measured after 4 weeks of storage at 25°C of less than 3.70%, 3.62% or less, 3.50% or less, 3.40% or less, 3.30% or less, 3.20% or less, 3.10% or less, 3.00% or less, 2.90% or less, 2.80% or less, 2.70% or less, 2.60% or less, 2.50% or less, 2.40% or less, 2.30% or less, 2.20% or less, or 2.10% or less.

[0168] According to one aspect, the sugar-free liquid formulation may have a reduced %HMW compared to Dupixent. In one embodiment, the sugar-free liquid formulation according to one aspect may have a reduced %HMW compared to 2.03% of antibody measured immediately after preparation of 200 mg of Dupixent.

[0169] In one embodiment, the sugar-free liquid formulation comprising the amino acid combination of histidine and methionine may have a %HMW of antibody measured immediately after manufacture reduced by at least 2%, at least 5%, at least 10%, at least 15%, or at least 20% compared to the Dupixent formulation.

[0170] The above sugar-free liquid formulation may have a %HMW of antibody measured immediately after manufacture of less than 2.03%, 2.00% or less, 1.90% or less, 1.80% or less, or 1.70% or less.

[0171] (9) Device

[0172] Another aspect provides a device comprising a liquid formulation according to the above aspect.

[0173] The device is primarily used for parenteral administration. Parenteral administration may include, for example, subcutaneous, intramuscular, intravenous, intraperitoneal, intracerebrospinal, intraarticular, intrasynovial, or intrathecal administration. The device may be accompanied by instructions for administration.

[0174] The device may contain the liquid formulation in a container selected from, but not limited to, a syringe, a pre-filled syringe, a pre-filled pen, a microinfusor, an autoinjector, a bottle, a vial, and a tube.

[0175] The above device may be in a single-dose form or a multiple-dose form.

[0176] In one embodiment, the device may comprise the liquid formulation in a prefilled syringe. The prefilled syringe may be a single-dose prefilled syringe.

[0177] In one specific embodiment, the device may comprise the liquid formulation in a prefilled pen. The prefilled pen may be a single-dose prefilled pen.

[0178] (10) Treatment of diseases

[0179] Another aspect provides a method for treating an IL-4Rα-associated condition, comprising administering to a subject in need thereof a liquid formulation according to the above aspect. The liquid formulation may be in a form contained in a device.

[0180] Another aspect provides the use of a liquid formulation according to the above aspect in the manufacture of a medicament for treating an IL-4Rα associated condition.

[0181] The method of treating the IL-4Rα associated condition may further comprise, prior to the administering step, a step of identifying a subject in need of administration of an anti-IL-4Rα antibody (e.g., dupilumab).

[0182] The subject may be a subject requiring administration of a liquid formulation containing the anti-IL-4Rα antibody (e.g., dupilumab). The subject requiring administration of the liquid formulation containing the anti-IL-4Rα antibody (e.g., dupilumab) may be a subject having a disease or disorder that can be significantly treated (e.g., symptoms can be eliminated, alleviated, relieved, or improved, etc.) by administration of the anti-IL-4Rα antibody. The subject may be selected from mammals, including humans.

[0183] The above liquid formulation can be administered in a pharmaceutically effective amount.

[0184] The IL-4Rα associated condition may include any condition, disease, or disorder that can be treated by administration of an anti-IL-4Rα antibody. The IL-4Rα associated condition that can be treated by administration of an anti-IL-4Rα antibody (e.g., dupilumab) may include any indication currently approved or that may be approved in the future for an anti-IL-4Rα antibody (e.g., dupilumab).

[0185] The IL-4Rα-associated condition may be an IL-4-mediated disease and / or an IL-13-mediated disease. The IL-4-mediated disease may include any disease that can be treated by inhibition of IL-4 signaling. The IL-13-mediated disease may include any disease that can be treated by inhibition of IL-13 signaling. The IL-4Rα-associated condition may include any disease that can be treated by dual blockade of IL-4 and IL-13.

[0186] The IL-4Rα-related condition may include an inflammatory disease, an allergic disease, or an autoimmune disease. The inflammatory disease may be a Type 2 inflammatory disease.

[0187] The IL-4Rα-related condition may be any one selected from, but is not limited to, atopic dermatitis, asthma, chronic rhinosinusitis (CRS), chronic rhinosinusitis with nasal polyposis (CRSwNP), allergic fungal rhinosinusitis (AFRS), eosinophilic esophagitis (EoE), prurigo nodularis (PN), bullous pemhigoid (BP), chronic spontaneous urticarial (CSU), chronic inducible urticarial (CIndU), and chronic obstructive pulmonary disease (COPD).

[0188] The above atopic dermatitis may be moderate-to-severe atopic dermatitis.

[0189] The above asthma may be moderate-to-severe asthma.

[0190] (11) Route of administration and dosage

[0191] Liquid formulations, depending on the mode of administration, may be administered parenterally. Such parenteral routes may include subcutaneous administration, intravenous administration, etc. Parenteral administration may be by bolus injection or continuous infusion.

[0192] In certain embodiments, the liquid formulation may be for subcutaneous injection.

[0193] The above liquid formulation may be formulated into a formulation suitable for the above administration route. For example, the above liquid formulation may be formulated into an injection, a ready-to-use injectable, etc., but is not limited thereto.

[0194] The liquid formulation may be formulated to contain the entire amount or a pharmaceutically effective amount of the anti-IL-4Rα antibody (e.g., dupilumab) in one formulation, or may be formulated to contain two or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) formulations. The liquid formulation may be included in a single-dose or multi-dose form of the device.

[0195] The above liquid formulation may be administered to the body in one dose (e.g., within 1 minute, within 30 seconds, within 20 seconds, or within 10 seconds); or may be administered to the body gradually over a period of, but not limited to, 5 minutes, 10 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, or 240 minutes.

[0196] The target of administration of the above liquid formulation may be selected from mammals including primates (e.g., humans, etc.), rodents (e.g., mice, rats, guinea pigs, hamsters, rabbits, etc.), cats, dogs, pigs, cows, horses, etc.

[0197] The pharmaceutically effective amount of the above liquid formulation or the anti-IL-4Rα antibody (e.g., dupilumab) contained therein may refer to an amount or dosage that can exhibit a desired pharmacological effect, such as elimination, reduction, alleviation, or improvement of symptoms. The pharmaceutically effective amount may be determined in various ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition (severity of condition), food, administration time, administration interval, administration route, excretion rate, response sensitivity, previous therapy, clinical history, etc. The dosage may be adjusted according to the judgment of the physician in charge. The pharmaceutically effective amount may be administered at once or administered in two or more divided doses.

[0198] For example, the liquid formulation may be administered once every two to four weeks over a period of two weeks or more at a dose such that the anti-IL-4Rα antibody (e.g., dupilumab) is 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg.

[0199] The above liquid formulation can be prepared as a general bulk formulation, and the components of the liquid formulation can be adjusted to a higher concentration than that required for administration and used after being suitably diluted before administration.

[0200] A sugar-free liquid formulation of an anti-IL-4Rα antibody according to one aspect may have improved stability and viscosity compared to existing commercially available formulations. Therefore, the liquid formulation may have high stability and low viscosity even when containing a high concentration of the antibody, thereby increasing patient convenience during injection. Accordingly, the liquid formulation may be useful as a pharmaceutical agent for treating IL-4Rα-related conditions.

[0201] Figure 1 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation.

[0202] Figure 2 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of a sugar-free formulation and a sugar-containing formulation.

[0203] Figure 3 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a Dupixent formulation.

[0204] Figure 4 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of a sugar-free formulation and a Dupixent formulation.

[0205] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0206]

[0207] [Experimental Method]

[0208] 1. Viscosity measurement

[0209] The viscosity of the sample was measured using a viscometer (manufacturer: RheoSense, model number: VROC initium one plus). The analysis was conducted at a temperature of 25°C. The same sample was divided into 11 segments and the slope fit R was calculated. 2 The viscosity value of each sample was calculated by taking the average value for values ​​greater than 0.9995.

[0210] 2. Analysis of high molecular weight species content (% high molecular weight species, %HMW)

[0211] ​The percentage of high molecular weight species (%HMW) was determined using size exclusion chromatography (SEC) using a HPLC system from Waters. The protein was separated into three peaks based on its molecular weight. These three peaks correspond to the HMW peak (protein aggregation), the Monomer peak, and the LMW peak (protein degradation), in descending order of retention time (i.e., increasing protein molecular weight).

[0212] - %HMW = {area of ​​HMW / area of ​​(HMW + monomer + LMW)}*100

[0213] Each formulation sample for stability testing was stored in a chamber maintaining accelerated stability conditions of 25±2℃ and 60±5% relative humidity (RH).

[0214] [Example]

[0215] Example 1. Evaluation of viscosity and %HMW according to the presence or absence of sugar

[0216] For formulations containing sugars, improvements in viscosity and %HMW were evaluated when sugars were removed after fixing buffer concentration, amino acid concentration, and pH concentration.

[0217] Using dupilumab (CAS No. 1190264-60-8) as an anti-IL-4Rα antibody, aqueous liquid formulations having the compositions shown in Table 1 below were prepared. The viscosity and %HMW of each formulation were measured after 4 weeks of storage at 25°C.

[0218] No. Excipient 1 (saccharide) Excipient 2 (amino acid) Excipient 3 (amino acid) Viscosity (cP) %HMW (25℃, 4 weeks) 1. Sugar-free 120 mM arginine - 8.1 2.9 3 2.4 3% (w / v) Trehalose 70 mM arginine - 12.7 3.1 4 3.8% (w / v) Sorbitol 70 mM arginine - 11.6 3.2 1.4 1.8% (w / v) Mannitol 70 mM arginine - 14.2 3.3 8 5. Sugar-free 120 mM arginine 30 mM lysine 7.9 2.8 0 6.4 3% (w / v) Trehalose 70 mM arginine 30 mM lysine 10.8 2.9 3 7 1.8% (w / v) Sorbitol 70 mM arginine 30 mM Lysine 11.9 3.0 2 8 1.8% (w / v) Mannitol 70 mM Arginine 30 mM Lysine 13.5 3.10 9 Sugar-free 120 mM Arginine 30 mM Methionine 7.8 2.59 10 4.3% (w / v) Trehalose 70 mM Arginine 30 mM Methionine 11.5 2.7 1 1 1.8% (w / v) Sorbitol 70 mM Arginine 30 mM Methionine 11.2 2.76 12 1.8% (w / v) Mannitol 70 mM Arginine 30 mM Methionine 14.9 2.9 4 13 Sugar-free 145 mM Histidine-8.7 ​​2.26 14 4.3% (w / v) Trehalose 80 mM Histidine-16.8 2.59 15 1.8% (w / v) Sorbitol 80 mM Histidine-14.82.58161.8% (w / v) Mannitol 80 mM Histidine-13.82.5617Saccharide-free 145 mM Histidine 30 mM Lysine 8.82.19184.3% (w / v) Trehalose 80 mM Histidine 30 mM Lysine 11.12.49191.8% (w / v) Sorbitol 80 mM Histidine 30 mM Lysine 12.82.51201.8% (w / v) Mannitol 80 mM Histidine 30 mM Lysine 15.32.4921Saccharide-free 145 mM Histidine 30 mM Methionine 9.42.09224.3% (w / v) Trehalose 80 mM Histidine 30 mM Methionine 12.42.33231.8% (w / v) Sorbitol 80 mM histidine 30 mM methionine 13.0 2.3 4 2 4 1.8% (w / v) Mannitol 80 mM histidine 30 mM methionine 13.4 2.3525 Sugar-free 220 mM glycine - 14.9 3.62 264.3% (w / v) Trehalose 120 mM glycine - 23.5 3.69 271.8% (w / v) Sorbitol 120 mM glycine - 43.2 3.72 281.8% (w / v) Mannitol 120 mM glycine - 35.8 3.69 29 Sugar-free 220 mM glycine 30 mM lysine 10.8 3.41 304.3% (w / v) Trehalose 120 mM glycine 30 mM lysine 31.4 3.68 311.8% (w / v) Sorbitol 120 mM glycine 30 mM lysine 38.2 3.79 321.8% (w / v) Mannitol 120 mM glycine 30 mM Lysine22.03.6833Saccharide-free220 mM Glycine30 mM Methionine16.83.10344.3% (w / v) Trehalose120 mM Glycine30 mM Methionine27.63.25351.8% (w / v) Sorbitol120 mM Glycine30 mM Methionine38.03.26361.8% (w / v) Mannitol120 mM Glycine30 mM Methionine30.93.23.

[0219] a All formulations contained 175 mg / mL dupilumab, 10 mM sodium acetate, 0.2% (w / v) polysorbate 80, and had a pH of 6.0.

[0220] Figure 1 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation.

[0221] Figure 2 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of a sugar-free formulation and a sugar-containing formulation.

[0222] As a result, as shown in Table 1, Figure 1, and Figure 2, when the buffer concentration, amino acid concentration, surfactant concentration, and pH were fixed in the formulation containing sugars and then the sugars were removed, the viscosity and %HMW 25℃ / 4주 It was confirmed that improvements were made simultaneously.

[0223] Example 2. Comparative evaluation of viscosity and %HMW of sugar-free formulations and Dupixent

[0224] As shown in Table 2 below, viscosity and %HMW immediately after manufacturing (0 day, Initial) were measured for 25 sugar-free formulations with different buffer concentrations, amino acid concentrations, and pHs and Dupixent formulations containing sugars.

[0225] No. a Buffer pH Excipient 1 (Sugar) Excipient 2 (Amino Acid) Excipient 3 (Amino Acid) Viscosity %HMW (Initial) 376 mM Sodium Acetate 5.9 Sugar-Free 145 mM Histidine 30 mM Methionine 8.1 1.76 388 mM Sodium Acetate 5.6 115 mM Histidine 25 mM Methionine 7.6 1.71 39 6.225 mM Methionine 9.7 1.92 40 5.635 mM Methionine 8.0 1.73 416.235 mM Methionine 9.9 1.88 42 5.61 75 mM Histidine 25 mM Methionine 7.7 1.69 43 6.225 mM Methionine 8.0 1.78 44 5.635 mM Methionine 7.7 1.62 45 6.235 mM Methionine 8.5 1.8 1.4 6 10 mM Sodium Acetate 5.9 85 mM Histidine 30 mM Methionine 9.5 1.8 4 4 7 5.3 1.45 mM Histidine 30 mM Methionine 7.4 1.6 4 4 8 5.930 mM Methionine 8.0 1.7 5 4 9 6.530 mM Methionine 10.0 1.9 8 5 0 5.920 mM Methionine 8.0 1.7 5 1 5.940 mM Methionine 8.3 1.7 8 5 2 5.92 0 5 mM Histidine 30 mM Methionine 7.4 1.6 2 5 3 12 mM Sodium Acetate 5.6 1 15 mM Histidine 25 mM Methionine 8.2 1.7 1 5 4 6.225 mM Methionine 8.9 1.9 0 5 5 5.635 mM Methionine 7.9 1.7 2.5 6.235 mM Methionine 9.11 2.5 7.5 6.175 mM Histidine 25 mM Methionine 8.0 1.6 6.5 8.6 225 mM Methionine 8.11 3.5 9.5 635 mM Methionine 8.11 6.9 60 6.235 mM Methionine 8.6 1.8 16 114 mM Sodium Acetate 5.9 1.45 mM Histidine 30 mM Methionine 8.3 1.7 4.62 b12.5 mM sodium acetate + 20 mM histidine 5.95% (w / v) sucrose 50 mM arginine - 11.12.03

[0226] a All formulations contain 175 mg / mL dupilumab and 0.2% (w / v) polysorbate 80

[0227] b Formulation 62 is a Dupixent formulation.

[0228] Figure 3 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a Dupixent formulation.

[0229] Figure 4 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of a sugar-free formulation and a Dupixent formulation.

[0230] As a result, as shown in Table 2, FIG. 3, and FIG. 4, it was confirmed that viscosity and %HMW were simultaneously improved in the sugar-free formulation containing 6 to 14 mM sodium acetate, 85 to 205 mM histidine, 20 to 40 mM methionine, and having a pH of 5.3 to 6.5 compared to the Dupixent formulation (Formulation 62).

[0231]

[0232] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. Anti-IL-4Rα antibody; Buffer; and Contains amino acids, Contains no sugar, The pH is about 4.5 to about 6.5, Liquid formulation.

2. A liquid formulation according to claim 1, wherein the anti-IL-4Rα antibody is dupilumab.

3. A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is from about 5 mg / mL to about 300 mg / mL.

4. A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is about 100 mg / mL to about 200 mg / mL.

5. A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is from about 125 mg / mL to about 200 mg / mL.

6. A liquid formulation according to claim 1, wherein the buffer comprises at least one selected from acetate, phosphate, citrate, succinate, malate, tartrate, and carbonate.

7. A liquid formulation according to claim 1, wherein the buffer comprises acetate.

8. A liquid formulation according to claim 1, wherein the buffer is sodium acetate.

9. A liquid formulation according to any one of claims 1 to 8, wherein the concentration of the buffer is from about 5 mM to about 50 mM.

10. A liquid formulation according to claim 7, wherein the concentration of the acetate is from about 6 mM to about 14 mM.

11. A liquid formulation according to claim 7, wherein the concentration of the acetate is from about 20 mM to about 40 mM.

12. A liquid formulation according to claim 1, wherein the amino acid comprises at least one selected from arginine, histidine, glycine, methionine, and lysine.

13. A liquid formulation according to claim 1, wherein the amino acid is selected from the following: 1) Arginine; 2) Combination of arginine and lysine; 3) Combination of arginine and methionine; 4) Histidine; 5) Combination of histidine and lysine; 6) Combination of histidine and methionine; 7) Glycine; 8) Combination of glycine and lysine; 9) A combination of glycine and methionine; or 10) A combination of histidine, arginine and methionine.

14. A liquid formulation according to claim 12 or 13, wherein the concentration of arginine is from about 75 mM to about 165 mM.

15. A liquid formulation according to claim 12 or 13, wherein the concentration of histidine is from about 85 mM to about 205 mM.

16. A liquid formulation according to claim 12 or 13, wherein the concentration of histidine is from about 30 mM to about 70 mM.

17. A liquid formulation according to claim 12 or 13, wherein the concentration of glycine is from about 125 mM to about 315 mM.

18. A liquid formulation according to claim 12 or 13, wherein the concentration of methionine is from about 10 mM to about 40 mM.

19. A liquid formulation according to claim 12 or 13, wherein the concentration of lysine is about 20 mM to about 40 mM.

20. A liquid formulation according to claim 1, wherein the amino acid is a combination of histidine and methionine.

21. In claim 20, The concentration of the histidine is about 85 mM to about 205 mM, A liquid formulation wherein the concentration of methionine is about 20 mM to about 40 mM.

22. A liquid formulation according to claim 1, wherein the amino acid is a combination of histidine, arginine, and methionine.

23. In claim 22, The concentration of the above histidine is about 30 mM to about 70 mM, The concentration of the above arginine is about 80 mM to about 120 mM, A liquid formulation wherein the concentration of methionine is from about 10 mM to about 40 mM.

24. A liquid formulation according to any one of claims 1 to 23, further comprising a surfactant.

25. A liquid formulation according to claim 24, wherein the surfactant comprises a nonionic surfactant.

26. A liquid formulation according to claim 24, wherein the surfactant comprises polysorbate 20, polysorbate 80, or a combination thereof.

27. A liquid formulation according to any one of claims 24 to 26, wherein the concentration of the surfactant is 0.01% (w / v) to 0.9% (w / v).

28. A liquid formulation according to any one of claims 24 to 26, wherein the concentration of the surfactant is from about 0.1% (w / v) to about 0.3% (w / v).

29. A liquid formulation according to any one of claims 1 to 28, wherein the viscosity of the liquid formulation is reduced by 5% or more compared to the viscosity of the formulation containing sugar.

30. A liquid formulation according to any one of claims 1 to 28, wherein the viscosity of the liquid formulation is less than 17.0 cP.

31. A liquid formulation according to any one of claims 1 to 28, wherein the viscosity of the liquid formulation is less than 11.1 cP.

32. In any one of claims 1 to 28, A liquid formulation, wherein the high molecular weight species content ratio (%HMW) of antibodies in the liquid formulation measured after 4 weeks of storage at 25°C is reduced by 1% or more compared to a formulation containing sugar.

33. In any one of claims 1 to 28, A liquid formulation, wherein the high molecular weight species content (%HMW) of the antibody measured after 4 weeks of storage at 25°C is less than 3.70%.

34. In any one of claims 1 to 28, A liquid formulation, wherein the high molecular weight species content ratio (%HMW) of antibodies in the liquid formulation measured immediately after manufacturing is reduced by 2% or more compared to a formulation containing sugar.

35. In any one of claims 1 to 28, A liquid formulation, wherein the high molecular weight species content ratio (%HMW) of the antibody measured immediately after manufacture is less than 2.03%.

36. Dupilumab at about 100 mg / mL to about 200 mg / mL; About 6 mM to about 14 mM acetate; About 20 mM to about 355 mM of an amino acid, said amino acid comprising at least one selected from arginine, histidine, glycine, methionine, and lysine; and Containing about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, Contains no sugar, The pH is about 5.3 to about 6.5, Liquid formulation.

37. Dupilumab at about 100 mg / mL to about 200 mg / mL; About 6 mM to about 14 mM acetate; Histidine at about 85 mM to about 205 mM; about 20 mM to about 40 mM methionine; and Containing about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, Contains no sugar, The pH is about 5.3 to about 6.5, Liquid formulation.

38. Dupilumab at about 100 mg / mL to about 200 mg / mL; Acetate of about 20 mM to about 40 mM; About 40 mM to about 60 mM histidine; About 80 mM to about 120 mM arginine; about 10 mM to about 40 mM methionine; and Containing about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, Contains no sugar, The pH is about 4.5 to about 5.9, Liquid formulation.

39. A liquid formulation for subcutaneous injection according to any one of claims 1 to 38.

40. A device comprising a liquid formulation of any one of claims 1 to 39.

41. A device according to claim 40, comprising the liquid formulation in a container selected from a syringe, a pre-filled syringe, a pre-filled pen, a microinfusor, an autoinjector, a bottle, a vial, and a tube.

42. A method of treating an IL-4Rα associated condition, comprising administering to a subject in need thereof a liquid formulation of any one of claims 1 to 39.

43. A method for treating an IL-4Rα-associated condition according to claim 42, wherein the IL-4Rα-associated condition is an IL-4-mediated disease or an IL-13-mediated disease.

44. In claim 42, the IL-4Rα related condition is any one selected from atopic dermatitis, asthma, chronic rhinosinusitis (CRS), chronic rhinosinusitis with nasal polyposis (CRSwNP), allergic fungal rhinosinusitis (AFRS), eosinophilic esophagitis (EoE), prurigo nodularis (PN), bullous pemhigoid (BP), chronic spontaneous urticarial (CSU), chronic inducible urticarial (CIndU), and chronic obstructive pulmonary disease (COPD). A method for treating a condition associated with IL-4Rα.

45. Use of a liquid formulation of any one of claims 1 to 39 in the manufacture of a medicament for treating an IL-4Rα associated condition.

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