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

Abstract

The invention relates to an anti-IL-4Rα antibody, a buffer, a liquid formulation containing amino acids, not containing sugars, and having a pH of 4.5 to 6.5, a device containing the same, and the use thereof for treating IL-4Rα-related conditions. Since the liquid formulation can ensure the stability of the antibody while improving viscosity without containing sugars, it can be usefully used as a medicine for treating IL-4Rα-related conditions.

Description

Technology Field

[0001] The invention relates to a stable sugar-free liquid formulation of an anti-IL-4Rα antibody, a device comprising the same, and the use thereof for treating IL-4Rα-related conditions. Background Technology

[0002] Compared to conventional protein drugs, antibody drugs have larger molecular weights and complex secondary and higher-order structures, which poses a risk of physicochemical instability. For this reason, there is a need to develop optimal formulations for antibody drugs that guarantee quality and stability throughout the entire process of manufacturing, storage, and patient administration. Protein instability can originate from various external factors, such as temperature, light, and chemical elements; this can lead to reduced activity and efficacy, or cause immunogenicity upon administration to the human body. Therefore, it is crucial to mitigate such instability in antibody drugs to maintain optimal quality until they are administered to patients. Methods such as modifying buffer solutions, evaluating optimal pH, and adding stabilizers are used to achieve this optimal quality. Since the material properties of each antibody protein differ, and the optimal combination of buffer solutions, pH, and stabilizers may vary, it is necessary to derive formulations suitable for the target substance to address these challenges.

[0003] For example, dupilumab, an anti-IL-4Rα antibody, is Dupixent ®It is manufactured and sold under the brand name ). Dupixent 200 mg is a 1.14 mL liquid formulation composed 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 composed 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 regarding the type and concentration of each component are being reviewed and applied, such as adding sugars, amino acids, buffers, surfactants, etc., as in the product composition of Dupixent, or applying a specific pH.

[0004] Furthermore, in addition to ensuring the stability described above, there is a need to develop high-concentration formulations that enhance therapeutic activity while reducing the frequency of administration through high-dose injections in small volumes, taking into account patient convenience during injection. When developing high-concentration formulations, limitations arise as protein concentration increases, such as protein instability due to aggregation and impaired injectability caused by increased viscosity. Therefore, it is crucial to develop formulations that can improve viscosity while ensuring protein stability. Typically, sugars are used as stabilizers for protein stabilization; however, formulations containing such stabilizers exhibit accelerated viscosity growth as protein concentration increases, limiting the ability to improve viscosity while simultaneously ensuring protein stability. Consequently, the development of formulations capable of overcoming these limitations is necessary. The problem to be solved

[0005] This specification relates to a stable sugar-free liquid formulation of an anti-IL-4Rα antibody such as dupilumab. Patient convenience may be increased because the sugar-free liquid formulation has improved stability and viscosity compared to commercial formulations of anti-IL-4Rα antibodies such as dupilumab (e.g., Dupixent), making it applicable even to high-concentration formulations.

[0006] One aspect provides a liquid formulation comprising an anti-IL-4Rα antibody; a buffer; and an amino acid, which does not contain sugars and has a pH of about 4.5 to about 6.5.

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

[0008] Another aspect provides a method for treating an IL-4Rα-related condition, comprising the step of administering the above-mentioned liquid formulation to an individual in need thereof.

[0009] Another aspect is to provide the use of the liquid formulation in the manufacture of a drug for treating IL-4Rα-related conditions. means of solving the problem

[0010] All technical terms used herein shall be used in the sense generally understood by those skilled in the art in the relevant field of the present invention, unless otherwise defined. Furthermore, while preferred methods or samples are described herein, similar or equivalents are also included within the scope of the present invention. Additionally, numerical values ​​described herein are deemed to include the meaning of "approximately" unless explicitly stated otherwise. The contents of all publications cited as references herein are incorporated by reference in their entirety.

[0011] In this specification, the terms “about” or “approximately” may be interpreted to mean a value or range 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] It does not contain sugars,

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

[0018] It provides a liquid formulation.

[0019] (1) Antibody

[0020] In this specification, the term "antibody" may be interpreted to mean a full-length antibody or an antigen-binding fragment thereof. The antibody includes monoclonal antibodies, polyclonal antibodies, humanized antibodies, human antibodies, and chimeric antibodies.

[0021] The term "antigen-binding fragment" means a fragment containing 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 a scFv fragment.

[0022] In this 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 ® It is sold under the brand name ). After receiving approval from the U.S. FDA (Food and Drug Administration) as a treatment for 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 can be produced by general methods known in the art. Further information regarding dupilumab is readily available to those skilled in the art from known databases.

[0024] In this specification, the term "dupilumab" may also be interpreted to include dupilumab in which the amino acid sequence is modified (deleted, inserted, and / or substituted) and / or the glycosylation properties are modified to the extent that polypeptide function is not affected.

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

[0026] The concentration of the above 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 to about It may be 176 mg / mL.

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

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

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

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

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

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

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

[0034] In a specific embodiment, 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 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, but is not limited thereto.

[0036] (2) Buffer and pH

[0037] A liquid formulation according to one aspect includes a buffer. The buffer can function to control the pH of the formulation. The pH of the liquid formulation can be maintained at a certain value or range by the buffer. Therefore, the buffer can play a role in providing a pH of a certain value or range to the liquid formulation.

[0038] The above buffer can be used without restriction on its type as long as it is applicable to biopharmaceuticals.

[0039] The above buffer may include one or more 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 inorganic salts, organic salts, metal salts, etc. of a compound. Inorganic salts may be hydrochlorides, bromates, phosphates, sulfates, or disulfates. Organic salts may be formates, acetates, propionates, lactates, oxalates, tartrates, malates, maleates, citrates, fumarates, besylates, camsylates, edicils, trichloroacetic acid, trifluoroacetates, benzosates, gluconates, methanesulfonates, glycolates, succinates, 4-toluenesulfonates, galacturoneates, emvonates, glutamates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, or aspartates. Metal salts may be calcium salts, sodium salts, magnesium salts, strontium salts, or potassium salts.

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

[0042] The pH of the liquid formulation according to one aspect may be 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 may be any range selected from about 4.5 to about 6.5 or any value. For example, the above pH is about 4.5 to about 6.5, about 4.5 to about 6.0, about 4.5 to about 5.5, about 4.5 to about 5.3, about 4.5 to about 5.2, about 5.0 to about 6.5, about 5.0 to about 6.0, about 5.0 to about 5.5, about 5.0 to about 5.3, about 5.0 to about 5.2, about 5.1 to about 6.5, about 5.1 to about 6.0, about 5.1 to about 5.5, about 5.1 to about 5.3, about 5.1 to about 5.2, about 5.2 to about 6.5, about 5.2 to about 6.0, about 5.2 to about 5.5, about 5.2 to about 5.3, about 5.1 to about 5.3, about 5.1 to about 5.2, about 5.2 to about 6.5, about 5.2 to about 6.0, about 5.2 to about 5.5, about 5.2 to about 5.3, about 5.2 to about 5.2, It may be 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 may 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 comprise one or more selected from acetate, salts thereof, and hydrates thereof. In one embodiment, the buffer may comprise acetate. In one embodiment, the buffer may be acetate. In one embodiment, the buffer may comprise sodium acetate. In one embodiment, the buffer may be sodium acetate.

[0046] The concentration of the above buffer may be any range or any value selected within about 0.1 mM to about 50 mM. For example, the concentration of the buffer is 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 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 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 about It can be 30 mM.

[0047] The concentration of the acetate may be any range or any value selected within about 0.1 mM to about 50 mM. For example, the concentration of the acetate is 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 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 about It can be 30 mM.

[0048] In one embodiment, the concentration of the acetate may 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 embodiment, the concentration of the acetate may be 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 about 30 mM.

[0050] (3) Sugars

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

[0052] Although the above liquid formulation is a saccharide-free formulation, it may have improved stability and improved viscosity compared to commercially available formulations.

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

[0054] In this specification, the phrase “does not contain sugars” may be interpreted as meaning that sugar components are not present in the formulation, or are included in an amount that is insufficient to function as an intended stabilizer within the formulation.

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

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

[0057] The above sugar alcohol is a general term for polyols having two or more hydroxyl groups, formed by reducing the aldehyde or ketone group of a sugar to an alcohol group. The above sugar alcohol may include one or more selected from mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol. The above sugar alcohol includes anhydrous or hydrated sugar alcohols. 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] A liquid formulation according to one aspect contains 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 embodiment, the amino acid may include one or more selected from arginine, histidine, glycine, methionine, and lysine.

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

[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) Combination of histidine, arginine, and methionine.

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

[0075] In one embodiment, the concentration of the 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 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, about 105 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 the arginine may be about 100 mM or about 120 mM.

[0076] In one embodiment, the concentration of histidine may 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 specific embodiment, the concentration of histidine may be about 145 mM.

[0077] In one embodiment, the concentration of histidine may 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 specific embodiment, the concentration of histidine may be about 50 mM.

[0078] The concentration of the above 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 mM, about It may be 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 a specific embodiment, 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 a specific embodiment, the concentration of the lysine may be about 30 mM.

[0081] In one embodiment, 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 embodiment, 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 one or more functions among a viscosity reducer and a stabilizer. The above amino acid may have both functions of a viscosity reducer and a stabilizer.

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

[0085] The term "stabilizer" refers to a substance added to prevent changes in state or chemical changes when preserving a substance. The stabilizer may be a thermal stabilizer. The stabilizer may inhibit the aggregation of antibodies.

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

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

[0088] The above liquid formulation does not contain sugars but contains a specific type of amino acid or a specific combination of amino acids, so that the %HMW of the antibody in the liquid formulation may be reduced immediately after preparation or when stored under the same conditions (e.g., 4 weeks at 25°C) compared to an anti-IL-4Rα antibody liquid formulation containing sugars.

[0089] The above liquid formulation does not contain sugars but contains a specific type of amino acid or a specific combination of amino acids, and since both viscosity and %HMW are reduced compared to Dupixent containing sugars, viscosity and stability may be improved simultaneously.

[0090] (5) Surfactant

[0091] A liquid formulation according to one aspect may additionally include a surfactant.

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

[0093] The above 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 one or more 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, etc.

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

[0098] The sorbitan ester of the other fatty acid mentioned above may refer to a sorbitan ester of a fatty acid other than polysorbate, and may include, for example, sorbitan polyethoxylates.

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

[0100] In one embodiment, the surfactant may be 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 a specific embodiment, the surfactant may include polysorbate 80. In a specific embodiment, the surfactant may be polysorbate 80.

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

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

[0106] (6) Diluent

[0107] A liquid formulation according to one aspect may additionally include a diluent.

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

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

[0110] (7) Formulation

[0111] The term "liquid formulation" refers to a formulation in a liquid state.

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

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

[0114] The terms "pharmaceutical composition" or "pharmaceutical preparation" refer to a preparation that enables the biological activity of an active ingredient to function effectively and does not contain additional ingredients that are severely toxic to the subject to whom the preparation is to be administered.

[0115] The term "pharmaceutical formulation" refers to the product of a process in which an active drug is combined with a chemical substance to produce a final pharmaceutical product.

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

[0117] The liquid formulation according to the aspect is Dupixent ® It may be a biosimilar. A liquid formulation according to one 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 drug. Since biopharmaceuticals are produced using cells rather than synthesized chemical products, it is impossible to replicate a product that is perfectly identical to the original drug. Therefore, a copy of a biopharmaceutical drug is called a biosimilar because, while not identical to the original drug, it is similar.

[0119] A liquid formulation according to one aspect may be selected from the following items:

[0120] 1) an anti-IL-4Rα antibody; a buffer; and a liquid formulation comprising amino acids, not containing sugars, 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, which does not contain sugars and has a pH of about 4.5 to about 6.5;

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

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

[0124] 5) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer containing acetate; an amino acid containing arginine and methionine; and a surfactant, wherein the liquid formulation does not contain sugars and has a pH of about 4.5 to about 6.5;

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

[0126] 7) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer containing acetate; an amino acid containing histidine and lysine; and a surfactant, wherein the liquid formulation does not contain sugars and has a pH of about 4.5 to about 6.5;

[0127] 8) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer containing acetate; an amino acid containing histidine and methionine; and a surfactant, wherein the liquid formulation does not contain sugars and has a pH of about 4.5 to about 6.5;

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

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

[0130] 11) A liquid formulation comprising an anti-IL-4Rα antibody; a buffer containing acetate; an amino acid containing glycine and methionine; and a surfactant, wherein the liquid formulation does not contain sugars and has 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 amino acids, said amino acids comprising one or more selected from arginine, histidine, glycine, methionine, and lysine; and about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, which does not contain sugars and has a pH of 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, which does not contain sugars 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 acetate, 145 mM±20 mM histidine; 30 mM±2 mM methionine; and 0.2%±0.1% (w / v) of polysorbate 80, which does not contain sugars and has 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 acetate, 115 mM to 175 mM histidine; 30 mM±2 mM methionine; and 0.2%±0.1% (w / v) of polysorbate 80, which does not contain sugars and has 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 acetate, 85 mM to 205 mM histidine; 20 mM to 40 mM methionine; and 0.2%±0.1% (w / v) of polysorbate 80, which does not contain sugars and has 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 acetate, 115 mM to 175 mM histidine; 25 mM to 35 mM methionine; and 0.2%±0.1% (w / v) of polysorbate 80, which does not contain sugars and has 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 acetate, 145 mM±20 mM histidine; 30 mM±2 mM methionine; and 0.2%±0.1% (w / v) of polysorbate 80, which does not contain sugars and has 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, which 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, which does not contain sugars and has a pH of 5.2±0.2.

[0140] (8) Stability and viscosity

[0141] A liquid formulation according to one aspect can ensure antibody stability while having low viscosity.

[0142] In the examples of this specification, two experiments were performed. First, the viscosity and the percentage of high molecular weight species (%HMW) were compared and evaluated for a sugar-free formulation and a sugar-containing formulation, and it was confirmed that the sugar-free formulation had improved viscosity and improved 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 liquid formulations of anti-IL-4Rα antibodies with different buffer concentrations, amino acid concentrations, and pH simultaneously showed improved stability and viscosity compared to commercially available formulations.

[0143] The above liquid formulation may have improved viscosity. The 'improvement' of viscosity may mean a 'reduction' of viscosity. Therefore, the above liquid formulation may have reduced viscosity. The unit of viscosity may be expressed in 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 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, or 60% or more compared to the viscosity of the anti-IL-4Rα antibody liquid formulation containing sugars.

[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] A liquid formulation according to one aspect may have a reduced viscosity compared to Dupixent. In one embodiment, a 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, a liquid formulation according to one aspect may have a reduced viscosity compared to the viscosity of Dupixent 300 mg.

[0148] In one embodiment, a sugar-free liquid formulation comprising an amino acid selected from the following may have a viscosity reduced by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, or 30% or more relative to the viscosity of the 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) Combination of histidine, arginine, and methionine.

[0159] In one embodiment, a sugar-free liquid formulation comprising an amino acid combination of histidine and methionine may have a viscosity reduced by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, or 30% or more compared 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 to 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 to 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 to 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 8.0 It may be cP, 8.0 cP or more to 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 the antibody contained in the formulation (e.g., dupilumab) substantially retains its physical stability, chemical stability, and / or biological activity before and after administration, during additional manufacturing processes, or during storage. For example, it may be understood to mean that the degree of loss of stability, such as agglutination, degradation, denaturation (acidic or basic), or oxidation 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 state of storage. Accordingly, "excellent stability" or "improved stability" may mean a low rate of protein agglutination, low rate of protein degradation, low rate of protein denaturation, low rate of amino acid oxidation, etc. Physical stability, chemical stability, and / or biological activity may be evaluated by commonly known methods.

[0162] The term "aggregate" may refer to high molecular weight (HMW) species formed by the aggregation of antibody proteins. The term "protein aggregation rate" may be expressed as the percentage of high molecular weight species (%HMW) of antibodies within the formulation at any given time. %HMW may be measured by size exclusion chromatography (SEC), but is not limited thereto. For example, "improved stability" may mean that the %HMW of the antibody measured for the formulation has decreased by 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, or 20% or more compared to the existing formulation. A decrease in %HMW may indicate improved stability resulting from a reduced degree of antibody aggregation within the formulation.

[0163] The above stability evaluation may be performed immediately after manufacturing the formulation; or after storage for a certain period under accelerated stability conditions or severe stability conditions. The above accelerated stability conditions may include conditions used in accelerated tests for pharmaceuticals, for example, a temperature of 25±2°C and a relative humidity (RH) of 60±5%. The above severe stability conditions may include conditions used in stress tests for pharmaceuticals, for example, 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 ratio (%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 storage at 25°C for 4 weeks reduced by 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 12% or more, 15% or more, or 20% or more compared to a formulation containing sugars.

[0167] The above sugar-free liquid formulation may have a %HMW of antibody measured after storage at 25°C for 4 weeks 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] A sugar-free liquid formulation according to one aspect may have a reduced %HMW compared to Dupixent. In one embodiment, compared to the %HMW of the antibody measured immediately after preparation of Dupixent 200 mg being 2.03%, a sugar-free liquid formulation according to one aspect may have a reduced %HMW.

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

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

[0171] (9) Device

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

[0173] The above device is primarily used for parenteral administration. The parenteral administration may include, for example, subcutaneous, intramuscular, intravenous, intraperitoneal, intracerebrospinal, intra-articular, synovial, or intrathecal administration. The device may be accompanied by instructions for administration.

[0174] The above device may contain 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, but is not limited thereto.

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

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

[0177] In one embodiment, the device may contain the liquid formulation in a pre-filled pen. The pre-filled pen may be a single-dose pre-filled pen.

[0178] (10) Treatment of disease

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

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

[0181] The method for treating the above IL-4Rα-related condition may further include, prior to the administration step, a step of identifying an individual requiring administration of an anti-IL-4Rα antibody (e.g., dupilumab).

[0182] The above individual may be an individual requiring administration of a liquid formulation containing the above anti-IL-4Rα antibody (e.g., dupilumab). The individual requiring administration of the above liquid formulation containing the above anti-IL-4Rα antibody (e.g., dupilumab) may be an individual having a disease or disorder that can be significantly treated (e.g., removal, alleviation, remission, or improvement of symptoms, etc.) by administration of the anti-IL-4Rα antibody. The above individual may be selected from mammals, including humans.

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

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

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

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

[0187] The above IL-4Rα-related conditions may be 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 pemmhigoid (BP), chronic spontaneous urticarial (CSU), chronic inducible urticarial (CIndU), and chronic obstructive pulmonary disease (COPD), but are not limited thereto.

[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] A liquid formulation according to one aspect may be administered via a parenteral route. The parenteral route may include subcutaneous administration, intravenous administration, etc. Parenteral administration may be by bolus injection or continuous infusion.

[0192] In a specific embodiment, the liquid formulation may be for subcutaneous injection.

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

[0194] The liquid formulation may be formulated so that the entire amount or a pharmaceutically effective amount of an anti-IL-4Rα antibody (e.g., dupilumab) is contained in a single formulation, or may be formulated so that it is divided among two or more formulations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). The liquid formulation may be included in the single-dose or multiple-dose forms of the device.

[0195] The above liquid formulation may be administered into the body in a single dose of the entire amount of the anti-IL-4Rα antibody (e.g., dupilumab) contained in one formulation (e.g., within 1 minute, within 30 seconds, within 20 seconds, or within 10 seconds); or administered slowly into the body over a period of 5 minutes or more, 10 minutes or more, 30 minutes or more, 60 minutes or more, 90 minutes or more, 120 minutes or more, 150 minutes or more, 180 minutes or more, 210 minutes or more, or 240 minutes or more, but is not limited thereto.

[0196] The subjects for 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, cattle, horses, etc.

[0197] The pharmaceutically effective dose of the above liquid formulation or the anti-IL-4Rα antibody (e.g., dupilumab) contained therein may refer to an amount or dosage capable of producing a desired pharmacological effect, e.g., the elimination, alleviation, or improvement of symptoms. The pharmaceutically effective dose may vary depending on factors such as the formulation method, mode of administration, patient's age, weight, sex, pathological condition (severity of condition), food, time of administration, interval of administration, route of administration, elimination rate, response responsiveness, prior therapy, clinical history, etc. The dose may be adjusted at the discretion of the attending physician. The pharmaceutically effective dose may be administered as a single dose or divided into two or more doses.

[0198] For example, the above liquid formulation may be administered once every 2 to 4 weeks over a period of 2 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 manufactured as a general bulk formulation, and the components of the liquid formulation are adjusted to a concentration higher than that required for administration and can be appropriately diluted before administration. Effects of the invention

[0200] A sugar-free liquid formulation of an anti-IL-4Rα antibody according to one aspect may have improved stability and improved viscosity compared to existing commercial formulations. Therefore, even when containing a high concentration of antibody, the liquid formulation exhibits high stability and low viscosity, which can increase patient convenience during injection. Accordingly, the liquid formulation can be usefully employed as a medicine for treating IL-4Rα-related conditions. Brief explanation of the drawing

[0201] Figure 1 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation. Figure 2 is a graph showing the results of measuring the ratio of high molecular weight species content (%HMW) of sugar-free formulations and sugar-containing formulations. Figure 3 is a graph showing the results of measuring the viscosity of the sugar-free formulation and the Dupixent formulation. Figure 4 is a graph showing the results of measuring the ratio of high molecular weight species content (%HMW) of sugar-free formulations and Dupixent formulations. Specific details for implementing the invention

[0202] The present invention will be explained in more detail below through the following examples. However, the following examples are merely illustrative of the present invention and do not limit the scope of the present invention.

[0203] [Experimental Method]

[0204] 1. Viscosity measurement

[0205] The viscosity of the sample was measured using a viscometer (Manufacturer: RheoSense, Model: VROC initium one plus). The analysis was conducted at a temperature of 25°C. After measuring the same sample in 11 segments, the slope fit R 2 The viscosity value of each sample was calculated by finding the average value for values ​​greater than or equal to 0.9995.

[0206] 2. Analysis of %high molecular weight species (%HMW) content

[0207] The percentage of high molecular weight species (%HMW) was determined using size exclusion chromatography (SEC) with a Water HPLC system. The proteins were separated into a total of three peaks according to their molecular weight. These three peaks correspond to the HMW peak (protein aggregation), Monomer peak, and LMW peak (protein degradation), in order of decreasing retention time, i.e., increasing molecular weight.

[0208] - %HMW = {area of ​​HMW / area of ​​(HMW + monomer + LMW)}*100

[0209] Each formulation sample for the stability test was stored in a chamber maintaining accelerated stability conditions at a temperature of 25±2℃ and a relative humidity (RH) of 60±5%.

[0210] [Example]

[0211] Example 1. Evaluation of viscosity and %HMW according to the presence or absence of sugars

[0212] For formulations containing sugars, the improvement in viscosity and %HMW was evaluated by removing the sugars while keeping the buffer concentration, amino acid concentration, and pH concentration constant.

[0213] An aqueous liquid formulation having the composition of Table 1 below was prepared using dupilumab (CAS No. 1190264-60-8) as the anti-IL-4Rα antibody. The viscosity and %HMW of each formulation were measured after storage at 25°C for 4 weeks.

[0214] No. Excipient 1 (Sugars) Excipient 2 (amino acid) Excipient 3 (amino acid) Viscosity (cP) %HMW(25℃, 4 weeks) 1 Sugar-free 120 mM arginine - 8.1 2.93 2 4.3% (w / v) Trehalose 70 mM arginine - 12.7 3.14 3 1.8% (w / v) Sorbitol 70 mM arginine - 11.6 3.21 4 1.8% (w / v) Mannitol 70 mM arginine - 14.2 3.38 5 Sugar-free 120 mM arginine 30 mM lysine 7.9 2.80 6 4.3% (w / v) Trehalose 70 mM arginine 30 mM lysine 10.8 2.93 7 1.8% (w / v) Sorbitol 70 mM arginine 30 mM lysine 11.9 3.02 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 2.71 11 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 2.94 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 - 14.8 2.58 16 1.8% (w / v) Mannitol 80 mM histidine - 13.8 2.56 17 Sugar-free 145 mM histidine 30 mM lysine 8.8 2.19 18 4.3% (w / v) Trehalose 80 mM histidine 30 mM lysine 11.1 2.49 19 1.8% (w / v) Sorbitol 80 mM histidine 30 mM lysine 12.8 2.51 20 1.8% (w / v) Mannitol 80 mM histidine 30 mM lysine 15.3 2.49 21 Sugar-free 145 mM histidine 30 mM methionine 9.4 2.09 22 4.3% (w / v) Trehalose 80 mM histidine 30 mM methionine 12.4 2.33 23 1.8% (w / v) Sorbitol 80 mM histidine 30 mM methionine 13.0 2.34 24 1.8% (w / v) Mannitol 80 mM histidine 30 mM methionine 13.4 2.35 25 Sugar-free 220 mM glycine - 14.9 3.62 26 4.3% (w / v) Trehalose 120 mM glycine - 23.5 3.69 27 1.8% (w / v) Sorbitol 120 mM glycine - 43.2 3.72 28 1.8% (w / v) Mannitol 120 mM glycine - 35.8 3.69 29 Sugar-free 220 mM glycine 30 mM lysine 10.8 3.41 30 4.3% (w / v) Trehalose 120 mM glycine 30 mM lysine 31.4 3.68 31 1.8% (w / v) Sorbitol 120 mM glycine 30 mM lysine 38.2 3.79 32 1.8% (w / v) Mannitol 120 mM glycine 30 mM lysine 22.0 3.68 33 Sugar-free 220 mM glycine 30 mM methionine 16.8 3.10 34 4.3% (w / v) Trehalose 120 mM glycine 30 mM methionine 27.6 3.25 35 1.8% (w / v) Sorbitol 120 mM glycine 30 mM methionine 38.0 3.26 36 1.8% (w / v) Mannitol 120 mM glycine 30 mM methionine 30.9 3.23

[0215] aAll formulations contain 175 mg / mL dupilumab, 10 mM sodium acetate, 0.2% (w / v) polysorbate 80, and have a pH of 6.0.

[0216] Figure 1 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation.

[0217] Figure 2 is a graph showing the results of measuring the ratio of high molecular weight species content (%HMW) of sugar-free formulations and sugar-containing formulations.

[0218] As a result, as shown in Table 1, Figure 1, and Figure 2, when sugars were removed from a sugar-containing formulation while keeping the buffer concentration, amino acid concentration, surfactant concentration, and pH constant, the viscosity and %HMW 25℃ / 4주 It was confirmed that it was improved simultaneously.

[0219] Example 2. Comparative evaluation of viscosity and %HMW between sugar-free formulation and Dupixent

[0220] As shown in Table 2 below, viscosity and %HMW immediately after preparation (0 day, Initial) were measured for 25 sugar-free formulations and a Dupixent formulation containing sugars, with different buffer concentrations, amino acid concentrations, and pH.

[0221] No. a buffer pH Excipient 1 (Sugars) Excipient 2 (amino acid) Excipient 3 (amino acid) viscosity %HMW (Initial) 37 6 mM sodium acetate 5.9 Sugar-free 145 mM histidine 30 mM methionine 8.1 1.76 38 8 mM sodium acetate 5.6 115 mM histidine 25 mM methionine 7.6 1.71 39 6.2 25 mM methionine 9.7 1.92 40 5.6 35 mM methionine 8.0 1.73 41 6.2 35 mM methionine 9.9 1.88 42 5.6 175 mM histidine 25 mM methionine 7.7 1.69 43 6.2 25 mM methionine 8.0 1.78 44 5.6 35 mM methionine 7.7 1.62 45 6.2 35 mM methionine 8.5 1.81 46 10 mM sodium acetate 5.9 85 mM histidine 30 mM methionine 9.5 1.84 47 5.3 145 mM histidine 30 mM methionine 7.4 1.64 48 5.9 30 mM methionine 8.0 1.75 49 6.5 30 mM methionine 10.0 1.98 50 5.9 20 mM methionine 8.0 1.7 51 5.9 40 mM methionine 8.3 1.78 52 5.9 205 mM histidine 30 mM methionine 7.4 1.62 53 12 mM sodium acetate 5.6 115 mM histidine 25 mM methionine 8.2 1.71 54 6.2 25 mM methionine 8.9 1.90 55 5.6 35 mM methionine 7.9 1.72 56 6.2 35 mM methionine 9.1 1.92 57 5.6 175 mM histidine 25 mM methionine 8.0 1.66 58 6.2 25 mM methionine 8.1 1.83 59 5.6 35 mM methionine 8.1 1.69 60 6.2 35 mM methionine 8.6 1.81 61 14 mM sodium acetate 5.9 145 mM histidine 30 mM methionine 8.3 1.74 62 b 12.5 mM sodium acetate + 20 mM histidine 5.9 5% (w / v) sucrose 50 mM arginine - 11.1 2.03

[0222] a All formulations contain 175 mg / mL dupilumab and 0.2% (w / v) polysorbate 80.

[0223] b Formulation 62 is the Dupixent formulation.

[0224] Figure 3 is a graph showing the results of measuring the viscosity of the sugar-free formulation and the Dupixent formulation.

[0225] Figure 4 is a graph showing the results of measuring the ratio of high molecular weight species content (%HMW) of sugar-free formulations and Dupixent formulations.

[0226] As a result, as shown in Table 2, Figure 3, and Figure 4, it was confirmed that viscosity and %HMW were simultaneously improved in a sugar-free formulation containing 6 to 14 mM sodium acetate, 85 to 205 mM histidine, and 20 to 40 mM methionine with a pH of 5.3 to 6.5 compared to the Dupixent formulation (Formulation 62).

[0227] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

Claim 1 A liquid formulation comprising an anti-IL-4Rα antibody; a buffer; and amino acids, not comprising sugars, and having a pH of about 4.5 to about 6.

5. Claim 2 A liquid formulation according to claim 1, wherein the anti-IL-4Rα antibody is dupilumab. Claim 3 A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is about 5 mg / mL to about 300 mg / mL. Claim 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. Claim 5 A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is about 125 mg / mL to about 200 mg / mL. Claim 6 A liquid formulation according to claim 1, wherein the buffer comprises one or more selected from acetate, phosphate, citrate, succinate, maleate, tartarate, and carbonate. Claim 7 A liquid formulation according to claim 1, wherein the buffer comprises acetate. Claim 8 A liquid formulation according to claim 1, wherein the buffer is sodium acetate. Claim 9 A liquid formulation according to any one of claims 1 to 8, wherein the concentration of the buffer is about 5 mM to about 50 mM. Claim 10 A liquid formulation according to claim 7, wherein the concentration of the acetate is about 6 mM to about 14 mM. Claim 11 A liquid formulation according to claim 7, wherein the concentration of the acetate is about 20 mM to about 40 mM. Claim 12 A liquid formulation according to claim 1, wherein the amino acid comprises one or more selected from arginine, histidine, glycine, methionine, and lysine. Claim 13 A liquid formulation according to claim 1, wherein the amino acid is selected from the following: 1) arginine; 2) a combination of arginine and lysine; 3) a combination of arginine and methionine; 4) histidine; 5) a combination of histidine and lysine; 6) a combination of histidine and methionine; 7) glycine; 8) a combination of glycine and lysine; 9) a combination of glycine and methionine; or 10) a combination of histidine, arginine, and methionine. Claim 14 A liquid formulation according to claim 12 or 13, wherein the concentration of arginine is about 75 mM to about 165 mM. Claim 15 A liquid formulation according to claim 12 or 13, wherein the concentration of histidine is about 85 mM to about 205 mM. Claim 16 A liquid formulation according to claim 12 or 13, wherein the concentration of histidine is about 30 mM to about 70 mM. Claim 17 A liquid formulation according to claim 12 or 13, wherein the concentration of glycine is about 125 mM to about 315 mM. Claim 18 A liquid formulation according to claim 12 or 13, wherein the concentration of methionine is about 10 mM to about 40 mM. Claim 19 A liquid formulation according to claim 12 or 13, wherein the concentration of lysine is about 20 mM to about 40 mM. Claim 20 A liquid formulation according to claim 1, wherein the amino acid is a combination of histidine and methionine. Claim 21 A liquid formulation according to claim 20, wherein the concentration of histidine is about 85 mM to about 205 mM and the concentration of methionine is about 20 mM to about 40 mM. Claim 22 A liquid formulation according to claim 1, wherein the amino acid is a combination of histidine, arginine, and methionine. Claim 23 A liquid formulation according to claim 22, wherein the concentration of histidine is about 30 mM to about 70 mM, the concentration of arginine is about 80 mM to about 120 mM, and the concentration of methionine is about 10 mM to about 40 mM. Claim 24 A liquid formulation according to any one of claims 1 to 23, further comprising a surfactant. Claim 25 A liquid formulation according to claim 24, wherein the surfactant comprises a nonionic surfactant. Claim 26 A liquid formulation according to claim 24, wherein the surfactant comprises polysorbate 20, polysorbate 80, or a combination thereof. Claim 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). Claim 28 A liquid formulation according to any one of claims 24 to 26, wherein the concentration of the surfactant is about 0.1% (w / v) to about 0.3% (w / v). Claim 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 sugars. Claim 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. Claim 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. Claim 32 A liquid formulation according to any one of claims 1 to 28, wherein the ratio of the high molecular weight species content (%HMW) of the antibody in the liquid formulation measured after storage at 25°C for 4 weeks is reduced by 1% or more compared to a formulation containing sugars. Claim 33 A liquid formulation according to any one of claims 1 to 28, wherein the ratio of the high molecular weight species content (%HMW) of the antibody measured after storage at 25°C for 4 weeks is less than 3.70%. Claim 34 A liquid formulation according to any one of claims 1 to 28, wherein the ratio of the high molecular weight species content (%HMW) of the antibody in the liquid formulation measured immediately after preparation is reduced by 2% or more compared to a formulation containing sugars. Claim 35 A liquid formulation according to any one of claims 1 to 28, wherein the high molecular weight species content ratio (%HMW) of the antibody measured immediately after preparation is less than 2.03%. Claim 36 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 amino acids, wherein the amino acids comprise one or more selected from arginine, histidine, glycine, methionine, and lysine; and about 0.1% (w / v) to about 0.9% (w / v) of polysorbate 80, which does not contain sugars, and has a pH of about 5.3 to about 6.

5. Claim 37 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, which does not contain sugars and has a pH of about 5.3 to about 6.

5. Claim 38 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, which does not contain sugars and has a pH of about 4.5 to about 5.

9. Claim 39 A liquid formulation for subcutaneous injection, in any one of claims 1 to 38. Claim 40 A device comprising a liquid formulation of any one of claims 1 to 39. Claim 41 A device according to claim 40, wherein the liquid formulation is contained 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. Claim 42 A method for treating an IL-4Rα-related condition, comprising the step of administering a liquid formulation of any one of claims 1 to 39 to an individual in need thereof. Claim 43 A method for treating an IL-4Rα-related condition according to claim 42, wherein the IL-4Rα-related condition is an IL-4-mediated disease or an IL-13-mediated disease. Claim 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 pemphigoid (BP), chronic spontaneous urticarial (CSU), chronic inducible urticarial (CIndU), and chronic obstructive pulmonary disease (COPD). Methods to treat related conditions. Claim 45 Use of a liquid formulation of any one of claims 1 to 39 in the manufacture of a drug for treating an IL-4Rα-related condition.

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