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WO2018179138A1 - Préparation de liquide contenant des anticorps - Google Patents

Préparation de liquide contenant des anticorps Download PDF

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Publication number
WO2018179138A1
WO2018179138A1 PCT/JP2017/012901 JP2017012901W WO2018179138A1 WO 2018179138 A1 WO2018179138 A1 WO 2018179138A1 JP 2017012901 W JP2017012901 W JP 2017012901W WO 2018179138 A1 WO2018179138 A1 WO 2018179138A1
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WO
WIPO (PCT)
Prior art keywords
liquid preparation
antibody
recombinant monoclonal
monoclonal antibody
preparation according
Prior art date
Application number
PCT/JP2017/012901
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English (en)
Japanese (ja)
Inventor
龍 奥脇
Original Assignee
持田製薬株式会社
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Publication date
Application filed by 持田製薬株式会社 filed Critical 持田製薬株式会社
Priority to PCT/JP2017/012901 priority Critical patent/WO2018179138A1/fr
Priority to JP2019508426A priority patent/JPWO2018179138A1/ja
Publication of WO2018179138A1 publication Critical patent/WO2018179138A1/fr

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Classifications

    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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

Definitions

  • the present invention relates to an antibody-containing liquid preparation.
  • Recombinant monoclonal antibodies such as tocilizumab are currently used as active ingredients in pharmaceuticals.
  • antibody pharmaceutical preparations often have a higher protein concentration than other biopharmaceutical preparations, and attention must be paid to aggregate formation.
  • the dose of the recombinant monoclonal antibody per administration may be large. For example, when a preparation for subcutaneous injection capable of self-injection is used, one injection There is a limit to the amount of liquid. Therefore, it may be necessary to increase the concentration of the recombinant monoclonal antibody contained in the preparation.
  • injections are known for various administration routes such as subcutaneous administration and intravenous administration, and any preparation is generally used because it is required to be a liquid preparation for convenience of immediate use.
  • any preparation is generally used because it is required to be a liquid preparation for convenience of immediate use.
  • simply dissolving a lyophilized drug formulation has not been able to satisfy long-term practical stability as a pharmaceutical product.
  • Patent Document 1 a pharmaceutical formulation containing a specific amount of arginine, methionine, polysorbate
  • Patent Document 2 a pharmaceutical formulation containing a specific amount of arginine hydrochloride, histidine, polysorbate
  • the content of the recombinant monoclonal antibody is 150 mg / mL or more
  • the content of amino acid components such as arginine is 100 mM or more.
  • liquid preparation containing a recombinant monoclonal antibody there is a demand for stability that can be used as a pharmaceutical product.
  • liquid preparations containing different concentrations of recombinant monoclonal antibodies such as subcutaneous injection preparations and intravenous injection preparations, it is required to use aqueous solutions of the same components.
  • the present invention provides a stable recombinant monoclonal antibody liquid preparation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity reduction and deamidation suppression during long-term storage.
  • it is a stable recombinant monoclonal antibody liquid formulation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity reduction and deamidation suppression during long-term storage, and the formulation can be produced at low cost.
  • it is a stable high-concentration recombinant monoclonal antibody liquid formulation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity reduction and deamidation suppression during long-term storage, and subcutaneous injection.
  • a liquid preparation containing a high-concentration recombinant monoclonal antibody exhibiting kinematic viscosity enabling it is provided at low cost.
  • it is a stable recombinant monoclonal antibody liquid preparation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity reduction and deamidation suppression during long-term storage, and is practically feasible intravenous injection Preparations and subcutaneous injections at low cost.
  • the present invention provides a method for producing a stable recombinant monoclonal antibody liquid preparation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity reduction and deamidation suppression during long-term storage.
  • the present invention provides a method for stabilizing a recombinant monoclonal antibody liquid preparation that achieves at least one of suppression of dimer formation, degradation product generation, biological activity reduction, and deamidation suppression during long-term storage.
  • an aqueous solution for preparing a recombinant monoclonal antibody-containing preparation is provided. It is an object of the present invention to provide a recombinant monoclonal antibody-containing preparation that improves at least one of these, a production method thereof, a stabilization method, and an aqueous solution for producing a recombinant monoclonal antibody-containing preparation.
  • the first aspect of the present invention is the following liquid preparation containing a recombinant monoclonal antibody.
  • ⁇ 1-2> A recombinant monoclonal antibody containing 10 mg / mL to 200 mg / mL recombinant monoclonal antibody, 45 mM to 94 mM amino acid component having a histidine component of less than 5 mM, and a pH of 5.5 to 6.7 Monoclonal antibody-containing liquid preparation.
  • ⁇ 1-3> The liquid preparation according to ⁇ 1-1> or ⁇ 1-2>, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride and methionine.
  • ⁇ 1-4> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-3>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.
  • ⁇ 1-5> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-4>, comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 1-6> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-5>, containing 90 mM amino acid component.
  • ⁇ 1-7> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-6>, which has a pH of 5.8 to 6.4.
  • ⁇ 1-8> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-7>, which has a pH of 6.0 to 6.2.
  • ⁇ 1-9> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-8>, which contains 150 to 200 mg / mL recombinant monoclonal antibody.
  • ⁇ 1-10> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-9>, which contains 170 to 190 mg / mL recombinant monoclonal antibody.
  • ⁇ 1-11> The recombinant monoclonal antibody liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-10>, which contains 180 mg / mL recombinant monoclonal antibody.
  • ⁇ 1-12> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-11>, further containing a polyol.
  • ⁇ 1-13> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-12>, further containing a surfactant.
  • ⁇ 1-14> The liquid preparation according to ⁇ 1-13>, wherein the surfactant is a nonionic surfactant.
  • ⁇ 1-15> The liquid preparation according to ⁇ 1-14>, wherein the nonionic surfactant is polysorbate or polyoxyethylene polyoxypropylene glycol.
  • the polysorbate is at least one selected from the group consisting of polysorbate 80, polysorbate 40, and polysorbate 20.
  • the recombinant monoclonal antibody is at least one selected from the group consisting of a recombinant monoclonal antibody derived from an animal (human, mouse, rat, etc.), a chimeric antibody, a humanized antibody, an antibody fragment, and a low molecular weight antibody.
  • the immunoglobulin class of the recombinant monoclonal antibody is at least one selected from the group consisting of IgG (IgG1, IgG2, IgG3, IgG4), IgA, IgD, IgE, and IgM ⁇ 1-1 >
  • IgG IgG1, IgG2, IgG3, IgG4
  • IgA IgD
  • IgE IgM
  • To ⁇ 1-18> The liquid preparation according to any one of ⁇ 1-18>.
  • ⁇ 1-20> The liquid according to any one of ⁇ 1-1> to ⁇ 1-19>, wherein the immunoglobulin class of the recombinant monoclonal antibody is human-derived IgG1 (humanized IgG1 or fully human IgG1). Formulation.
  • the recombinant monoclonal antibody is an anti-tumor necrosis factor (TNF) antibody (eg, anti-TNF ⁇ antibody), anti-interleukin (IL) receptor antibody (eg, anti-IL-6 receptor antibody, anti-IL- 17 receptor antibody), anti-IL antibody (eg, anti-IL-5 antibody, anti-IL-17 antibody, anti-IL-17A antibody, anti-IL-1 ⁇ antibody, anti-IL12 / IL23-p40 antibody), anti-surface antigen antibody ( For example, anti-CD3 antibody, anti-CD20 antibody, anti-CD25 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD52 antibody, anti-RANKL antibody, anti-SLAMF7 antibody, anti-CTLA-4 antibody, anti-VEGFR-2 antibody, anti-CCR4 antibody, Anti-PD-1 antibody), anti-virus antibody (eg, anti-RS virus antibody), anti-integrin antibody (eg, anti- ⁇ 4 integrin antibody), anti-vascular endothelial cell proliferating
  • TNF
  • Recombinant monoclonal antibody indications include rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, ankylosing spondylitis, Crohn's disease, ulcerative colitis, pancreatitis, vasculitis, Kawasaki disease, Systemic lupus erythematosus, psoriasis, psoriatic arthritis, Sjogren's disease, Still's disease, multiple sclerosis, osteoporosis, bone lesions, thrombosis, cancer (eg, breast cancer, leukemia, ovarian cancer, melanoma, prostate cancer, pancreatic cancer, lymphoma) Lung cancer, stomach cancer, renal cell carcinoma, colorectal cancer, mesothelioma, soft tissue sarcoma, multiple myeloma, etc.), cachexia, chronic rejection of transplanted organs and cells, heart failure, ischemia-induced severe arrhythmia, high cholesterol Group consisting of
  • ⁇ 1-24> The liquid preparation according to any one of ⁇ 1-1> to ⁇ 1-23>, wherein the liquid preparation is a subcutaneous injection preparation or an intravenous injection preparation.
  • ⁇ 1-25> The liquid preparation according to any one of the above ⁇ 1-1> to ⁇ 1-24> is treated for a patient in need of at least one treatment of the applicable disease according to ⁇ 1-22> ⁇ 1-22>.
  • the second aspect of the present invention is the following liquid preparation containing a recombinant monoclonal antibody.
  • a recombinant monoclonal antibody comprising 10 mg / mL to 200 mg / mL recombinant monoclonal antibody, 45 mM to 94 mM amino acid component having a histidine component of less than 5 mM, and a pH of 5.5 to 7.0 Monoclonal antibody-containing liquid preparation.
  • ⁇ 2-2> A recombinant monoclonal antibody containing 10 mg / mL to 200 mg / mL recombinant monoclonal antibody, 45 mM to 94 mM amino acid component having a histidine component of less than 5 mM, and a pH of 5.5 to 6.7 Monoclonal antibody-containing liquid preparation.
  • ⁇ 2-3> The liquid preparation according to ⁇ 2-1> or ⁇ 2-2>, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride and methionine.
  • ⁇ 2-4> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-3>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.
  • ⁇ 2-5> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-4>, comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 2-6> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-5>, containing 90 mM amino acid component.
  • ⁇ 2-7> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-6>, which has a pH of 5.8 to 6.7.
  • ⁇ 2-8> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-7>, which has a pH of 6.0 to 6.5.
  • ⁇ 2-9> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-8>, which contains 10 to 30 mg / mL recombinant monoclonal antibody.
  • ⁇ 2-10> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-9>, which contains 20 mg / mL recombinant monoclonal antibody.
  • ⁇ 2-11> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-8>, which contains a recombinant monoclonal antibody of more than 30 mg / mL and less than 150 mg / mL.
  • ⁇ 2-12> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-11>, further containing a polyol.
  • ⁇ 2-13> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-12>, further containing a surfactant.
  • ⁇ 2-14> The liquid preparation according to ⁇ 2-13>, wherein the surfactant is a nonionic surfactant.
  • ⁇ 2-15> The liquid preparation according to ⁇ 2-14>, wherein the nonionic surfactant is polysorbate or polyoxyethylene polyoxypropylene glycol.
  • ⁇ 2-16> The liquid preparation according to ⁇ 2-15>, wherein the polysorbate is at least one selected from the group consisting of polysorbate 80, polysorbate 40, and polysorbate 20.
  • ⁇ 2-17> The liquid preparation according to ⁇ 2-15>, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (160) polyoxypropylene (30) glycol.
  • ⁇ 2-18> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-17>, wherein the immunoglobulin class of the recombinant monoclonal antibody is human IgG1.
  • ⁇ 2-19> The liquid preparation according to ⁇ 2-18>, wherein the human-derived IgG1 is tocilizumab.
  • ⁇ 2-20> The liquid preparation according to any one of ⁇ 2-1> to ⁇ 2-19>, wherein the liquid preparation is a subcutaneous injection preparation or an intravenous injection preparation.
  • ⁇ 2-21> A recombinant monoclonal antibody of 10 mg / mL to 200 mg / mL and an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM, wherein the amino acid components other than the histidine component are arginine, arginine hydrochloride
  • the surfactant is a nonionic surfactant.
  • ⁇ 2-23> The liquid preparation according to ⁇ 2-22>, wherein the nonionic surfactant is polysorbate or polyoxyethylene polyoxypropylene glycol.
  • the polysorbate is at least one selected from the group consisting of polysorbate 80, polysorbate 40, and polysorbate 20.
  • the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (160) polyoxypropylene (30) glycol.
  • ⁇ 2-26> The liquid preparation according to any one of ⁇ 2-21> to ⁇ 2-25>, wherein the immunoglobulin class of the recombinant monoclonal antibody is human-derived IgG1.
  • ⁇ 2-27> The liquid preparation according to ⁇ 2-26>, wherein the human IgG1 is tocilizumab.
  • ⁇ 2-28> The liquid preparation according to any one of ⁇ 2-21> to ⁇ 2-27>, which contains 20 mg / mL recombinant monoclonal antibody.
  • a liquid preparation containing a recombinant monoclonal antibody for intravenous injection comprising at least one selected from the group consisting of 0.05 to 20 mg / mL polysorbate 80, and having a pH of 5.5 to 7.0.
  • ⁇ 2-31> The liquid preparation according to any one of ⁇ 2-21> to ⁇ 2-30>, comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 2-32> containing 10 mg / mL to 30 mg / mL tocilizumab and an amino acid component of 85 mM to 92 mM having a histidine component of less than 5 mM, and the amino acid components other than the histidine component include arginine, arginine hydrochloride and methionine At least one selected from the group consisting of 0.15 to 0.25 mg / mL polysorbate 80, and having a pH of 5.5 to 7.0 for intravenous ⁇ 2-21> to ⁇ 2-31>.
  • ⁇ 2-33> The liquid preparation according to any one of ⁇ 2-21> to ⁇ 2-32>, containing 20 mg / mL tocilizumab.
  • the third aspect of the present invention is a pharmaceutically stable preparation of the following recombinant monoclonal antibody.
  • Recombinant monoclonal antibody consisting of 10 mg / mL to 200 mg / mL recombinant monoclonal antibody consisting of an aqueous solution having an amino acid component of 45 mM to 94 mM, a histidine component of less than 5 mM, and a pH of 5.5 to 7.0.
  • Pharmaceutically stable formulation of the antibody consisting of 10 mg / mL to 200 mg / mL recombinant monoclonal antibody consisting of an aqueous solution having an amino acid component of 45 mM to 94 mM, a histidine component of less than 5 mM, and a pH of 5.5 to 7.0.
  • ⁇ 3-2> Recombinant monoclonal antibody consisting of 10 mg / mL to 200 mg / mL recombinant monoclonal antibody consisting of an aqueous solution having an amino acid component of 45 mM to 94 mM, a histidine component of less than 5 mM, and a pH of 5.5 to 6.7.
  • Pharmaceutically stable formulation of the antibody ⁇ 3-3> The preparation according to ⁇ 3-1> or ⁇ 3-2>, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride and methionine.
  • ⁇ 3-4> The preparation according to any one of ⁇ 3-1> to ⁇ 3-3>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.
  • ⁇ 3-5> The preparation according to any one of ⁇ 3-1> to ⁇ 3-4>, comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 3-6> The preparation according to any one of ⁇ 3-1> to ⁇ 3-5>, which has a pH of 5.8 to 6.7.
  • ⁇ 3-7> The preparation according to any one of ⁇ 3-1> to ⁇ 3-6>, further containing a polyol.
  • ⁇ 3-8> The preparation according to any one of ⁇ 3-1> to ⁇ 3-7>, further containing a surfactant.
  • ⁇ 3-9> The preparation according to ⁇ 3-8>, wherein the surfactant is a nonionic surfactant.
  • ⁇ 3-10> The preparation according to ⁇ 3-9>, wherein the nonionic surfactant is polysorbate or polyoxyethylene polyoxypropylene glycol.
  • ⁇ 3-11> The preparation according to ⁇ 3-10>, wherein the polysorbate is at least one selected from the group consisting of polysorbate 80, polysorbate 40, and polysorbate 20.
  • ⁇ 3-12> The preparation according to ⁇ 3-10>, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (160) polyoxypropylene (30) glycol.
  • ⁇ 3-13> The preparation according to any one of ⁇ 3-1> to ⁇ 3-12>, wherein the immunoglobulin class of the recombinant monoclonal antibody is human IgG1.
  • ⁇ 3-14> The preparation according to ⁇ 3-13>, wherein the human-derived IgG1 is tocilizumab.
  • ⁇ 3-15> The preparation according to ⁇ 3-1> to ⁇ 3-14>, wherein the preparation is a subcutaneous injection or an intravenous preparation.
  • a fourth aspect of the present invention is the following method for producing a liquid preparation containing a recombinant monoclonal antibody.
  • ⁇ 4-2> Liquid containing 10 to 200 mg / mL recombinant monoclonal antibody having a pH of 5.5 to 6.7, including the step of adding an amino acid component of 45 to 94 mM having a histidine component of less than 5 mM Preparation method of the preparation.
  • ⁇ 4-3> The production method according to ⁇ 4-1> or ⁇ 4-2>, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride, and methionine.
  • ⁇ 4-4> The production method according to any one of ⁇ 4-1> to ⁇ 4-3>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.
  • ⁇ 4-5> The production method according to any one of ⁇ 4-1> to ⁇ 4-4>, comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 4-6> The production method according to any one of ⁇ 4-1> to ⁇ 4-5>, wherein the pH is 5.8 to 6.7.
  • ⁇ 4-7> The production method according to any one of ⁇ 4-1> to ⁇ 4-6>, which contains 150 to 200 mg / mL recombinant monoclonal antibody.
  • ⁇ 4-8> The production method according to any one of ⁇ 4-1> to ⁇ 4-6>, which contains 10 to 30 mg / mL recombinant monoclonal antibody.
  • ⁇ 4-9> The production method according to any one of ⁇ 4-1> to ⁇ 4-8>, further containing a polyol.
  • ⁇ 4-10> The production method according to any one of ⁇ 4-1> to ⁇ 4-9>, further containing a surfactant.
  • ⁇ 4-11> The production method according to ⁇ 4-10>, wherein the surfactant is a nonionic surfactant.
  • ⁇ 4-12> The production method according to ⁇ 4-11>, wherein the nonionic surfactant is polysorbate or polyoxyethylene polyoxypropylene glycol.
  • ⁇ 4-13> The production method according to ⁇ 4-12>, wherein the polysorbate is at least one selected from the group consisting of polysorbate 80, polysorbate 40, and polysorbate 20.
  • ⁇ 4-14> The production method according to ⁇ 4-12>, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (160) polyoxypropylene (30) glycol.
  • ⁇ 4-15> The production method according to any one of ⁇ 4-1> to ⁇ 4-14>, wherein the immunoglobulin class of the recombinant monoclonal antibody is human-derived IgG1.
  • ⁇ 4-16> The production method according to ⁇ 4-15>, wherein the human-derived IgG1 is tocilizumab.
  • ⁇ 4-17> Liquid containing 10 to 200 mg / mL recombinant monoclonal antibody having a pH of 5.5 to 7.0, including a step of adding an amino acid component of 45 to 94 mM having a histidine component of less than 5 mM
  • a method for producing a formulation comprising: The production method according to any one of ⁇ 4-1> to ⁇ 4-16>, which comprises the following steps A to C: Step A: Preparing an antibody drug substance including any one of the following processes A-1 to A-3 Step A-1: Step A of melting a frozen antibody drug substance in a liquid state -2: Step of preparing a liquid antibody drug substance containing an arbitrary solvent Step A-3: Step of preparing a powdered antibody drug substance Step B: Step C of adding an amino acid to the solvent to prepare an additive solution Step of mixing the drug substance prepared in the process A and the additive solution prepared in the process B.
  • Step D A step of adjusting the pH of the solution prepared in Step C to 5.5 to 7.0.
  • a method for producing a formulation comprising: The production method according to any one of ⁇ 4-1> to ⁇ 4-16>, which comprises the following steps A to C: Step A: Preparing an antibody drug substance including any one of the following processes A-1 to A-3 Step A-1: Step A of melting a frozen antibody drug substance in a liquid state -2: Step of preparing a liquid antibody drug substance containing an arbitrary solvent Step A-3: Step of preparing a powdered antibody drug substance Step B: Step C of adding an amino acid to the solvent
  • ⁇ 4-20> The production method according to ⁇ 4-19>, further comprising the following step D: Step D: Step of adjusting the pH of the solution adjusted in Step C to 5.5 to 6.7.
  • step D Step D: Step of adjusting the pH of the solution adjusted in Step C to 5.5 to 6.7.
  • step E Step E: Filter sterilizing the prepared solution.
  • step F Step F: Step of filling and plugging the solution prepared in Step E.
  • the fifth aspect of the present invention is the following method for stabilizing a recombinant monoclonal antibody-containing solution.
  • ⁇ 5-4> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-3>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.
  • the stabilization method according to any one of ⁇ 5-1> to ⁇ 5-4> comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 5-6> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-5>, wherein the pH is 5.8 to 6.4.
  • ⁇ 5-7> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-6>, which comprises 150 to 200 mg / mL recombinant monoclonal antibody.
  • ⁇ 5-8> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-6>, which contains 10 to 30 mg / mL recombinant monoclonal antibody.
  • ⁇ 5-9> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-6>, which contains a recombinant monoclonal antibody of more than 30 mg / mL and less than 150 mg / mL.
  • ⁇ 5-10> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-9>, further comprising a polyol.
  • ⁇ 5-11> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-10>, further comprising a surfactant.
  • ⁇ 5-12> The stabilization method according to ⁇ 5-11>, wherein the surfactant is a nonionic surfactant.
  • ⁇ 5-13> The stabilization method according to ⁇ 5-12>, wherein the nonionic surfactant is polysorbate or polyoxyethylene polyoxypropylene glycol.
  • ⁇ 5-14> The stabilization method according to ⁇ 5-13>, wherein the polysorbate is at least one selected from the group consisting of polysorbate 80, polysorbate 40, and polysorbate 20.
  • ⁇ 5-15> The stabilization method according to ⁇ 5-13>, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (160) polyoxypropylene (30) glycol.
  • ⁇ 5-16> The stabilization method according to any one of ⁇ 5-1> to ⁇ 5-15>, wherein the immunoglobulin class of the recombinant monoclonal antibody is human-derived IgG1.
  • ⁇ 5-17> The stabilization method according to ⁇ 5-16>, wherein the human-derived IgG1 is tocilizumab.
  • the sixth aspect of the present invention is an aqueous solution for producing the following liquid preparation containing a recombinant monoclonal antibody.
  • ⁇ 6-1> An aqueous solution for producing a liquid preparation containing a recombinant monoclonal antibody containing a 45 to 94 mM amino acid component having a histidine component of less than 5 mM and a pH of 5.5 to 7.0.
  • ⁇ 6-2> The aqueous solution according to ⁇ 6-1>, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride, and methionine.
  • ⁇ 6-3> The aqueous solution according to ⁇ 6-1> or ⁇ 6-2>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.
  • ⁇ 6-4> The aqueous solution according to any one of ⁇ 6-1> to ⁇ 6-3>, comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 6-5> The aqueous solution according to any one of ⁇ 6-1> to ⁇ 6-4>, containing 90 mM amino acid component.
  • ⁇ 6-6> The aqueous solution according to any one of ⁇ 6-1> to ⁇ 6-5>, which has a pH of 5.5 to 6.7.
  • ⁇ 6-7> The aqueous solution according to any one of ⁇ 6-1> to ⁇ 6-6> for diluting the concentration of the recombinant monoclonal antibody to 10 mg / mL to 200 mg / mL.
  • ⁇ 6-8> The aqueous solution according to any one of ⁇ 6-1> to ⁇ 6-7>, further containing a polyol.
  • ⁇ 6-9> The aqueous solution according to any one of ⁇ 6-1> to ⁇ 6-8>, further containing a surfactant.
  • ⁇ 6-10> The aqueous solution according to ⁇ 6-9>, wherein the surfactant is a nonionic surfactant.
  • ⁇ 6-11> The aqueous solution according to ⁇ 6-10>, wherein the nonionic surfactant is polysorbate or polyoxyethylene polyoxypropylene glycol.
  • ⁇ 6-12> The aqueous solution according to ⁇ 6-11>, wherein the polysorbate is at least one selected from the group consisting of polysorbate 80, polysorbate 40, and polysorbate 20.
  • ⁇ 6-13> The aqueous solution according to ⁇ 6-11>, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (160) polyoxypropylene (30) glycol.
  • ⁇ 6-14> The aqueous solution according to any one of ⁇ 6-1> to ⁇ 6-13>, wherein the immunoglobulin class of the recombinant monoclonal antibody is human-derived IgG1.
  • ⁇ 6-15> The aqueous solution according to ⁇ 6-14>, wherein the human-derived IgG1 is tocilizumab.
  • a stable recombinant monoclonal antibody liquid formulation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity decrease suppression, and deamidation suppression during long-term storage. It can.
  • it is a stable recombinant monoclonal antibody liquid formulation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity decrease suppression, and deamidation suppression during long-term storage, and the formulation is low-cost.
  • it is a stable recombinant monoclonal antibody liquid formulation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity reduction suppression, and deamidation suppression during long-term storage, and can be injected subcutaneously
  • a liquid preparation containing a recombinant monoclonal antibody exhibiting kinematic viscosity can be provided at low cost.
  • it is a stable recombinant monoclonal antibody liquid preparation that achieves at least one of dimer formation suppression, degradation product generation suppression, biological activity decrease suppression, and deamidation suppression during long-term storage, and is also a practical static
  • a preparation for injection or a preparation for subcutaneous injection can be provided.
  • a method for producing a stable recombinant monoclonal antibody liquid preparation that realizes at least one of suppression of dimer formation, degradation product generation, biological activity reduction, and deamidation during long-term storage.
  • a method for stabilizing a recombinant monoclonal antibody liquid preparation that achieves any one of suppression of dimer formation, degradation product generation, biological activity reduction, and deamidation during long-term storage.
  • an aqueous solution for preparing a recombinant monoclonal antibody-containing preparation can be provided.
  • a recombinant monoclonal antibody-containing liquid preparation in the present invention is a recombinant monoclonal antibody of 10 mg / mL to 200 mg / mL and an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM. (Total), and the pH is 5.5 to 7.0 or 5.5 to 6.7.
  • the liquid preparation may contain other components. Liquid preparations can also be provided at low cost.
  • the liquid preparation may be prepared by any route of administration.
  • the liquid preparation in the present invention contains a 45 to 94 mM amino acid component having a histidine component of less than 5 mM, and a pH of 5.5 to 6.7, whereby a recombinant monoclonal antibody having a concentration of 150 to 200 mg / mL. Even in the liquid formulation, it achieves at least one of dimer formation inhibition, degradation product formation inhibition, biological activity reduction inhibition and deamidation inhibition during long-term storage in liquid formulations, and subcutaneous injection is possible It is useful as a preparation for subcutaneous injection because it can exhibit the effect of exhibiting kinematic viscosity.
  • liquid preparation in the present invention contains a low-dose amino acid component of 45 mM to 94 mM amino acid component, it can be provided at a lower cost than conventional liquid preparations containing recombinant monoclonal antibodies.
  • liquid preparations containing 10 to 30 mg / mL recombinant monoclonal antibody have dimer formation suppression, degradation product generation suppression, biological activity decrease suppression and desorption during long-term storage.
  • it can be used as an intravenous preparation that achieves at least one of the suppression of amidation.
  • Liquid preparations containing recombinant monoclonal antibodies of more than 30 mg / mL to less than 150 mg / mL can suppress dimer formation, decomposition product generation, biological activity reduction and deamidation during long-term storage during storage and storage. Realized at least one of the following. For example, it can be diluted and used as an intravenous preparation at the time of use.
  • the aqueous solution for producing a recombinant monoclonal antibody-containing liquid preparation in the present invention (hereinafter also referred to as “aqueous solution for antibody preparation”) contains 45 mM to 94 mM amino acid components (total) having a histidine component of less than 5 mM, The pH is 5.5 to 7.0 or 5.5 to 6.7.
  • the aqueous solution for antibody preparation production may contain other components.
  • the aqueous solution for producing an antibody preparation in the present invention contains an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM, and has a pH of 5.5 to 7.0 or 5.5 to 6.7.
  • a recombinant monoclonal antibody-containing preparation can also be prepared by replacing an arbitrary solution containing an antibody with an aqueous solution for antibody preparation production by dialysis or the like.
  • a preparation having a relatively low concentration for example, an intravenous preparation
  • a preparation having a high antibody concentration for example, a preparation for subcutaneous injection
  • an aqueous solution for producing the antibody preparation for example, a preparation for subcutaneous injection
  • common antibody preparations for example, subcutaneous injection preparations and intravenous injection preparations
  • Industrial convenience is great, such as cost reduction.
  • long-term storage includes, for example, storage at 2 ° C. to 8 ° C. for 1 year or longer, preferably storage at 2 ° C. to 8 ° C. for 2 years or longer, more preferably 2
  • long-term storage includes, for example, storage at 2 ° C. to 8 ° C. for 1 year or longer, preferably storage at 2 ° C. to 8 ° C. for 2 years or longer, more preferably 2
  • it may be stored at 2 ° C. to 8 ° C. for 2 to 5 years, particularly preferably stored at 2 ° C. to 8 ° C. for 2 to 3 years.
  • it may be stored at 25 ° C.
  • a recombinant monoclonal antibody is an antibody produced by cells transformed by applying recombinant DNA technology.
  • the recombinant monoclonal antibody is preferable if it is expressed or secreted in animal cells, but the type of the recombinant monoclonal antibody is not particularly limited.
  • a recombinant monoclonal antibody that can be used as a pharmaceutical is preferable.
  • Recombinant monoclonal antibodies that can be contained in the liquid preparation of the present invention include not only recombinant monoclonal antibodies derived from animals such as humans, mice, and rats, but also recombinant monoclonal antibodies such as chimeric antibodies and humanized antibodies. .
  • the immunoglobulin class of the antibody is not particularly limited, and any class such as IgG such as IgG1, IgG2, IgG3, and IgG4, IgA, IgD, IgE, and IgM may be used.
  • human-derived IgG1 for example, humanized IgG1, fully human IgG1 is particularly preferable.
  • Tocilizumab is particularly preferred as the human IgG1.
  • Recombinant monoclonal antibodies include antibody fragments such as Fv, Fab, F (ab) 2, and monovalent or bivalent or higher single-chain Fv (in which variable regions of antibodies are bound by a linker such as a peptide linker ( scFv, sc (Fv) 2 , Diabodies such as scFv dimer) and the like are also included.
  • linker such as a peptide linker ( scFv, sc (Fv) 2 , Diabodies such as scFv dimer
  • the type of the recombinant monoclonal antibody is not limited, and examples thereof include an anti-tumor necrosis factor (TNF) antibody and an anti-interleukin (IL) receptor antibody.
  • TNF tumor necrosis factor
  • IL interleukin
  • the types of indications for recombinant monoclonal antibodies are not limited, but for example, rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, ankylosing spondylitis, Crohn's disease, ulcerative colitis, pancreatitis, Vasculitis, Kawasaki disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Sjogren's disease, Still's disease, multiple sclerosis, osteoporosis, bone lesions, thrombosis, cancer (eg, breast cancer, leukemia, ovarian cancer, melanoma, Prostate cancer, pancreatic cancer, lymphoma, lung cancer, gastric cancer, renal cell carcinoma, colorectal cancer, mesothelioma, soft tissue sarcoma, multiple myeloma, etc.), cachexia, chronic rejection of transplanted organs and cells, heart failure, ischemia Induced severe arrhythm
  • Examples of the recombinant monoclonal antibody include, but are not limited to, for example, trastuzumab, rituximab, palivizumab, infliximab, basiliximab, gemtuzumab ozogamicin, bevacizumab, ibritumomab tiuxetane, tocilizumab, adalimumab, , Ranibizumab, Omalizumab, Eculizumab, Panitumumab, Usutekinumab, Golimumab, Kanakinumab, Denosumab, Mogamulizumab, Offatumumab, Pertuzumab, Trastuzumab Emtansin, Brentuximab, Beduminumab
  • Recombinant monoclonal antibodies include tocilizumab, trastuzumab, rituximab, paclitumumab, infliximab, infliximab, basiliximab, bevacizumab, adalimumab, cetuximab, ranibizumab, omalizumab, eculizumab, panitumabum , Nivolumab, alemtuzumab, secukinumab, ramcilumab or ipilimumab are preferred, trastuzumab, tocilizumab, infliximab, bevacizumab, adalimumab, ustekinumab, golimumab or denosumab, more preferred tocilizumab, infliximab, infliximab, infliximab
  • tocilizumab is most preferred as the recombinant monoclonal antibody.
  • Tocilizumab has only to have the same amino acid sequence as the amino acid sequence (Gln1-Gly448) and L chain amino acid sequence (Asp1-Cys214) of Actemra (registered trademark), which are generally commercially available.
  • the amino acid sequence of Actemura H chain (Glu1-Gly448) and L chain amino acid sequence (Asp1-Cys214) are described in the sequence listing attached to International Publication No. 2005/090405.
  • the N-terminal residue of the H chain may be pyroglutamic acid (pGlu) instead of glutamic acid.
  • the C-terminal residue of the H chain may be up to 447 proline (Pro) instead of the 448 amino acid residue, or 449 amino acid residue in which lysine (Lys) is added to the 448th glycine (Gly). Also good.
  • Antibody drugs are generally at high concentrations compared to other biopharmaceuticals.
  • the liquid preparation in the present invention contains 10 mg / mL to 200 mg / mL recombinant monoclonal antibody. Further, from the viewpoint that the effects of the present invention can be sufficiently exerted, it is preferable to contain 170 mg / mL to 190 mg / mL recombinant monoclonal antibody, and more preferably 180 mg / mL recombinant monoclonal antibody. Alternatively, it preferably contains 90 mg / mL to 110 mg / mL recombinant monoclonal antibody, more preferably 100 mg / mL recombinant monoclonal antibody.
  • the recombinant monoclonal antibody used in the present invention is preferably not lyophilized or reconstituted in the production method.
  • the liquid preparation in the present invention contains an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM.
  • the amino acid component other than the histidine component is not limited in type, but examples include arginine, arginine hydrochloride, methionine, glycine, phenylalanine, aspartic acid, glutamic acid, lysine, asparagine, tryptophan, cysteine and cysteine hydrochloride. Can be mentioned.
  • amino acid components other than the histidine component include arginine, arginine hydrochloride It is preferably at least one selected from the group consisting of a salt and methionine.
  • the amino acid component other than the histidine component preferably contains arginine, arginine hydrochloride and methionine, and more preferably contains arginine hydrochloride and methionine.
  • the histidine component is preferably at least one selected from the group consisting of histidine and histidine hydrochloride, and more preferably histidine and histidine hydrochloride.
  • the liquid preparation in the present invention may be any liquid preparation that contains less than 5 mM histidine, but preferably contains 1 mM or more and 4 mM or less histidine component from the viewpoint that the pH can be adjusted to a preferred range. More preferably, it contains a histidine component of 2 mM or more and 4 mM or less.
  • amino acid component it is preferable to contain an amino acid component of 45 mM to 94 mM in which the histidine component is less than 5 mM with respect to the entire liquid formulation. Further, it preferably contains an amino acid component of 75 mM to 93 mM, more preferably contains an amino acid component of 85 mM to 92 mM, particularly preferably contains an amino acid component of 88 mM to 91 mM, and contains an amino acid component of 90 mM. Most preferred.
  • the liquid preparation may further contain a polyol.
  • the polyol include propylene glycol, glycerin (glycerol), threose, threitol, erythrose, erythritol, ribose, arabinose, arabitol, lyxose, maltitol, sorbitol, sorbose, glucose, mannose, mannitol, levulose, dextrose, maltose, Examples include trehalose, fructose, xylitol, inositol, galactose, xylose, fructose, sucrose, and 1,2,6-hexanetriol.
  • sucrose As the polyol, sucrose, trehalose and the like are preferable, and sucrose is most preferable.
  • the liquid preparation may contain one or a combination of two or more of these polyols.
  • content of an amino acid component less than 70 mM, it is preferable to use combining a polyol from a viewpoint of dimer production
  • the content of the polyol is not particularly limited, and may be appropriately determined from the viewpoint of isotonicity of the liquid preparation. For example, it may be 30 mg / mL to 80 mg / mL, 40 mg / mL to 70 mg / mL, 50 mg / mL to 60 mg / mL.
  • the liquid preparation may further contain a surfactant.
  • a surfactant a cationic surfactant, an anionic surfactant, an amphoteric surfactant, a nonionic surfactant and the like can be selected, and a nonionic surfactant is preferable.
  • the surfactant include polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.), polyoxyethylene castor oil, castor oil fatty acid ethyl ester, nicotinamide, Polyoxyethylene sorbitan fatty acid ester (also referred to as polysorbate, Tween, etc.
  • polyoxyethylene (20) sorbitan monolaurate (NIKKOL TL-10, polysorbate 20, Tween 20), polyoxyethylene (20) sorbitan monopalmitate (NIKOL TP) -10V, polysorbate 40, Tween 40), polyoxyethylene (20) sorbitan monostearate (NIKKOL TS-10MV, polysorbate 60, Tween 60), Triste Polyoxyethylene phosphate (20) sorbitan (NIKKOL TS-30V, polysorbate 65), polyoxyethylene (20) sorbitan monoisostearate (NIKKOL TI-10V), polyoxyethylene (20) sorbitan monooleate (NIKKOL TO-) 10 MV, polysorbate 80, Tween 80), polyoxyethylene trioleate (20) sorbitan (NIKKOL TO-30V, polysorbate 85)), and polyoxyethylene polyoxypropylene glycol (pluronic, poloxamer, etc.)
  • polyoxyethylene 160) Polyoxypropylene (30) glycol (Pl) glycol (
  • polysorbate and polyoxyethylene polyoxypropylene glycol are preferable, polysorbate 80, polysorbate 40, polysorbate 20, and polyoxyethylene (160) polyoxypropylene (30) glycol are particularly preferable, and polysorbate 80 is the most. preferable.
  • the liquid preparation may contain one or a combination of two or more of these surfactants.
  • a surfactant is provided from the viewpoint of realizing at least one of dimer formation suppression, degradation product generation suppression, biological activity reduction, and deamidation suppression. Are preferably used in combination.
  • the content of the surfactant is not particularly limited and may be appropriately determined.
  • 0.05 mg / mL to 20 mg / mL, 0.1 mg / mL to 10 mg / mL, 0.1 mg / mL to 5 mg / mL, 0.1 mg / mL to 0.5 mg / mL, 0.15 mg / mL to It may be 0.25 mg / mL.
  • any combination of amino acids and surfactants can be selected.
  • the liquid formulation may contain other components necessary for formulating the liquid formulation.
  • a solubilizing agent for example, an isotonic agent, a preservative, an adsorption inhibitor, a sulfur-containing reducing agent, an antioxidant, preferably a solubilizing agent may be contained.
  • solubilizers include surfactants, particularly nonionic surfactants, specifically, polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.), Examples include polysorbate (polysorbate 80, polysorbate 40, polysorbate 20, etc.), polyoxyethylene sorbitan monolaurate, polyoxyethylene castor oil, castor oil fatty acid ethyl ester, and nicotinamide.
  • surfactants particularly nonionic surfactants
  • polyoxyethylene hydrogenated castor oil polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.
  • examples include polysorbate (polysorbate 80, polysorbate 40, polysorbate 20, etc.), polyoxyethylene sorbitan monolaurate, polyoxyethylene castor oil, castor oil fatty acid ethyl ester, and nicotinamide.
  • isotonic agent examples include salts such as sodium chloride, potassium chloride, calcium chloride in addition to polyol.
  • preservative examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, sorbic acid, phenol, cresol, metacresol, and chlorocresol.
  • adsorption inhibitor examples include human serum albumin, lecithin, dextran, hydroxypropylcellulose, methylcellulose, and macrogol.
  • sulfur-containing reducing agent examples include N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and salts thereof, sodium thiosulfate, and glutathione. Can be mentioned.
  • antioxidants examples include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, ⁇ -tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbyl palmitate, L-ascorbic acid stearate, sodium bisulfite Sodium sulfite, triamyl gallate, propyl gallate, disodium ethylenediaminetetraacetate (EDTA ⁇ 2Na), sodium pyrophosphate, sodium metaphosphate.
  • a recombinant monoclonal antibody-containing liquid formulation containing a recombinant monoclonal antibody of 30 mg / mL or less for example, 20 mg / mL, 10 mg / mL, 5 mg / mL, 45 mM to 94 mM having a histidine component of less than 5 mM. It is also possible to prepare a liquid preparation containing a recombinant monoclonal antibody having a pH of 5.5 to 7.0.
  • the pH of the liquid preparation is preferably 5.5 to 7.0, more preferably 5.5 to 6.7, from the viewpoint of long-term stabilization effect, and 5.8 to 6.7. Is more preferably 6.0 to 6.5, and particularly preferably 6.0 to 6.2.
  • the pH is preferably 5.5 to 6.7 from the viewpoint of adjusting the kinematic viscosity of the liquid preparation within a range where subcutaneous injection is possible, or ensuring the stability of the preparation. It is more preferably 8 to 6.7, further preferably 6.0 to 6.5, and particularly preferably 6.0 to 6.2.
  • the pH of the liquid formulation is 5. from the viewpoint of ensuring the stability of the formulation. It is preferably 5 to 7.0, more preferably 5.5 to 6.7, further preferably 6.0 to 6.5, and particularly preferably 6.0 to 6.2.
  • the pH can be measured by, for example, a pH meter (model number: HM-30G, manufactured by Toa DKK Corporation). The pH can be measured according to the method described in the 16th revised Japanese pharmacopoeia, for example, at room temperature (15 ° C. to 25 ° C.).
  • the pH of the liquid preparation can be adjusted by, for example, a histidine component contained in the liquid preparation. However, if necessary, the pH of the liquid preparation can be adjusted using another buffer.
  • Other buffering agents include, for example, phosphate (sodium or potassium), sodium bicarbonate, citrate (sodium or potassium), sodium acetate, sodium oxalate, phosphoric acid, carbonic acid, citric acid, succinic acid, apple Examples include acids, gluconic acid, and glycine.
  • the method for producing a liquid preparation in the present invention includes the following steps A to C, and optionally includes at least one of steps D to F.
  • Step B Step C of adding an amino acid to the solvent to prepare an additive solution : Mixing the drug substance prepared in step A with the additive solution prepared in step B
  • An antibody drug substance is, for example, an antibody drug substance purified by producing recombinant monoclonal antibodies in cells transformed by applying recombinant DNA technology. If the activity of the antibody is not impaired, a stored (for example, refrigerated) antibody drug substance can be used. Alternatively, it is an antibody drug substance in which recombinant monoclonal antibodies are produced in cells transformed by applying recombinant DNA technology, purified, and frozen. Alternatively, it is a commercially available frozen antibody drug substance.
  • Step A is a step of preparing an antibody including any one of Step A-1 to Step A-3.
  • Step A-1 is a step of thawing the antibody drug substance that has been cryopreserved into a liquid state.
  • Frozen antibody drug substance can be thawed into a liquid state by any method that does not impair the activity of the antibody. For example, melting at room temperature, melting by refrigeration, and the like can be mentioned.
  • the antibody drug substance may be frozen with any solvent.
  • the aqueous solution for production of the recombinant monoclonal antibody-containing liquid preparation of the present invention is preferable, but water, physiological saline, glucose solution, any buffer solution, ethanol solution, and other pharmaceutically usable solvents may be used.
  • the melted antibody drug substance can be dialyzed and solvent exchanged using any solvent.
  • Step A-2 is a step of preparing a liquid antibody drug substance containing an arbitrary solvent. Liquid antibody drug substances can be dialyzed and solvent exchanged using any solvent.
  • Step A-3 is a step of preparing a powdery antibody drug substance.
  • Step B is a step of preparing an additive solution containing an amino acid.
  • an amino acid can be added to a solvent (for example, water, physiological saline, dextrose solution, arbitrary buffer solution, ethanol solution, and other pharmaceutically usable solvents) to form an additive solution.
  • Process C is a step of mixing the drug substance melted in Process A with the additive solution prepared in Process B. The final concentration of the amino acid component in the whole liquid is adjusted, for example, to 45 mM to 94 mM where the histidine component is less than 5 mM.
  • Step D is a step of adjusting the pH of the solution prepared in Step C to 5.5 to 7.0.
  • Step D is a step of adjusting the pH of the solution prepared in Step C to 5.5 to 6.7.
  • the pH of the liquid preparation can be adjusted to pH 5.5 to 7.0 or 5.5 to 6.7 according to Step C. For example, it can be adjusted by the histidine component contained in the liquid preparation, but other additions can be made.
  • An agent can be used to adjust the pH of the liquid formulation.
  • Step E is a step of filter sterilizing the solution prepared in Step C or Step D.
  • Step F is a step in which the solution prepared in Step C, Step D or Step E is filled and plugged. Alternatively, it may be filled in an ampoule or prefilled syringe, or a premixed bag.
  • the liquid preparation in the present invention comprises a prepared antibody drug substance (for example, a frozen antibody drug substance thawed), and a solvent (for example, water, physiological saline, glucose solution, arbitrary buffer solution, ethanol solution).
  • a solvent for example, water, physiological saline, glucose solution, arbitrary buffer solution, ethanol solution.
  • an amino acid can also be added for production.
  • Ingredients optionally contained in the liquid preparation of the present invention may be added to the additive solution in advance, or after the antibody is added to the solvent, it may be added together with the amino acid or before and after the addition of the amino acid.
  • the liquid preparation in the present invention can be administered, for example, by injection (subcutaneous injection, intravenous injection, intramuscular injection, etc.), transdermal, transmucosal, nasal, or transpulmonary.
  • subcutaneous injection is performed, the dose of recombinant monoclonal antibody per administration is as large as 150 mg / mL to 200 mg / mL, but the amount of injection solution is limited.
  • the liquid preparation in the present invention contains 150 mg / mL to 200 mg / mL recombinant monoclonal antibody and exhibits a kinematic viscosity that enables subcutaneous injection.
  • the liquid preparation containing 150 mg / mL to 200 mg / mL recombinant monoclonal antibody in the present invention is preferably used for subcutaneous injection from the viewpoint that the effects of the present invention can be obtained.
  • Subcutaneous injection is not only performed by doctors and other specialists as medical professionals, but may be self-injected by the patient himself, and depending on ethnicity and region, many patients are concerned about self-injection, It is preferable that the kinematic viscosity is low and the stability over time is excellent.
  • the liquid preparation containing 10 to 30 mg / mL recombinant monoclonal antibody is preferably used as an intravenous preparation.
  • it is highly industrially convenient that a preparation for subcutaneous injection and a preparation for intravenous injection having different concentrations can be prepared in a solution having the same composition during the production of these preparations.
  • the kinematic viscosity of the liquid formulations of the present invention (e.g., a formulation having an antibody concentration of 150mg / mL ⁇ 200mg / mL), for example, immediately after the liquid formulation prepared, preferably 6mm 2 / s ⁇ 15mm 2 / s, 7mm 2 / s It is more preferably ⁇ 14 mm 2 / s, and more preferably 8 mm 2 / s to 12 mm 2 / s.
  • the kinematic viscosity may be measured with an Ubbelohde viscometer (16th revision Japanese Pharmacopoeia General Test Method 2.53 Viscosity Measurement Method Method 1).
  • the tension generated in the pusher when the evaluation sample solution is sucked with the injection needle attached to the glass syringe is measured, and the obtained tension is used for viscometer calibration with a kinematic viscosity of 2 mm2 / s to 20 mm2 / s.
  • the kinematic viscosity may be obtained by applying a standard solution (Japanese grease) to a calibration curve created from the tension and kinematic viscosity obtained by measuring in the same manner.
  • the dimer product and the low molecular weight decomposition product can be measured by size exclusion chromatography using, for example, a high performance liquid chromatograph system (Prominence, manufactured by Shimadzu Corporation).
  • Biological activity can be assessed by measuring the binding effect to the antigen.
  • the inhibitory action of IL-6 binding to soluble IL-6 receptor by tocilizumab can be measured using an ELISA method.
  • the biological activity measurement evaluates an effect of an antigen and an influence on suppression or promotion of an in vivo reaction via the antigen.
  • the effect of tocilizumab on the expression of IL-6 activity via membrane-bound IL-6 receptor can be evaluated from the IL-6-dependent cell growth inhibitory action.
  • the deamidated substance can be measured by ion exchange chromatography using, for example, a high performance liquid chromatograph system (Prominence, manufactured by Shimadzu Corporation).
  • Example 1 Confirmation of Stabilizing Effect of Liquid Formulation
  • a liquid formulation containing a recombinant monoclonal antibody 180 mg / mL as tocilizumab
  • the influence of the formulation of the present invention containing 94 mM amino acid component on stabilization at each pH was evaluated.
  • 1-No. Five evaluation samples were prepared. The prescription of each evaluation sample is as follows. Note that “-” in the compositions in Tables 1 and 5 indicates not blended.
  • tocilizumab used in the examples should be prepared according to the methods described in International Publication No. 92/0197759, International Publication No. 2005/090405, International Publication No. 99/063058, and International Publication No. 2002/072615. Can do.
  • the evaluation sample was diluted with a mobile phase so that the protein concentration became 1 mg / mL, and used as an evaluation sample solution.
  • evaluation sample was diluted with mobile phase A so that the protein concentration would be 2 mg / mL to obtain an evaluation sample solution.
  • a 20 ⁇ L evaluation sample solution was tested by the liquid chromatograph method under the following conditions, and the peak areas of the acidic fraction, the main fraction, and the basic fraction were measured by an automatic analysis method, and the amount (%) was determined. .
  • the evaluation sample was directly used as an evaluation sample solution.
  • the tension generated in the pusher when the evaluation sample solution was aspirated with the injection needle (22G ⁇ 1) attached to the glass syringe (0.25 mL) was measured.
  • the obtained tension was applied to a calibration curve prepared from the tension and kinematic viscosity obtained by measuring a viscometer calibration standard solution (Nippon Grease) having a kinematic viscosity of 2 mm 2 / s to 20 mm 2 / s in the same manner.
  • the viscosity was determined.
  • the kinematic viscosity measurement temperature was 20 ° C.
  • the evaluation results of the size exclusion chromatography method obtained in this example are shown in Table 2, the evaluation results of the ion exchange chromatography method are shown in Table 3, and the kinematic viscosity evaluation results are shown in Table 4.
  • the formulation containing 94 mM amino acid component and adjusted to pH 6 had a total amount of amino acids and a small content of histidine component, but at 60 ° C. for 2 weeks, 50 ° C. In the thermal acceleration test stored for 2 weeks at 40 ° C for 4 weeks, the amount of high molecular fraction containing dimer and low molecular fraction containing degradation products, etc., the total amount of amino acids and the content of histidine component
  • a deamidated product which is a product of a deamidation reaction that adversely affects the stability of the protein preparation, is detected in an acidic fraction in ion exchange chromatography. Evaluation sample No. No.
  • evaluation sample No. 5 shows that the increase in the acidic fraction containing the deamidated product in the ion exchange chromatography method is the evaluation sample no. It was confirmed that it was suppressed similarly to 1.
  • Evaluation sample No. 5 shows the evaluation sample No. 5 for the basic fraction in the ion exchange chromatography method. It was confirmed that the increase was suppressed to the same extent as 1. This is thought to be due to reduced degradation product formation and improved stability.
  • evaluation sample No. 2 adjusted to pH 5
  • evaluation sample No. 3, 3 and 4 adjusted to pH 6.8, evaluation sample No. of the polymer fraction containing the dimer .
  • Example 2 Confirmation of stability effect when content of amino acid component is further reduced Stabilizing effect for liquid preparation containing recombinant monoclonal antibody (180 mg / mL as tocilizumab) when content of amino acid component is further reduced below 94 mM Evaluated.
  • evaluation sample No. 6-1 to No. 8 was prepared. The prescription of each evaluation sample is as follows.
  • each evaluation sample is filled into a 2 mL glass vial, and a thermal acceleration test (60 ° C.-1 week, 50 ° C.-2 weeks, 40 ° C.-8) of each evaluation sample is performed. Weekly and at 25 ° C. for 4 months).
  • the purity of the recombinant monoclonal antibody before and after thermal acceleration was evaluated by size exclusion chromatography and ion exchange chromatography, and its usability was evaluated by kinematic viscosity.
  • the analysis conditions are as shown in Example 1.
  • the evaluation results of the size exclusion chromatography method obtained in this example are shown in Table 6, the evaluation results of the ion exchange chromatography method are shown in Table 7, and the kinematic viscosity evaluation results are shown in Table 8.
  • each formulation was compared with the evaluation sample (evaluation sample No. 1) in which the amino acid component concentration shown in Example 1 had an amino acid content higher than 94 mM.
  • evaluation sample No. 1 the amino acid component concentration shown in Example 1 had an amino acid content higher than 94 mM.
  • the size exclusion chromatography method From the evaluation at 50 ° C. for 2 weeks, which is a test under the same thermal stability conditions, it was confirmed that an increase in the polymer fraction containing the dimer and the like can be suppressed. In addition, it was confirmed that the increase in the low molecular fraction containing degradation products and the like was suppressed as in the case of the high molecular fraction.
  • Example 3 Confirmation of Stabilizing Effect of Liquid Formulation
  • a liquid formulation containing a recombinant monoclonal antibody (20 mg / mL as tocilizumab) the effect of the formulation of the present invention containing 94 mM amino acid component on stabilization at each pH is evaluated.
  • 9-No. 15 evaluation samples are prepared. The prescription of each evaluation sample is as follows. In Tables 9 and 10, “-” in the composition indicates not blended.
  • tocilizumab used in the examples should be prepared according to the methods described in International Publication No. 92/0197759, International Publication No. 2005/090405, International Publication No. 99/063058, and International Publication No. 2002/072615. Can do.
  • the evaluation sample is diluted with the mobile phase so that the protein concentration is 1 mg / mL to obtain an evaluation sample solution.
  • a 20 ⁇ L evaluation sample solution is tested by the liquid chromatographic method under the following conditions, and the peak areas of the high molecular fraction, the main fraction, and the low molecular fraction are measured by an automatic analysis method, and the amount (%) is obtained. .
  • the evaluation sample is diluted with mobile phase A so that the protein concentration is 2 mg / mL, and used as an evaluation sample solution.
  • a 20 ⁇ L evaluation sample solution is tested by the liquid chromatographic method under the following conditions, and the peak areas of the acidic fraction, the main fraction, and the basic fraction are measured by an automatic analysis method, and the amount (%) is obtained.
  • Example 4 Confirmation of stability effect when content of amino acid component is further reduced Stabilizing effect for liquid preparation containing recombinant monoclonal antibody (20 mg / mL as tocilizumab) when content of amino acid component is further reduced below 94 mM To evaluate.
  • evaluation sample No. 16-1 to No. 18 is prepared. The prescription of each evaluation sample is as follows. The same evaluation results as in Example 2 can be expected.
  • each evaluation sample is filled into a 2 mL glass vial, and a thermal acceleration test (60 ° C.-1 week, 50 ° C.-2 weeks, 40 ° C.-8) of each evaluation sample is performed. Weekly and storage at 25 ° C. for 4 months).
  • the purity of the recombinant monoclonal antibody before and after thermal acceleration is evaluated by size exclusion chromatography and ion exchange chromatography, and its usability is evaluated by kinematic viscosity.
  • the analysis conditions are as shown in Example 1.
  • the preparation of the present invention is a stable recombinant monoclonal antibody liquid preparation that realizes suppression of dimer formation and suppression of deamidation during long-term storage, and can provide the preparation at low cost, and thus has high industrial utility.
  • the preparation of the present invention is a stable recombinant monoclonal antibody liquid preparation realizing suppression of dimer formation and deamidation during long-term storage, and a recombinant monoclonal antibody exhibiting kinematic viscosity enabling subcutaneous injection Since the contained liquid preparation can be provided at low cost, it is highly industrially useful.

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Abstract

La présente invention concerne une préparation liquide contenant un anticorps monoclonal recombinant qui a un pH de 5,5 à 7,0 et contient : 10 à 200 mg/ml d'un anticorps monoclonal recombinant ; et 45 à 94 mM d'un composant d'acide aminé dans lequel un composant d'histidine est inférieur à 5 mM. La préparation liquide d'anticorps monoclonal recombinant est stable et permet la suppression d'au moins l'une parmi la génération de dimère, la génération de produit de dégradation, et la réduction d'activité biologique et la désamidation, qui se produisent pendant la conservation pendant une longue durée.
PCT/JP2017/012901 2017-03-29 2017-03-29 Préparation de liquide contenant des anticorps WO2018179138A1 (fr)

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JP2019508426A JPWO2018179138A1 (ja) 2017-03-29 2017-03-29 抗体含有液体製剤

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021181317A1 (fr) * 2020-03-11 2021-09-16 Lupin Limited Composition pharmaceutique à base d'anticorps monoclonal
WO2022151940A1 (fr) * 2021-01-15 2022-07-21 浙江博锐生物制药有限公司 Composition pharmaceutique stable de pertuzumab
US11634485B2 (en) 2019-02-18 2023-04-25 Eli Lilly And Company Therapeutic antibody formulation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003068260A1 (fr) * 2002-02-14 2003-08-21 Chugai Seiyaku Kabushiki Kaisha Produits pharmaceutiques en solution contenant des anticorps
WO2009084659A1 (fr) * 2007-12-27 2009-07-09 Chugai Seiyaku Kabushiki Kaisha Préparation de solution contenant un anticorps à haute concentration
WO2011090088A1 (fr) * 2010-01-20 2011-07-28 中外製薬株式会社 Préparation en solution contenant un anticorps stabilisé
JP2011526880A (ja) * 2007-07-06 2011-10-20 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー 抗体処方
JP2015528465A (ja) * 2012-08-31 2015-09-28 バイエル・ヘルスケア・エルエルシーＢａｙｅｒ ＨｅａｌｔｈＣａｒｅＬＬＣ 抗プロラクチン受容体抗体製剤
WO2017057644A1 (fr) * 2015-09-30 2017-04-06 持田製薬株式会社 Formulation liquide contenant une concentration élevée en anticorps

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003068260A1 (fr) * 2002-02-14 2003-08-21 Chugai Seiyaku Kabushiki Kaisha Produits pharmaceutiques en solution contenant des anticorps
JP2011526880A (ja) * 2007-07-06 2011-10-20 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー 抗体処方
WO2009084659A1 (fr) * 2007-12-27 2009-07-09 Chugai Seiyaku Kabushiki Kaisha Préparation de solution contenant un anticorps à haute concentration
WO2011090088A1 (fr) * 2010-01-20 2011-07-28 中外製薬株式会社 Préparation en solution contenant un anticorps stabilisé
JP2015528465A (ja) * 2012-08-31 2015-09-28 バイエル・ヘルスケア・エルエルシーＢａｙｅｒ ＨｅａｌｔｈＣａｒｅＬＬＣ 抗プロラクチン受容体抗体製剤
WO2017057644A1 (fr) * 2015-09-30 2017-04-06 持田製薬株式会社 Formulation liquide contenant une concentration élevée en anticorps

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11634485B2 (en) 2019-02-18 2023-04-25 Eli Lilly And Company Therapeutic antibody formulation
WO2021181317A1 (fr) * 2020-03-11 2021-09-16 Lupin Limited Composition pharmaceutique à base d'anticorps monoclonal
WO2022151940A1 (fr) * 2021-01-15 2022-07-21 浙江博锐生物制药有限公司 Composition pharmaceutique stable de pertuzumab

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