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, a saccharide, and an amino acid without comprising a buffer; a device comprising same; and a use thereof for treating IL-4Rα-related conditions. The liquid formulation can ensure stability and improve viscosity without comprising a buffer of an antibody, and thus can be effectively used as a medicine for treating IL-4Rα-related conditions.

Description

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

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

[0002] Compared to typical protein drugs, antibody drugs have larger molecular weights and complex secondary and higher-order structures, which can lead to physicochemical instability. For these reasons, the development of optimal formulations that ensure quality and stability throughout the entire antibody drug manufacturing, storage, and patient administration process is essential. Protein instability can be caused by various external factors, including temperature, light, and chemicals, which can lead to decreased activity, reduced efficacy, or immunogenicity when administered to the human body.

[0003] Additionally, in the case of high-concentration protein pharmaceuticals, increasing protein concentration can lead to increased viscosity of the solution due to increased protein-protein interactions and aggregation. This high viscosity of these pharmaceuticals can lead to problems such as increased syringe stopper gliding force and injection time, which can reduce patient usability.

[0004] Therefore, it is crucial to improve the instability and viscosity of such antibody drugs to maintain optimal quality before administration to patients. To achieve optimal quality, methods such as modifying buffers and stabilizers are used. Because the material properties of each antibody protein vary, and the optimal combination of buffers, stabilizers, and other ingredients may vary, developing a formulation appropriate for the target substance is essential to address this issue.

[0005] Meanwhile, high-concentration protein pharmaceuticals can sometimes maintain a constant pH without the use of buffers due to the self-buffering effect of high protein concentration. Furthermore, some buffers are prone to self-degradation under stress conditions, which can affect the stability of antibody pharmaceuticals.

[0006] Therefore, there is a need for the development of a formulation capable of stabilizing antibody proteins without including buffers that may affect the stability of anti-IL-4Rα antibody pharmaceutical formulations.

[0007] The present disclosure relates to a stable, buffer-free liquid formulation of an anti-IL-4Rα antibody, such as dupilumab. Specifically, the present disclosure provides a liquid formulation of an anti-IL-4Rα antibody, such as dupilumab, that has high stability and low viscosity without the inclusion of a buffer.

[0008] One aspect is to provide a liquid formulation comprising an anti-IL-4Rα antibody; a sugar; and an amino acid, and no buffer.

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

[0010] Another aspect provides a method of treating an IL-4Rα associated condition, comprising administering the liquid formulation to a subject in need thereof.

[0011] Another aspect provides the use of the liquid formulation in the manufacture of a medicament for treating an IL-4Rα associated condition.

[0012] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art in the relevant field of the present invention. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Furthermore, numerical values ​​described herein are considered to include the meaning of "about," even if not explicitly stated. The contents of all publications cited as references herein are incorporated herein by reference in their entirety.

[0013] The terms "about" or "approximately" in this specification can generally be interpreted to mean a value or range that is within 10%, 5%, 4%, 3%, 2%, or 1% above or below a given value or range.

[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] Does not contain buffer,

[0019] Provides liquid formulation.

[0020] (1) Antibodies

[0021] The term "antibody" as used herein may be interpreted to mean a full-length antibody or an antigen-binding fragment thereof. The antibody includes a monoclonal antibody, a polyclonal antibody, a humanized antibody, a human antibody, and a chimeric antibody.

[0022] The term "antigen-binding fragment" refers to a fragment comprising the antigen-binding site of an antibody. For example, an antigen-binding fragment includes, but is not limited to, a Fab fragment, an F(ab')2 fragment, an Fc fragment, or an scFv fragment.

[0023] In the present specification, the antibody may be an anti-IL-4Rα antibody. The anti-IL-4Rα antibody may refer to any antibody that binds to the interleukin-4 receptor alpha chain (IL-4Rα). The anti-IL-4Rα antibody may inhibit IL-4 and IL-13 signaling.

[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. ® ) is sold under the trade name Dupixent. After receiving approval from the U.S. Food and Drug Administration (FDA) for the treatment of atopic dermatitis, Dupixent is expanding its indications to various type 2 inflammatory diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and eosinophilic esophagitis (EoE). The sequence of dupilumab is known, and it can be produced by general methods known in the art. More detailed information on dupilumab can be easily obtained by those skilled in the art from known databases.

[0025] The term "dupilumab" herein may also be interpreted to mean dupilumab having a modified amino acid sequence (deletion, insertion, and / or substitution) and / or a modified glycosylation characteristic, as long as it does not affect the polypeptide function.

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

[0027] The concentration of the anti-IL-4Rα antibody is about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 175 mg / mL, about 5 mg / mL to about 300 mg / mL, about 5 mg / mL to about 250 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 175 mg / mL, about 10 mg / mL to about 300 mg / mL, about 10 mg / mL to about 250 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 175 mg / mL, about 25 mg / mL to about 300 mg / mL, about 25 mg / mL to about 250 mg / mL, about 25 mg / mL to about 200 mg / mL, about 25 mg / mL to about 175 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 250 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 175 mg / mL, about 75 mg / mL to about 300 mg / mL, about 75 mg / mL to about 250 mg / mL, about 75 mg / mL to about 200 mg / mL, about 75 mg / mL to about 175 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 250 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 175 mg / mL, about 125 mg / mL to about 300 mg / mL, about 125 mg / mL to about 250 mg / mL, about 125 mg / mL to about 200 mg / mL, about 125 mg / mL to about 175 mg / mL, about 145 mg / mL to about 300 mg / mL, about 145 mg / mL to about 250 mg / mL, about 145 mg / mL to about 200 mg / mL, about 145 mg / mL to about 180 mg / mL,About 145 mg / mL to about 175 mg / mL, about 149 mg / mL to about 151 mg / mL, about 150 mg / mL to about 300 mg / mL, about 150 mg / mL to about 250 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 170 mg / mL to about 300 mg / mL, about 170 mg / mL to about 250 mg / mL, about 170 mg / mL to about 225 mg / mL, about 170 mg / mL to about 200 mg / mL, about 170 mg / mL to about 180 mg / mL, or about 174 mg / mL may be about 176 mg / mL.

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

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

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

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

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

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

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

[0035] In certain embodiments, 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, but is not limited to, 100 mg / mL or more or 150 mg / mL or more, for example, 100 mg / mL to 300 mg / mL or 150 mg / mL to 300 mg / mL.

[0037] (2) Buffer and pH

[0038] The liquid formulation according to one aspect does not contain a 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 term 'free of component A' or 'substantially free of A' may be interpreted to include cases where component A is not present at all, or where component A is present in trace amounts that do not substantially affect the properties of the formulation, or where it is present in undetectable amounts.

[0041] In this specification, the phrase "does not contain a buffer" may be interpreted to mean that the formulation does not contain a buffer component, or that the formulation contains such a component that it cannot function as the intended buffer within the formulation.

[0042] The above liquid formulation does not contain, or substantially does not contain, a buffering agent.

[0043] The buffer may include at least one 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 an inorganic acid salt, an organic acid salt, a metal salt, etc. of the compound. The inorganic acid salt may be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfate. The organic acid salt may be a formate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a besylate, a camsylate, an edisyl salt, a trichloroacetic acid, a trifluoroacetate, a benzoate, a gluconate, a methanesulfonate, a glycolate, a succinate, a 4-toluenesulfonate, a galacturonate, an embonate, a glutamate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, or an aspartate. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.

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

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

[0047] In one specific embodiment, the buffer may comprise a combination of acetate and histidine. Accordingly, the liquid formulation may comprise neither acetate nor histidine as a buffer.

[0048] The pH of the liquid formulation according to the aspect may be any range or any value selected from about 4.0 to about 8.5. For example, the pH may be from about 4.0 to about 8.5, from about 4.0 to about 8.0, from about 4.0 to about 7.5, from about 4.0 to about 7.0, from about 4.0 to about 6.5, from about 4.0 to about 6.0, from about 4.5 to about 8.5, from about 4.5 to about 8.0, from about 4.5 to about 7.5, from about 4.5 to about 7.0, from about 4.5 to about 6.5, from about 4.5 to about 6.0, from about 4.7 to about 8.5, from about 4.7 to about 8.0, from about 4.7 to about 7.5, from about 4.7 to about 7.4, from about 4.7 to about 7.0, from about 4.7 to about 6.5, from about 4.7 to about 6.0, from 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 It can be from about 5.8 to about 7.0, from about 5.8 to about 6.5, from about 5.8 to about 6.2, from about 5.8 to about 6.1, from about 5.8 to about 6.0, from about 5.9 to about 8.5, from about 5.9 to about 8.0, from about 5.9 to about 7.5, from about 5.9 to about 7.0, from about 5.9 to about 6.5, from about 5.9 to about 6.2, from about 5.9 to about 6.1, or from about 5.9 to about 6.0.

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

[0050] In certain embodiments, the pH of the liquid formulation may be about 5.9.

[0051] In certain embodiments, the pH of the liquid formulation may be about 6.0.

[0052] (3) Sugars

[0053] Liquid formulations according to the aspect of the invention contain saccharides.

[0054] Liquid formulations according to the invention may contain sugars as stabilizers.

[0055] The above sugar may include at least one selected from sugar and sugar alcohol.

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

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

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

[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 the type of each specific sugar alcohol. The concentration of the sugar alcohol can be any range or any value selected from about 0.1% (w / v) to about 20% (w / v). For example, the concentration of the sugar alcohol may be from about 0.1% (w / v) to about 20% (w / v), from about 0.1% (w / v) to about 15% (w / v), from about 0.1% (w / v) to about 12% (w / v), from about 0.1% (w / v) to about 10% (w / v), from about 0.1% (w / v) to about 8% (w / v), from about 0.1% (w / v) to about 5% (w / v), from about 1% (w / v) to about 20% (w / v), from about 1% (w / v) to about 15% (w / v), from about 1% (w / v) to about 12% (w / v), from about 1% (w / v) to about 10% (w / v), from about 1% (w / v) to about 8% (w / v), from about It can be from 1% (w / v) to about 7% (w / v), from about 1% (w / v) to about 6% (w / v), from about 1% (w / v) to about 5% (w / v), from about 1% (w / v) to about 4% (w / v), from about 1% (w / v) to about 3% (w / v), or from about 1% (w / v) to about 2% (w / v).

[0060] In certain embodiments, the sugar may comprise sucrose. In certain embodiments, the sugar may be sucrose.

[0061] The concentration of the sucrose may be any range or any value selected from about 0.1% (w / v) to about 20% (w / v). For example, the concentration of sucrose may be from about 0.1% (w / v) to about 20% (w / v), from about 0.1% (w / v) to about 15% (w / v), from about 0.1% (w / v) to about 12% (w / v), from about 0.1% (w / v) to about 10% (w / v), from about 0.1% (w / v) to about 8% (w / v), from about 0.1% (w / v) to about 6% (w / v), from about 1% (w / v) to about 20% (w / v), from about 1% (w / v) to about 15% (w / v), from about 1% (w / v) to about 12% (w / v), from about 1% (w / v) to about 10% (w / v), from about 1% (w / v) to about 8% (w / v), from 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 certain embodiments, the concentration of sucrose may be about 5% (w / v).

[0063] (4) Amino acids

[0064] Liquid formulations according to the aspect of the invention contain amino acids.

[0065] Liquid formulations according to the invention may contain amino acids as stabilizers.

[0066] The term "stabilizer" refers to a substance added to a substance during preservation to prevent changes in state or chemical change. The stabilizer may inhibit antibody aggregation or denaturation.

[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 specific example, the amino acid may comprise arginine.

[0069] The concentration of the amino acid can be freely adjusted within a range that maintains the stability of the antibody, and may vary individually depending on each specific amino acid type. The concentration of the amino acid can be any range or value selected from about 1 mM to about 400 mM. For example, the concentration of the amino acid may be 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, 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] Liquid formulations according to the aspect may additionally contain a surfactant.

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

[0073] The 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 at least one selected from the group consisting of polysorbate, poloxamer, sorbitan ester of other fatty acids, polyethylene-polypropylene glycol, polyoxyethylene compound, and sodium dodecyl sulfate (SDS).

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

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

[0078] The above sorbitan esters of other fatty acids may mean sorbitan esters of other fatty acids than polysorbates, and may include, for example, sorbitan polyethoxylates.

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

[0080] In one specific embodiment, the surfactant may be a 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 certain embodiments, the surfactant may comprise polysorbate 80. In certain embodiments, the surfactant may be polysorbate 80.

[0084] The concentration of the surfactant may be any range or any value selected from about 0.01% (w / v) to about 0.9% (w / v). For example, the concentration of the surfactant may be from about 0.01% (w / v) to about 0.9% (w / v), from about 0.01% (w / v) to about 0.5% (w / v), from about 0.1% (w / v) to about 0.9% (w / v), from about 0.1% (w / v) to about 0.5% (w / v), from about 0.1% (w / v) to about 0.4% (w / v), from about 0.1% (w / v) to about 0.3% (w / v), from about 0.15% (w / v) to about 0.9% (w / v), from about 0.15% (w / v) to about 0.5% (w / v), from about 0.15% (w / v) to about 0.4% (w / v), from about 0.15% (w / v) to about 0.3% (w / v), or about 0.15% (w / v) to about 0.25% (w / v).

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

[0086] (6) Diluent

[0087] Liquid formulations according to the aspect may additionally contain a diluent.

[0088] The diluent may be an aqueous carrier. The aqueous carrier may be a pharmaceutically acceptable carrier that is safe and non-toxic when administered to humans, such as water, saline solution, Ringer's solution, dextrose, or a mixture thereof.

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

[0090] (7) Formulation

[0091] The term "liquid formulation" means a formulation in liquid form.

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

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

[0094] The term "pharmaceutical composition" or "pharmaceutical preparation" means a preparation that allows the biological activity of the active ingredient to be effectively carried out and does not contain additional components that are seriously toxic to the subject to which the preparation is administered.

[0095] The term "pharmaceutical formulation" refers to the product of a process that combines an active drug with chemicals to produce the final drug product.

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

[0097] Liquid formulations according to the daily pattern are Dupixent ® ) may be a biosimilar.

[0098] The term "biosimilar," also known as "biogeneric," refers to a copy of an original biopharmaceutical. Because biopharmaceuticals are produced through cells rather than synthetic chemicals, they cannot be perfectly identical to the original drug. Therefore, a biopharmaceutical copy is called a biosimilar, meaning it is similar, though not identical, to the original drug.

[0099] Liquid formulations according to the aspect of the work may be selected from the following items:

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

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

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

[0103] 4) A liquid formulation comprising an anti-IL-4Rα antibody; a sugar; and an amino acid, and containing neither acetate nor histidine as a buffer;

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

[0105] 6) A liquid formulation comprising about 5 mg / mL to about 300 mg / mL of an anti-IL-4Rα antibody; a sugar; an amino acid; and a surfactant, and no buffer;

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

[0107] 8) A liquid formulation comprising an anti-IL-4Rα antibody; a sugar; an amino acid; and a surfactant, and containing neither acetate nor histidine as a buffer;

[0108] 9) A liquid formulation containing dupilumab; sucrose; arginine; and polysorbate 80, and not containing a buffer; 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, without a buffer, and having a pH of about 5.6 to about 6.5.

[0110] (8) Stability and viscosity

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

[0112] The term "stability" means that an antibody (e.g., dupilumab) contained in a formulation substantially retains its physical stability, chemical stability, and / or biological activity before and after administration, during further manufacturing processes, storage, or preservation. For example, it can be understood to mean that the degree of loss of stability, such as aggregation, degradation, denaturation (acidic or basic), oxidation, etc. of the antibody contained in the formulation is 20% or less, 15% or less, 10% or less, or 5% or less compared to the initial storage. Accordingly, "excellent stability" or "improved stability" can mean a low protein aggregation rate, a low protein degradation rate, a low protein denaturation rate, a low amino acid oxidation rate, etc. during storage. Physical stability, chemical stability, and / or biological activity can be evaluated by conventionally known methods.

[0113] The term "aggregate" may refer to high molecular weight (HMW) species formed by aggregation of antibody proteins. The term "protein aggregation rate" may be expressed as the percentage of high molecular weight species content (%HMW) of the antibody in the formulation at a given point in time. %HMW may be measured by, but is not limited to, size exclusion chromatography (SEC). For example, "improved stability" may mean that the %HMW of the antibody measured for the formulation is reduced by at least 0.01%, at least 0.1%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, or at least 20% compared to the original formulation. A decrease in %HMW may mean that the degree to which the antibody in the formulation undergoes aggregation is reduced, thereby improving stability.

[0114] The stability assessment may be performed immediately after manufacturing the formulation; or after a certain period of storage under accelerated stability conditions or stress stability conditions. The accelerated stability conditions may include conditions used in accelerated tests for pharmaceuticals, such as a temperature of 25±2°C and a relative humidity (RH) of 60±5%. The stress stability conditions may include conditions used in stress tests for pharmaceuticals, such as a temperature of 40±2°C and a relative humidity (RH) of 75+5%.

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

[0116] The above liquid formulation may have a reduced %HMW compared to a liquid formulation of anti-IL-4Rα antibody containing a buffer, by not including a buffer.

[0117] The liquid formulation may have a %HMW of the antibody measured after 4 weeks of storage at 25°C that is reduced by at least 1%, at least 2%, or at least 3% compared to the formulation containing the buffer.

[0118] The above liquid formulation may have a %HMW of antibody 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 measured after storage at 25°C for 4 weeks.

[0119] The above liquid formulation may have improved viscosity. "Improving" the viscosity may mean "reducing" the viscosity. Accordingly, the above liquid formulation may have reduced viscosity.

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

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

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

[0123] (9) Device

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

[0125] The device is primarily used for parenteral administration. Parenteral administration may include, for example, subcutaneous, intramuscular, intravenous, intraperitoneal, intracerebrospinal, intraarticular, intrasynovial, or intrathecal administration. The device may be accompanied by instructions for administration.

[0126] The device may contain the liquid formulation in a container selected from, but not limited to, a syringe, a pre-filled syringe, a pre-filled pen, a microinfusor, an autoinjector, a bottle, a vial, and a tube.

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

[0128] In one embodiment, the device may comprise the liquid formulation in a prefilled syringe. The prefilled syringe may be a single-dose prefilled syringe.

[0129] In one specific embodiment, the device may comprise the liquid formulation in a prefilled pen. The prefilled pen may be a single-dose prefilled pen.

[0130] (10) Treatment of diseases

[0131] Another aspect provides a method for treating an IL-4Rα-associated condition, comprising administering to a subject in need thereof a liquid formulation according to the above aspect. The liquid formulation may be in a form contained in a device.

[0132] Another aspect provides the use of a liquid formulation according to the above aspect in the manufacture of a medicament for treating an IL-4Rα associated condition.

[0133] The method of treating the IL-4Rα associated condition may further comprise, prior to the administering step, a step of identifying a subject in need of administration of an anti-IL-4Rα antibody (e.g., dupilumab).

[0134] The subject may be a subject requiring administration of a liquid formulation containing the anti-IL-4Rα antibody (e.g., dupilumab). The subject requiring administration of the liquid formulation containing the anti-IL-4Rα antibody (e.g., dupilumab) may be a subject having a disease or disorder that can be significantly treated (e.g., symptoms can be eliminated, alleviated, relieved, or improved, etc.) by administration of the anti-IL-4Rα antibody. The subject may be selected from mammals, including humans.

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

[0136] The IL-4Rα associated condition may include any condition, disease, or disorder that can be treated by administration of an anti-IL-4Rα antibody. The IL-4Rα associated condition that can be treated by administration of an anti-IL-4Rα antibody (e.g., dupilumab) may include any indication currently approved or that may be approved in the future for an anti-IL-4Rα antibody (e.g., dupilumab).

[0137] The IL-4Rα-associated condition may be an IL-4-mediated disease and / or an IL-13-mediated disease. The IL-4-mediated disease may include any disease that can be treated by inhibition of IL-4 signaling. The IL-13-mediated disease may include any disease that can be treated by inhibition of IL-13 signaling. The IL-4Rα-associated condition may include any disease that can be treated by dual blockade of IL-4 and IL-13.

[0138] The IL-4Rα-related condition may include an inflammatory disease, an allergic disease, or an autoimmune disease. The inflammatory disease may be a Type 2 inflammatory disease.

[0139] The IL-4Rα-related condition may be any one selected from, but is not limited to, atopic dermatitis, asthma, chronic rhinosinusitis (CRS), chronic rhinosinusitis with nasal polyposis (CRSwNP), allergic fungal rhinosinusitis (AFRS), eosinophilic esophagitis (EoE), prurigo nodularis (PN), bullous pemhigoid (BP), chronic spontaneous urticarial (CSU), chronic inducible urticarial (CIndU), and chronic obstructive pulmonary disease (COPD).

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

[0144] In certain embodiments, the liquid formulation may be for subcutaneous injection.

[0145] The above liquid formulation may be formulated into a formulation suitable for the above administration route. For example, the above liquid formulation may be formulated into an injection, a ready-to-use injectable, etc., but is not limited thereto.

[0146] The liquid formulation may be formulated to contain the entire amount or a pharmaceutically effective amount of the anti-IL-4Rα antibody (e.g., dupilumab) in one formulation, or may be formulated to contain two or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) formulations. The liquid formulation may be included in a single-dose or multi-dose form of the device.

[0147] The above liquid formulation may be administered to the body in one dose (e.g., within 1 minute, within 30 seconds, within 20 seconds, or within 10 seconds); or may be administered to the body gradually over a period of, but not limited to, 5 minutes, 10 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, or 240 minutes.

[0148] The target of administration of the above liquid formulation may be selected from mammals including primates (e.g., humans, etc.), rodents (e.g., mice, rats, guinea pigs, hamsters, rabbits, etc.), cats, dogs, pigs, cows, horses, etc.

[0149] The pharmaceutically effective amount of the above liquid formulation or the anti-IL-4Rα antibody (e.g., dupilumab) contained therein may refer to an amount or dosage that can exhibit a desired pharmacological effect, such as elimination, reduction, alleviation, or improvement of symptoms. The pharmaceutically effective amount may be determined in various ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition (severity of condition), food, administration time, administration interval, administration route, excretion rate, response sensitivity, previous therapy, clinical history, etc. The dosage may be adjusted according to the judgment of the physician in charge. The pharmaceutically effective amount may be administered at once or administered in two or more divided doses.

[0150] For example, the liquid formulation may be administered once every two to four weeks over a period of two weeks or more at a dose such that the anti-IL-4Rα antibody (e.g., dupilumab) is 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg.

[0151] The above liquid formulation can be prepared as a general bulk formulation, and the components of the liquid formulation can be adjusted to a higher concentration than that required for administration and used after being suitably diluted before administration.

[0152] Liquid formulations of anti-IL-4Rα antibodies according to one aspect may exhibit improved stability and viscosity compared to formulations that include a buffer, despite not including a buffer. Therefore, the liquid formulation may exhibit high stability and low viscosity even when containing a high concentration of antibody, thereby increasing patient convenience during injection. Accordingly, the liquid formulation may be useful as a pharmaceutical agent for treating IL-4Rα-related conditions.

[0153] Figure 1 is a graph showing the results of analyzing the high molecular weight species content ratio (%HMW) for buffer-free formulations and buffer-containing formulations.

[0154] Figure 2 is a graph showing the results of viscosity analysis for buffer-free formulations and buffer-containing formulations.

[0155] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0156]

[0157] [Experimental Method]

[0158] 1. Viscosity measurement

[0159] The viscosity of the sample was measured using a viscometer (manufacturer: RheoSense, model name: VROC initium one plus). The analysis was conducted at a temperature of 25°C during the viscosity measurement. The same sample was divided into 11 segments and the slope fit R was calculated. 2 The viscosity value of each sample was calculated by taking the average value for values ​​greater than 0.9995.

[0160] 2. Analysis of high molecular weight species content (% high molecular weight species, %HMW)

[0161] The percentage of high molecular weight species (%HMW) was determined using size exclusion chromatography (SEC) using a Waters HPLC system. The protein was separated into three peaks based on its molecular weight. These three peaks correspond to the HMW peak (protein aggregation), the Monomer peak, and the LMW peak (protein degradation), in descending order of retention time (i.e., increasing protein molecular weight).

[0162] - %HMW = {area of ​​HMW / area of ​​(HMW + monomer + LMW)}*100

[0163] ​Each formulation sample for stability testing was stored in a chamber maintaining accelerated stability conditions of 25±2℃ and 60±5% relative humidity (RH).

[0164]

[0165] [Example]

[0166] Example 1. Stability test of buffer-free formulation

[0167] An experiment was conducted to determine the effect of buffers on the stability of liquid formulations containing anti-IL-4Rα antibodies such as dupilumab.

[0168] Using dupilumab (CAS No. 1190264-60-8) as an anti-IL-4Rα antibody, aqueous liquid formulations having the compositions shown in Table 1 below were prepared. After exposing each formulation to temperature conditions of 25°C for 4 weeks, the purity of the sample was measured through size exclusion chromatography (SEC) analysis.

[0169] No. Classification Antibody Concentration Buffer pH Excipient 1 Excipient 2 Surfactant % HMW (25℃, 4 weeks) 1 Buffer-free 175 mg / mL-5.95% (w / v) Sucrose 50 mM Arginine 0.2% (w / v) PS803.13 25.95% (w / v) Sucrose 50 mM Arginine 0.2% (w / v) PS803.10 35.95% (w / v) Sucrose 50 mM Arginine 0.2% (w / v) PS803.15 4 Buffer included 10 mM Sodium Acetate 6.0 4.3% (w / v) Trehalose 70 mM Arginine 0.2% (w / v) PS803.14 56.0 1.8% (w / v) Sorbitol 70 mM Arginine 0.2% (w / v) PS803.2166.01.8% (w / v) mannitol70 mM arginine0.2% (w / v) PS803.38

[0170] Figure 1 is a graph showing the results of analyzing the high molecular weight species content ratio (%HMW) for buffer-free formulations and buffer-containing formulations.

[0171] 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.

[0172] Therefore, it was confirmed that the buffer-free formulation was more stable than the buffer-containing formulation.

[0173]

[0174] Example 2. Viscosity test of buffer-free formulation

[0175] An experiment was conducted to determine the effect of buffers on the viscosity of liquid formulations containing anti-IL-4Rα antibodies such as dupilumab.

[0176] The viscosity was measured for the formulation prepared in Example 1 above.

[0177] No. Classification Antibody Concentration Buffer pH Excipient 1 Excipient 2 Surfactant Viscosity (cP) 1 Buffer-free 175 mg / mL-5.95% (w / v) Sucrose 50 mM Arginine 0.2% (w / v) PS80 11.4 2 5.95% (w / v) Sucrose 50 mM Arginine 0.2% (w / v) PS80 10.4 3 5.95% (w / v) Sucrose 50 mM Arginine 0.2% (w / v) PS80 11.0 4 Buffer Included 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) PS8011.666.01.8% (w / v) mannitol70 mM arginine0.2% (w / v) PS8014.2

[0178] Figure 2 is a graph showing the results of viscosity analysis for buffer-free formulations and buffer-containing formulations.

[0179] 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.

[0180] Therefore, it was confirmed that the buffer-free formulation had a lower viscosity than the buffer-containing formulation.

[0181]

[0182] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. Anti-IL-4Rα antibody; sugars; and Contains amino acids, Does not contain buffer, Liquid formulation.

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

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

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

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

6. A liquid formulation according to any one of claims 1 to 5, wherein the pH of the liquid formulation is about 4.7 to about 7.

4.

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.

8. A liquid formulation according to claim 1, wherein the sugar comprises at least one selected from sugar and sugar alcohol.

9. A liquid formulation according to claim 8, wherein the sugar comprises at least one selected from sucrose, trehalose, galactose, mannose, maltose, lactose, fructose, and glucose.

10. A liquid formulation according to claim 8, wherein the sugar alcohol comprises at least one selected from mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol.

11. A liquid formulation according to claim 8, wherein the sugar is sucrose.

12. A liquid formulation according to claim 8, wherein the concentration of the sugar is from about 0.1% (w / v) to about 20% (w / v).

13. A liquid formulation according to claim 8, wherein the concentration of the sugar alcohol is from about 0.1% (w / v) to about 20% (w / v).

14. A liquid formulation according to claim 11, wherein the concentration of sucrose is from about 2% (w / v) to about 10% (w / v).

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

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

17. A liquid formulation according to claim 1, wherein the concentration of the amino acid is from about 1 mM to about 400 mM.

18. A liquid formulation according to claim 1, wherein the concentration of the amino acid is from about 10 mM to about 100 mM.

19. A liquid formulation according to any one of claims 1 to 18, further comprising a surfactant.

20. A liquid formulation according to claim 19, wherein the surfactant comprises a nonionic surfactant.

21. A liquid formulation according to claim 19, wherein the surfactant comprises polysorbate 20, polysorbate 80, or a combination thereof.

22. A liquid formulation according to claim 19, wherein the concentration of the surfactant is 0.01% (w / v) to 0.9% (w / v).

23. In any one of claims 1 to 22, A liquid formulation, wherein the high molecular weight species content ratio (%HMW) of the antibody measured after 4 weeks of storage at 25°C is 3.15% or less.

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.

25. A liquid formulation for subcutaneous injection according to any one of claims 1 to 24.

26. A device comprising a liquid formulation of any one of claims 1 to 25.

27. A device according to claim 26, comprising the liquid formulation in a container selected from a syringe, a pre-filled syringe, a pre-filled pen, a microinfusor, an autoinjector, a bottle, a vial, and a tube.

28. A method of treating an IL-4Rα associated condition, comprising administering to a subject in need thereof a liquid formulation of any one of claims 1 to 25.

29. A method for treating an IL-4Rα-associated condition according to claim 28, wherein the IL-4Rα-associated condition is an IL-4-mediated disease or an IL-13-mediated disease.

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 pemhigoid (BP), chronic spontaneous urticarial (CSU), chronic inducible urticarial (CIndU), and chronic obstructive pulmonary disease (COPD). A method for treating a condition associated with IL-4Rα.

31. Use of a liquid formulation of any one of claims 1 to 25 in the manufacture of a medicament for treating an IL-4Rα associated condition.

Images