Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • 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
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • 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
  • A61K47/06—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
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
• • 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
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • 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
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/565—Complementarity determining region [CDR]

Definitions

• the present invention has a heavy chain variable region comprising CDR1 having a sequence of SEQ ID NO: 1, CDR2 having a sequence of SEQ ID NO: 2, and CDR3 having a sequence of SEQ ID NO: 3, and a sequence of SEQ ID NO: 4.
• a stable formulation comprising an antibody comprising a light chain variable region comprising CDR1, CDR2 having the sequence of SEQ ID NO: 5, and CDR3 having the sequence of SEQ ID NO: 6.
• the present invention also relates to a method for stabilizing a solution containing an anti-IL-6 receptor antibody, a method for suppressing association (for example, dimerization) of the antibody, and an insoluble particle in a solution containing the antibody. It relates to a method of suppressing the generation.
• SA237 (Satralizumab) is a humanized anti-human IL-6 receptor neutralizing antibody of modified IgG2 designed to modify the amino acid sequence of the IgG1 antibody tocilizumab and prolong the half-life in plasma. Compared with tocilizumab, SA237 1) prolongs plasma half-life by pH-dependent binding to IL-6 receptor, lowering of antibody isoelectric point, and enhanced binding to FcRn under acidic conditions. 2) It has features such as reduced binding ability to Fc ⁇ receptor and reduced effector action such as ADCC / CDC by adopting IgG2 skeleton. A clinical trial of SA237 has been conducted in patients with neuromyelitis optica spectrum disease (Non-Patent Documents 1 to 6), and it is in the manufacturing and marketing approval application stage in Japan, the United States, and Europe.
• Solutions containing high concentrations of antibody cause unwanted degradation, including the formation of insoluble and / or soluble aggregates. These insoluble and soluble aggregates are likely to be formed in the liquid state by the association of antibody molecules. When the liquid product is stored for a long period of time, deamidation of asparagine residues may cause the bioactivity of the antibody molecule to be lost or reduced. The freeze and thaw cycle also causes the formation of degraded and aggregated antibody molecules.
• Patent Document 1 a stabilizing effect by using glutamic acid has been reported.
• Patent Document 2 As an effect of the surfactant added to the pharmaceutical product, it has been reported that poloxamer 188 has a better effect of suppressing oxidation of the protein solution pharmaceutical product than polysorbates (Patent Document 2).
• Patent Document 3 an example in which histidine-HCl or citric acid is used as a buffer and arginine or a saccharide (trehalose or the like) is used as a stabilizer has been reported (Patent Document 3).
• Patent Document 3 there is a need for the development of a more stable SA237-containing formulation that suppresses the formation of aggregates and / or the formation of insoluble particles for a long period of time under storage conditions.
• an object of the present disclosure is to provide a long-term stable formulation containing an anti-IL-6 receptor antibody (Satralizumab: SA237) as an active ingredient.
• the present inventors used arginine as an isotonic agent in the preparation containing the anti-IL-6 receptor antibody (satralizumab: SA237) rather than the case where the saccharide was used. It was found that a good effect of suppressing the formation of aggregates can be obtained in the case of arginine. It was also found that a better effect of suppressing aggregate formation can be obtained when aspartic acid or glutamic acid is used as the counterion species of the histidine buffer solution than when chloride ion is used. Furthermore, it was found that the production of insoluble particles was suppressed in the pharmaceutical product by adding Poloxamer 188 at a predetermined concentration to the pharmaceutical product.
• an antibody comprising a light chain variable region comprising CDR1 having the sequence of SEQ ID NO: 4, CDR2 having the sequence of SEQ ID NO: 5, and CDR3 having the sequence of SEQ ID NO: 6.
• a lyophilized formulation that is ⁇ 6.6.
• the preparation according to any one of [1] to [3], which is substantially free of saccharides.
• [5] The formulation according to any one of [1] to [4], wherein the association of an antibody is suppressed.
• Formulation. [6] The preparation according to any one of [1] to [5], wherein the dimerization of the antibody is reduced.
• [7] The preparation according to any one of [1] to [6], wherein the dimerization of the antibody is inhibited.
• [8] The preparation according to any one of [1] to [7], wherein the production of foreign substances is suppressed.
• [9] The preparation according to any one of [1] to [8], wherein the formation of insoluble particles is suppressed.
• [16] The preparation according to any one of [1] to [15], which is for subcutaneous administration.
• [17] The preparation according to any one of [1] to [16], which is stable at 2 to 8 ° C. for at least 6 months.
• [18] The proportion of aggregates at 2-8 ° C. for at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or at least 30 months.
• the preparation according to any one of [1] to [17] which is 2.0% or less, 1.4% or less, or 0.8% or less.
• a method for stabilizing a solution containing an antibody which comprises a step of adding L-aspartic acid or L-glutamic acid to the solution, wherein the antibody is: A heavy chain variable region containing CDR1 having a sequence of SEQ ID NO: 1, CDR2 having a sequence of SEQ ID NO: 2, and CDR3 having a sequence of SEQ ID NO: 3. And an antibody comprising a light chain variable region comprising CDR1 having the sequence of SEQ ID NO: 4, CDR2 having the sequence of SEQ ID NO: 5, and CDR3 having the sequence of SEQ ID NO: 6.
• a method for suppressing the association of an antibody which comprises a step of adding L-aspartic acid or L-glutamic acid to a solution containing the antibody, wherein the antibody comprises a step of adding L-aspartic acid or L-glutamic acid.
• an antibody comprising a light chain variable region comprising CDR1 having the sequence of SEQ ID NO: 4, CDR2 having the sequence of SEQ ID NO: 5, and CDR3 having the sequence of SEQ ID NO: 6.
• a method for suppressing dimerization of an antibody which comprises a step of adding L-aspartic acid or L-glutamic acid to a solution containing the antibody.
• a method for suppressing the formation of insoluble particles in a solution containing an antibody which comprises a step of adding L-aspartic acid or L-glutamic acid to the solution, wherein the antibody comprises.
• an antibody comprising a light chain variable region comprising CDR1 having the sequence of SEQ ID NO: 4, CDR2 having the sequence of SEQ ID NO: 5, and CDR3 having the sequence of SEQ ID NO: 6.
• the numerical value in the smallest digit is rounded off to the next lower digit (for example, if the minimum digit is one digit, the first decimal place). May contain numbers.
• the numerical value of 5 is intended to include a numerical value in the range of 4.5 to 5.4.
• poloxamer 188 which is a nonionic surfactant in a specific concentration range
• poloxamer 188 is a nonionic surfactant in a specific concentration range
• the present disclosure is a solution preparation containing an anti-IL-6 receptor antibody as an active ingredient, that is, histidine-aspartate buffer or histidine-glutamate buffer, Poloxamer 188, And for solution formulations containing arginine and having a pH of 5.5-6.6.
• the solution formulation of the present disclosure includes a solution formulation that is not a redissolved solution of a lyophilized formulation, and a solution of the lyophilized formulation after redissolution.
• the solution formulation of the present disclosure is a solution formulation that is not a redissolve of a lyophilized formulation.
• the present disclosure is a lyophilized preparation containing an anti-IL-6 receptor antibody as an active ingredient, which is a histidine-aspartate buffer or a histidine-glutamate buffer, Poloxamer. 188, and a lyophilized formulation containing arginine and having a pH of 5.5-6.6 after redissolving in water.
• the formulations of the present disclosure contain aspartates or glutamates of basic amino acids (eg, histidine and / or arginine) and are substantially free of chloride and acetate ions.
• the pharmaceuticals of the present disclosure are substantially free of sugars.
• the saccharides are, for example, sucrose, trehalose, meglumine, and sorbitol. "Substantially free” in relation to the pharmaceutical product of the present disclosure means that the pharmaceutical product does not contain an amount that functions as an ingredient.
• the osmotic pressure ratio of the pharmaceutical product of the present disclosure is 0.9 to 1.3 (ratio to saline solution).
• the formation of antibody aggregates is suppressed (eg, reduced or inhibited).
• the formulations of the present disclosure suppress the formation of foreign substances (eg, insoluble particles, eg, insoluble visible particles).
• the formulations of the present disclosure are for subcutaneous administration.
• the pharmaceuticals of the present disclosure are stable at 2-8 ° C. for at least 6 months.
• the formulations of the present disclosure are at 2-8 ° C. for at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or at least 30 months.
• the proportion of aggregates is 2.0% or less, 1.8% or less, 1.6% or less, 1.4% or less, 1.2% or less, 1.0% or less, 0.8% or less, 0.7% or less, 0.6% or less, or 0.5% or less.
• the formulations of the present disclosure have an aggregate ratio of 2.0% or less, 1.8% or less, 1. 6% or less, 1.4% or less, 1.2% or less, 1.0% or less, 0.9% or less, 0.8% or less, or 0.7% or less.
• the formulations of the present disclosure are at 2-8 ° C. for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months.
• the proportion of insoluble particles is 25% or less, 20% or less, 15% or less, 10% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3 % Or less, 2% or less, 1% or less, or 0.5% or less.
• the pharmaceutical product of the present disclosure comprises a histidine buffer as a buffer.
• the histidine is preferably L-histidine.
• histidine may be included as a salt, examples of such salts include histidine-hydrochloride, histidine-aspartate, histidine-glutamate. It will be understood by those skilled in the art that when histidine is expressed by weight (for example, mg), the weight may be the weight of histidine alone or the weight of histidine contained in a salt containing histidine. Further, in the present disclosure, the weight or concentration of histidine may be the sum of the weight or concentration of histidine alone and the weight or concentration of histidine contained in the salt containing histidine.
• the pharmaceutical product of the present disclosure comprises arginine as an isotonic agent.
• the arginine is preferably L-arginine.
• arginine may be included as a salt, examples of such salts include arginine-hydrochloride, arginine-aspartate, arginine-glutamate. It will be understood by those skilled in the art that when arginine is expressed by weight (for example, mg), the weight may be the weight of arginine alone or the weight of arginine contained in a salt containing arginine. Further, in the present disclosure, the weight or concentration of arginine may be the sum of the weight or concentration of arginine alone and the weight or concentration of arginine contained in a salt containing arginine.
• the pharmaceutical product of the present disclosure comprises aspartic acid and / or glutamic acid as counterions.
• Aspartic acid and glutamic acid are preferably L-aspartic acid and L-glutamic acid, respectively.
• aspartic acid and glutamic acid may be included as salts, examples of such salts include histidine-aspartate, arginine-aspartate, histidine-glutamate, arginine-glutamic acid. Can be mentioned.
• weight may be the weight of the amino acid alone or the weight of the amino acid contained in the salt containing the amino acid. Understood by those skilled in the art.
• the weight or concentration of aspartic acid or glutamic acid may be the sum of the weight or concentration of the amino acid alone and the weight or concentration of the amino acid contained in the salt containing the amino acid.
• the pharmaceutical product of the present disclosure further comprises Poloxamer 188 as a nonionic surfactant.
• Poloxamer 188 may be referred to as "polyoxyethylene (160) polyoxypropylene (30) glycol” in the Japanese Pharmacopoeia standard.
• the amount and concentration of the anti-IL-6 receptor antibody contained in the pharmaceutical product of the present disclosure are not particularly limited, and depending on the subject to which the anti-IL-6 receptor antibody is administered, for example, whether it is for adults, for children, for prophylaxis, or for treatment. It can be appropriately adjusted depending on the type or severity of the disease or symptom to be prevented or treated. Therefore, the molar ratio and the weight ratio of the anti-IL-6 receptor antibody contained in the pharmaceutical product of the present disclosure to other components can take various values.
• the concentration of the anti-IL-6 receptor antibody contained in the formulation of the present disclosure in solution ie, the concentration in solution formulation, the concentration of freeze-dried formulation in solution before freeze-drying, or freezing.
• the concentration of the dry preparation in the solution after redissolution is 10 to 500 mg / mL, for example, 50 to 250 mg / mL, 60 to 200 mg / mL, 100 to 200 mg / mL, 120 to 200 mg / mL, It is 180 to 200 mg / mL, for example, 60 mg / mL, 100 mg / mL, 120 mg / mL, 180 mg / mL, and 200 mg / mL.
• the concentration of the histidine buffer (eg, histidine-aspartate buffer or histidine-glutamate buffer) contained in the formulations of the present disclosure in solution is 1 to 500 mM (eg, histidine-aspartate buffer or histidine-glutamate buffer). mmol / L), for example, 10-100 mM, 10-40 mM, for example 20 mM.
• the concentrations of Poloxamer 188 contained in the formulations of the present disclosure in solution are 0.06 to 5.0 mg / mL, such as 0.1 to 2.0 mg / mL, 0.15 to 1.0 mg / mL, 0.2. ⁇ 0.5 mg / mL, for example 0.2 mg / mL, 0.5 mg / mL.
• the concentration of arginine and / or a salt thereof contained in the present disclosure in a solution state is 3 to 500 mM (mmol / L), for example, 5 to 300 mM, 10 to 200. mM, 50-150 mM, for example 50 mM, 100 mM, 150 mM.
• the pH of the pharmaceutical product of the present disclosure in solution is 5.2 to 6.9, for example 5.5 to 6.6, 5.8 to 6.2, for example 5.5, 6.0, 6.3.
• the formulations of the present disclosure are: ⁇ 10-500 mg / mL anti-IL-6 receptor antibody, 1-500 mM histidine-aspartate buffer or histidine-glutamate buffer, -A solution preparation containing 0.06-5.0 mg / mL Poloxamer 188 and-3-500 mM arginine and having a pH of 5.2-6.9.
• the solution formulations of the present disclosure are: ⁇ 50-250 mg / mL anti-IL-6 receptor antibody, 10-100 mM histidine-aspartate buffer or histidine-glutamate buffer, -Contains 0.1-2.0 mg / mL Poloxamer 188, and-Contains 5-300 mM arginine and has a pH of 5.5-6.6.
• the formulations of the present disclosure are: (I) a container (eg, vial, cartridge or syringe); and (ii) 50-250 mg of anti-IL-6 receptor antibody per 1 mL of solution in the container.
• the formulations of the present disclosure are: (I) a container (eg, vial, cartridge or syringe); and (ii) 60-200 mg of anti-IL-6 receptor antibody per 1 mL of solution in the container.
• the formulations of the present disclosure are: (I) a container (eg, vial, cartridge or syringe); and (ii) 120 mg of anti-IL-6 receptor antibody per 1 mL of solution in the container.
• the formulations of the present disclosure are: ⁇ 10-500 mg / mL anti-IL-6 receptor antibody, 1-500 mM histidine-aspartate buffer or histidine-glutamate buffer, It is a lyophilized preparation in which a solution containing 0.06 to 5.0 mg / mL Poloxamer 188 and 3 to 500 mM arginine is freeze-dried, and the pH after redissolving in water is 5.2 to 6.9. It is a lyophilized preparation.
• the lyophilized formulations of the present disclosure are: ⁇ 50-250 mg / mL anti-IL-6 receptor antibody, 10-100 mM histidine-aspartate buffer or histidine-glutamate buffer, A solution containing 0.1-2.0 mg / mL Poloxamer 188 and 5-300 mM arginine is a lyophilized composition with a pH of 5.5-6.6 after redissolving in water.
• the formulations of the present disclosure are: (I) Container (eg, vial, cartridge or syringe); and (ii) 50-250 mg of anti-IL-6 receptor antibody per container, ⁇ 0.9-52.3 mg of L-arginine, ⁇ 1.6 to 15.5 mg of L-histidine, Lyophilized composition containing 0.1-2.0 mg of Poloxamer 188, and L-aspartic acid or L-glutamic acid, lyophilized at pH 5.5-6.6 after redissolving in water. It is an injectable preparation including the preparation.
• the pharmaceutical product of the present disclosure comprises 120 mg of anti-IL-6 receptor antibody (eg, satralizumab) per syringe (1 mL). 26.1 mg L-arginine, 3.1 mg L-histidine, -Contains 0.5 mg of Poloxamer 188, and-L-aspartic acid or L-glutamic acid as a counterion, and has a pH of 5.8 to 6.2 in solution.
• anti-IL-6 receptor antibody eg, satralizumab
• the description of the numerical value is such that the numerical value in the smallest digit (for example, one digit) is rounded off to the next lower digit (for example, if the minimum digit is one digit, the
• the formulation is 120 mg (119.5-120.4 mg) of anti-IL-6 receptor antibody (eg, satralizumab) per syringe (1 mL), ⁇ 26.1 mg (26.05 to 26.14 mg) of L-arginine, ⁇ 3.1 mg (3.05 to 3.14 mg) of L-histidine, It can also be described as containing 0.5 mg (0.45-0.54 mg) of Poloxamer 188, and L-aspartic acid or L-glutamic acid as counterions.
• anti-IL-6 receptor antibody eg, satralizumab
• the present disclosure relates to an injectable formulation or kit comprising (i) a container; and (ii) a solution formulation of the present disclosure.
• the disclosure comprises (i) a container; (ii) a lyophilized formulation of the present disclosure; and (iii) optionally, water for injection to redissolve the lyophilized formulation.
• the container for the injectable formulation or kit of the present disclosure is a plastic or glass syringe, cartridge, or vial.
• the injectable formulation of the present disclosure is a plastic syringe.
• syringes are particularly suitable for use as syringes for filling tray fillers used in mass production in industrial production. More preferably, the injectable formulation of the present disclosure is a plastic syringe with a needle.
• the material of the needle cap of the injectable preparation of the present disclosure needs to be a material that can be attached to and detached from the syringe body, has elasticity, and has low water vapor permeability, and can be in close contact with the syringe body.
• Butyl rubber (IIR) and the like can be mentioned.
• the butyl rubber may be a halogenated butyl rubber such as bromobutyl rubber (BIIR) or chlorobutyl rubber (CIIR) in addition to normal butyl rubber.
• the structure of the cap especially if the above-mentioned material is formed in a tubular shape and one end is closed and the other end has an opening that can be attached by closely surrounding the outer circumference of the injection needle or the syringe body.
• the inside of the opening may be provided with a groove or a protrusion for attaching / detaching the cap.
• the cap may be attached so as to cover from the needle tip to one end of the outer cylinder which is the syringe body, or may be attached so as to cover from the needle tip to the connector portion between the injection needle and the syringe body.
• the container for the injectable formulation or kit of the present disclosure is a dual-chamber syringe (DCS) or dual-chamber cartridge (DCC) in which the lyophilized formulation and water for injection are encapsulated in a separate compartment within the container. That is, one of the two chambers is filled with the lyophilized formulation of the present disclosure and the other is filled with water for injection.
• the water for injection is water, and optionally meets the standard of "water for injection" defined by the Japanese Pharmacopoeia.
• the pharmaceutical product of the present invention contains, if necessary, a cryoprotectant, a suspending agent, a lysis aid, an tonicity agent, a preservative, an adsorption inhibitor, a diluent, an excipient, a pH adjuster, and a painlessening agent.
• a cryoprotectant e.g., a cryoprotectant, a suspending agent, a lysis aid, an tonicity agent, a preservative, an adsorption inhibitor, a diluent, an excipient, a pH adjuster, and a painlessening agent.
• a cryoprotectant e.g., a suspending agent, e.g., a lysis aid, an tonicity agent, a preservative, an adsorption inhibitor, a diluent, an excipient, a pH adjuster, and a painlessening agent.
• the present disclosure is a method for stabilizing an antibody in a preparation containing an anti-IL-6 receptor antibody (for example, a solution preparation), which comprises L-aspartic acid (as a counterion) or L-aspartic acid.
• the present invention relates to a method comprising the step of adding L-glutamic acid.
• the present disclosure is a method of suppressing antibody association (eg, dimerization) in a formulation containing an anti-IL-6 receptor antibody (eg, a solution formulation). It relates to a method comprising the step of adding L-aspartic acid or L-glutamic acid (as a counterion).
• the present disclosure is a method for suppressing the formation of foreign substances and insoluble particles in a preparation containing an anti-IL-6 receptor antibody (for example, a solution preparation), in which L-aspartic acid or L-glutamic acid (as a counterion) is added.
• a preparation containing an anti-IL-6 receptor antibody for example, a solution preparation
• L-aspartic acid or L-glutamic acid as a counterion
• the method of the present disclosure further comprises the step of adding Poloxamer 188 to a concentration of 0.1-2.0 mg / mL in solution.
• the insoluble particles are insoluble visible particles.
• the “stable antibody-containing preparation” in the present invention means that it is difficult to form an aggregate of a protein such as an antibody and / or insoluble particles in the preparation, that is, an insoluble aggregate, a soluble aggregate, or another insoluble particle in the preparation. It refers to a pharmaceutical product that is unlikely to undergo deterioration reactions such as the formation of particles.
• the "method for stabilizing a solution containing an antibody” refers to a method for preventing the formation of an aggregate and / or insoluble particles of a protein such as an antibody in the solution, and the association of the antibody. A method of suppressing antibody dimerization, a method of suppressing antibody-containing solution, and a method of suppressing the formation of insoluble particles in a solution containing the antibody are included.
• association refers to a state in which two or more components (eg, a polypeptide, such as an antibody) interact with each other, for example, in a composition (eg, an antibody-containing preparation, an antibody-containing solution), for example, a dimer. Embodying is mentioned.
• a composition eg, an antibody-containing preparation, an antibody-containing solution
• “suppressing association”, “suppressing aggregate”, “suppressing aggregate formation”, and “suppressing aggregate formation” are used interchangeably, and the composition (for example, an antibody-containing preparation) is used.
• An antibody-containing solution means to suppress the association between components (for example, a polypeptide, for example, an antibody).
• association eg, dimerization of the antibody is suppressed
• association of the antibody eg, dimerization
• Is reduced is used synonymously to mean that antibody association (eg, dimerization) during storage of the formulation in solution or frozen state is suppressed and that of the components of the formulation. It suffices if there are fewer antibody aggregates (eg, dimers) in the formulation compared to when at least one of them is not included (at a given concentration), and “association (eg, dimerization) is inhibited. Is included.
• association eg, dimerization
• association is suppressed (reduced or inhibited)
• association is at least 10%, 20%, 30%, 40. It refers to a decrease of%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.
• Aggregates include insoluble aggregates, soluble aggregates, etc., and aggregates and HMWS (High molecular weight) are synonymous.
• the main aggregate is the dimer.
• the amount of aggregate is determined by size exclusion chromatography (SEC), SDS polyacrylamide gel electrophoresis (SDS-PAGE), capillary SDS gel electrophoresis (CE-SDS), dynamic light scattering method (DLS), and light shielding type automatic. It can be measured by a microparticle measuring device (HIAC), flow imaging, ultracentrimetric analysis (AUC), etc., and in the present invention, it is preferably measured by size exclusion chromatography (SEC).
• SEC size exclusion chromatography
• the amount of aggregate is measured by the method described in the examples herein.
• foreign matter formation is suppressed means that foreign matter formation during storage of the preparation in a solution state or a frozen state is suppressed. This means that less foreign matter is produced in the pharmaceutical product as compared with the case where at least one of the components of the pharmaceutical product is not contained (at a predetermined concentration), and insoluble particles (for example, insoluble visible particles) are produced. It includes being suppressed.
• foreign matter formation is suppressed means that foreign matter formation is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%. , Or it means that it is reduced by 100%.
• Foreign substances include insoluble particles and the like, and insoluble particles include insoluble fine particles such as insoluble aggregates and insoluble visible particles.
• Insoluble particles can be measured by a known visual inspection machine (17th revised Japanese Pharmacopoeia general test method 6. formulation test method 6.06 insoluble foreign matter inspection method for injections), for example, the implementation of the present specification. It is measured by the method described in the example, but is not limited to this.
• anti-IL-6 receptor antibody The anti-IL-6 receptor antibody used in the present invention inhibits the binding of IL-6 to the IL-6 receptor by binding to the IL-6 receptor, and the biological activity of IL-6. Blocks the intracellular transmission of.
• anti-IL-6 receptor antibodies are CDR1 having a sequence of SEQ ID NO: 1 (heavy chain CDR1 of SA237), CDR2 having a sequence of SEQ ID NO: 2 (heavy chain CDR2 of SA237), and.
• Heavy chain variable region containing CDR3 having a sequence of SEQ ID NO: 3 (heavy chain CDR3 of SA237), and CDR1 having a sequence of SEQ ID NO: 4 (light chain CDR1 of SA237), CDR2 having a sequence of SEQ ID NO: 5.
• SA237 light chain CDR2 and an antibody comprising a light chain variable region comprising CDR3 having the sequence of SEQ ID NO: 6 (SA237 light chain CDR3).
• the antibody may be a full-length antibody or an antibody fragment, but is preferably an IgG type (for example, IgG1, IgG2, IgG3, IgG4) antibody.
• the antibody is preferably an antibody containing a heavy chain variable region of SEQ ID NO: 8 (heavy chain variable region of SA237) and a light chain variable region of SEQ ID NO: 7 (light chain variable region of SA237), and more preferably.
• antibody is used in the broadest sense and is a monoclonal antibody, polyclonal antibody, dimer, multimer, multispecific antibody (eg, two) as long as it exhibits the desired biological activity. It may be a heavily specific antibody), an antibody fragment, an antibody derivative and an antibody variant (Miller K et al. J Immunol. 2003, 170 (9), 4854-61). Antibodies may be mouse, human, humanized, chimeric, derived from other species, or artificially synthesized.
• Antibodies disclosed herein are any type (eg, IgG, IgE, IgM, IgD and IgA), class (eg, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecules.
• the immunoglobulin can be of any species (eg, human, mouse or rabbit).
• the terms "antibody”, “immunoglobulin” and “immunoglobulin” are used in a broad sense with compatibility.
• Antibody fragment refers to a molecule other than the complete antibody, which comprises a portion of the complete antibody that binds to the antigen to which the complete antibody binds.
• Examples of antibody fragments are, but are not limited to, Fv, Fab, Fab', Fab'-SH, F (ab') 2 ; Diabody; Linear antibody; Single chain antibody molecule (eg, scFv). ); And includes a multispecific antibody formed from an antibody fragment.
• a recombinant antibody produced by using the gene recombination technology can be used.
• the DNA encoding it is cloned from antibody-producing cells such as hybridomas or sensitized lymphocytes that produce the antibody, incorporated into a vector, and introduced into a host (host cell) for production.
• a host host cell
• the antibody of the present invention can be produced by a method known to those skilled in the art. Specifically, the DNA encoding the target antibody is incorporated into the expression vector. At that time, it is incorporated into an expression vector so that it is expressed under the control of an expression control region, for example, an enhancer or a promoter. Next, the host cell is transformed with this expression vector to express the antibody. In that case, a combination of an appropriate host and expression vector can be used.
• the antibody of the present invention thus obtained can be isolated intracellularly or extracellularly (medium, etc.) and purified as a substantially pure and uniform antibody.
• the separation and purification of the antibody may be performed by using the separation and purification method used in the usual purification of the antibody, and is not limited in any way. For example, chromatographic column, filter, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, etc. are appropriately selected. When combined, the antibody can be separated and purified.
• the method of defining CDR includes the method of Kabat et al. (Sequences of Proteins of Immunological Interest, 5th Ed (1991), Bethesda, MD), the method of Chothia et al. (Science (1986) 233, 755-758), antigen-antibody. Methods based on the contact region of (J Mol Biol (1996) 262, 732-745) are known, and any of these methods may be followed, or a combination thereof may be followed. Specifically, the CDR of each method is defined as follows.
• the pharmaceutical product of the present disclosure can be used to prevent and / or treat IL-6-related diseases or associated symptoms.
• the present disclosure is a solution preparation and freeze-drying which is a pharmaceutical composition for preventing and / or treating an IL-6-related disease, which comprises an anti-IL-6 receptor antibody as an active ingredient.
• the pharmaceutical product is an anti-IL-6 receptor antibody of 10 to 500 mg / mL (for example, 50 to 250 mg / mL), histidine-aspartate buffer or histidine of 1 to 500 mM (for example, 10 to 100 mM).
• - contains glutamate buffer, 0.06-5.0 mg / mL (eg 0.1-2.0 mg / mL) Poloxamer 188, and 3-500 mM (eg 5-300 mM) arginine, with a pH of 5.2- in solution. It relates to a pharmaceutical product (pharmaceutical composition), which is 6.9 (for example, 5.5 to 6.6).
• the preferable administration schedule of the antibody-containing preparation (pharmaceutical composition) of the present disclosure can be adjusted by appropriately extending the administration interval while observing the medical condition and the trend of the blood test value.
• the antibody-containing formulations (pharmaceutical compositions) of the present disclosure are at the same dose as the usual dose (eg, 120 mg / dose of antibody), eg, at regular dosing intervals (eg, as described in WO2016 / 136933). It is usually administered after a short-interval administration period in which it is administered at intervals shorter than (4 week intervals) (for example, at 2-week intervals).
• the administration of the antibody-containing preparation of the present invention can be administered to the patient via any suitable route.
• it is administered to a patient as a bolus or by an intravenous, intramuscular, or subcutaneous route by continuous infusion over a period of time.
• the antibody-containing formulations of the present invention are administered intravenously or subcutaneously.
• the antibody-containing formulations of the present invention are for subcutaneous administration.
• the "IL-6-related disease” in the present invention is an IL-6-related disease, for example, rheumatoid arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, Castleman's disease, systemic erythematosus (SLE).
• IL-6-related disease for example, rheumatoid arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, Castleman's disease, systemic erythematosus (SLE).
• the present disclosure is an anti-IL-6 receptor antibody for use in the prevention and / or treatment of IL-6 related diseases, wherein 10 to 500 mg / mL (eg, 50 to 50). 250 mg / mL) anti-IL-6 receptor antibody, 1-500 mM (eg 10-100 mM) histidine-aspartate buffer or histidine-glutamate buffer, 0.06-5.0 mg / mL (eg 0.1-100 mM) It is characterized by being used as a solution preparation containing Poloxamer 188 ( ⁇ 2.0 mg / mL) and arginine at 3 ⁇ 500 mM (eg 5 ⁇ 300 mM) and having a pH of 5.2 ⁇ 6.9 (eg 5.5 ⁇ 6.6).
• the present disclosure is an anti-IL-6 receptor antibody for use in the prevention and / or treatment of IL-6 related diseases, wherein 10 to 500 mg / mL (eg, 50 to 50). 250 mg / mL) anti-IL-6 receptor antibody, 1-500 mM (eg 10-100 mM) histidine-aspartate buffer or histidine-glutamate buffer, 0.06-5.0 mg / mL (eg 0.1-100 mM) Polyoxamer 188 ( ⁇ 2.0 mg / mL) and arginine at 3-500 mM (eg 5-300 mM), pH 5.2-6.9 (eg 5.5-6.6), lyophilized solution.
• the present invention relates to the anti-IL-6 receptor antibody, which is characterized in that it is redissolved and used.
• the present disclosure is a method of preventing and / or treating an IL-6-related disease, wherein the anti-IL-6 is 10 to 500 mg / mL (eg, 50 to 250 mg / mL).
• Receptor antibody 1-500 mM (eg 10-100 mM) histidine-aspartate buffer or histidine-glutamate buffer, 0.06-5.0 mg / mL (eg 0.1-2.0 mg / mL) Poloxamer 188,
• solution formulations containing 3 to 500 mM (eg 5 to 300 mM) of arginine and having a pH of 5.2 to 6.9 (eg 5.5 to 6.6) have or may be affected by IL-6 related diseases.
• the present disclosure is a method of preventing and / or treating an IL-6 related disease, wherein the anti-IL-6 is 10 to 500 mg / mL (eg, 50 to 250 mg / mL).
• Receptor antibody 1-500 mM (eg 10-100 mM) histidine-aspartate buffer or histidine-glutamate buffer, 0.06-5.0 mg / mL (eg 0.1-2.0 mg / mL) Poloxamer 188, And to prepare a lyophilized preparation by lyophilizing the solution containing 3 to 500 mM (eg, 5 to 300 mM) of arginine and having a pH of 5.2 to 6.9 (eg, 5.5 to 6.6); It relates to the above-mentioned method, which comprises re-dissolving to prepare a re-dissolved solution; and administering the re-dissolved solution to a subject who has or may have an IL-6-related disease.
• mM eg 10-100 mM
• histidine-aspartate buffer or histidine-glutamate buffer 0.06-5.0 mg / mL (eg 0.1-2.0 mg / mL) Poloxamer 188
• the "subject” is preferably an animal, more preferably a mammal (mouse, rat, rabbit, dog, monkey (eg, cynomolgus monkey), etc.), particularly preferably a human, and is a human. May be an adult (18 years or older) or a child (0-18 years or younger, eg, 6 months-18 years or younger).
• the present disclosure is the use of an anti-IL-6 receptor antibody in the manufacture of a pharmaceutical for the prevention and / or treatment of IL-6 related diseases, 10-500 mg / mg /. mL (eg 50-250 mg / mL) anti-IL-6 receptor antibody, 1-500 mM (eg 10-100 mM) histidine-aspartate buffer or histidine-glutamate buffer, 0.06-5.0 mg
• 10-500 mg / mg /. mL eg 50-250 mg / mL
• 1-500 mM eg 10-100 mM
• histidine-aspartate buffer or histidine-glutamate buffer 0.06-5.0 mg
• the present invention relates to the above-mentioned use.
• the present disclosure is the use of an anti-IL-6 receptor antibody in the manufacture of a pharmaceutical for the prevention and / or treatment of IL-6 related diseases, 10-500 mg / mg /.
• mL eg 50-250 mg / mL
• anti-IL-6 receptor antibody 1-500 mM (eg 10-100 mM) histidine-aspartate buffer or histidine-glutamate buffer, 0.06-5.0 mg Freeze-dry the solution containing / mL (eg 0.1-2.0 mg / mL) of Poloxamer 188 and 3-500 mM (eg 5-300 mM) of arginine and pH 5.2-6.9 (eg 5.5-6.6).
• the present invention relates to the above-mentioned use, which comprises preparing a lyophilized preparation.
• Example 1 Effect of pH and histidine buffer on the effect of suppressing increase in aggregates during the thermal harsh test and freeze-thaw test of satralysmab
• Example 1 Stability evaluation of satralysmab preparation in harsh tests
• Material Satralysmab is used. It is a humanized anti-IL-6 receptor monoclonal antibody for the indication of neuromyelitis optica, which is suggested to be involved in IL-6.
• N / A The measurement could not be performed because the chemical solution evaporated during storage.
• pH 4.5 and 5.0 showed a significant increase in aggregates compared with pH 5.5, 6.0 and 6.3.
• the L-histidine buffer solution showed a better aggregate inhibitory effect than the citric acid buffer solution.
• Example 2 Effect of L-arginine on suppressing increase in aggregates during heat harsh test and freeze-thaw test of satralizumab
• Example 1-1 Stability evaluation of satrarizumab preparation in harsh test (1)
• Material Example 1-1 The antibody described in 1 was used.
• Test sample 100 mg / mL satralizumab, 20 mmol / L L-histidine / hydrochloric acid buffer, 50 mmol / L NaCl, 100 mmol / L L-arginine, 100 mmol / L sucrose, and 100 mmol / L trehalose.
• Test sample 100 mg / mL satralizumab, 20 mmol / L L-histidine / hydrochloric acid buffer, 50 mmol / L NaCl, 100 mmol / L L-arginine, 100 mmol / L sucrose, and 100 mmol / L trehalose.
• the prepared drug solution was allowed to stand in a constant temperature bath at 40 ° C. for 2, 4 or 8 weeks, and used as a test sample.
• Test sample 100 mg / mL satralyzumab, 20 mmol / L L-histidine / hydrochloric acid buffer, 50 mmol / L NaCl, 100 mmol / L L-arginine, 100 mmol / L sucrose, and 100 mmol / L trehalose.
• the prepared drug solution was freeze-thawed (-20 ° C / room temperature, 5 cycles and 10 cycles) and used as a test sample.
• Example 3 Effect of L-aspartic acid on the accelerated test of satralizumab and the effect of suppressing the increase in aggregates during the freeze-thaw test
• Example 1-1 Stability evaluation of the satrarisumab preparation in the accelerated test (1)
• Material Example 1-1 The antibody described in 1 was used.
• the buffer solution was 20 mmol / L L-histidine / hydrochloric acid, 20 mmol / L histidine / L-aspartic acid and 20 mmol / L histidine / L-.
• a chemical solution having a pH of 6.0 was prepared by adding glutamic acid. The prepared drug solution was allowed to stand in a constant temperature bath at 25 ° C. for 2, 4 or 12 weeks, and used as a test sample.
• L-aspartic acid and L-glutamic acid showed a better effect of suppressing aggregate formation than chloride ions.
• the buffer solution was 20 mmol / L L-histidine / hydrochloric acid, 20 mmol / L histidine / L-aspartic acid and 20 mmol / L histidine / L-.
• a drug solution having a pH of 6.0 to which glutamic acid was added was prepared. The prepared drug solution was freeze-thawed (-20 ° C / room temperature, 5 cycles and 10 cycles) and used as a test sample.
• L-aspartic acid and L-glutamic acid showed a better effect of suppressing aggregate formation than chloride ions. Since L-glutamic acid is known to cause significant pain when administered subcutaneously, L-aspartic acid was considered to be preferable.
• Example 4 Effect of poloxamer 188 on suppressing foreign substance formation during recommended storage conditions of satralizumab
• a drug solution containing Polysorbate 20 and 0.5 mg / mL Poloxamer 188 was prepared and filled in glass vials by 1.5 mL each.
• Example 5 Stability test result of commercial formulation
• HMWS was 0.9% and 0.8%, respectively, showing a good aggregate inhibitory effect when stored for 6 months under accelerated conditions and 30 months under recommended storage conditions, respectively.
• the pharmaceutical product of the present invention is a highly stable pharmaceutical product that exhibits a high aggregate inhibitory effect in harsh tests, accelerated tests, freeze-thaw tests, and long-term storage tests under recommended storage conditions.
• the pharmaceutical product of the present invention is characterized in that foreign body production is suppressed for a long period of time despite containing a high concentration of antibody (satralizumab: SA237), for example, neuromyelitis optica spectrum (NMOSD) by subcutaneous administration. It is useful for the treatment of IL-6 related diseases such as.

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