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WO2025116640A1 - Formulation liquide stable sans saccharide d'anticorps anti-il-4rα - Google Patents

Formulation liquide stable sans saccharide d'anticorps anti-il-4rα Download PDF

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Publication number
WO2025116640A1
WO2025116640A1 PCT/KR2024/019361 KR2024019361W WO2025116640A1 WO 2025116640 A1 WO2025116640 A1 WO 2025116640A1 KR 2024019361 W KR2024019361 W KR 2024019361W WO 2025116640 A1 WO2025116640 A1 WO 2025116640A1
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Prior art keywords
liquid formulation
concentration
methionine
histidine
antibody
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Korean (ko)
Inventor
박진혜
김한수
이승하
김인애
이헌주
장성근
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Samsung Bioepis Co Ltd
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Samsung Bioepis Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • Stable, sugar-free liquid formulations of anti-IL-4R ⁇ antibodies, devices comprising same, and uses thereof for treating IL-4R ⁇ -associated conditions are provided.
  • Antibody drugs have a large molecular weight compared to general protein drugs, and their secondary/higher order structures are complex, which can cause physicochemical instability. For this reason, antibody drugs require the development of an optimal formulation that guarantees quality and stability throughout the entire process from manufacturing, storage, and administration to patients. Protein instability can be caused by various external factors such as temperature, light, and chemical factors, which can lead to decreased activity, decreased efficacy, or immunogenicity when administered to the human body. Therefore, it is important to improve the instability of such antibody drugs and maintain optimal quality until they are administered to patients. To achieve optimal quality, methods such as changing the buffer solution, evaluating the optimal pH, and adding stabilizers are used. Since the material properties of each antibody protein are different, and the optimal combination of buffer solution, pH, and stabilizer may be different, a formulation suitable for the target substance is required to solve this problem.
  • dupilumab an anti-IL-4R ⁇ antibody
  • Dupixent ® is manufactured and sold under the trade name Dupixent ® .
  • Dupixent 200 mg is a 1.14 mL liquid formulation containing 200 mg anti-IL4R ⁇ IgG, 1.2 mg sodium acetate, 3.5 mg histidine, 12 mg arginine, 57 mg sucrose, and 2.3 mg polysorbate 80
  • Dupixent 300 mg is a 2.00 mL liquid formulation containing 300 mg anti-IL4R ⁇ IgG, 2.0 mg sodium acetate, 6.2 mg histidine, 10.5 mg arginine, 100 mg sucrose, and 4 mg polysorbate 80.
  • sugars are used as stabilizers for protein stabilization, but in the case of formulations containing such stabilizers, there is a phenomenon in which the viscosity increase is accelerated when the protein concentration increases, so there is a limit to improving viscosity while ensuring protein stability. Therefore, it is necessary to develop a formulation that can overcome these limitations.
  • the present disclosure relates to a stable, sugar-free liquid formulation of an anti-IL-4R ⁇ antibody such as dupilumab.
  • the sugar-free liquid formulation has improved stability and viscosity compared to commercially available formulations of anti-IL-4R ⁇ antibodies such as dupilumab (e.g., Dupixent), and thus can be applied to high-concentration formulations, thereby increasing patient convenience.
  • dupilumab e.g., Dupixent
  • One aspect is to provide a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer; and an amino acid, wherein the formulation does not contain a sugar, and wherein the pH is from about 4.5 to about 6.5.
  • Another aspect is to provide a device comprising the liquid formulation.
  • Another aspect provides a method of treating an IL-4R ⁇ associated condition, comprising administering the liquid formulation to a subject in need thereof.
  • Another aspect provides use of the liquid formulation in the manufacture of a medicament for treating an IL-4R ⁇ associated condition.
  • One aspect provides a stable, sugar-free liquid formulation of an anti-IL-4R ⁇ antibody, specifically:
  • the pH is about 4.5 to about 6.5
  • 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.
  • an antigen-binding fragment refers to a fragment comprising an antigen-binding site of an antibody.
  • an antigen-binding fragment includes, but is not limited to, a Fab fragment, a F(ab') 2 fragment, an Fc fragment, or a scFv fragment.
  • the antibody may be an anti-IL-4R ⁇ antibody.
  • the anti-IL-4R ⁇ antibody may refer to any antibody that binds to the interleukin-4 receptor alpha chain (IL-4R ⁇ ).
  • the anti-IL-4R ⁇ antibody may inhibit IL-4 and IL-13 signaling.
  • the above anti-IL-4R ⁇ antibody may be dupilumab (CAS No. 1190264-60-8). Therefore, the liquid formulation may be a stable liquid formulation of dupilumab.
  • Dupilumab is a fully human monoclonal antibody that binds to IL-4R ⁇ and belongs to IgG4.
  • Dupilumab is sold under the trade name Dupixent ® .
  • FDA U.S. Food and Drug Administration
  • 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. More detailed information about dupilumab is readily available to those skilled in the art from publicly known databases.
  • 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.
  • the above anti-IL-4R ⁇ antibody may be included in a therapeutically effective amount in a liquid formulation.
  • the concentration of the anti-IL-4R ⁇ 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,
  • the concentration of the anti-IL-4R ⁇ antibody can be about 100 mg/mL to about 200 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody can be about 125 mg/mL to about 200 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody can be about 150 mg/mL to about 200 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody can be about 150 mg/mL to about 175 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody can be from 135 mg/mL to 165 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody can be from 158 mg/mL to 192 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody may be about 150 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody may be about 175 mg/mL.
  • the concentration of the anti-IL-4R ⁇ antibody may be a high concentration.
  • the liquid formulation may be a high concentration liquid formulation of the anti-IL-4R ⁇ 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.
  • the liquid formulation according to the aspect includes a buffer.
  • the buffer can have the function of controlling the pH of the formulation.
  • the pH of the liquid formulation can be maintained at a certain value or a certain range by the buffer. Therefore, the buffer can play a role of providing a certain value or a certain range of pH to the liquid formulation.
  • the above buffering agent can be used without limitation in its type as long as it is applicable to biopharmaceuticals.
  • the above buffer may include at least one selected from acetate, phosphate, citrate, succinate, malate, tartarate, carbonate, salts thereof, and hydrates thereof.
  • salt can be a pharmaceutically acceptable salt.
  • the salt can include an inorganic acid salt, an organic acid salt, a metal salt, and the like of the compound.
  • the inorganic acid salt can be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfate.
  • the organic acid salt can 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 can be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.
  • hydrate means a substance containing water molecules within its molecules.
  • the hydrate may be a monohydrate, a dihydrate, or a trihydrate.
  • the pH of the liquid formulation may be from about 5.3 to about 6.5.
  • the pH of the liquid formulation may be provided by a buffer.
  • the pH of the liquid formulation may be adjusted by the addition of any acid (e.g., HCl) or base (e.g., NaOH).
  • the pH of the formulation can be any range or any value selected from about 4.5 to about 6.5.
  • the pH can be from about 4.5 to about 6.5, from about 4.5 to about 6.0, from about 4.5 to about 5.5, from about 4.5 to about 5.3, from about 4.5 to about 5.2, from about 5.0 to about 6.5, from about 5.0 to about 6.0, from about 5.0 to about 5.5, from about 5.0 to about 5.3, from about 5.0 to about 5.2, from about 5.1 to about 6.5, from about 5.1 to about 6.0, from about 5.1 to about 5.5, from about 5.1 to about 5.3, from about 5.1 to about 5.2, from about 5.2 to about 6.5, from about 5.2 to about 6.0, from about 5.2 to about 5.5, from about 5.2 to about 5.3, from about 5.2 to about 5.2, about 5.3 to about 6.5, about 5.3 to about 6.4, about 5.3 to about 6.3, about 5.3 to about 6.2, about 5.3 to about 6.1, about 5.3
  • the pH of the liquid formulation can be about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.
  • the buffering agent can include one or more selected from acetate, a salt thereof, and a hydrate thereof. In one embodiment, the buffering agent can include acetate. In one embodiment, the buffering agent can be acetate. In one embodiment, the buffering agent can include sodium acetate. In one embodiment, the buffering agent can be sodium acetate.
  • the concentration of the buffer can be any range or any value selected from about 0.1 mM to about 50 mM.
  • the concentration of the buffer may be about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 15 mM, about 0.1 mM to about 14 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 14 mM, about 3 mM to about 50 mM, about 3 mM to about 40 mM, about 3 mM to about 30 mM, about 3 mM to about 20 mM, about 3 mM to about 15 mM, about 3 mM to about 40
  • the concentration of the acetate can be any range or any value selected from about 0.1 mM to about 50 mM.
  • the concentration of the acetate may be about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 15 mM, about 0.1 mM to about 14 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 14 mM, about 3 mM to about 50 mM, about 3 mM to about 40 mM, about 3 mM to about 30 mM, about 3 mM to about 20 mM, about 3 mM to about 15 mM, about 1 m
  • the concentration of acetate can be about 6 mM to about 14 mM, about 6 mM to about 12 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, about 8 mM to about 14 mM, about 8 mM to about 12 mM, about 8 mM to about 10 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, or about 12 mM to about 14 mM.
  • the concentration of acetate can be from about 10 mM to about 50 mM, from about 10 mM to about 40 mM, from about 10 mM to about 35 mM, from about 10 mM to about 30 mM, from about 20 mM to about 50 mM, from about 20 mM to about 40 mM, from about 20 mM to about 35 mM, from about 20 mM to about 30 mM, from about 25 mM to about 50 mM, from about 25 mM to about 40 mM, from about 25 mM to about 35 mM, or from about 25 mM to about 30 mM.
  • the liquid formulation according to one aspect is free of saccharide. Accordingly, the liquid formulation may be a saccharide-free formulation.
  • the above liquid formulation can have improved stability and improved viscosity compared to commercialized formulations, despite being a saccharide-free formulation.
  • 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.
  • the phrase "does not contain sugars" may be interpreted to mean that no sugar component is present in the formulation, or that the sugar component is contained in an amount that cannot function as the intended stabilizer in the formulation.
  • the above-mentioned sugar may include sugar and sugar alcohol. Accordingly, the liquid formulation may not include either sugar or sugar alcohol.
  • the sugar may be a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide.
  • the sugar may include at least one selected from sucrose, trehalose, galactose, mannose, maltose, lactose, fructose, and glucose.
  • the above sugar alcohol is a general term for polyols having two or more hydroxy groups, which are made into alcohol groups by reducing an aldehyde group or a ketone group of a sugar.
  • 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.
  • trehalose may include not only trehalose but also trehalose dihydrate.
  • the liquid formulation may not contain any of sucrose, trehalose, sorbitol, and mannitol.
  • the liquid formulation according to the aspect contains amino acids.
  • 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.
  • the amino acid may include one or more selected from arginine, histidine, glycine, methionine, and lysine.
  • amino acid may be selected from:
  • the concentration of the amino acid can be any range or any value selected from about 20 mM to about 355 mM.
  • the concentration of arginine is about 75 mM to about 165 mM, about 75 mM to about 150 mM, about 75 mM to about 135 mM, about 75 mM to about 125 mM, about 75 mM to about 115 mM, about 75 mM to about 105 mM, about 75 mM to about 100 mM, about 90 mM to about 165 mM, about 90 mM to about 150 mM, about 90 mM to about 135 mM, about 90 mM to about 125 mM, about 90 mM to about 115 mM, about 90 mM to about 105 mM, about 90 mM to about 100 mM, about 95 mM to about 165 mM, about 95 mM to about 150 mM, about 95 mM to about 135 mM, about 95 mM to about 125 mM, about 95 mM to about 115 mM,
  • the concentration of histidine can be about 85 mM to about 205 mM, about 85 mM to about 175 mM, about 85 mM to about 145 mM, about 85 mM to about 115 mM, about 115 mM to about 205 mM, about 115 mM to about 175 mM, about 115 mM to about 145 mM, about 145 mM to about 205 mM, about 145 mM to about 175 mM, or about 140 mM to about 150 mM.
  • the concentration of histidine can be about 145 mM.
  • the concentration of histidine can be about 30 mM to about 70 mM, about 30 mM to about 60 mM, about 30 mM to about 55 mM, about 30 mM to about 50 mM, 40 mM to about 70 mM, about 40 mM to about 60 mM, about 40 mM to about 55 mM, about 40 mM to about 50 mM, 45 mM to about 70 mM, about 45 mM to about 60 mM, about 45 mM to about 55 mM, about 45 mM to about 50 mM, 50 mM to about 70 mM, about 50 mM to about 60 mM, or about 50 mM to about 55 mM.
  • the concentration of histidine can be about 50 mM.
  • the concentration of said glycine is about 125 mM to about 315 mM, about 125 mM to about 290 mM, about 125 mM to about 270 mM, about 125 mM to about 250 mM, about 125 mM to about 230 mM, about 150 mM to about 315 mM, about 150 mM to about 290 mM, about 150 mM to about 270 mM, about 150 mM to about 250 mM, about 150 mM to about 230 mM, about 170 mM to about 315 mM, about 170 mM to about 290 mM, about 170 mM to about 270 mM, about 170 mM to about 250 mM, about 170 mM to about 230 mM, about 190 mM to about 315 mM, about 190 mM to about 290 mM, about 190 mM to about 290 mM, about
  • the concentration of said methionine can be about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, or about 25 mM to about 30 mM. In certain embodiments, the concentration of methionine can be about 25 mM or about 30 mM.
  • the concentration of said lysine can be about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, or about 25 mM to about 30 mM. In certain embodiments, the concentration of said lysine can be about 30 mM.
  • the amino acid may be a combination of histidine and methionine.
  • the concentration of histidine may be about 85 mM to about 205 mM
  • the concentration of methionine may be about 20 mM to about 40 mM.
  • the amino acid may be a combination of histidine, arginine, and methionine.
  • the concentration of the histidine may be about 30 mM to about 70 mM
  • the concentration of the arginine may be about 80 mM to about 120 mM
  • the concentration of the methionine may be about 10 mM to about 40 mM.
  • the above amino acid may have at least one function of a viscosity reducing agent and a stabilizer.
  • the above amino acid may have both the functions of a viscosity reducing agent and a stabilizer.
  • viscosity reducing agent or “viscosity reducer” refers to a substance that lowers the viscosity of a liquid substance.
  • the term "stabilizer” refers to a substance added to prevent a change in state or chemical change when preserving a substance.
  • the stabilizer may be a thermal stabilizer.
  • the stabilizer may inhibit the aggregation of antibodies.
  • the above liquid formulation may have improved viscosity compared to a liquid formulation of anti-IL-4R ⁇ antibody containing a sugar by including a specific type of amino acid or a specific combination of amino acids instead of containing a sugar.
  • the above liquid formulation can reduce the high molecular weight species content (%HMW) of the antibody in the liquid formulation by including a specific type of amino acid or a specific combination of amino acids instead of including a sugar.
  • %HMW high molecular weight species content
  • the above liquid formulation may contain a specific type of amino acid or a specific combination of amino acids instead of a sugar, thereby reducing the %HMW of the antibody in the liquid formulation immediately after preparation or when stored under the same conditions (e.g., at 25°C for 4 weeks) compared to a liquid formulation of anti-IL-4R ⁇ antibody containing a sugar.
  • liquid formulation contains a specific type of amino acid or a specific combination of amino acids instead of containing sugar, both viscosity and %HMW are reduced compared to Dupixent containing sugar, so viscosity and stability may be improved simultaneously.
  • Liquid formulations according to the aspect may additionally contain a surfactant.
  • the liquid formulation may be a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer; an amino acid; and a surfactant, and does not contain a sugar, and having a pH of about 5.3 to about 6.5.
  • the above surfactant can be selected from any pharmaceutically acceptable surfactants capable of evenly dispersing a protein (e.g., antibody) in a liquid formulation medium.
  • the above surfactant may be a nonionic surfactant.
  • the surfactant may be at least one selected from the group consisting of polysorbate, poloxamer, sorbitan esters of other fatty acids, polyethylene-polypropylene glycol, polyoxyethylene compounds, and sodium dodecyl sulphate (SDS).
  • the above polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85.
  • the above poloxamer may include a PEO-PPO-PEO copolymer (PEO is poly(ethylene oxide) and PPO is poly(propylene oxide)).
  • PEO poly(ethylene oxide)
  • PPO poly(propylene oxide)
  • sorbitan esters of other fatty acids may mean sorbitan esters of other fatty acids than polysorbates, and may include, for example, sorbitan polyethoxylates.
  • the above polyoxyethylene compound may include polyoxyethylene-stearate, polyoxyethylene alkyl ether (alkyl: C1-C30), polyoxyethylene monoryl ether, alkylphenyl polyoxyethylene copolymer (alkyl: C1-C30), and the like.
  • the surfactant may be a polysorbate.
  • the surfactant may include one or more selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85.
  • the surfactant may include polysorbate 20, polysorbate 80, or a combination thereof.
  • the surfactant may comprise polysorbate 80. In certain embodiments, the surfactant may be polysorbate 80.
  • the concentration of the surfactant can be any range or value selected from about 0.01% (w/v) to about 0.9% (w/v).
  • 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).
  • the concentration of the surfactant may be about 0.2% (w/v).
  • Liquid formulations may additionally contain a diluent.
  • the above 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.
  • the diluent may be water.
  • the liquid formulation may be an aqueous liquid formulation.
  • liquid formulation means a formulation in liquid form.
  • the liquid formulation according to the aspect is a stable liquid formulation of anti-IL-4R ⁇ antibody.
  • the liquid formulation according to one aspect may be a pharmaceutical formulation of an anti-IL-4R ⁇ antibody.
  • composition or “pharmaceutical preparation” means a preparation which allows the biological activity of an active ingredient to be effectively carried out and which does not contain additional components which have significant toxicity to the subject to which the preparation is administered.
  • pharmaceutical formulation refers to the product of a process that combines an active drug with chemicals to produce the final drug product.
  • pharmaceutically acceptable may refer to excipients, carriers, vehicles, diluents, additives, salts, etc. that are suitable for administration to a subject.
  • the liquid formulation according to one aspect may be a Dupixent ® biosimilar.
  • the liquid formulation according to one aspect has improved stability and improved viscosity compared to Dupixent.
  • biosimilar is also called “biogeneric” and refers to a copy of an original biopharmaceutical. Since biopharmaceuticals are not synthesized chemical products but are produced through cells, they cannot be exactly the same as the original drug. Therefore, a copy of a biopharmaceutical is called a biosimilar because it is similar, but not identical, to the original drug.
  • Liquid formulations according to the aspect of the work may be selected from the following items:
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer; and an amino acid, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer; an amino acid; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; an amino acid comprising arginine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; amino acids comprising arginine and lysine; and a surfactant, and free of sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; amino acids comprising arginine and methionine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; an amino acid comprising histidine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; an amino acid comprising histidine and lysine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; an amino acid comprising histidine and methionine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; an amino acid comprising glycine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; an amino acid comprising glycine and lysine; and a surfactant, and does not contain a sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a buffer comprising acetate; amino acids comprising glycine and methionine; and a surfactant, and free of sugar, and having a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab; about 6 mM to about 14 mM of acetate; about 20 mM to about 355 mM of an amino acid, wherein the amino acid comprises at least one selected from arginine, histidine, glycine, methionine, and lysine; and about 0.1% (w/v) to about 0.9% (w/v) of polysorbate 80, wherein the formulation does not contain a sugar, and has a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab; about 6 mM to about 14 mM of acetate; about 85 mM to about 205 mM of histidine; about 20 mM to about 40 mM of methionine; and about 0.1% (w/v) to about 0.9% (w/v) of polysorbate 80, wherein the formulation does not contain a sugar, and has a pH of about 4.5 to about 6.5;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab; 6 mM ⁇ 1 mM acetate, 145 mM ⁇ 20 mM histidine; 30 mM ⁇ 2 mM methionine; and 0.2% ⁇ 0.1% (w/v) polysorbate 80, free of sugars, and having a pH of 5.9 ⁇ 0.2;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab; 8 mM ⁇ 1 mM of acetate, 115 mM to 175 mM of histidine; 30 mM ⁇ 2 mM of methionine; and 0.2% ⁇ 0.1% (w/v) of polysorbate 80, free of sugars, and having a pH of 4.5 to 6.2;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab; 10 mM ⁇ 1 mM of acetate, 85 mM to 205 mM of histidine; 20 mM to 40 mM of methionine; and 0.2% ⁇ 0.1% (w/v) of polysorbate 80, wherein the formulation does not contain a sugar, and has a pH of 4.5 to 6.5;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab; 12 mM ⁇ 1 mM of acetate, 115 mM to 175 mM of histidine; 25 mM to 35 mM of methionine; and 0.2% ⁇ 0.1% (w/v) of polysorbate 80, wherein the formulation does not contain a sugar, and has a pH of 4.5 to 6.2;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab; 14 mM ⁇ 1 mM of acetate, 145 mM ⁇ 20 mM of histidine; 30 mM ⁇ 2 mM of methionine; and 0.2% ⁇ 0.1% (w/v) of polysorbate 80, free of sugars, and having a pH of 5.9 ⁇ 0.2;
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab, about 20 mM to about 40 mM of acetate, about 40 mM to about 60 mM of histidine, about 80 mM to about 120 mM of arginine, about 10 mM to about 40 mM of methionine, and about 0.1% (w/v) to about 0.9% (w/v) of polysorbate 80, wherein the formulation does not contain a sugar, and has a pH of about 4.5 to about 5.9; or
  • a liquid formulation comprising about 100 mg/mL to about 200 mg/mL of dupilumab, 30 mM ⁇ 5 mM of acetate, 50 mM ⁇ 5 mM of histidine, 100 mM ⁇ 5 mM of arginine, 25 mM ⁇ 5 mM of methionine, and about 0.1% (w/v) to about 0.9% (w/v) of polysorbate 80, wherein the formulation does not contain a sugar, and has a pH of 5.2 ⁇ 0.2.
  • Liquid formulations according to the aspect can have low viscosity while ensuring the stability of antibodies.
  • the above liquid formulation may have improved viscosity.
  • the 'improvement' of the viscosity may mean a 'reduction' of the viscosity. Accordingly, the above liquid formulation may have reduced viscosity.
  • the unit of the viscosity may be expressed as cP (centiPoise).
  • the above sugar-free liquid formulation may have improved viscosity compared to a sugar-containing anti-IL-4R ⁇ antibody liquid formulation.
  • the viscosity of the above sugar-free liquid formulation may be reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% relative to the viscosity of the anti-IL-4R ⁇ antibody liquid formulation containing sugar.
  • the viscosity of the above sugar-free liquid formulation can be less than 17.0 cP, less than 16.8 cP, less than 16.0 cP, less than 15.0 cP, less than 14.0 cP, less than 13.0 cP, less than 12.0 cP, less than 11.0 cP, less than 10.0 cP, less than 9.0 cP, less than 8.0 cP, or less than 7.0 cP.
  • the liquid formulation according to one aspect can have a reduced viscosity relative to Dupixent. In one embodiment, the liquid formulation according to one aspect can have a reduced viscosity relative to the viscosity of 11.1 cP (centiPoise) of Dupixent 200 mg. In another embodiment, the liquid formulation according to one aspect can have a reduced viscosity relative to the viscosity of 300 mg of Dupixent.
  • a sugar-free liquid formulation comprising an amino acid selected from the following can have a viscosity reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% relative to the viscosity of a Dupixent formulation:
  • the sugar-free liquid formulation comprising the amino acid combination of histidine and methionine can have a viscosity reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% relative to the viscosity of the Dupixent formulation.
  • the viscosity of the liquid formulation may be less than 11.1 cP.
  • the viscosity of the liquid formulation may be less than 11.1 cP, 11.0 cP or less, 10.5 cP or less, 10.0 cP or less, 9.5 cP or less, 9.0 cP or less, 8.5 cP or less, 8.0 cP or less, 7.5 cP or less, 7.0 cP or less, or 6.5 cP or less.
  • the viscosity of the above liquid formulation is 5.0 cP or more and less than 11.1 cP, 5.0 cP to 11.0 cP, 5.0 cP to 10.5 cP, 5.0 cP to 10.0 cP, 5.0 cP to 9.5 cP, 5.0 cP to 9.0 cP, 5.0 cP to 8.5 cP, 5.0 cP to 8.0 cP, 5.0 cP to 7.5 cP, 5.0 cP to 7.0 cP, 5.0 cP to 6.5 cP, 5.5 cP or more and less than 11.1 cP, 5.5 cP to 11.0 cP, 5.5 cP to 10.5 cP, 5.5 cP to 10.0 cP, 5.5 cP to 9.5 cP, 5.5 cP to 9.0 cP, 5.5 cP to 8.5 cP, 5.5 cP to 8.0 cP, 5.5 cP to
  • the term “stability” means that the antibody (e.g., dupilumab) contained in the formulation substantially retains its physical stability, chemical stability and/or biological activity before and after administration, during further manufacturing processes, storage or preservation.
  • the degree of loss of stability such as aggregation, decomposition, denaturation (acidic or alkaline), 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.
  • excellent stability “improved stability” can mean low protein aggregation rate, low protein degradation rate, low protein denaturation rate, low amino acid oxidation rate, etc. during storage.
  • Physical stability, chemical stability and/or biological activity can be evaluated by methods commonly known in the art.
  • aggregate may refer to high molecular weight (HMW) species formed by the aggregation of antibody proteins.
  • protein aggregation percentage may be expressed as the percentage of high molecular weight species content (%HMW) of antibody in the formulation at a given point in time.
  • the %HMW may be measured by, but is not limited to, size exclusion chromatography (SEC).
  • SEC size exclusion chromatography
  • improved stability may mean that the %HMW of antibody measured for the formulation decreases 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 prior formulation.
  • a decrease in %HMW may mean that the degree to which antibodies in the formulation aggregate is reduced, thereby improving stability.
  • the above stability evaluation can 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 can include conditions used in an accelerated test for a drug product, and can be, for example, a temperature of 25 ⁇ 2°C and a relative humidity (RH) of 60 ⁇ 5%.
  • the stress stability conditions can include conditions used in a stress test for a drug product, and can be, for example, a temperature of 40 ⁇ 2°C and a relative humidity (RH) of 75+5%.
  • the liquid formulation may have a reduced high molecular weight species content (%HMW).
  • the above sugar-free liquid formulation may have a reduced %HMW compared to a sugar-containing anti-IL-4R ⁇ antibody liquid formulation.
  • the above sugar-free liquid formulation may have a %HMW of antibody reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 12%, at least 15%, or at least 20% compared to the sugar-containing formulation after 4 weeks of storage at 25°C.
  • the above sugar-free liquid formulation can have a %HMW of antibody of less than 3.70%, or less than 3.62%, or less than 3.50%, or less than 3.40%, or less than 3.30%, or less than 3.20%, or less than 3.10%, or less than 3.00%, or less than 2.90%, or less than 2.80%, or less than 2.70%, or less than 2.60%, or less than 2.50%, or less than 2.40%, or less than 2.30%, or less than 2.20%, or less than 2.10%, as measured after storage at 25°C for 4 weeks.
  • the sugar-free liquid formulation according to one aspect can have a reduced %HMW compared to Dupixent.
  • the sugar-free liquid formulation according to one aspect can have a reduced %HMW compared to 2.03% of antibody measured immediately after preparation of Dupixent 200 mg.
  • the sugar-free liquid formulation comprising the amino acid combination of histidine and methionine can have a %HMW of antibody measured immediately after manufacture reduced by at least 2%, at least 5%, at least 10%, at least 15%, or at least 20% compared to the Dupixent formulation.
  • the above sugar-free liquid formulation can have a %HMW of antibody measured immediately after manufacture of less than 2.03%, less than or equal to 2.00%, less than or equal to 1.90%, less than or equal to 1.80%, or less than or equal to 1.70%.
  • Another aspect provides a device comprising a liquid formulation according to the above aspect.
  • the device is primarily intended for parenteral administration.
  • the 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.
  • 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.
  • 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.
  • the above device may be in a single-dose form or a multiple-dose form.
  • the device may comprise the liquid formulation in a prefilled syringe.
  • the prefilled syringe may be a single-dose prefilled syringe.
  • the device may comprise the liquid formulation in a prefilled pen.
  • the prefilled pen may be a single-dose prefilled pen.
  • Another aspect provides a method of treating an IL-4R ⁇ associated condition, comprising administering to a subject in need thereof a liquid formulation according to one aspect of the invention.
  • the liquid formulation may be in a form contained in a device.
  • Another aspect provides the use of a liquid formulation according to the above aspect in the manufacture of a medicament for treating an IL-4R ⁇ associated condition.
  • the method of treating the above IL-4R ⁇ associated condition may further comprise, prior to the administering step, a step of identifying a subject in need of administration of an anti-IL-4R ⁇ antibody (e.g., dupilumab).
  • an anti-IL-4R ⁇ antibody e.g., dupilumab
  • the subject may be a subject in need of administration of a liquid formulation containing the anti-IL-4R ⁇ antibody (e.g., dupilumab).
  • a liquid formulation containing the anti-IL-4R ⁇ antibody e.g., dupilumab
  • the subject in need of administration of the liquid formulation containing the anti-IL-4R ⁇ antibody may be a subject having a disease or disorder that can be significantly treated (e.g., elimination, reduction, alleviation, or improvement of symptoms, etc.) by administration of the anti-IL-4R ⁇ antibody.
  • the subject may be selected from mammals, including humans.
  • the above liquid formulation can be administered in a pharmaceutically effective amount.
  • the IL-4R ⁇ associated condition can include any condition, disease, or disorder that can be treated by administration of an anti-IL-4R ⁇ antibody.
  • the IL-4R ⁇ associated condition that can be treated by administration of an anti-IL-4R ⁇ antibody e.g., dupilumab
  • can include any indication currently approved or that may be approved in the future for an anti-IL-4R ⁇ antibody e.g., dupilumab.
  • the IL-4R ⁇ 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-4R ⁇ associated condition may include any disease that can be treated by dual blockade of IL-4 and IL-13.
  • the IL-4R ⁇ -related condition may include an inflammatory disease, an allergic disease, or an autoimmune disease.
  • the inflammatory disease may be a Type 2 inflammatory disease.
  • the above IL-4R ⁇ -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).
  • CCS chronic rhinosinusitis
  • CSwNP chronic rhinosinusitis with nasal polyposis
  • AFRS allergic fungal rhinosinusitis
  • EoE eosinophilic esophagitis
  • PN bullous pemhigoid
  • CSU chronic spontaneous urticarial
  • CndU chronic inducible urticarial
  • COPD chronic
  • the above atopic dermatitis may be moderate-to-severe atopic dermatitis.
  • the above asthma may be moderate-to-severe asthma.
  • Liquid formulations according to the aspect may be administered by parenteral route.
  • the parenteral route may include subcutaneous administration, intravenous administration, etc.
  • Parenteral administration may be by bolus injection or continuous infusion.
  • the liquid formulation may be for subcutaneous injection.
  • the above liquid formulation may be formulated into a formulation suitable for the above administration route.
  • the above liquid formulation may be formulated into an injection, an injectable ready-to-use, etc., but is not limited thereto.
  • the liquid formulation may be formulated to contain the entire amount or a pharmaceutically effective amount of the anti-IL-4R ⁇ antibody (e.g., dupilumab) in a single formulation or divided into two or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) formulations.
  • the liquid formulation may be contained in a single-dose or multi-dose form of the device.
  • the above liquid formulation may be administered to the body in one dose, such that the entire amount of the anti-IL-4R ⁇ antibody (e.g., dupilumab) contained in the formulation is administered to the body at one time (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 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.
  • the entire amount of the anti-IL-4R ⁇ antibody e.g., dupilumab
  • the administration target of the above liquid formulation can 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.
  • mammals including primates (e.g., humans, etc.), rodents (e.g., mice, rats, guinea pigs, hamsters, rabbits, etc.), cats, dogs, pigs, cows, horses, etc.
  • the pharmaceutically effective amount of the above liquid formulation or the anti-IL-4R ⁇ 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 variously determined by 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, and the like.
  • 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.
  • the liquid formulation can be administered once every two to four weeks over a period of two weeks or more at a dose such that the anti-IL-4R ⁇ antibody (e.g., dupilumab) is 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg.
  • the anti-IL-4R ⁇ antibody e.g., dupilumab
  • 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.
  • a sugar-free liquid formulation of an anti-IL-4R ⁇ antibody may have improved stability and improved viscosity compared to existing commercialized formulations. Therefore, the liquid formulation may have high stability and low viscosity even when containing a high concentration of antibody, thereby increasing patient convenience upon injection. Accordingly, the liquid formulation may be usefully used as a pharmaceutical for treating IL-4R ⁇ -related conditions.
  • Figure 1 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation.
  • Figure 2 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of sugar-free formulations and sugar-containing formulations.
  • Figure 3 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a Dupixent formulation.
  • Figure 4 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of sugar-free formulations and Dupixent formulations.
  • the viscosity of the sample was measured using a viscometer (manufacturer: RheoSense, model name: VROC initium one plus). The analysis was conducted under a temperature condition of 25°C when measuring the viscosity. After measuring 11 segments for the same sample, the average value was calculated for the values with a slope fit R 2 value of 0.9995 or higher, and the viscosity value of each sample was calculated.
  • the percentage of high molecular weight species was determined using size exclusion chromatography (SEC) through an HPLC system from Waters. It is separated into three peaks according to the molecular weight of the protein, and these three peaks correspond to HMW peak (protein aggregation), Monomer peak, and LMW peak (protein degradation) in order of decreasing retention time, i.e. increasing protein molecular weight.
  • SEC size exclusion chromatography
  • Each formulation sample for stability testing was stored in a chamber maintaining accelerated stability conditions of 25 ⁇ 2°C and 60 ⁇ 5% relative humidity (R.H).
  • the viscosity and %HMW were evaluated for improvement when the sugar was removed after fixing the buffer concentration, amino acid concentration, and pH concentration.
  • dupilumab (CAS No. 1190264-60-8) as an anti-IL-4R ⁇ antibody
  • aqueous liquid formulations having the compositions shown in Table 1 below were prepared. The viscosity and %HMW of each formulation were measured after 4 weeks of storage at 25°C.
  • a All formulations contained 175 mg/mL dupilumab, 10 mM sodium acetate, 0.2% (w/v) polysorbate 80, and had a pH of 6.0.
  • Figure 1 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a sugar-containing formulation.
  • Figure 2 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of sugar-free formulations and sugar-containing formulations.
  • Formulation 62 is a Dupixent formulation.
  • Figure 3 is a graph showing the results of measuring the viscosity of a sugar-free formulation and a Dupixent formulation.
  • Figure 4 is a graph showing the results of measuring the high molecular weight species content ratio (%HMW) of sugar-free formulations and Dupixent formulations.

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Abstract

La présente invention concerne : une formulation liquide qui contient un anticorps anti-IL-4Rα, un agent tampon et un acide aminé mais qui ne comprend pas de saccharides, et qui a un pH compris entre 4,5 et 6,5 ; un dispositif le contenant ; et une utilisation de celui-ci pour traiter des états liés à IL-4Rα de celui-ci. La formulation liquide peut améliorer la viscosité tout en garantissant la stabilité d'un anticorps sans inclure de saccharides, et peut ainsi être efficacement utilisée en tant que médicament pour le traitement d'états liés à IL-4Rα.
PCT/KR2024/019361 2023-12-01 2024-11-29 Formulation liquide stable sans saccharide d'anticorps anti-il-4rα Pending WO2025116640A1 (fr)

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US20190091335A1 (en) * 2011-10-28 2019-03-28 Excelse Bio, Inc. Antibody formulations containing amino acids
KR20210137489A (ko) * 2019-03-13 2021-11-17 쑤저우 커넥트 바이오파마슈티컬즈, 엘티디. 인간 인터루킨-4 수용체 알파의 항체를 포함하는 액체 조성물
US20230277453A1 (en) * 2017-02-24 2023-09-07 Arecor Limited Stabilized antibody protein solutions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101867279B1 (ko) * 2010-10-06 2018-06-15 리제너론 파아마슈티컬스, 인크. 항―인터류킨―４ 수용체（ｉｌ－４ｒ） 항체를 함유하는 안정화된 제형
US20190091335A1 (en) * 2011-10-28 2019-03-28 Excelse Bio, Inc. Antibody formulations containing amino acids
KR20150070384A (ko) * 2012-10-25 2015-06-24 메디뮨 엘엘씨 안정한 저점도 항체 제제
US20230277453A1 (en) * 2017-02-24 2023-09-07 Arecor Limited Stabilized antibody protein solutions
KR20210137489A (ko) * 2019-03-13 2021-11-17 쑤저우 커넥트 바이오파마슈티컬즈, 엘티디. 인간 인터루킨-4 수용체 알파의 항체를 포함하는 액체 조성물

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