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WO2025116648A1 - FORMULATION LIQUIDE STABLE SANS TAMPON D'ANTICORPS ANTI-IL-4Rα - Google Patents

FORMULATION LIQUIDE STABLE SANS TAMPON D'ANTICORPS ANTI-IL-4Rα Download PDF

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Publication number
WO2025116648A1
WO2025116648A1 PCT/KR2024/019379 KR2024019379W WO2025116648A1 WO 2025116648 A1 WO2025116648 A1 WO 2025116648A1 KR 2024019379 W KR2024019379 W KR 2024019379W WO 2025116648 A1 WO2025116648 A1 WO 2025116648A1
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Prior art keywords
liquid formulation
antibody
formulation according
concentration
buffer
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English (en)
Korean (ko)
Inventor
박진혜
김한수
남명주
김인애
이헌주
장성근
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Samsung Bioepis Co Ltd
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Samsung Bioepis Co Ltd
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Publication of WO2025116648A1 publication Critical patent/WO2025116648A1/fr
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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
    • A61K47/16—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
    • A61K47/26—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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • Stable buffer-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 larger molecular weight than general protein drugs and have complex secondary/higher structures, which can cause problems of physical and chemical instability. For this reason, antibody drugs require the development of an optimal formulation that guarantees quality and stability throughout the entire process from manufacturing to 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 problems of causing immunogenicity when administered to the human body.
  • a certain pH can be maintained without including a buffer due to the self-buffering effect through high protein concentration.
  • some buffers are prone to self-decomposition under stress conditions, which may affect the stability of antibody drugs.
  • the present disclosure relates to a stable buffer-free liquid formulation of an anti-IL-4R ⁇ antibody, such as dupilumab.
  • the present disclosure provides a liquid formulation of an anti-IL-4R ⁇ antibody, such as dupilumab, which has high stability and low viscosity even without including a buffer.
  • One aspect is to provide a liquid formulation comprising an anti-IL-4R ⁇ antibody; a sugar; and an amino acid, and no buffering agent.
  • Another aspect is to provide a device comprising the liquid formulation.
  • 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 buffer-free liquid formulation of an anti-IL-4R ⁇ antibody, specifically,
  • 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 one aspect does not contain a buffer (free of buffer). Accordingly, the liquid formulation may be a buffer-free formulation or a bufferless formulation.
  • the above liquid formulation can have high stability and low viscosity despite being a buffer-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 a buffer” may be interpreted to mean that no buffering component is present in the formulation, or that the formulation contains such an amount that it cannot function as the intended buffering component in the formulation.
  • the above liquid formulation does not contain, or substantially does not contain, a buffering agent.
  • 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.
  • hydrate means a substance containing water molecules within its molecules.
  • the hydrate may be a monohydrate, a dihydrate, or a trihydrate.
  • the buffer may comprise acetate. Accordingly, the liquid formulation may not comprise acetate as the buffer.
  • the buffer may comprise a combination of acetate and histidine. Accordingly, the liquid formulation may comprise neither acetate nor histidine as the buffer.
  • the pH of the liquid formulation according to the aspect can be any range or any value selected from about 4.0 to about 8.5.
  • the pH can 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
  • the pH of the liquid formulation may be from about 4.7 to about 7.4.
  • the pH of the liquid formulation may be about 5.9.
  • the pH of the liquid formulation may be about 6.0.
  • Liquid formulations according to the aspect of the invention contain saccharides.
  • Liquid formulations according to the invention may contain sugars as stabilizers.
  • the above sugar may include at least one selected from sugar and 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 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 any value selected from about 0.1% (w/v) to about 20% (w/v).
  • 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
  • the concentration of the sugar alcohol can be freely adjusted within a range that maintains the stability of the antibody, and can vary individually depending on each specific sugar alcohol type.
  • 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).
  • 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 1% (w/v) to about 7% (w/v), about 1% (w/v) to about 6% (w/v), about 1% (w/v) to about 5% (w/v),
  • the sugar may comprise sucrose. In certain embodiments, the sugar may be sucrose.
  • the concentration of the sucrose can be any range or value selected from about 0.1% (w/v) to about 20% (w/v).
  • 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
  • the concentration of sucrose may be about 5% (w/v).
  • the liquid formulation according to the aspect contains amino acids.
  • Liquid formulations according to the invention may contain amino acids as stabilizers.
  • stabilizer refers to a substance added to prevent a change in state or chemical change when preserving a substance.
  • the stabilizer may inhibit aggregation or denaturation of antibodies.
  • the above amino acids may include 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.
  • the amino acid may comprise arginine.
  • the concentration of the above amino acid can be freely adjusted within a range that maintains the stability of the antibody, and can vary individually depending on each specific amino acid type.
  • the concentration of the above amino acid can be any range or any value selected from about 1 mM to about 400 mM.
  • 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
  • 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 sugar; an amino acid; and a surfactant, and not comprising a buffer.
  • 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 a liquid state.
  • 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.
  • 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 anti-IL-4R ⁇ antibody; sugar; and amino acid, and not containing a buffer;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody at about 5 mg/mL to about 300 mg/mL; a sugar; and an amino acid, and no buffer;
  • a liquid formulation comprising anti-IL-4R ⁇ antibody; sugar; and amino acid, and not containing acetate as a buffer;
  • a liquid formulation comprising anti-IL-4R ⁇ antibody; a sugar; and an amino acid, and not containing either acetate or histidine as a buffer;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a sugar; an amino acid; and a surfactant, and not containing a buffer;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody at about 5 mg/mL to about 300 mg/mL; a sugar; an amino acid; and a surfactant, and no buffer;
  • a liquid formulation comprising an anti-IL-4R ⁇ antibody; a sugar; an amino acid; and a surfactant, and not containing acetate as a buffer;
  • 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 liquid formulation may have a reduced high molecular weight species content (%HMW).
  • the above liquid formulation may have a reduced %HMW compared to a liquid formulation of anti-IL-4R ⁇ antibody containing a buffer, as the liquid formulation does not contain a buffer.
  • the liquid formulation may exhibit a decrease in %HMW of the antibody measured after 4 weeks of storage at 25°C of at least 1%, at least 2%, or at least 3% compared to the formulation containing the buffer.
  • the above liquid formulation may have improved viscosity compared to a liquid formulation of anti-IL-4R ⁇ antibody containing a buffer, by not containing a buffer.
  • 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 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 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 form, 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 liquid formulation of an anti-IL-4R ⁇ antibody may have improved stability and improved viscosity compared to a formulation including a buffer, even though it does not include a buffer. Therefore, the liquid formulation may have high stability and low viscosity even if it includes a high concentration of the antibody, thereby increasing patient convenience upon injection. Accordingly, the liquid formulation may be usefully used as a medicament for treating an IL-4R ⁇ -related condition.
  • Figure 1 is a graph showing the results of analyzing the high molecular weight species content ratio (%HMW) for buffer-free and buffer-containing formulations.
  • Figure 2 is a graph showing the results of viscosity analysis for buffer-free formulations and buffer-containing 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 a HPLC system from Waters. It was separated into three peaks according to the molecular weight of the protein, and these three peaks correspond to the HMW peak (protein aggregation), Monomer peak, and LMW peak (protein degradation) in order of decreasing retention time, i.e. increasing 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).
  • 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. After exposing each formulation to a temperature condition of 25°C for 4 weeks, the purity of the sample was measured through size exclusion chromatography (SEC) analysis.
  • SEC size exclusion chromatography
  • Figure 1 is a graph showing the results of analyzing the high molecular weight species content ratio (%HMW) for buffer-free and buffer-containing formulations.
  • 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.
  • 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.

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Abstract

La présente invention concerne : une formulation liquide comprenant un anticorps anti-IL-4Rα, un saccharide et un acide aminé sans comprendre un tampon ; un dispositif la comprenant ; et son utilisation pour le traitement d'états liés à IL-4Rα. La formulation liquide peut assurer la stabilité et améliorer la viscosité sans comprendre un tampon d'un anticorps, et peut ainsi être utilisée efficacement en tant que médicament pour le traitement d'états liés à IL-4Rα.
PCT/KR2024/019379 2023-12-01 2024-11-29 FORMULATION LIQUIDE STABLE SANS TAMPON D'ANTICORPS ANTI-IL-4Rα Pending WO2025116648A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025202487A3 (fr) * 2024-03-28 2025-11-06 Fresenius Kabi Deutschland Gmbh Composition pharmaceutique de dupilumab

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KR101867279B1 (ko) * 2010-10-06 2018-06-15 리제너론 파아마슈티컬스, 인크. 항―인터류킨―４ 수용체（ｉｌ－４ｒ） 항체를 함유하는 안정화된 제형
WO2018200918A1 (fr) * 2017-04-28 2018-11-01 Amgen Inc. Formulations d'anticorps anti-rankl humains, et leurs méthodes d'utilisation
KR20200029374A (ko) * 2018-09-10 2020-03-18 삼성바이오에피스 주식회사 단백질을 포함하는 액상 조성물
KR20210137489A (ko) * 2019-03-13 2021-11-17 쑤저우 커넥트 바이오파마슈티컬즈, 엘티디. 인간 인터루킨-4 수용체 알파의 항체를 포함하는 액체 조성물
KR20220115803A (ko) * 2019-12-13 2022-08-18 삼성바이오에피스 주식회사 안정한 항-pd-1 항체 약제학적 제제
US20230088052A1 (en) * 2020-02-21 2023-03-23 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Pharmaceutical composition containing anti-il-4r antibody and use thereof

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KR20080031684A (ko) * 2005-06-14 2008-04-10 암젠 인코포레이티드 자가 - 완충성 단백질 제형
KR101867279B1 (ko) * 2010-10-06 2018-06-15 리제너론 파아마슈티컬스, 인크. 항―인터류킨―４ 수용체（ｉｌ－４ｒ） 항체를 함유하는 안정화된 제형
WO2018200918A1 (fr) * 2017-04-28 2018-11-01 Amgen Inc. Formulations d'anticorps anti-rankl humains, et leurs méthodes d'utilisation
KR20200029374A (ko) * 2018-09-10 2020-03-18 삼성바이오에피스 주식회사 단백질을 포함하는 액상 조성물
KR20210137489A (ko) * 2019-03-13 2021-11-17 쑤저우 커넥트 바이오파마슈티컬즈, 엘티디. 인간 인터루킨-4 수용체 알파의 항체를 포함하는 액체 조성물
KR20220115803A (ko) * 2019-12-13 2022-08-18 삼성바이오에피스 주식회사 안정한 항-pd-1 항체 약제학적 제제
US20230088052A1 (en) * 2020-02-21 2023-03-23 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Pharmaceutical composition containing anti-il-4r antibody and use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025202487A3 (fr) * 2024-03-28 2025-11-06 Fresenius Kabi Deutschland Gmbh Composition pharmaceutique de dupilumab

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