Stable liquid formulation of Anti-il-4rα antibody

Abstract

The present invention relates to: a liquid formulation comprising an anti-IL-4Rα antibody, a saccharide, and an amino acid and not comprising a buffer; a device comprising same; and a use thereof for treating IL-4Rα-related conditions. The liquid formulation can improve the viscosity of the antibody while ensuring the stability thereof, and thus can be effectively used as a medicine for treating IL-4Rα-related conditions.

Description

Stable liquid formulation of anti-IL-4Rα antibody

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

[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] 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, there are limitations such as protein instability caused by aggregation and impaired injectability due to increased viscosity as protein concentration increases; therefore, it is important 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 increase as protein concentration rises, limiting the ability to improve viscosity while simultaneously ensuring protein stability. To address this, formulations can be developed that improve viscosity and ensure protein stability by inhibiting protein aggregation through the inclusion of viscosity-reducing agents.

[0005] However, verifying the developed formulation requires a long period of time because key quality must be evaluated up to the shelf life under storage temperature conditions to confirm whether viscosity has been improved and whether protein stability has been enhanced until administration to the patient. To effectively maintain protein stability and evaluate the optimal formulation in a short period, the optimal formulation combination can be selected by analyzing novel quality indicators after exposure to heat (temperature) and chemicals, which are factors that cause structural and physicochemical denaturation of proteins.

[0006] This specification relates to a stable liquid formulation of an anti-IL-4Rα antibody, such as dupilumab. Specifically, this specification provides a liquid formulation capable of improving the viscosity of the formulation while ensuring the stability of the anti-IL-4Rα antibody, such as dupilumab, throughout the entire process of manufacturing, storage, and administration to a patient. Since the liquid formulation has improved stability and viscosity compared to commercially available formulations of the anti-IL-4Rα antibody, such as dupilumab (e.g., Dupixent), it is applicable even to high-concentration formulations, thereby increasing patient convenience.

[0007] One aspect provides an anti-IL-4Rα antibody; and a liquid formulation comprising amino acids and not containing sugars.

[0008] Another aspect is to provide a device comprising the above-mentioned liquid formulation.

[0009] 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.

[0010] Another aspect is to provide the use of the liquid formulation in the manufacture of a drug for treating IL-4Rα-related conditions.

[0011] 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.

[0012] 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.

[0013] One aspect provides a liquid formulation comprising an anti-IL-4Rα antibody and an amino acid, and not comprising sugars. In this specification, the liquid formulation according to the aspect may be referred to as a "sugar-free and amino acid-containing formulation."

[0014] (1) Antibody

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] The above anti-IL-4Rα antibody may be included in a therapeutically effective amount in a liquid formulation.

[0021] 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.

[0022] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 100 mg / mL to about 200 mg / mL.

[0023] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 125 mg / mL to about 200 mg / mL.

[0024] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL to about 200 mg / mL.

[0025] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL to about 175 mg / mL.

[0026] In one embodiment, the concentration of the anti-IL-4Rα antibody may be 135 mg / mL to 165 mg / mL.

[0027] In one embodiment, the concentration of the anti-IL-4Rα antibody may be 158 mg / mL to 192 mg / mL.

[0028] In a specific embodiment, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL.

[0029] In a specific embodiment, the concentration of the anti-IL-4Rα antibody may be about 175 mg / mL.

[0030] 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.

[0031] (2) amino acids

[0032] A liquid formulation according to one aspect contains amino acids.

[0033] In one embodiment, the amino acid may include at least one type.

[0034] In one embodiment, the amino acid may include at least two types.

[0035] In one embodiment, the amino acids may include at least three types.

[0036] In one embodiment, the amino acids may include a combination of two or three types.

[0037] 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.

[0038] In one embodiment, the amino acid may include one or more selected from glycine, arginine, histidine, methionine, lysine, and proline.

[0039] In one embodiment, the amino acid may include a combination of two or three selected from glycine, arginine, histidine, methionine, lysine, and proline.

[0040] In one embodiment, the amino acid may include one or more selected from arginine, histidine, methionine, lysine, and proline.

[0041] In one embodiment, the amino acid may include a combination of two or three selected from arginine, histidine, methionine, lysine, and proline.

[0042] In one embodiment, the amino acid may include at least a cationic amino acid.

[0043] In one embodiment, the cationic amino acid may include one or more selected from arginine, histidine, and lysine.

[0044] In one embodiment, the amino acid may include one, two, or three types of cationic amino acids.

[0045] In one embodiment, the amino acid comprises at least a cationic amino acid and may optionally further comprise methionine.

[0046] In one embodiment, the amino acid may include at least one cationic amino acid and may additionally include methionine.

[0047] In one embodiment, the amino acid comprises one or two cationic amino acids and may additionally comprise methionine.

[0048] In one embodiment, the amino acid may include one or more selected from arginine, histidine, methionine, and lysine.

[0049] In one embodiment, the amino acid may include a combination of two or three selected from arginine, histidine, methionine, and lysine.

[0050] In one embodiment, the amino acid may be selected from the following:

[0051] 1) Arginine;

[0052] 2) Combination of arginine and lysine;

[0053] 3) Combination of arginine and methionine;

[0054] 4) A combination of arginine, methionine, and proline;

[0055] 5) A combination of arginine, glycine, and methionine;

[0056] 6) Combination of arginine, histidine, and methionine

[0057] 7) Histidine;

[0058] 8) Combination of histidine and lysine;

[0059] 9) Combination of histidine and methionine;

[0060] 10) Combination of histidine and arginine;

[0061] 11) Combination of histidine and proline;

[0062] 12) A combination of histidine, methionine, and lysine;

[0063] 13) A combination of histidine, methionine, and proline;

[0064] 14) A combination of histidine, methionine, and glycine;

[0065] 15) Proline;

[0066] 16) Combination of proline and methionine;

[0067] 17) Glycine;

[0068] 18) Combination of glycine and lysine;

[0069] 19) A combination of glycine and methionine; or

[0070] 20) Methionine.

[0071] In another embodiment, the amino acid may include a combination selected from the following:

[0072] 1) Combination of histidine and methionine;

[0073] 2) Combination of arginine and histidine;

[0074] 3) Combination of arginine and methionine;

[0075] 4) Combination of arginine and lysine;

[0076] 5) A combination of arginine, histidine, and lysine;

[0077] 6) A combination of histidine, methionine, and proline; and

[0078] 7) Combination of histidine, methionine, and arginine.

[0079] In another embodiment, the amino acid may include a combination selected from the following:

[0080] 1) Combination of histidine and methionine;

[0081] 2) Combination of arginine and histidine;

[0082] 3) Combination of arginine and methionine;

[0083] 4) Combination of arginine and lysine;

[0084] 5) A combination of arginine, histidine, and lysine; and

[0085] 6) Combination of histidine, methionine, and arginine.

[0086] In certain embodiments, the amino acids may include a combination of histidine, methionine, and arginine.

[0087] The concentration of the above amino acids can be freely adjusted within a range that maintains the stability of the antibody and may vary individually depending on each specific type of amino acid. The concentration of the above amino acids may be any range selected from about 1 mM to about 400 mM or any value. For example, the concentration of the above amino acid is about 1 mM to about 400 mM, about 1 mM to about 300 mM, about 1 mM to about 200 mM, about 1 mM to about 100 mM, about 10 mM to about 400 mM, about 10 mM to about 300 mM, about 10 mM to about 200 mM, about 10 mM to about 100 mM, about 20 mM to about 400 mM, about 20 mM to about 300 mM, about 20 mM to about 200 mM, about 20 mM to about 150 mM, about 20 mM to about 100 mM, about 20 mM to about 50 mM, about 20 mM to about 40 mM, about 20 mM to about 30 mM, about 30 mM to about 400 mM, about 30 mM to about 300 mM, about 30 mM to about 200 mM, about 30 mM to about 150 mM, about 30 mM to about 100 mM, about 30 mM to about 80 mM, about 30 mM to about 50 mM, about 30 mM to about 40 mM, about 40 mM to about 400 mM, about 40 mM to about 300 mM, about 40 mM to about 200 mM, about 40 mM to about 150 mM, about 40 mM to about 100 mM, about 40 mM to about 80 mM, about 40 mM to about 50 mM, about 50 mM to about 400 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, about 50 mM to about 100 mM, about 50 mM to about 80 mM, about 60 mM to about 400 mM, about 60 mM to about 300 mM,About 60 mM to about 250 mM, about 60 mM to about 200 mM, about 60 mM to about 150 mM, about 60 mM to about 100 mM, about 60 mM to about 80 mM, about 70 mM to about 400 mM, about 70 mM to about 300 mM, about 70 mM to about 250 mM, about 70 mM to about 200 mM, about 70 mM to about 150 mM, about 70 mM to about 100 mM, about 70 mM to about 90 mM, about 70 mM to about 80 mM, about 80 mM to about 400 mM, about 80 mM to about 300 mM, about 80 mM to about 250 mM, about 80 mM to about 200 mM, about 80 mM to about 150 mM, about 80 mM to about 120 mM, about 80 mM to about 100 mM, about 90 mM to about 400 mM, about 90 mM to about 300 mM, about 90 mM to about 250 mM, about 90 mM to about 200 mM, about 90 mM to about 150 mM, about 90 mM to about 100 mM, about 100 mM to about 400 mM, about 100 mM to about 300 mM, about 100 mM to about 280 mM, about 100 mM to about 250 mM, about 100 mM to about 220 mM, about 100 mM to about 200 mM, about 100 mM to about 180 mM, about 100 mM to about 150 mM, about 110 mM to about 400 mM, about 110 mM to about 300 mM, about 110 mM to about 280 mM, about 110 mM to about 250 mM, about 110 mM to about 220 mM, about 110 mM to about 200 mM, about 110 mM to about 180 mM, about 110 mM to about 150 mM, about 120 mM to about 400 mM, about 120 mM to about 300 mM, about 120 mM to about 280 mM, about 120 mM to about 250 mM,About 120 mM to about 220 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 150 mM, about 130 mM to about 400 mM, about 130 mM to about 300 mM, about 130 mM to about 280 mM, about 130 mM to about 250 mM, about 130 mM to about 220 mM, about 130 mM to about 200 mM, about 130 mM to about 180 mM, about 130 mM to about 150 mM, about 130 mM to about 140 mM, about 140 mM to about 400 mM, about 140 mM to about 300 mM, about 140 mM to about 280 mM, about 140 mM to about 250 mM, about 140 mM to about It may be 220 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 150 mM, about 150 mM to about 400 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 150 mM to about 200 mM, about 200 mM to about 400 mM, about 200 mM to about 350 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, about 220 mM to about 400 mM, about 220 mM to about 350 mM, about 220 mM to about 300 mM, about 220 mM to about 300 mM, or about 220 mM to about 280 mM.

[0088] The concentration of the above amino acid may be any range or any value selected within about 20 mM to about 355 mM.

[0089] In one embodiment, the concentration of arginine is about 20 mM to about 250 mM, about 20 mM to about 200 mM, about 20 mM to about 165 mM, about 20 mM to about 155 mM, about 20 mM to about 150 mM, about 20 mM to about 135 mM, about 20 mM to about 125 mM, about 20 mM to about 120 mM, about 20 mM to about 110 mM, about 20 mM to about 105 mM, about 20 mM to about 100 mM, about 30 mM to about 250 mM, about 30 mM to about 200 mM, about 30 mM to about 165 mM, about 30 mM to about 155 mM, about 30 mM to about 150 mM, about 30 mM to about 135 mM, about 30 mM to about 125 mM mM, about 30 mM to about 120 mM, about 30 mM to about 110 mM, about 30 mM to about 105 mM, about 30 mM to about 100 mM, about 45 mM to about 250 mM, about 45 mM to about 200 mM, about 45 mM to about 165 mM, about 45 mM to about 155 mM, about 45 mM to about 150 mM, about 45 mM to about 135 mM, about 45 mM to about 125 mM, about 45 mM to about 120 mM, about 45 mM to about 110 mM, about 45 mM to about 105 mM, about 45 mM to about 100 mM, about 60 mM to about 250 mM, about 60 mM to about 200 mM, about 60 mM to about 165 mM, about 60 mM to about 155 mM, about 60 mM to about 150 mM, about 60 mM to about 140 mM, about 60 mM to about 135 mM, about 60 mM to about 125 mM, about 60 mM to about 120 mM, about 60 mM to about 110 mM, about 60 mM to about 105 mM, about 60 mM to about 100 mM, about 75 mM to about 250 mM,About 75 mM to about 200 mM, about 75 mM to about 165 mM, about 75 mM to about 155 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 120 mM, about 75 mM to about 110 mM, about 75 mM to about 105 mM, about 75 mM to about 100 mM, about 90 mM to about 250 mM, about 90 mM to about 200 mM, about 90 mM to about 165 mM, about 90 mM to about 155 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 120 mM, about 90 mM to about 110 mM, about 90 mM to about 105 mM, about 90 mM to about 100 mM, about 95 mM to about 250 mM, about 95 mM to about 200 mM, about 95 mM to about 165 mM, about 95 mM to about 155 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 120 mM, about 95 mM to about 110 mM, about 95 mM to about 105 mM, about 95 mM to about 100 mM, about 100 mM to about 250 mM, about 100 mM to about 200 mM, about 100 mM to about 165 mM, about 100 mM to about 155 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 120 mM, about 100 mM to about 110 mM, about 100 mM to about 105 mM, about 105 mM to about 250 mM, about 105 mM to about 200 mM, about 105 mM to about 165 mM, about 105 mM to about 155 mM,About 105 mM to about 150 mM, about 105 mM to about 135 mM, about 105 mM to about 125 mM, about 105 mM to about 120 mM, about 105 mM to about 110 mM, about 110 mM to about 250 mM, about 110 mM to about 200 mM, about 110 mM to about 165 mM, about 110 mM to about 155 mM, about 110 mM to about 150 mM, about 110 mM to about 135 mM, about 110 mM to about 125 mM, about 110 mM to about 120 mM, about 115 mM to about 250 mM, about 115 mM to about 200 mM, about 115 mM to about 165 mM, about 115 mM to about 155 mM, about 115 mM to about It may be 150 mM, about 115 mM to about 135 mM, about 115 mM to about 125 mM, about 115 mM to about 120 mM, about 120 mM to about 250 mM, about 120 mM to about 200 mM, about 120 mM to about 165 mM, about 120 mM to about 155 mM, about 120 mM to about 150 mM, about 120 mM to about 135 mM, or about 120 mM to about 125 mM.

[0090] In one embodiment, the concentration of the arginine may be greater than 50 mM.

[0091] In one embodiment, the concentration of the arginine may be greater than 50 mM to about 250 mM.

[0092] In one embodiment, the concentration of the arginine may be less than 150 mM.

[0093] In one embodiment, the concentration of the arginine may be greater than 50 mM and less than 150 mM.

[0094] In one embodiment, the concentration of the arginine may be about 60 mM to about 140 mM.

[0095] In one embodiment, the concentration of the arginine may be about 75 mM to about 200 mM.

[0096] In one embodiment, the concentration of the arginine may be about 75 mM to about 150 mM.

[0097] In one embodiment, the concentration of the arginine may be about 75 mM to about 135 mM.

[0098] In one embodiment, the concentration of the arginine may be about 100 mM to about 200 mM.

[0099] In one embodiment, the concentration of the arginine may be about 125 mM or about 175 mM.

[0100] In a specific embodiment, the concentration of the arginine may be about 125 mM.

[0101] The concentration of the above histidine may be about 0.1 mM to about 400 mM, about 0.1 mM to about 205 mM, about 0.1 mM to about 92.4 mM, about 0.5 mM to about 400 mM, about 0.5 mM to about 205 mM, about 0.5 mM to about 92.4 mM, about 1 mM to about 400 mM, about 1 mM to about 205 mM, about 1 mM to about 92.4 mM, about 10 mM to about 400 mM, about 10 mM to about 205 mM, about 10 mM to about 92.4 mM, about 20 mM to about 400 mM, about 20 mM to about 205 mM, or about 20 mM to about 92.4 mM.

[0102] In one embodiment, the concentration of the histidine may be any range or any value selected within about 20 mM to about 92.4 mM. For example, the concentration of the histidine is about 20 mM to about 92.4 mM, about 20 mM to about 90 mM, about 20 mM to about 80 mM, about 20 mM to about 70 mM, about 20 mM to about 60 mM, about 20 mM to about 55 mM, about 20 mM to about 50 mM, about 30 mM to about 92.4 mM, about 30 mM to about 90 mM, about 30 mM to about 80 mM, 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, about 40 mM to about 92.4 mM, about 40 mM to about 90 mM, about 40 mM to about 80 mM, about 40 mM to about 70 mM, about 40 mM to about 60 mM, about It may be 40 mM to about 55 mM, about 40 mM to about 50 mM, about 45 mM to about 92.4 mM, about 45 mM to about 90 mM, about 45 mM to about 80 mM, about 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, about 50 mM to about 92.4 mM, about 50 mM to about 90 mM, about 50 mM to about 80 mM, about 50 mM to about 70 mM, about 50 mM to about 60 mM, about 55 mM to about 65 mM, or about 55 mM to about 60 mM.

[0103] In one embodiment, the concentration of the 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.

[0104] In a specific embodiment, the concentration of the histidine may be about 59 mM.

[0105] The concentration of the above methionine is about 1 mM to about 400 mM, about 2.7 mM to about 400 mM, about 2.7 mM to about 300 mM, about 2.7 mM to about 200 mM, about 2.7 mM to about 100 mM, about 2.7 mM to about 90 mM, about 2.7 mM to about 50 mM, about 2.7 mM to about 40 mM, about 2.7 mM to about 35 mM, about 2.7 mM to about 30 mM, about 2.7 mM to about 25 mM, about 10 mM to about 400 mM, about 10 mM to about 300 mM, about 10 mM to about 200 mM, about 10 mM to about 100 mM, about 10 mM to about 90 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 10 mM to about 25 mM, about 15 mM to about 100 mM, about 15 mM to about 50 mM, about 15 mM to about 40 mM, about 15 mM to about 35 mM, about 15 mM to about 30 mM, about 15 mM to about 25 mM, about 20 mM to about 100 mM, about 20 mM to about 90 mM, about 20 mM to about 80 mM, about 20 mM to about 70 mM, about 20 mM to about 60 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 28 mM, about 20 mM to about 25 mM, about 22 mM to about 100 mM, about 22 mM to about 90 mM, about 22 mM to about 50 mM, about 22 mM to about 40 mM, about 22 mM to about 35 mM, about 22 mM to about 30 mM, about 22 mM to about 28 mM, about 22 mM to about 25 mM, about 25 mM to about 100 mM, about 25 mM to about 90 mM, about 25 mM to about 50 mM, about 25 mM to about 40 mM, about 25 mM It may be up to about 35 mM, or about 25 mM to about 30 mM.

[0106] In a specific embodiment, the concentration of the methionine may be about 30 mM.

[0107] The concentration of the above lysine is about 1 mM to about 250 mM, about 1 mM to about 200 mM, about 1 mM to about 150 mM, about 1 mM to about 100 mM, about 1 mM to about 75 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 5 mM to about 250 mM, about 5 mM to about 200 mM, about 5 mM to about 150 mM, about 5 mM to about 100 mM, about 5 mM to about 75 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 10 mM to about 250 mM, about 10 mM to about 200 mM, about 10 mM to about 150 mM, about 10 mM to about 100 mM, about 10 It may be mM to about 75 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 30 mM, about 20 mM to about 250 mM, about 20 mM to about 200 mM, about 20 mM to about 150 mM, about 20 mM to about 100 mM, about 20 mM to about 75 mM, about 20 mM to about 50 mM, about 20 mM to about 40 mM, or about 20 mM to about 30 mM.

[0108] In one embodiment, 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.

[0109] In a specific embodiment, the concentration of the lysine may be about 25 mM.

[0110] The concentration of the above proline is about 1 mM to about 400 mM, about 1 mM to about 300 mM, about 1 mM to about 250 mM, about 1 mM to about 200 mM, about 10 mM to about 400 mM, about 10 mM to about 300 mM, about 10 mM to about 250 mM, about 10 mM to about 200 mM, about 20 mM to about 400 mM, about 20 mM to about 300 mM, about 20 mM to about 250 mM, about 20 mM to about 200 mM, about 50 mM to about 400 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 100 mM to about 400 mM, about 100 mM to about 300 mM, about 100 mM to about 100 mM It may be about 250 mM, about 100 mM to about 200 mM, about 150 mM to about 400 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 150 mM to about 200 mM, about 180 mM to about 400 mM, about 180 mM to about 300 mM, about 180 mM to about 250 mM, or about 180 mM to about 200 mM.

[0111] In one embodiment, the concentration of the proline may be about 10 mM to about 200 mM, about 10 mM to about 190 mM, about 10 mM to about 185 mM, about 10 mM to about 180 mM, about 20 mM to about 200 mM, about 20 mM to about 190 mM, about 20 mM to about 185 mM, about 20 mM to about 180 mM, about 25 mM to about 200 mM, about 25 mM to about 190 mM, about 25 mM to about 185 mM, or about 25 mM to about 180 mM.

[0112] In a specific embodiment, the concentration of the proline may be about 210 mM.

[0113] 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.

[0114] In a specific embodiment, the concentration of the glycine may be about 220 mM.

[0115] The concentration of the above glycine may be about 10 mM to about 70 mM, about 10 mM to about 60 mM, about 10 mM to about 55 mM, about 10 mM to about 50 mM, about 20 mM to about 70 mM, about 20 mM to about 60 mM, about 20 mM to about 55 mM, about 20 mM to about 50 mM, about 25 mM to about 70 mM, about 25 mM to about 60 mM, about 25 mM to about 55 mM, or about 25 mM to about 50 mM.

[0116] The above amino acid may have one or more functions among a viscosity reducer, a stabilizer, and an antioxidant. The above amino acid may have all of the functions of a viscosity reducer, a stabilizer, and an antioxidant. The above amino acid may have the functions of a viscosity reducer and a stabilizer.

[0117] The term "viscosity reducing agent" refers to a substance that lowers the viscosity of a liquid.

[0118] 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 or denaturation of antibodies.

[0119] The term "antioxidant" is a general term for a substance that prevents oxidation, and specifically in this specification, it may refer to a substance that prevents the oxidation of proteins (e.g., antibodies).

[0120] A liquid formulation according to one aspect may contain a specific combination of amino acids instead of sugars. Since this "sugar-free and amino acid-containing formulation" contains acetate and histidine as buffers and sucrose as a sugar, both viscosity and %HMW are reduced compared to Dupixent, thus allowing for simultaneous improvement in viscosity and stability. Additionally, the "sugar-free and amino acid-containing formulation" may have both reduced viscosity and %HMW compared to the "sugar-containing formulation."

[0121] (3) pH

[0122] The pH of the liquid formulation according to one aspect may be any range selected from about 4.0 to about 8.5 or any value. For example, the above pH is about 4.0 to about 8.5, about 4.0 to about 8.0, about 4.0 to about 7.5, about 4.0 to about 7.0, about 4.0 to about 6.5, about 4.0 to about 6.0, about 4.5 to about 8.5, about 4.5 to about 8.0, about 4.5 to about 7.5, about 4.5 to about 7.0, about 4.5 to about 6.5, about 4.5 to about 6.0, about 4.7 to about 8.5, about 4.7 to about 8.0, about 4.7 to about 7.5, about 4.7 to about 7.4, about 4.7 to about 7.0, about 4.7 to about 6.5, about 4.7 to about 6.0, about 4.8 to about 8.5, About 4.8 to about 8.0, about 4.8 to about 7.5, about 4.8 to about 7.4, about 4.8 to about 7.0, about 4.8 to about 6.5, about 4.8 to about 6.0, about 4.8 to about 5.6, about 4.8 to about 5.5, about 4.8 to about 5.4, about 4.8 to about 5.3, about 4.9 to about 8.5, about 4.9 to about 8.0, about 4.9 to about 7.5, about 4.9 to about 7.0, about 4.9 to about 6.5, about 4.9 to about 6.0, about 4.9 to about 6.0, about 4.9 to about 5.6, about 4.9 to about 5.5, about 4.9 to about 5.4, about 4.9 to about 5.3, about 5.0 to About 8.5, about 5.0 to about 8.0, about 5.0 to about 7.5, about 5.0 to about 7.0, 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 5.4, about 5.0 to about 5.3, about 5.1 to about 8.5, about 5.1 to about 8.0, about 5.1 to about 7.5, about 5.1 to about 7.0, 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 5.4, or about 5.It can be 1 to about 5.3 days.

[0123] In one embodiment, the pH of the liquid formulation may be about 4.8 to about 5.6.

[0124] In one embodiment, the pH of the liquid formulation may be about 4.9 to about 5.5.

[0125] In a specific embodiment, the pH of the liquid formulation may be about 5.2.

[0126] The pH of the above liquid formulation may be provided by an organic or inorganic anionic salt. Alternatively, the pH of the above liquid formulation may be adjusted by the addition of any acid (e.g., HCl) or base (e.g., NaOH).

[0127] A liquid formulation according to one embodiment may optionally include an organic or inorganic anionic salt.

[0128] A liquid formulation according to one embodiment may include an organic or inorganic anionic salt.

[0129] A liquid formulation according to one embodiment may substantially not contain organic or inorganic anionic salts.

[0130] The above organic anionic salt may include one or more selected from acetate, citrate, succinate, malate, tartarate, and their hydrates.

[0131] The above inorganic anionic salt may include one or more selected from phosphate, carbonate, and hydrates thereof.

[0132] The term "hydrate" refers to a substance containing water molecules within its molecule. The hydrate may be a monohydrate, a dihydrate, or a trihydrate.

[0133] The concentration of the above organic or inorganic anionic salt may be any range or any value selected within about 0.1 mM to about 50 mM. For example, the concentration of the organic or inorganic anionic salt is about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 35 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 35 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 35 mM, about 3 mM to about 30 mM, about 3 mM to about 20 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 35 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 35 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 10 mM to about 20 mM, about 10 mM to about 15 mM, about 10 mM to about 15 mM, about 10 mM to about 14 mM, about 15 mM to about 50 mM, about 15 mM to about 40 mM, about 15 mM to about 35 mM,It may be about 15 mM to about 30 mM, about 15 mM to about 20 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, about 25 mM to about 30 mM, about 27 mM to about 50 mM, about 27 mM to about 40 mM, about 27 mM to about 35 mM, about 27 mM to about 33 mM, or about 25 mM to about 30 mM.

[0134] (4) Sugar-free

[0135] A liquid formulation according to one aspect does not contain sugars (free of saccharide). Therefore, the liquid formulation may be a saccharide-free formulation.

[0136] Although the above liquid formulation is a saccharide-free formulation, it may have improved stability and improved viscosity compared to commercially available formulations.

[0137] 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.

[0138] In this specification, the phrase “not containing 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 in the formulation.

[0139] The above sugars may include sugar and sugar alcohol. Accordingly, the above liquid formulation may not contain either sugar or sugar alcohol.

[0140] 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.

[0141] 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.

[0142] In one embodiment, the liquid formulation may not contain any of sucrose, trehalose, sorbitol, and mannitol.

[0143] (5) Surfactant

[0144] A liquid formulation according to one aspect may additionally include a surfactant.

[0145] 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.

[0146] The above surfactant may be a nonionic surfactant.

[0147] 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).

[0148] The above polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85, etc.

[0149] The above poloxamer may include a PEO-PPO-PEO copolymer (where PEO is poly(ethylene oxide) and PPO is poly(propylene oxide)). For example, the above poloxamer may include poloxamer 188, poloxamer 407, etc.

[0150] 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.

[0151] The above polyoxyethylene compound may include polyoxyethylene stearate, polyoxyethylene alkyl ether (alkyl: C1-C30), polyoxyethylene monorylate ether, alkylphenyl polyoxyethylene copolymer (alkyl: C1-C30), etc.

[0152] In one embodiment, the surfactant may be polysorbate.

[0153] 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, poloxamer 188, and poloxamer 407.

[0154] In one embodiment, the surfactant may include one or more selected from polysorbate 20, polysorbate 80, and poloxamer 188.

[0155] In a specific embodiment, the surfactant may include polysorbate 80. In a specific embodiment, the surfactant may be polysorbate 80.

[0156] 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).

[0157] In a specific embodiment, the concentration of the surfactant may be about 0.2% (w / v).

[0158] (6) Diluent

[0159] A liquid formulation according to one aspect may additionally include a diluent.

[0160] 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.

[0161] In one embodiment, the diluent may be water. The water may be water in a standard state. Accordingly, the liquid formulation may be an aqueous liquid formulation.

[0162] The term “standard state” is a standard specifying the temperature and pressure used to describe a solution having a specific composition, and may mean, for example, a temperature of 25°C ± 2°C and 1 atmosphere. A person skilled in the art will recognize that liquid formulations equivalent to those disclosed herein may be produced at different temperatures and pressures. Whether such liquid formulations are equivalent to those disclosed herein may be determined under standard state conditions.

[0163] (7) Formulation

[0164] The term "liquid formulation" refers to a formulation in a liquid state.

[0165] The liquid formulation according to one aspect is a stable liquid formulation of the anti-IL-4Rα antibody.

[0166] A liquid formulation according to one aspect may be a pharmaceutical formulation of an anti-IL-4Rα antibody.

[0167] 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.

[0168] 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.

[0169] The term "pharmaceuticalally acceptable" may refer to excipients, carriers, vehicles, diluents, additives, salts, etc. suitable for administration to a subject.

[0170] 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.

[0171] 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.

[0172] A liquid formulation according to one aspect may be selected from the following items:

[0173] 1) an anti-IL-4Rα antibody; and a liquid formulation comprising amino acids and not containing sugars;

[0174] 2) A liquid formulation comprising an anti-IL-4Rα antibody; an amino acid; and a surfactant, and not comprising sugars;

[0175] 3) A liquid formulation comprising an anti-IL-4Rα antibody; acetate; an amino acid including arginine; and a surfactant, and not comprising sugars;

[0176] 4) A liquid formulation comprising an anti-IL-4Rα antibody; acetate; amino acids including arginine and lysine; and a surfactant, and not comprising sugars;

[0177] 5) an anti-IL-4Rα antibody; acetate; amino acids including arginine and methionine; and a surfactant, comprising a liquid formulation that does not contain sugars;

[0178] 6) A liquid formulation comprising an anti-IL-4Rα antibody; acetate; an amino acid including histidine; and a surfactant, and not comprising sugars;

[0179] 7) A formulation comprising an anti-IL-4Rα antibody; acetate; an amino acid including histidine and lysine; and a surfactant, and not comprising sugars;

[0180] 8) A liquid formulation comprising an anti-IL-4Rα antibody; acetate; an amino acid including histidine and methionine; and a surfactant, and not comprising sugars;

[0181] 9) an anti-IL-4Rα antibody; acetate; amino acids including arginine, histidine, and methionine; and a surfactant, comprising a liquid formulation that does not contain sugars;

[0182] 10) A liquid formulation comprising an anti-IL-4Rα antibody; acetate; an amino acid including glycine; and a surfactant, and not comprising sugars;

[0183] 11) A liquid formulation comprising an anti-IL-4Rα antibody; acetate; an amino acid including glycine and lysine; and a surfactant, and not comprising sugars;

[0184] 12) A liquid formulation comprising an anti-IL-4Rα antibody; acetate; an amino acid including glycine and methionine; and a surfactant, and not comprising sugars;

[0185] 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 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;

[0186] 14) 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;

[0187] 15) 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;

[0188] 16) 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 5.6 to 6.2;

[0189] 17) 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;

[0190] 18) 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 5.6 to 6.2;

[0191] 19) 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;

[0192] 20) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; about 10 mM to about 40 mM of acetate; about 30 mM to about 70 mM of histidine; about 12 mM±1 mM of methionine; about 70 mM to about 130 mM of arginine; 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;

[0193] 21) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; about 30 mM±5 mM of acetate; about 50 mM±5 mM of histidine; about 25 mM±5 mM of methionine; about 100 mM±5 mM of arginine; 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 5.2;

[0194] 22) an anti-IL-4Rα antibody; and a liquid formulation comprising amino acids and not containing sugars;

[0195] 23) an anti-IL-4Rα antibody; and a liquid formulation comprising at least two amino acids and not containing sugars;

[0196] 24) an anti-IL-4Rα antibody; and a liquid formulation comprising at least three amino acids and not containing sugars;

[0197] 25) an anti-IL-4Rα antibody; and a liquid formulation comprising a combination of two or three amino acids and not containing sugars;

[0198] 26) an anti-IL-4Rα antibody; and a liquid formulation comprising an amino acid, wherein the amino acid comprises at least a cationic amino acid;

[0199] 27) an anti-IL-4Rα antibody; and a liquid formulation comprising an amino acid, wherein the amino acid comprises at least a cationic amino acid and optionally further comprises methionine;

[0200] 28) an anti-IL-4Rα antibody; and a liquid formulation comprising amino acids, not containing sugars, and having a viscosity of less than 10 cP at 25°C;

[0201] 29) an anti-IL-4Rα antibody; and a liquid formulation comprising amino acids, not containing sugars, and having a high molecular weight species content ratio (%HMW) of the antibody measured after storage at 25°C for 4 weeks of 3% or less;

[0202] 30) an anti-IL-4Rα antibody; and a liquid formulation comprising amino acids, not containing sugars, and having a pH of about 4.5 to about 7.0;

[0203] 31) an anti-IL-4Rα antibody; and a liquid formulation comprising amino acids, not containing sugars, and having a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0204] 32) A liquid formulation comprising an anti-IL-4Rα antibody; an amino acid; and a surfactant, which does not contain sugars and has a pH of about 4.5 to about 7.0;

[0205] 33) A liquid formulation comprising an anti-IL-4Rα antibody; an amino acid; and a surfactant, wherein the liquid formulation does not contain sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0206] 34) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 20 mM to about 92.4 mM of histidine and about 2.7 mM to about 90 mM of methionine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0207] 35) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 20 mM to about 250 mM of arginine and about 20 mM to about 92.4 mM of histidine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0208] 36) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 20 mM to about 250 mM of arginine and about 2.7 mM to about 90 mM of methionine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0209] 37) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 20 mM to about 250 mM of arginine and about 10 mM to about 100 mM of lysine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0210] 38) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 20 mM to about 250 mM of arginine, about 20 mM to about 92.4 mM of histidine, and about 10 mM to about 100 mM of lysine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0211] 39) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 20 mM to about 92.4 mM of histidine, about 2.7 mM to about 90 mM of methionine, and about 20 mM to about 250 mM of arginine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0212] 40) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of 59 mM±6 mM of histidine and 30 mM±3 mM of methionine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0213] 41) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 125 mM to about 175 mM of arginine and 59 mM±6 mM of histidine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0214] 42) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 125 mM to about 175 mM of arginine and 30 mM ± 3 mM of methionine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0215] 43) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 125 mM to about 175 mM of arginine and 25 mM ± 3 mM of lysine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0216] 44) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of about 125 mM to about 175 mM of arginine, 59 mM±6 mM of histidine, and 25 mM±3 mM of lysine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5;

[0217] 45) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of 59 mM±6 mM histidine, 30 mM±3 mM methionine, and 210 mM±20 mM proline; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5; or

[0218] 46) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; a combination of 59 mM±6 mM of histidine, 30 mM±3 mM of methionine, and about 125 mM to about 175 mM of arginine; and 0.01% (w / v) to 0.9% (w / v) of surfactant, which is free of sugars and has a pH of about 4.8 to about 5.6 or about 4.9 to about 5.5.

[0219] (8) Stability and viscosity

[0220] A liquid formulation according to one aspect can ensure antibody stability while having low viscosity.

[0221] 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.

[0222] A method for evaluating the stability of antibodies contained in a formulation over a short period involves exposing the formulation to factors that cause structural and physicochemical denaturation of proteins, such as heat (temperature), followed by the agglutination temperature (T agg ), diffusion interaction parameter (K D There are methods to measure ), etc. For example, "improved stability" is T measured for the formulation agg or K D It may mean that the value has increased by 0.01% or more, 0.1% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, or 20% or more compared to the existing formulation. agg or K D An increase in the value may indicate improved stability as the degree of antibody aggregation within the formulation due to external factors (e.g., heat, temperature) has decreased.

[0223] 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.

[0224] The term "protein denaturation rate" may be expressed as the percentage of acidic species (%Acidic) of the antibody in the formulation at any given time. %Acidic may be measured by imaged capillary isoelectric focusing (icIEF), but is not limited thereto. For example, "improved stability" may mean that the %Acidic of the antibody measured for the formulation is reduced 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 %Acidic may indicate improved stability due to a reduced degree of denaturation of the antibody in the formulation.

[0225] The term "amino acid oxidation rate" may refer to the ratio of oxidized amino acids among the amino acids of an antibody protein (e.g., the ratio of oxidized methionine). In one embodiment, the amino acid oxidation rate is methionine (Met 257th amino acid residue of dupilumab, an anti-IL-4Rα antibody). 257 Oxidation ratio of ) (%Met 257 It can mean ). %Met 257 It may be measured by LC-MS (liquid chromatography-mass spectrometry), but is not limited thereto. For example, "improved stability" refers to the %Met of dupilumab measured for the formulation. 257 This may mean a decrease of 0.01% or more, 0.1% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, or 20% or more compared to the existing formulation. %Met 257 A decrease in may mean that the degree of oxidation of the antibody within the formulation has decreased, thereby improving stability.

[0226] 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%.

[0227] The above liquid formulation has an increased aggregation temperature (T agg It may have ).

[0228] The above liquid formulation has an increased diffusion interaction parameter (K D It may have ).

[0229] 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.

[0230] A liquid formulation according to one aspect may have reduced viscosity compared to Dupixent. In one embodiment, a liquid formulation according to one aspect may have reduced viscosity compared to the viscosity of Dupixent 200 mg. In another embodiment, a liquid formulation according to one aspect may have reduced viscosity compared to the viscosity of Dupixent 300 mg.

[0231] The above liquid formulation may have a viscosity reduced by 10% or more, 15% or more, 20% or more, 25% or more, or 30% or more compared to the viscosity of the Dupixent formulation.

[0232] In this specification, viscosity may mean viscosity measured at a standard temperature. For example, viscosity may mean viscosity measured at 25°C.

[0233] In one embodiment, the liquid formulation may have a viscosity of less than 10.8 cP (centiPoise). Specifically, the liquid formulation may have a viscosity of less than 10.8 cP, less than 10.5 cP, less than 10 cP, less than 9.9 cP, less than 9.5 cP, less than 9 cP, or less than 8.5 cP.

[0234] The above liquid formulation may have a reduced high molecular weight species content ratio (%HMW).

[0235] The above liquid formulation may reduce the %HMW of the antibody measured after storage at 40°C for 4 weeks by 5% or more, 10% or more, 15% or more, or 20% or more compared to the Dupixent formulation.

[0236] The above liquid formulation may reduce the %HMW of the antibody measured after storage at 25°C for 4 weeks by 5% or more, 10% or more, or 15% or more compared to the Dupixent formulation.

[0237] In one embodiment, the liquid formulation may have a %HMW of antibody measured after storage at 25°C for 4 weeks of 3% or less.

[0238] In one embodiment, the liquid formulation may have a %HMW of antibody measured after storage at 25°C for 4 weeks of less than 2.28%. Specifically, the liquid formulation may have a %HMW of antibody measured after storage at 25°C for 4 weeks of less than 2.28%, 2.2% or less, 2.1% or less, 2.0% or less, 1.9% or less, or 1.8% or less.

[0239] The above liquid formulation may have a reduced acidic species content ratio (%Acidic).

[0240] The above liquid formulation may reduce the %Acidic of the antibody measured after storage at 25°C for 4 weeks by 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, or 7% or more compared to the Dupixent formulation.

[0241] The above liquid formulation has a reduced oxidation rate of methionine residues (%Met 257 Can have ).

[0242] The %Met of the antibody measured after storage at 25°C for 4 weeks for the above liquid formulation 257 Compared to this Dupixent formulation, it can be reduced by more than 50%, more than 55%, or more than 60%.

[0243] (9) Device

[0244] Another aspect provides a device comprising a liquid formulation according to the above-mentioned aspect.

[0245] 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.

[0246] 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.

[0247] The above device may be in a single-dose or multiple-dose form.

[0248] 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.

[0249] 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.

[0250] (10) Treatment of disease

[0251] 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.

[0252] 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.

[0253] 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).

[0254] 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.

[0255] The above liquid formulation can be administered in a pharmaceutically effective amount.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] The above atopic dermatitis may be moderate-to-severe atopic dermatitis.

[0261] The above asthma may be moderate-to-severe asthma.

[0262] (11) Route of administration and dosage

[0263] 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.

[0264] In a specific embodiment, the liquid formulation may be for subcutaneous injection.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] A 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 if the liquid formulation contains a high concentration of antibody, it 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.

[0273] Figure 1 shows the aggregation temperature (T) for 10 formulations with different types of excipients and a formulation having a Dupixent composition. agg This is a graph showing the results of measuring ).

[0274] Figure 2 shows the diffusion interaction parameter (K) for 10 formulations with different types of excipients and a formulation having the Dupixent composition. D This is a graph showing the results of measuring ).

[0275] Figure 3 is a graph showing the results of measuring viscosity for a formulation containing methionine and a formulation not containing methionine.

[0276] Figure 4 is a graph showing the results of analyzing the ratio of high molecular weight species content (%HMW) for a formulation containing methionine and a formulation not containing methionine.

[0277] Figure 5 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation.

[0278] Figure 6 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.

[0279] Figure 7 is a graph showing the results of measuring the viscosity of the sugar-free formulation and the Dupixent formulation.

[0280] Figure 8 is a graph showing the results of measuring the ratio of high molecular weight species content (%HMW) of sugar-free formulations and Dupixent formulations.

[0281] 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.

[0282] [Experimental Method]

[0283] 1. Measurement of Coagulation Temperature (Tagg)

[0284] The aggregation temperature was measured using Dynamic Light Scattering (DLS). Specifically, each sample was diluted with its respective buffer and loaded into a 96-well plate. The plate was then loaded onto a DynoPro® Plate Reader™ II (Wyatt Technology) instrument. The size of aggregates within the formulation was measured via DLS while increasing the temperature of the samples within a range of 25 to 80°C at a rate of 0.25°C / min. The evaluation of stability involves measuring the temperature at which the aggregate size changes, and the aggregation temperature (T agg The higher the value, the more stable the formulation.

[0285] 2. Diffusion Interaction Parameter Kd Analysis

[0286] To evaluate whether the binding force in the fluid phase is attractive or repulsive as protein concentration increases when the sample is exposed at room temperature, the diffusion interaction parameter K D ...was analyzed. This is a parameter that enables the evaluation or ranking of superior formulations based on aggregation tendencies by assessing the binding forces between substances that cause irreversible aggregation. Specifically, each sample was diluted using a buffer (protein concentrations: 2, 4, 6, 8, 10 mg / mL) and loaded into a 96-well plate. The plate was loaded into a DynaPro® Plate Reader™ II (Wayatt Technology) instrument. After measuring the diffusion coefficient values ​​according to the protein concentration of the prepared samples, K was calculated using the slope and y-intercept of the corresponding graph. D Calculate . If the corresponding value is positive, repulsive forces between substances are dominant, indicating a weak tendency to aggregate; if it is negative, attractive forces are dominant, indicating a strong tendency to aggregate, K D The more positive and larger the value, the more stable the formulation.

[0287] 3. Viscosity measurement

[0288] 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.

[0289] 4. Analysis of %high molecular weight species (%HMW) content

[0290] The percentage of high molecular weight species (%HMW) was determined using Waters size exclusion chromatography (SEC). The proteins were separated into a total of three peaks according to their molecular weight, and these three peaks correspond to the HMW peak (protein aggregation), Monomer peak, and LMW peak (protein degradation), in order of decreasing retention time, that is, in order of decreasing molecular weight.

[0291] - %HMW = {area of ​​HMW / area of ​​(HMW + monomer + LMW)}*100

[0292] Each formulation sample for the stability test was stored in a chamber maintaining accelerated stability conditions of 25±2℃ and 60±5% relative humidity (RH), or in a chamber maintaining severe stability conditions of 40±2℃ and 75±5% RH.

[0293] 5. Analysis of Acid Species Content Ratio (%Acidic)

[0294] The % acidity (Acidic) value of the sample was measured using Imaging Capillary Isoelectric Focusing (icIEF). The sample was injected into the iCE3 system (Protein Simple, USA), and the isoelectric point (pI) and the relative area of ​​protein charge variants were measured using iCE CFR software. % acidity represents the relative area of ​​protein charge variants detected prior to the main peak. Measuring these values ​​is intended to identify protein charge variants. When a protein changes under stress, aggregation occurs or its charge changes. Therefore, protein charge variation can serve as a factor in verifying its stability.

[0295] - %Acidic = {area of ​​Acidic / area of ​​(Acidic + Main + Basic)}*100

[0296] Each formulation sample for the stability test was stored in a chamber maintaining accelerated stability conditions of 25±2℃ and 60±5% RH.

[0297] 6. Analysis of oxidation level

[0298] Using Waters' LC-MS (liquid-chromatography-mass spectrometry), methionine (Met), the 257th amino acid residue of the protein 257 The mass of ) was measured. MassLynx after performing the LC-MS experiment TM and BioPharmaLynx TM Using the program, the oxidation rate (%Met) of methionine, the 257th amino acid residue 257 ) was analyzed.

[0299] %Met 257= {intensity of oxidated Met 257 / (intensity of oxidized Met 257 + intensity of non-oxidized Met 257 )}*100

[0300] Each formulation sample for the stability test was stored in a chamber maintaining accelerated stability conditions of 25±2℃ and 60±5% RH.

[0301] [Example]

[0302] Example 1. Tagg evaluation based on the presence or absence of methionine

[0303] Aqueous liquid formulations having the compositions shown in Table 1 below were prepared using dupilumab (CAS No. 1190264-60-8) as the anti-IL-4Rα antibody. The agglutination temperature (T) of each formulation agg ) was measured.

[0304] T agg An increase in means that the temperature at which aggregation occurs has increased. Therefore, the increased T agg It means improved thermal stability.

[0305] No. a Buffer pH Excipient T agg (°C) A120 mM Histidine 6.08% (w / v) Sucrose 68.51 A29% (w / v) Trehalose 69.41 A34.7% (w / v) Sorbitol 69.54 A43.13% (w / v) Mannitol 68.62 A5140 mM Arginine 66.76 A6135 mM Lysine 67.61 A770 mM Histidine 67.36 A890 mM Methionine 67.44 A9250 mM Glycine 68.32 A100.8% (w / v) NaCl 67.44 A11 b 12.5 mM acetate + 20 mM histidine 5.95% (w / v) sucrose + 50 mM arginine 67.89

[0306] a In all formulations The antibody concentration is T agg Set to 5 mg / mL depending on the required concentration of the analysis method.

[0307] b Formulation A11 has the same composition as Dupixent in terms of buffer, pH, sugars, and amino acid conditions.

[0308] Figure 1 shows the aggregation temperature (T) for 10 formulations with different types of excipients and a formulation having a Dupixent composition. agg This is a graph showing the results of measuring ).

[0309] As a result, as shown in Table 1 and Figure 1, formulation A8 containing methionine has a higher aggregation temperature (T) compared to formulations A5 and A7 containing other types of amino acids, such as arginine or histidine. agg It represented ).

[0310] Therefore, formulation A8 containing methionine is T agg It was confirmed that this increased and improved thermal stability was achieved.

[0311] Example 2. Evaluation of Kd based on the presence or absence of methionine

[0312] Table 2 below shows K for the same formulation as Example 1. D This is the result of measuring. Attractive interactions between proteins are a major cause of protein aggregation. K D An increase in implies that the attractive force between proteins has decreased. Therefore, the increased K D means improved stability.

[0313] No. a Buffer pH Excipient K D(mL / g) A120 mM Histidine 6.08% (w / v) Sucrose-20 A29% (w / v) Trehalose-14 A34.7% (w / v) Sorbitol-6 A43.13% (w / v) Mannitol-5 A5140 mM Arginine-3 A6135 mM Lysine-6 ​​A770 mM Histidine-7 A890 mM Methionine-1 A9250 mM Glycine-0 A100.8% (w / v) NaCl-6 A11 b 12.5 mM acetate + 20 mM histidine 5.95% (w / v) sucrose + 50 mM arginine-9

[0314] a In all formulations, the antibody concentration is K D Set to 2, 4, 6, 8, or 10 mg / mL depending on the required concentration of the analysis method.

[0315] b Formulation A11 has the same composition as Dupixent in terms of buffer, pH, sugars, and amino acid conditions.

[0316] Figure 2 shows the diffusion interaction parameter (K) for 10 formulations with different types of excipients and a formulation having the Dupixent composition. D This is a graph showing the results of measuring ).

[0317] As a result, as shown in Table 2 and Figure 2, formulation A8 containing methionine has K compared to formulations A1 to A7 and A10 containing sucrose, trehalose, sorbitol, mannitol, arginine, lysine, histidine, or NaCl. D It was confirmed that it increased. In addition, formulation A8 containing methionine showed K compared to formulation A11 having the Dupixent composition. D It was confirmed that it increased significantly.

[0318] Therefore, it was confirmed that formulation A8 containing methionine possesses excellent stability by reducing the intermolecular forces, which are the main cause of protein aggregation.

[0319] Example 3. Evaluation of viscosity and %HMW depending on the presence or absence of methionine

[0320] An aqueous liquid formulation having the composition of Table 3 below was prepared. For each formulation, the viscosity was measured at a temperature of 25°C, and the %HMW was measured under accelerated stability conditions (25°C, 4 weeks) or severe stability conditions (40°C, 4 weeks).

[0321] Formulations A9', A10', and A11' are formulations that additionally contain methionine in formulations A9, A10, and A11 that contain sugars.

[0322] Formulations A12' and A13' are formulations in which lysine is replaced with methionine in formulations A12 and A13, which contain sugars and lysine.

[0323] No. a Classification Excipients Part 1 Excipients Part 2 Excipients 3 Viscosity (cP) %HMW (25℃, 4 weeks) %HMW (40℃, 4 weeks) A9 Add methionine 8% (w / v) Trehalose 33.9 4.2 7 7.18 A9'8% (w / v) Trehalose 30 mM Methionine 23.7 3.3 6 6.01 A10'4.3% (w / v) Trehalose 80 mM Histidine 16.8 2.5 9 4.42 A10'4.3% (w / v) Trehalose 80 mM Histidine 30 mM Methionine 12.4 2.3 3 4.01 A11'4.3% (w / v) Trehalose 70 mM Arginine 12.7 3.1 4 5.20 A11'4.3% (w / v) Trehalose 70 mM Arginine 30 mM Methionine 11.5 2.7 14.6 3A12 Lysine replaced with methionine 4.3% (w / v) Trehalose 120 mM Glycine 30 mM Lysine 3 1.4 3.6 86.8 8A12' 4.3% (w / v) Trehalose 120 mM Glycine 30 mM Methionine 2 7.6 3.2 55.8 6A13 1.8% (w / v) Mannitol 80 mM Histidine 30 mM Lysine 15.3 2.4 94.3 2A13' 1.8% (w / v) Mannitol 80 mM Histidine 30 mM Methionine 13.4 2.3 54.05

[0324] aAll formulations contain 175 mg / mL dupilumab, 10 mM sodium acetate, 0.2% (w / v) polysorbate 80, and have a pH of 6.0.

[0325] As a result, as shown in Table 3, when methionine was added to formulations containing sugars, viscosity, %HMW 25℃ / 4주 , %HMW 40℃ / 4주 It was confirmed from the results of formulations A9', A10', and A11' that these were simultaneously improved. Through these results, it was found that methionine functions excellently as a viscosity reducer and stabilizer.

[0326] In addition, viscosity, %HMW when lysine is replaced with methionine in formulations containing sugars and lysine 25℃ / 4주 , %HMW 40℃ / 4주 It was confirmed from the results of formulations A12' and A13' that these were simultaneously improved. Through these results, it was found that methionine functions superiorly to lysine as a viscosity reducer and stabilizer.

[0327] Example 4. Evaluation of %HMW, %Acidic, and %Met257 with and without methionine

[0328] Aqueous liquid formulations having the compositions shown in Table 4 below were prepared. %HMW, %Acidic, and %Met of each formulation under accelerated stability conditions (25°C, 4 weeks) 257 Measured.

[0329] Formulation A14' excludes histidine from Formulation A14, which contains sugars and amino acids (i.e., histidine and methionine).

[0330] Formulation A14'' excludes methionine from Formulation A14, which contains sugars and amino acids (i.e., histidine and methionine).

[0331] No. a Excipients 1 Excipient 2 Excipients 3% HMW (25℃ / 4 weeks)% Acidic (25℃ / 4 weeks)% Met 257(25℃ / 4 weeks) A144% (w / v) Sucrose 70 mM Histidine 25 mM Methionine 2.26 38.5 4.6 A14'4% (w / v) Sucrose Histidine-free 25 mM Methionine 3.10 39.7 5.4 A14''4% (w / v) Sucrose 70 mM Histidine Methionine-free 2.56 41.6 12.5

[0332] a All formulations contain 175 mg / mL dupilumab, 15 mM sodium acetate, 0.2% (w / v) polysorbate 80, and have a pH of 5.5.

[0333] As a result, as shown in Table 4, when methionine was excluded from formulations containing sugars and amino acids, %HMW, %Acidic, and %Met at 25°C / 4-week accelerated stability conditions 257 It was confirmed from the results of Formulation A14'' that these values ​​increased simultaneously. In particular, %Acidic and %Met of the formulation excluding methionine (Formulation A14'') compared to the formulation excluding histidine (Formulation A14'). 257 This increased significantly. Through these results, the function of methionine as a stabilizer and antioxidant could be confirmed.

[0334] Example 5. Evaluation of viscosity and %HMW of methionine-containing and methionine-free formulations

[0335] An aqueous liquid formulation having the composition of Table 5 below was prepared. The viscosity of each formulation was measured at a temperature of 25°C, and the %HMW was measured immediately after preparation (0 day, Initial).

[0336] Formulations A15 to A20 are methionine-containing formulations with different histidine concentrations and pH.

[0337] Formulation A21 is a methionine-free formulation and has the same composition as Dupixent.

[0338] No. aBuffer pH Excipient 1 Excipient 2 Excipient 3 Viscosity (cP)%HMW(Initial) A15 30 mM Sodium Acetate 4.94% (w / v) Sucrose 20 mM Histidine 25 mM Methionine 8.7 1.93 A16 4.84% (w / v) Sucrose 50 mM Histidine 25 mM Methionine 8.3 1.94 A17 5.24% (w / v) Sucrose 50 mM Histidine 25 mM Methionine 9.0 1.97 A18 4.94% (w / v) Sucrose 80 mM Histidine 25 mM Methionine 7.6 1.95 A19 5.54% (w / v) Sucrose 80 mM Histidine 25 mM Methionine 8.7 2.01 A20 5.24% (w / v) Sucrose 92.4 mM Histidine 25 mM Methionine 8.8 1.9 3A21 b 12.5 mM Sodium Acetate + 20 mM Histidine 5.95% (w / v) Sucrose 50 mM Arginine-11.12.03

[0339] a All formulations contain 175 mg / mL dupilumab and 0.2% (w / v) polysorbate 80.

[0340] b Formulation A21 is a Dupixent formulation.

[0341] Figure 3 is a graph showing the results of measuring viscosity for a formulation containing methionine and a formulation not containing methionine.

[0342] Figure 4 is a graph showing the results of analyzing the ratio of high molecular weight species content (%HMW) for a formulation containing methionine and a formulation not containing methionine.

[0343] As a result, as shown in Table 5, Figure 3, and Figure 4, it was confirmed that formulations containing 20 to 92.4 mM histidine and 25 mM methionine with a pH range of 4.9 to 5.5 (Formulations A15 to A20) simultaneously improved viscosity and %HMW compared to Dupixent formulations that do not contain methionine (Formulation A21).

[0344] Example 6. Evaluation of viscosity and %HMW according to the presence or absence of sugars

[0345] For formulations containing sugars, the improvement in viscosity and %HMW was evaluated after removing the sugars while fixing the type of amino acids and other conditions.

[0346] An aqueous liquid formulation having the composition of Table 6 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.

[0347] No. Excipient 1 (Sugars) Excipient 2 (Amino Acids) Excipient 3 (Amino Acids) Viscosity (cP) %HMW (25℃, 4 weeks) B1 Sugars-Free 120 mM Arginine - 8.1 2.9 3 B2 4.3% (w / v) Trehalose 70 mM Arginine - 12.7 3.1 4 B3 1.8% (w / v) Sorbitol 70 mM Arginine - 11.6 3.2 1 B4 1.8% (w / v) Mannitol 70 mM Arginine - 14.2 3.3 8 B5 Sugars-Free 120 mM Arginine 30 mM Lysine 7.9 2.8 0 B6 4.3% (w / v) Trehalose 70 mM Arginine 30 mM Lysine 10.8 2.9 3 B7 1.8% (w / v) Sorbitol 70 mM Arginine 30 mM Lysine 11.9 3.0 2B 81.8% (w / v) Mannitol 70 mM Arginine 30 mM Lysine 13.5 3.10 B 9 Saccharide-Free 120 mM Arginine 30 mM Methionine 7.8 2.5 9B 104.3% (w / v) Trehalose 70 mM Arginine 30 mM Methionine 11.5 2.7 1B 111.8% (w / v) Sorbitol 70 mM Arginine 30 mM Methionine 11.2 2.7 6B 121.8% (w / v) Mannitol 70 mM Arginine 30 mM Methionine 14.9 2.9 4B 13 Saccharide-Free 145 mM Histidine 8.7 2.2 6B 144.3% (w / v) Trehalose 80 mM Histidine 16.8 2.5 9B 151.8% (w / v) Sorbitol 80 mM Histidine-14.8 2.5 8B 16 1.8% (w / v) Mannitol 80 mM Histidine-13.8 2.5 6B 17 Saccharide-Free 145 mM Histidine 30 mM Lysine 8.8 2.1 9B 18 4.3% (w / v) Trehalose 80 mM Histidine 30 mM Lysine 11.1 2.4 9B 19 1.8% (w / v) Sorbitol 80 mM Histidine 30 mM Lysine 12.8 2.5 1B 20 1.8% (w / v) Mannitol 80 mM Histidine 30 mM Lysine 15.3 2.4 9B 21 Saccharide-Free 145 mM Histidine 30 mM Methionine 9.4 2.0 9B 22 4.3% (w / v) Trehalose 80 mM Histidine 30 mM Methionine 12.4 2.33B23 1.8% (w / v) Sorbitol 80 mM Histidine 30 mM Methionine 13.0 2.34B24 1.8% (w / v) Mannitol 80 mM Histidine 30 mM Methionine 13.4 2.3 5B 25 Sugar-Free 220 mM Glycine 14.9 3.6 2B 26 4.3% (w / v) Trehalose 120 mM Glycine 23.5 3.6 9B 27 1.8% (w / v) Sorbitol 120 mM Glycine 43.2 3.7 2B 28 1.8% (w / v) Mannitol 120 mM Glycine 35.8 3.6 9B 29 Sugar-Free 220 mM Glycine 30 mM Lysine 10.8 3.4 1B 30 4.3% (w / v) Trehalose 120 mM Glycine 30 mM Lysine 31.4 3.6 8B 31 1.8% (w / v) Sorbitol 120 mM Glycine 30 mM Lysine 38.23.79 B32 1.8% (w / v) Mannitol 120 mM Glycine 30 mM Lysine 22.03.68 B3 Trisaccharide-Free 220 mM Glycine 30 mM Methionine 16.83.10 B34 4.3% (w / v) Trehalose 120 mM Glycine 30 mM Methionine 27.63.25 B35 1.8% (w / v) Sorbitol 120 mM Glycine 30 mM Methionine 38.03.26 B36 1.8% (w / v) Mannitol 120 mM Glycine 30 mM Methionine 30.93.23.

[0348] a All formulations contain 175 mg / mL dupilumab, 10 mM sodium acetate, 0.2% (w / v) polysorbate 80, and have a pH of 6.0.

[0349] Figure 5 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation.

[0350] Figure 6 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.

[0351] As a result, as shown in Table 6, Figure 5, and Figure 6, when sugars were removed from a sugar-containing formulation while fixing the amino acid type and other conditions, the viscosity and %HMW 25℃ / 4주 It was confirmed that it was improved simultaneously.

[0352] Example 7. Comparative evaluation of viscosity and %HMW between sugar-free formulation and Dupixent

[0353] As shown in Table 7 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.

[0354] No. aBuffer pH Excipient 1 (Sugars) Excipient 2 (Amino Acids) Excipient 3 (Amino Acids) Viscosity (cP) %HMW (Initial) B3 76 mM Sodium Acetate 5.9g Sugars-Free 145 mM Histidine 30 mM Methionine 8.1 1.76 B3 88 mM Sodium Acetate 5.6 115 mM Histidine 25 mM Methionine 7.6 1.71 B3 96.225 mM Methionine 9.7 1.92 B4 05.635 mM Methionine 8.0 1.73 B4 16.235 mM Methionine 9.9 1.88 B4 25.6 175 mM Histidine 25 mM Methionine 7.7 1.69 B4 36.225 mM Methionine 8.0 1.78 B4 45.635 mM Methionine 7.7 1.6 2B 45 6.235 mM Methionine 8.5 1.8 1B 46 10 mM Sodium Acetate 5.985 mM Histidine 30 mM Methionine 9.5 1.8 4B 47 5.31 45 mM Histidine 30 mM Methionine 7.4 1.6 4B 48 5.930 mM Methionine 8.01 1.7 5B 49 6.530 mM Methionine 10.01 1.9 8B 50 5.920 mM Methionine 8.01 1.7 5B 51 5.940 mM Methionine 8.3 1.7 8B 52 5.92 05 mM Histidine 30 mM Methionine 7.4 1.6 2B 53 12 mM Sodium Acetate 5.61 15 mM Histidine 25 mM Methionine 8.2 1.7 1B 54 6.225 mM Methionine 8.91.90B555.635 mM Methionine 7.91.72B566.235 mM Methionine 9.11.92B575.6175 mM Histidine 25 mM Methionine 8.01.66B586.225 mM Methionine 8.11.83B595.635 mM Methionine 8.11.69B606.235 mM Methionine 8.61.81B6114 mM Sodium Acetate 5.9145 mM Histidine 30 mM Methionine 8.31.74B62 b 12.5 mM Sodium Acetate + 20 mM Histidine 5.95% (w / v) Sucrose 50 mM Arginine-11.12.03

[0355] a All formulations contain 175 mg / mL dupilumab and 0.2% (w / v) polysorbate 80.

[0356] b Formulation B62 is the Dupixent formulation.

[0357] Figure 7 is a graph showing the results of measuring the viscosity of the sugar-free formulation and the Dupixent formulation.

[0358] Figure 8 is a graph showing the results of measuring the ratio of high molecular weight species content (%HMW) of sugar-free formulations and Dupixent formulations.

[0359] As a result, as shown in Table 7, Figure 7, and Figure 8, 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 B62).

[0360] Example 8. Evaluation of %HMW and Viscosity of Sugar-Free Formulations

[0361] %HMW and viscosity were evaluated according to the presence or absence of sugars and the type of excipient.

[0362] Specifically, formulations having the compositions of Tables 8 and 9 below were prepared, and viscosity and %HMW were measured after storage at 25°C for 4 weeks.

[0363] No. a Type c Part 1 dExcipient 2 Excipient 3% HMW (25℃, 4 weeks) Type Concentration Type Concentration Type Concentration C1S + AA-free Suc 11% (w / v)----4.39 C2S + AA-free + Salt Suc 2.5% (w / v) NaCl 145 mM--3.51 C3S + AA-free + Salt Man 1.5% (w / v) NaCl 145 mM--3.54 C4S + AA-free + Salt + Antioxidant Suc 2.5% (w / v) NaCl 145 mM EDTA 0.37 mM 3.17 C5S-free + 2AAArg 0 mM His 59 mM Met 30 mM 2.05 C6S-free + 2AAArg 125 mM His 59 mM Met 0 mM 1.97 C7S-free + 2AAArg 125 mM His 0 mM Met 30 mM 2.13 C8S-free + 2AAArg175mMHis0mMLys25mM2.15C9S-free + 3AAHis59mMMet30mMArg125mM1.77C10 b DupixentSuc5% (w / v)His20mMArg50mM2.28

[0364] a All formulations contain 175 mg / mL dupilumab and 0.2% (w / v) polysorbate 80. The target pH of formulations C1 to C9 is 5.2±0.3, and the target pH of formulation C10 is 5.9±0.3.

[0365] b Formulation C10 additionally contains 12.5 mM acetate and is a Dupixent formulation.

[0366] C S: Contains sugars, S-free: Sugar-free, nAA: Contains amino acids (n: Number of amino acids), AA-free: Amino acid-free.

[0367] d Suc: Sucrose, Man: Mannitol, Arg: Arginine, His: Histidine, Met: Methionine, Lys: Lysine.

[0368] No. a Type c Part 1d Excipient 2 Excipient 3 Viscosity (cP) Type Concentration Type Concentration Type Concentration C1S + AA-free Suc 11% (w / v)----20.5 C2S + AA-free + Salt Suc 2.5% (w / v)NaCl 145 mM--11.1 C3S + AA-free + Salt Man 1.5% (w / v)NaCl 145 mM--10.5 C4S + AA-free + Salt + Antioxidant Suc 2.5% (w / v)NaCl 145 mM EDTA 0.37 mM 10.9 C5S-free + 2AAArg 0 mM His 59 mM Met 30 mM 9.8 C6S-free + 2AAArg 125 mM His 59 mM Met 0 mM 8.4 C7S-free + 2AAArg 125 mM His 0 mM Met 30 mM 8.7 C8S-free + 2AAArg 175 mMHis0 mMLys25 mM8.6C9S-free + 3AAHis59 mMMet30 mMArg125 mM8.1C10 b DupixentSuc5% (w / v)His20mMArg50mM10.8

[0369] a All formulations contain 175 mg / mL dupilumab and 0.2% (w / v) polysorbate 80. The target pH of formulations C1 to C9 is 5.2±0.3, and the target pH of formulation C10 is 5.9±0.3.

[0370] b Formulation C10 additionally contains 12.5 mM acetate and is a Dupixent formulation.

[0371] C S: Contains sugars, S-free: Sugar-free, nAA: Contains amino acids (n: Number of amino acids), AA-free: Amino acid-free.

[0372] d Suc: Sucrose, Man: Mannitol, Arg: Arginine, His: Histidine, Met: Methionine, Lys: Lysine.

[0373] As a result, as shown in Table 8, it was confirmed that the %HMW of the sugar-free and amino acid-containing formulations (formulations C5 to C9) was improved compared to the Dupixent formulation (formulation C10). In addition, it was confirmed that the %HMW of the sugar-free and amino acid-containing formulations (formulations C5 to C9) was significantly improved compared to the sugar-containing and amino acid-free formulations (formulations C1 to C4).

[0374] As shown in Table 9, it was confirmed that the viscosity of the sugar-free and amino acid-containing formulations (formulations C5 to C9) was improved compared to the Dupixent formulation (formulation C10). In addition, it was confirmed that the viscosity of the sugar-free and amino acid-containing formulations (formulations C5 to C9) was improved compared to the sugar-containing and amino acid-free formulations (formulations C1 to C4).

[0375] 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

1. Anti-IL-4Rα antibody; and Contains amino acids, Not containing sugars, Having a viscosity of less than 10 cP at 25℃, Liquid formulation.

2. A liquid formulation according to claim 1, wherein the amino acid comprises at least one type.

3. A liquid formulation according to claim 1, wherein the amino acid comprises at least two types.

4. A liquid formulation according to claim 1, wherein the amino acids comprise at least three types.

5. A liquid formulation according to claim 1, wherein the amino acid comprises 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.

6. A liquid formulation according to claim 1, wherein the amino acid comprises at least a cationic amino acid.

7. A liquid formulation according to claim 1, wherein the cationic amino acid comprises one or more selected from arginine, histidine, and lysine.

8. A liquid formulation according to claim 1, wherein the amino acid comprises one or more selected from arginine, histidine, methionine, and lysine.

9. A liquid formulation according to claim 1, wherein the amino acid comprises a combination of two or three selected from arginine, histidine, methionine, and lysine.

10. A liquid formulation according to claim 1, wherein the amino acid comprises a combination selected from the following: 1) Combination of histidine and methionine; 2) Combination of arginine and histidine; 3) Combination of arginine and methionine; 4) Combination of arginine and lysine; 5) A combination of arginine, histidine, and lysine; and 6) Combination of histidine, methionine, and arginine.

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

12. A liquid formulation according to any one of claims 5 to 11, wherein the concentration of the arginine is about 75 mM to about 200 mM.

13. A liquid formulation according to any one of claims 5 to 11, wherein the concentration of histidine is about 20 mM to about 92.4 mM.

14. A liquid formulation according to any one of claims 5 to 11, wherein the concentration of methionine is about 15 mM to about 100 mM.

15. A liquid formulation according to any one of claims 5 to 11, wherein the concentration of lysine is about 10 mM to about 100 mM.

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

17. 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.

18. 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.

19. A liquid formulation according to claim 1, wherein the pH of the liquid formulation is about 4.5 to about 7.

0.

20. A liquid formulation according to claim 1, wherein the pH of the liquid formulation is about 4.8 to about 5.

6.

21. A liquid formulation according to any one of claims 1 to 20, further comprising a surfactant.

22. A liquid formulation according to claim 21, wherein the surfactant comprises a nonionic surfactant.

23. A liquid formulation according to claim 21, wherein the surfactant comprises one or more selected from polysorbate 20, polysorbate 80, and poloxamer 188.

24. A liquid formulation according to claim 21, wherein the surfactant comprises polysorbate 80.

25. A liquid formulation according to any one of claims 21 to 24, wherein the concentration of the surfactant is 0.01% (w / v) to 0.9% (w / v).

26. A liquid formulation according to any one of claims 1 to 25, wherein the liquid formulation has a high molecular weight species content ratio (%HMW) of antibodies measured after storage at 25°C for 4 weeks of 3% or less.

27. A liquid formulation for subcutaneous injection, in any one of claims 1 to 26.

28. A device comprising a liquid formulation of any one of claims 1 to 27.

29. The device of claim 28, wherein the liquid formulation is contained in a container selected from a syringe, a pre-filled syringe, a pre-filled pen, a microinfuser, an autoinjector, a bottle, a vial, and a tube.

30. A method for treating an IL-4Rα-related condition, comprising the step of administering the liquid formulation of any one of claims 1 to 27 to an individual in need thereof.

31. A method for treating an IL-4Rα-related condition according to claim 30, wherein the IL-4Rα-related condition is an IL-4-mediated disease or an IL-13-mediated disease.

32. In claim 31, 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). A method for treating IL-4Rα-related conditions.

33. Use of a liquid formulation of any one of claims 1 to 27 in the manufacture of a drug for treating an IL-4Rα-related condition.

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