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

Abstract

The present invention relates to a liquid formulation comprising an anti-IL-4Rα antibody, sugars, and amino acids, and not containing a buffer, a device comprising the same, and the use thereof for treating IL-4Rα-related conditions. Since the liquid formulation can ensure stability and improve viscosity without including a buffer for the antibody, it can be usefully used as a pharmaceutical product for treating IL-4Rα-related conditions.

Description

Technology Field

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

[0002] Compared to conventional protein drugs, antibody drugs have larger molecular weights and complex secondary and higher-order structures, which poses a risk of physicochemical instability. For this reason, there is a need to develop optimal formulations for antibody drugs that guarantee quality and stability throughout the entire process of manufacturing, storage, and patient administration. Protein instability can originate from various external factors, such as temperature, light, and chemical elements, which can lead to reduced activity and efficacy, or cause immunogenicity when administered to the human body.

[0003] In addition, in the case of high-concentration protein drugs, as the protein concentration increases, the viscosity of the solution may increase due to high protein interactions and density. Due to the high viscosity characteristics of these drugs, problems such as reduced usability for patients may occur by increasing the gliding force of the syringe stopper and the injection time.

[0004] Therefore, it is important to improve the instability and viscosity of such antibody drugs to maintain optimal quality until administration to patients. Methods such as modifying buffers and stabilizers are used to achieve optimal quality. Since the material properties of each antibody protein differ and the optimal combination of buffers and stabilizers may vary, it is required to derive a formulation suitable for the target substance to address these issues.

[0005] On the other hand, in the case of high-concentration protein drugs, a constant pH can be maintained without the inclusion of buffers due to the self-buffering effect resulting from the high protein concentration. Additionally, some buffers are prone to self-degradation under stress conditions, which can affect the stability of antibody drugs.

[0006] Therefore, there is a need to develop formulations capable of stabilizing antibody proteins without including buffers that may affect the stability of anti-IL-4Rα antibody pharmaceutical formulations. The problem to be solved

[0007] This specification relates to a stable buffer-free liquid formulation of an anti-IL-4Rα antibody such as dupilumab. Specifically, this specification provides a liquid formulation of an anti-IL-4Rα antibody such as dupilumab that has high stability and low viscosity without containing a buffer.

[0008] One aspect provides a liquid formulation comprising an anti-IL-4Rα antibody; sugars; and amino acids, and not containing a buffer.

[0009] Another aspect is to provide a device comprising the above-mentioned liquid formulation.

[0010] 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.

[0011] Another aspect is to provide the use of the liquid formulation in the manufacture of a drug for treating IL-4Rα-related conditions. means of solving the problem

[0012] 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.

[0013] 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.

[0014] One aspect provides a stable buffer-free liquid formulation of an anti-IL-4Rα antibody, specifically,

[0015] Anti-IL-4Rα antibody;

[0016] Sugars; and

[0017] Contains amino acids,

[0018] Not containing a buffer,

[0019] It provides a liquid formulation.

[0020] (1) Antibody

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] The above anti-IL-4Rα antibody may be included in a therapeutically effective amount in a liquid formulation.

[0027] 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.

[0028] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 100 mg / mL to about 200 mg / mL.

[0029] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 125 mg / mL to about 200 mg / mL.

[0030] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL to about 200 mg / mL.

[0031] In one embodiment, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL to about 175 mg / mL.

[0032] In one embodiment, the concentration of the anti-IL-4Rα antibody may be 135 mg / mL to 165 mg / mL.

[0033] In one embodiment, the concentration of the anti-IL-4Rα antibody may be 158 mg / mL to 192 mg / mL.

[0034] In a specific embodiment, the concentration of the anti-IL-4Rα antibody may be about 150 mg / mL.

[0035] In a specific embodiment, the concentration of the anti-IL-4Rα antibody may be about 175 mg / mL.

[0036] 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.

[0037] (2) Buffer and pH

[0038] A liquid formulation according to one aspect is free of buffer. Therefore, the liquid formulation may be a buffer-free formulation or a bufferless formulation.

[0039] The above liquid formulation can have high stability and low viscosity despite being a buffer-free formulation.

[0040] 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.

[0041] In this specification, the phrase “does not contain a buffer” may be interpreted as meaning that a buffer component is not present in the formulation, or is included in an amount that is insufficient to perform its intended function as a buffer in the formulation.

[0042] The above liquid formulation does not contain or substantially does not contain a buffer.

[0043] The above buffer may include one or more selected from acetate, histidine, phosphate, citrate, succinate, malate, tartarate, carbonate, salts thereof, and hydrates thereof.

[0044] The term "salt" may be a pharmaceutically acceptable salt. The salt may include inorganic salts, organic salts, metal salts, etc. of a compound. Inorganic salts may be hydrochlorides, bromates, phosphates, sulfates, or disulfates. Organic salts may be formates, acetates, propionates, lactates, oxalates, tartrates, malates, maleates, citrates, fumarates, besylates, camsylates, edicils, trichloroacetic acid, trifluoroacetates, benzosates, gluconates, methanesulfonates, glycolates, succinates, 4-toluenesulfonates, galacturoneates, emvonates, glutamates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, or aspartates. Metal salts may be calcium salts, sodium salts, magnesium salts, strontium salts, or potassium salts.

[0045] The term "hydrate" refers to a substance containing water molecules within its molecule. The hydrate may be a monohydrate, a dihydrate, or a trihydrate.

[0046] In one embodiment, the buffer may include acetate. Accordingly, the liquid formulation may not include acetate as a buffer.

[0047] In one embodiment, the buffer may comprise a combination of acetate and histidine. Accordingly, the liquid formulation may not comprise either acetate or histidine as a buffer.

[0048] 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 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 5.5 to about 8.5, about 5.5 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 5.6 to about 8.5, about 5.6 to about 8.0, about 5.6 to about 7.5, about 5.6 to about 7.0, about 5.6 to about 6.5, about 5.6 to about 6.0, about 5.8 to about 8.5, about 5.8 to about 8.0, about 5.8 to about 7.5, about 5.8 to about 6.0, about 5.8 to about 7.5, about 5.8 to It may be about 7.0, about 5.8 to about 6.5, about 5.8 to about 6.2, about 5.8 to about 6.1, about 5.8 to about 6.0, about 5.9 to about 8.5, about 5.9 to about 8.0, about 5.9 to about 7.5, about 5.9 to about 7.0, about 5.9 to about 6.5, about 5.9 to about 6.2, about 5.9 to about 6.1, or about 5.9 to about 6.0.

[0049] In one embodiment, the pH of the liquid formulation may be about 4.7 to about 7.4.

[0050] In a specific embodiment, the pH of the liquid formulation may be about 5.9.

[0051] In a specific embodiment, the pH of the liquid formulation may be about 6.0.

[0052] (3) Sugars

[0053] A liquid formulation according to one aspect contains saccharides.

[0054] A liquid formulation according to one aspect may include sugars as a stabilizer.

[0055] The above sugars may include one or more selected from sugar and sugar alcohol.

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

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

[0058] The concentration of the above sugar can be freely adjusted within a range that maintains the stability of the antibody and may vary individually depending on each specific type of sugar. The concentration of the above sugar may be any range or any value selected within about 0.1% (w / v) to about 20% (w / v). For example, the concentration of the above sugar is about 0.1% (w / v) to about 20% (w / v), about 0.1% (w / v) to about 15% (w / v), about 0.1% (w / v) to about 12% (w / v), about 0.1% (w / v) to about 10% (w / v), about 0.1% (w / v) to about 8% (w / v), about 0.1% (w / v) to about 6% (w / v), about 1% (w / v) to about 20% (w / v), about 1% (w / v) to about 15% (w / v), about 1% (w / v) to about 12% (w / v), about 1% (w / v) to about 10% (w / v), about 1% (w / v) to about 8% (w / v), about 1% (w / v) Up to about 6% (w / v), about 2% (w / v) to about 20% (w / v), about 2% (w / v) to about 15% (w / v), about 2% (w / v) to about 12% (w / v), about 2% (w / v) to about 10% (w / v), about 2% (w / v) to about 8% (w / v), about 2% (w / v) to about 6% (w / v), about 3% (w / v) to about 20% (w / v), about 3% (w / v) to about 15% (w / v), about 3% (w / v) to about 12% (w / v), about 3% (w / v) to about 10% (w / v), about 3% (w / v) to about 8% (w / v), about 3% (w / v) to about 6% (w / v), It may be about 4% (w / v) to about 20% (w / v), about 4% (w / v) to about 15% (w / v), about 4% (w / v) to about 12% (w / v), about 4% (w / v) to about 10% (w / v), about 4% (w / v) to about 8% (w / v), or about 4% (w / v) to about 6% (w / v).

[0059] The concentration of the sugar alcohol can be freely adjusted within a range that maintains the stability of the antibody and may vary individually depending on each specific type of sugar alcohol. The concentration of the sugar alcohol may be any range or any value selected within about 0.1% (w / v) to about 20% (w / v). For example, the concentration of the sugar alcohol is about 0.1% (w / v) to about 20% (w / v), about 0.1% (w / v) to about 15% (w / v), about 0.1% (w / v) to about 12% (w / v), about 0.1% (w / v) to about 10% (w / v), about 0.1% (w / v) to about 8% (w / v), about 0.1% (w / v) to about 5% (w / v), about 1% (w / v) to about 20% (w / v), about 1% (w / v) to about 15% (w / v), about 1% (w / v) to about 12% (w / v), about 1% (w / v) to about 10% (w / v), about 1% (w / v) to about 8% (w / v), about 1% It may be (w / v) to about 7% (w / v), about 1% (w / v) to about 6% (w / v), about 1% (w / v) to about 5% (w / v), about 1% (w / v) to about 4% (w / v), about 1% (w / v) to about 3% (w / v), or about 1% (w / v) to about 2% (w / v).

[0060] In certain embodiments, the sugars may include sucrose. In certain embodiments, the sugars may be sucrose.

[0061] The concentration of the above sucrose may be any range or any value selected within about 0.1% (w / v) to about 20% (w / v). For example, the concentration of the sucrose is about 0.1% (w / v) to about 20% (w / v), about 0.1% (w / v) to about 15% (w / v), about 0.1% (w / v) to about 12% (w / v), about 0.1% (w / v) to about 10% (w / v), about 0.1% (w / v) to about 8% (w / v), about 0.1% (w / v) to about 6% (w / v), about 1% (w / v) to about 20% (w / v), about 1% (w / v) to about 15% (w / v), about 1% (w / v) to about 12% (w / v), about 1% (w / v) to about 10% (w / v), about 1% (w / v) to about 8% (w / v), about 1% (w / v) to about 6% (w / v), about 2% (w / v) to about 20% (w / v), about 2% (w / v) to about 15% (w / v), about 2% (w / v) to about 12% (w / v), about 2% (w / v) to about 10% (w / v), about 2% (w / v) to about 8% (w / v), about 2% (w / v) to about 6% (w / v), about 3% (w / v) to about 20% (w / v), about 3% (w / v) to about 15% (w / v), about 3% (w / v) to about 12% (w / v), about 3% (w / v) to about 10% (w / v), about 3% (w / v) to about 8% (w / v), about 3% (w / v) to about 6% (w / v), about 4% (w / v) to about 20% (w / v), about 4% (w / v) to about 15% (w / v), about 4% (w / v) to about 12% (w / v), about 4% (w / v) to about 10% (w / v), about 4% (w / v) to about 8% (w / v), or about 4% (w / v) to about 6% (w / v).

[0062] In a specific embodiment, the concentration of the sucrose may be about 5% (w / v).

[0063] (4) amino acids

[0064] A liquid formulation according to one aspect contains amino acids.

[0065] A liquid formulation according to one aspect may include an amino acid as a stabilizer.

[0066] The term "stabilizer" refers to a substance added to prevent changes in state or chemical changes when preserving a substance. The said stabilizer may inhibit the aggregation or denaturation of antibodies.

[0067] 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.

[0068] In one embodiment, the amino acid may include arginine.

[0069] 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 10 mM to about 80 mM, about 10 mM to about 60 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 100 mM, about 20 mM to about 80 mM, about 20 mM to about 60 mM, about 30 mM to about 400 mM, about 30 mM to about 300 mM, about 30 mM to about 200 mM mM, about 30 mM to about 100 mM, about 30 mM to about 80 mM, about 30 mM to about 60 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 100 mM, about 40 mM to about 80 mM, or about 40 mM to about 60 mM.

[0070] (5) Surfactant

[0071] A liquid formulation according to one aspect may additionally include a surfactant.

[0072] Accordingly, the above liquid formulation may be a liquid formulation comprising an anti-IL-4Rα antibody; sugars; amino acids; and a surfactant, and not comprising a buffer.

[0073] 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.

[0074] The above surfactant may be a nonionic surfactant.

[0075] 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).

[0076] The above polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85, etc.

[0077] The above poloxamer may include a PEO-PPO-PEO copolymer (where PEO is poly(ethylene oxide) and PPO is poly(propylene oxide)), etc.

[0078] 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.

[0079] The above polyoxyethylene compound may include polyoxyethylene stearate, polyoxyethylene alkyl ether (alkyl: C1-C30), polyoxyethylene monorylate ether, alkylphenyl polyoxyethylene copolymer (alkyl: C1-C30), etc.

[0080] In one embodiment, the surfactant may be polysorbate.

[0081] 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.

[0082] In one embodiment, the surfactant may include polysorbate 20, polysorbate 80, or a combination thereof.

[0083] In a specific embodiment, the surfactant may include polysorbate 80. In a specific embodiment, the surfactant may be polysorbate 80.

[0084] 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).

[0085] In a specific embodiment, the concentration of the surfactant may be about 0.2% (w / v).

[0086] (6) Diluent

[0087] A liquid formulation according to one aspect may additionally include a diluent.

[0088] 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.

[0089] In one embodiment, the diluent may be water. Accordingly, the liquid formulation may be an aqueous liquid formulation.

[0090] (7) Formulation

[0091] The term "liquid formulation" refers to a formulation in a liquid state.

[0092] The liquid formulation according to one aspect is a stable liquid formulation of the anti-IL-4Rα antibody.

[0093] A liquid formulation according to one aspect may be a pharmaceutical formulation of an anti-IL-4Rα antibody.

[0094] 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.

[0095] 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.

[0096] The term "pharmaceuticalally acceptable" may refer to excipients, carriers, vehicles, diluents, additives, salts, etc. suitable for administration to a subject.

[0097] The liquid formulation according to the aspect is Dupixent ® It can be a biosimilar.

[0098] 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.

[0099] A liquid formulation according to one aspect may be selected from the following items:

[0100] 1) A liquid formulation comprising an anti-IL-4Rα antibody; sugars; and amino acids, and not containing a buffer;

[0101] 2) A liquid formulation comprising about 5 mg / mL to about 300 mg / mL of anti-IL-4Rα antibody; sugars; and amino acids, and not comprising a buffer;

[0102] 3) A liquid formulation comprising an anti-IL-4Rα antibody; sugars; and amino acids, and not comprising acetate as a buffer;

[0103] 4) A liquid formulation comprising an anti-IL-4Rα antibody; sugars; and amino acids, and not comprising either acetate or histidine as a buffer;

[0104] 5) A liquid formulation comprising an anti-IL-4Rα antibody; sugars; amino acids; and a surfactant, and not comprising a buffer;

[0105] 6) A liquid formulation comprising about 5 mg / mL to about 300 mg / mL of anti-IL-4Rα antibody; sugars; amino acids; and a surfactant, and not comprising a buffer;

[0106] 7) A liquid formulation comprising an anti-IL-4Rα antibody; sugars; amino acids; and a surfactant, and not comprising acetate as a buffer;

[0107] 8) A liquid formulation comprising an anti-IL-4Rα antibody; sugars; amino acids; and a surfactant, and not comprising either acetate or histidine as a buffer;

[0108] 9) A liquid formulation comprising dupilumab; sucrose; arginine; and polysorbate 80, excluding buffers; or

[0109] 10) A liquid formulation comprising about 100 mg / mL to about 200 mg / mL of dupilumab; 2% (w / v) to 10% (w / v) of sucrose; 20 mM to 100 mM of arginine; and 0.1% (w / v) to 0.3% (w / v) of polysorbate 80, which does not contain a buffer and has a pH of about 5.6 to about 6.5.

[0110] (8) Stability and viscosity

[0111] A liquid formulation according to one aspect may have improved stability and improved viscosity compared to an anti-IL-4Rα antibody liquid formulation containing a buffer, even though it does not contain a buffer.

[0112] 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.

[0113] 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.

[0114] 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%.

[0115] The above liquid formulation may have a reduced high molecular weight species content ratio (%HMW).

[0116] The above liquid formulation does not contain a buffer, and thus may have a reduced %HMW compared to an anti-IL-4Rα antibody liquid formulation containing a buffer.

[0117] The above liquid formulation may reduce the %HMW of the antibody measured after storage at 25°C for 4 weeks by 1% or more, 2% or more, or 3% or more compared to the formulation containing the buffer.

[0118] The above liquid formulation may have an antibody %HMW of 3.15% or less, 3.14% or less, 3.13% or less, 3.12% or less, 3.11% or less, or 3.10% or less after storage at 25°C for 4 weeks.

[0119] 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.

[0120] The above liquid formulation may have improved viscosity compared to an anti-IL-4Rα antibody liquid formulation containing a buffer by not including a buffer.

[0121] The above liquid formulation may have a viscosity reduced by 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 25% or more compared to the viscosity of the formulation containing the buffer.

[0122] The viscosity of the above liquid formulation may be less than 11.5 cP (centiPoise). The viscosity of the above liquid formulation may be less than 11.5 cP, 11.4 cP or less, 11.2 cP or less, 11.0 cP or less, or 10.5 cP or less.

[0123] (9) Device

[0124] Another aspect provides a device comprising a liquid formulation according to the above-mentioned aspect.

[0125] 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.

[0126] 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.

[0127] The above device may be in a single-dose or multiple-dose form.

[0128] 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.

[0129] 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.

[0130] (10) Treatment of disease

[0131] 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.

[0132] 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.

[0133] 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).

[0134] 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.

[0135] The above liquid formulation can be administered in a pharmaceutically effective amount.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] The above atopic dermatitis may be moderate-to-severe atopic dermatitis.

[0141] The above asthma may be moderate-to-severe asthma.

[0142] (11) Route of administration and dosage

[0143] 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.

[0144] In a specific embodiment, the liquid formulation may be for subcutaneous injection.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] The above liquid formulation can be manufactured as a general bulk formulation, and the components of the liquid formulation are adjusted to a concentration higher than that required for administration and can be appropriately diluted before administration. Effects of the invention

[0152] A liquid formulation of an anti-IL-4Rα antibody according to one aspect may have improved stability and improved viscosity compared to formulations containing a buffer, even though it does not contain a buffer. Therefore, the liquid formulation possesses high stability and low viscosity even when containing a high concentration of the antibody, which can increase patient convenience during injection. Accordingly, the liquid formulation can be usefully employed as a medicine for treating IL-4Rα-related conditions. Brief explanation of the drawing

[0153] Figure 1 is a graph showing the results of analyzing the ratio of high molecular weight species (%HMW) for buffer-free formulations and buffer-containing formulations. Figure 2 is a graph showing the results of viscosity analysis for buffer-free formulations and buffer-containing formulations. Specific details for implementing the invention

[0154] 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.

[0155] [Experimental Method]

[0156] 1. Viscosity measurement

[0157] 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 ℃. 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.

[0158] 2. Analysis of %high molecular weight species (%HMW) content

[0159] The percentage of high molecular weight species (%HMW) was determined using size exclusion chromatography (SEC) with a Waters HPLC system. The proteins were separated into a total of three peaks according to their molecular weight. These three peaks correspond to the HMW peak (protein aggregation), Monomer peak, and LMW peak (protein degradation), in order of decreasing retention time, i.e., increasing molecular weight.

[0160] - %HMW = {area of ​​HMW / area of ​​(HMW + monomer + LMW)}*100

[0161] Each formulation sample for the stability test was stored in a chamber maintaining accelerated stability conditions at a temperature of 25±2℃ and a relative humidity (RH) of 60±5%.

[0162] [Example]

[0163] Example 1. Stability test of buffer-free formulation

[0164] Experiments were conducted to determine the effect of buffers on the stability of liquid formulations containing anti-IL-4Rα antibodies, such as dupilumab.

[0165] Aqueous liquid formulations having the composition of Table 1 below were prepared using dupilumab (CAS No. 1190264-60-8) as the anti-IL-4Rα antibody. After exposing each formulation to 25°C for 4 weeks, the purity of the samples was measured by size exclusion chromatography (SEC) analysis.

[0166] No. classification antibody concentration buffer pH Part 1 Excipient 2 surfactants %HMW(25℃, 4 weeks) 1 Buffer-free 175 mg / mL - 5.9 5% (w / v) sucrose 50 mM arginine 0.2% (w / v) PS80 3.13 2 5.9 5% (w / v) sucrose 50 mM arginine 0.2% (w / v) PS80 3.10 3 5.9 5% (w / v) sucrose 50 mM arginine 0.2% (w / v) PS80 3.15 4 Includes buffer 10 mM sodium acetate 6.0 4.3% (w / v) Trehalose 70 mM arginine 0.2% (w / v) PS80 3.14 5 6.0 1.8% (w / v) Sorbitol 70 mM arginine 0.2% (w / v) PS80 3.21 6 6.0 1.8% (w / v) Mannitol 70 mM arginine 0.2% (w / v) PS80 3.38

[0167] Figure 1 is a graph showing the results of analyzing the ratio of high molecular weight species (%HMW) for buffer-free formulations and buffer-containing formulations.

[0168] As a result, as shown in Table 1 and Figure 1, the average %HMW value of the buffer-free formulation and the average %HMW value of the buffer-containing formulation were 3.13% and 3.24%, respectively.

[0169] Therefore, it was confirmed that the buffer-free formulation is more stable than the buffer-containing formulation.

[0170] Example 2. Viscosity test of buffer-free formulation

[0171] Experiments were conducted to determine the effect of buffers on the viscosity of liquid formulations containing anti-IL-4Rα antibodies, such as dupilumab.

[0172] The viscosity of the formulation prepared in Example 1 above was measured.

[0173] No. classification antibody concentration buffer pH Part 1 Excipient 2 surfactants Viscosity (cP) 1 Buffer-free 175 mg / mL - 5.9 5% (w / v) sucrose 50 mM arginine 0.2% (w / v) PS80 11.4 2 5.9 5% (w / v) sucrose 50 mM arginine 0.2% (w / v) PS80 10.4 3 5.9 5% (w / v) sucrose 50 mM arginine 0.2% (w / v) PS80 11.0 4 Includes buffer 10 mM sodium acetate 6.0 4.3% (w / v) Trehalose 70 mM arginine 0.2% (w / v) PS80 12.7 5 6.0 1.8% (w / v) Sorbitol 70 mM arginine 0.2% (w / v) PS80 11.6 6 6.0 1.8% (w / v) Mannitol 70 mM arginine 0.2% (w / v) PS80 14.2

[0174] Figure 2 is a graph showing the results of viscosity analysis for buffer-free formulations and buffer-containing formulations.

[0175] As a result, as shown in Table 2 and Figure 2, the average viscosity of the buffer-free formulation and the average viscosity of the buffer-containing formulation were 10.9 cP and 12.8 cP, respectively.

[0176] Therefore, it was confirmed that the buffer-free formulation has lower viscosity compared to the buffer-containing formulation.

[0177] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

Claim 1 A liquid formulation containing anti-IL-4Rα antibody; sugars; and amino acids, and not containing a buffer. Claim 2 A liquid formulation according to claim 1, wherein the anti-IL-4Rα antibody is dupilumab. Claim 3 A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is about 5 mg / mL to about 300 mg / mL. Claim 4 A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is about 100 mg / mL to about 200 mg / mL. Claim 5 A liquid formulation according to claim 1, wherein the concentration of the anti-IL-4Rα antibody is about 125 mg / mL to about 200 mg / mL. Claim 6 A liquid formulation according to any one of claims 1 to 5, wherein the pH of the liquid formulation is about 4.7 to about 7.

4. Claim 7 A liquid formulation according to any one of claims 1 to 5, wherein the pH of the liquid formulation is about 5.5 to about 6.

5. Claim 8 A liquid formulation according to claim 1, wherein the sugars comprise one or more selected from sugars and sugar alcohols. Claim 9 A liquid formulation according to claim 8, wherein the sugar comprises one or more selected from sucrose, trehalose, galactose, mannose, maltose, lactose, fructose, and glucose. Claim 10 A liquid formulation according to claim 8, wherein the sugar alcohol comprises one or more selected from mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol. Claim 11 A liquid formulation according to claim 8, wherein the sugars are sucrose. Claim 12 A liquid formulation according to claim 8, wherein the concentration of the sugar is about 0.1% (w / v) to about 20% (w / v). Claim 13 A liquid formulation according to claim 8, wherein the concentration of the sugar alcohol is about 0.1% (w / v) to about 20% (w / v). Claim 14 A liquid formulation according to claim 11, wherein the concentration of the sucrose is about 2% (w / v) to about 10% (w / v). Claim 15 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. Claim 16 A liquid formulation according to claim 1, wherein the amino acid comprises arginine. Claim 17 A liquid formulation according to claim 1, wherein the concentration of the amino acid is about 1 mM to about 400 mM. Claim 18 A liquid formulation according to claim 1, wherein the concentration of the amino acid is about 10 mM to about 100 mM. Claim 19 A liquid formulation according to any one of claims 1 to 18, further comprising a surfactant. Claim 20 A liquid formulation according to claim 19, wherein the surfactant comprises a nonionic surfactant. Claim 21 A liquid formulation according to claim 19, wherein the surfactant comprises polysorbate 20, polysorbate 80, or a combination thereof. Claim 22 A liquid formulation according to claim 19, wherein the concentration of the surfactant is 0.01% (w / v) to 0.9% (w / v). Claim 23 A liquid formulation according to any one of claims 1 to 22, wherein the ratio of the high molecular weight species content (%HMW) of the antibody measured after storage at 25°C for 4 weeks is 3.15% or less. Claim 24 A liquid formulation according to any one of claims 1 to 22, wherein the viscosity of the liquid formulation is less than 11.5 cP. Claim 25 A liquid formulation for subcutaneous injection, in any one of claims 1 to 24. Claim 26 A device comprising a liquid formulation of any one of claims 1 to 25. Claim 27 A device according to claim 26, wherein the liquid formulation is contained in a container selected from a syringe, a pre-filled syringe, a pre-filled pen, a microinfusor, an autoinjector, a bottle, a vial, and a tube. Claim 28 A method for treating an IL-4Rα-related condition, comprising the step of administering a liquid formulation of any one of claims 1 to 25 to an individual in need thereof. Claim 29 A method for treating an IL-4Rα-related condition according to claim 28, wherein the IL-4Rα-related condition is an IL-4-mediated disease or an IL-13-mediated disease. Claim 30 In claim 28, the IL-4Rα-related condition is any one selected from atopic dermatitis, asthma, chronic rhinosinusitis (CRS), chronic rhinosinusitis with nasal polyposis (CRSwNP), allergic fungal rhinosinusitis (AFRS), eosinophilic esophagitis (EoE), prurigo nodularis (PN), bullous pemphigoid (BP), chronic spontaneous urticarial (CSU), chronic inducible urticarial (CIndU), and chronic obstructive pulmonary disease (COPD). Methods to treat related conditions. Claim 31 Use of a liquid formulation of any one of claims 1 to 25 in the manufacture of a drug for treating an IL-4Rα-related condition.

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