WO2020060192A1 - Formulation liquide stabilisante de trastuzumab contenant une concentration élevée de tensioactif - Google Patents

Formulation liquide stabilisante de trastuzumab contenant une concentration élevée de tensioactif Download PDF

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WO2020060192A1
WO2020060192A1 PCT/KR2019/012077 KR2019012077W WO2020060192A1 WO 2020060192 A1 WO2020060192 A1 WO 2020060192A1 KR 2019012077 W KR2019012077 W KR 2019012077W WO 2020060192 A1 WO2020060192 A1 WO 2020060192A1
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liquid formulation
surfactant
trastuzumab
formulation
acid
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Korean (ko)
Inventor
김미경
유원정
이승하
이재민
이헌주
김용국
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Samsung Bioepis Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a stabilized liquid formulation comprising a high concentration of surfactant, comprising trastuzumab or an antigen-binding fragment thereof, and a method for preparing the same.
  • Herceptin ® SC 120 mg / mL
  • Xolair ® 125 mg / mL
  • Simponi ® 100 mg / mL
  • pharmaceuticals such as Humira ® (50 mg / mL, 100 mg / mL) are commercially available.
  • Antibody pharmaceuticals may be exposed to various environments during manufacture, transportation, storage and administration or undergo phase changes such as air-liquid, solid-liquid, or liquid-liquid. In particular, when the antibody contacts the hydrophobic interface, problems such as protein aggregation or particle formation may occur.
  • the trastuzumab formulation contains polysorbate 20 as a surfactant. Trastuzumab formulations comprising polysorbate 20 are known to reduce protein absorption or aggregation.
  • One aspect of the present invention is to provide a liquid formulation capable of maintaining stability without causing aggregation of trastuzumab containing a surfactant.
  • Another aspect of the present invention adding a stabilizer and a buffering agent to the solvent to prepare a mixed solution; Adding 0.1 w / v% or more surfactant to the mixed solution; And adding trastuzumab to the solution to which the surfactant has been added.
  • trastuzumab or an antigen-binding fragment thereof (b) stabilizer; And (c) a buffering agent, and at least 0.1 w / v% of a surfactant.
  • Another aspect of the present invention adding a stabilizer and a buffering agent to the solvent to prepare a mixed solution; Adding a surfactant to the mixed solution; And adding 0.1 w / v% or more of trastuzumab to the solution to which the surfactant has been added.
  • liquid formulation according to one aspect of the present invention is capable of maintaining the stability of trastuzumab under temperature stress conditions.
  • Example 1 is a graph showing the results of analyzing the changes of% HMW of the formulations of Examples 1 to 4 and Comparative Example 1 under temperature stress conditions by size exclusion-high performance liquid chromatography (Size-Exclusion HPLC, SE-HPLC).
  • Example 1 For the preparation of Example 1, a buffer of 5L was added to sterile distilled water in a 5L biotainer container made of polycarbonate with a buffering agent and a stabilizer excluding trastuzumab and a surfactant in the composition shown in Table 1 below. The solution was prepared.
  • trastuzumab solution in 5 mM histidine buffer at pH 6.0 was placed in a dialysis cassette (MWCO 10 kDa) (Slide-A-Lyzer cassette, Thermo Fisher Scientific), and then the cassette containing this trastuzumab solution was placed in a 2L beaker containing 1,600 mL of the buffer solution to make dialysis, and the 5 mM histidine buffer at pH 6.0 was exchanged with the buffer solution. Thereafter, trastuzumab was concentrated to 120 mg / mL or more.
  • MWCO 10 kDa Slide-A-Lyzer cassette, Thermo Fisher Scientific
  • Concentration was achieved by passing the dialysis trastuzumab containing solution through an Amicon Filter with a cutoff molecular weight of 30 kDa. Finally, to the concentrated trastuzumab solution, surfactant prepared at a concentration of 20x in the buffer solution prepared above was added to a concentration of 1x.
  • Example 1 had a pH of about 5.5.
  • the formulations of Examples 2 to 4 and Comparative Example 1 were prepared in the same manner, except that the concentration of the surfactant was changed in the preparation of Example 1, or the surfactant poloxamer 188 was changed to polysorbate 20.
  • the pH of the formulations of Examples 2 to 4 and Comparative Example 1 was about 5.5.
  • the formulation of Example 5 was prepared in the same manner as in the preparation of the formulation of Example 1, except that 2,000 U / ml hyaluronidase was added to the formulation of Example 1. Specifically, hyaluronidase was added to the concentrated trastuzumab solution in a buffer solution prepared above at a concentration of 20x to a concentration of 1x, and hyaluronidase was also added.
  • the hyaluronidase was prepared by a method for producing a recombinant protein. Specifically, the hyaluronidase is Streptomyces Koganeiensis was used. The hyaluronidase has the amino acid sequence of SEQ ID NO: 1. The nt sequence of the gene encoding the hyaluronidase has the nucleotide sequence of SEQ ID NO: 2. The gene was synthesized by requesting GenScript (Singapore) to include the recognition sites of restriction enzymes NdeI and XhoI at both ends.
  • GenScript GenScript
  • the synthesized gene and pUC57-Kan vector were cut with NdeI and XhoI, and linked to each other to prepare a pUC57-Kan vector containing the hyaluronidase gene.
  • the vector was transformed into E. coli, and the transformed E. coli was cultured to amplify the pUC57-Kan vector.
  • an expression vector was prepared by introducing the hyaluronidase gene among the pUC57-Kan vectors into the NdeI and XhoI regions of the pFlag-STS vector (Addgene), which is an expression vector.
  • the expression vector was transformed into E. coli W3110 strain, and cultured to generate hyaluronidase in the medium. The hyaluronidase was isolated from the culture and used in this example.
  • Example 5 shows the compositions of Examples 1 to 4 and Comparative Example 1.
  • the formulation of Example 5 further comprises 2,000 U / ml hyaluronidase in the formulation of Example 1.
  • Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Trastuzumab (mg / mL) 120 120 120 120 120 120 Buffering agent Histidine (mM) 20 20 20 20 20 20 Stabilizer Methionine (mM) 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Trehalose (w / v%) 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 Surfactant (w / v%) PS20 - 0.4 0.8 0.04 Poloxamer 188 0.4 0.8 - -
  • Test example 1 SE- HPLC Check the stability of the formulation containing high concentration surfactant at the temperature stress used
  • Formulations containing high concentrations of poloxamer 188 as surfactants i.e., formulations containing Examples 1 to 2 and high concentrations of PS20, i.e., formulations of Examples 3 and 4, are used to determine whether the stability is maintained under stress conditions using SE-HPLC. Confirmed. For comparison, a formulation containing PS20 at a low concentration, that is, 0.04 w / v%, was used as Comparative Example 1.
  • Example 1 1 mL of each of the formulations of Examples 1 to 4 and Comparative Example 1 was placed in a 1.5 mL microtube (Axygen) made of polypropylene, and the tube was placed at 40 ° C in a stability thermostat (JEIO TECH). They were exposed to temperature stress conditions for 4 weeks. Specifically, the tube was placed in the stability thermostat and placed for 4 weeks under conditions of temperature 40 ⁇ 2 ° C. and relative humidity 75 ⁇ 5%. Then,% HMW was measured using SE-HPLC for the formulation. When the antibody loses stability in the formulation, it will be observed that aggregation is induced to increase the proportion of high molecular weight (HMW) material.
  • HMW high molecular weight
  • FIG. 1 is a graph showing the results of analyzing the changes in% HMW of the formulations of Examples 1 to 4 and Comparative Example 1 under temperature stress conditions by size exclusion-high performance liquid chromatography (Size-Exclusion HPLC, SE-HPLC).
  • Size-Exclusion HPLC Size-Exclusion HPLC
  • SE-HPLC standard deviation
  • Test example 2 SE- HPLC High concentration surfactant and used temperature stress Hyaluronidase Checking the stability of the containing formulation
  • Example 5 1 mL of each of the formulations of Example 5 and Comparative Example 1 was placed in a 1.5 mL microtube (Axygen) made of polypropylene, and the tube was subjected to a temperature stress of 40 ° C in a stability thermostat (JEIO TECH). Conditions were exposed for 8 weeks. Specifically, the tube was placed in the stability thermostat and placed for 8 weeks under conditions of temperature 40 ⁇ 2 ° C. and relative humidity 75 ⁇ 5%. Then,% HMW was measured using SE-HPLC for the formulation. When the antibody loses stability in the formulation, it will be observed that aggregation is induced to increase the proportion of high molecular weight (HMW) material.
  • HMW high molecular weight
  • Table 3 shows the results. Data obtained by analyzing each formulation prepared in 3 replicates per formulation. Compared to Comparative Example 1, the formulation of Example 5 showed a significantly lower ⁇ % HMW value. Specifically, when placed at 40 ° C. for 8 weeks, the formulations of Example 5 and Comparative Example 1 had an average ⁇ % HMW value of 1.24 and 1.38, respectively.
  • Comparative Example 1 contains the same amount of hyaluronidase as in Example 5.
  • Test Example 3 Check the stability of the formulation containing a high concentration of surfactant in freeze-thaw stress
  • % HMW was measured. If the antibody loses stability in the formulation, it will be observed that aggregation occurs and the proportion of high molecular weight (HMW) material increases.
  • HMW high molecular weight
  • MFI micro-flow imaging
  • a micro-flow image using MFI takes a snapshot image of flowing particles using orthogonal light, and converts it back to the number of particles present in a specific volume of liquid.
  • the conversion may be performed by an image analysis algorithm. This method provides information on the large amount of protein aggregates present in solution.
  • MFI 5200 Protein Simple
  • the experiment was carried out by injecting 0.4 mL of the formulations of Examples 1 to 4 into a 96-month plate, and mounting the 96-well plate in a device. After that, the autosampler sucked the sample and made it flow in a flow cell, and at the same time, images were taken in a direction perpendicular to the flow direction. The photographed image was analyzed by software using characteristics of each particle, that is, size, intensity, and the like. The results are shown in Table 5 below.
  • Examples 1 and 2 which are formulations containing 0.4 w / v% or 0.8 w / v% poloxamer 188 among the surfactants, include a high concentration, that is, 0.4 w / v% or 0.8 w / v% PS20. It was more stable than the formulations of Examples 3 and 4, which are formulations.
  • trastuzumab or an antigen-binding fragment thereof (b) stabilizers; And (c) a buffering agent, and at least 0.1 w / v% of a surfactant.
  • antigen binding fragment is a fragment of a portion capable of binding to an antigen in a Trastuzumab antibody, including, but not limited to, Fab, F (ab ′) 2 and Fv, for example.
  • the antigen can be a HER2 receptor.
  • Trastuzumab is a monoclonal antibody used to treat cancer, including breast cancer, and is marketed under the name Herceptin TM under one of several trade names. Trastuzumab is used for breast cancer that is positive for the desired HER2 receptor. In addition, trastuzumab can be used alone or in combination with other chemotherapeutic agents. Trastuzumab is administered by intravenous injection and subcutaneous injection. Trastuzumab works by binding to the HER2 receptor and slows cell replication. Trastuzumab is a recombinant IgG1 kappa humanized from mice that binds to the extracellular domain of human epidermal growth factor receptor protein (HER2), a whole antibody.
  • HER2 human epidermal growth factor receptor protein
  • the concentration of trastuzumab or an antigen-binding fragment thereof in the liquid may be 2 to 300 mg / mL.
  • the concentration of trastuzumab can be freely adjusted within a range that does not substantially affect the stability, viscosity and desired pH of the liquid formulation of the present invention.
  • the concentration of the trastuzumab or antigen binding fragment thereof is, for example, 10 to 300 mg / mL, 20 to 300 mg / mL, 30 to 300 mg / mL, 50 to 300 mg / mL, 80 To 300 mg / mL, 100 to 300 mg / mL, 80 to 250 mg / mL, 80 to 200 mg / mL, 80 to 180 mg / mL, 80 to 150 mg / mL, 100 to 150 mg / mL, 100 to 140 mg / mL, 105-135 mg / mL, 110-130 mg / mL, 115-125 mg / mL, 100-250 mg / mL, 100-200 mg / mL, 100-180 mg / mL, 100-150 mg / mL, 100-140 mg / mL, 150-300 mg / mL, 200-300 mg / mL, 220-300 mg / m
  • the liquid formulation of the present invention contains 0.1 w / v% or more of a surfactant.
  • the surfactant has a concentration of 0.1 w / v% or more, for example, more than 0.1 w / v%, 0.1 to 1.0 w / v%, 0.1 to 0.9 w / v%, 0.15 to 0.85 w / v%, 0.1 to 0.8 w / v%, 0.2-0.8 w / v%, 0.2-0.85 w / v%, 0.15-0.8 w / v%, 0.2-0.6 w / v%, 0.2-0.4 w / v%, 0.3-0.5 w / v%, 0.1 to 0.3w / v%, 0.6 to 1.0w / v%, 0.7 to 0.9w / v%, 0.2w / v% ⁇ 5%, 0.4w / v% ⁇ 5%, or 0.8w
  • the surfactant may be a nonionic surfactant.
  • the surfactant is, for example, polyoxyethylene sorbitan fatty acid ester (Tween), polyethylene-polypropylene glycol, polyoxyethylene stearate, polyoxyethylene alkyl ether, polyoxyethylene-polyoxypropylene copolymer (poloxamer) , Or sodium dodecyl sulfate.
  • the poloxamer may be poloxamer 188.
  • the polyoxyethylene alkyl ether may be, for example, polyoxyethylene monolauryl ether, or alkylphenylpolyoxyethylene 30 ether (Triton-X).
  • the polysorbate is a polyoxyethylene sorbitan fatty acid ester or a derivative thereof. Polysorbates are known to degrade through oxidation and hydrolysis, which in turn produce ROS and are known to cause oxidative damage to trastuzumab proteins.
  • the polysorbate may be polysorbate 20 or polysorbate
  • the surfactant may be poloxamer 188, polysorbate 20 or polysorbate 80.
  • the surfactant may be poloxamer 188 or polysorbate 20.
  • the stabilizer may be one or more selected from the group consisting of sugar, sugar alcohol, sugar acid, polyol, metal salt and amino acid.
  • the sugar may be selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, or derivatives thereof.
  • the sugar derivative may mean sugar alcohol or sugar acid.
  • the sugar, sugar alcohol or sugar acid is glucose, fructose, galactose, sucrose, lactose, maltose, trehalose, fructooligosaccharide, galactoligosaccharide, mango-oligosaccharide, starch, glycogen, cellulose, chitin, pectin , Glycerol, erythritol, thritol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, boletitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol ,
  • the concentration of the sugar, sugar alcohol or sugar acid may be 1 to 20w / v%. In another embodiment, the concentration of the sugar, sugar alcohol or sugar acid is 2 to 20w / v%, 4 to 20w / v%, 6 to 20w / v%, 6 to 12w / v%, 6 to 10w / v%, respectively.
  • the concentration of sugar, sugar alcohol or sugar acid can be freely adjusted within a desired range to maintain the stability of the trastuzumab or antigen-binding fragment thereof in the liquid formulation of the present invention and the viscosity of the liquid formulation, and each specific sugar, sugar alcohol or It can vary individually depending on the sugar acid.
  • polyol can mean an organic compound having two or more hydroxyl groups (-OH) in its molecule.
  • the polyol is at least one selected from the group consisting of propanediol, glycerin, butylene glycol, propylene glycol, dipropylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol, and sorbitol Can be.
  • the metal salt may be NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4 , NaSCN, or K 2 SO 4 , but is not limited thereto. In one embodiment, the metal salt may be NaCl. The concentration of the metal salt may be 0.1 to 10w / v%.
  • the concentration of the metal salt is 0.1 to 8w / v%, 0.1 to 6w / v%, 0.1 to 5w / v%, 0.1 to 3w / v%, 0.1 to 1w / v%, 0.3 to 10w / v %, 0.3 to 8 w / v%, 0.3 to 6 w / v%, 0.3 to 5 w / v%, 0.3 to 3 w / v% or 0.3 to 1 w / v%, 0.5 to 10 w / v%, 0.5 to 8 w / v% , 0.5 to 6w / v%, 0.5 to 5w / v%, 0.5 to 3w / v% or 0.5 to 1w / v%.
  • the concentration of the metal salt can be freely adjusted within a range in which the stability of trastuzumab or an antigen-binding fragment thereof in the liquid formulation of the present invention is not precipitated, and
  • the amino acid is glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, histidine, glutamine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine It may be one or more selected from the group consisting of.
  • the concentration of amino acids can be freely adjusted within a range that does not affect the desired pH of the liquid formulation of the present invention, and does not affect the stability of trastuzumab or antigen-binding fragments thereof, and can be individually adjusted for each specific amino acid. It may vary.
  • the amino acid may be methionine.
  • the stabilizer may include two or more stabilizers.
  • the stabilizer may be one or more selected from the group consisting of trehalose and methionine.
  • the stabilizer may be one or more selected from the group consisting of 1 to 15w / v% trehalose and 1 to 50 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 2 to 14w / v% trehalose and 1 to 30 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 3 to 13w / v% trehalose and 1 to 20 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 4 to 12w / v% trehalose and 1 to 20 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 5 to 11w / v% trehalose and 2 to 18 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 6 to 10w / v% trehalose and 2 to 18 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 6 to 10w / v% trehalose and 4 to 16 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 6 to 10w / v% trehalose and 6 to 14 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 7 to 9w / v% trehalose and 8 to 12 mM methionine.
  • the stabilizer may be at least one selected from the group consisting of 2 to 8w / v% trehalose and 1 to 20 mM methionine.
  • the buffering agent may be to provide a pH of 4.0 to 7.0.
  • the liquid formulation may have a pH of 4.0 to 7.0.
  • the pH of the liquid formulation may be 4.5 to 6.5, 5.0 to 6.0 or 5.5 ⁇ 0.2.
  • the pH of the liquid formulation can be freely adjusted within a range suitable for preventing aggregation of trastuzumab and maintaining activity.
  • the liquid formulation of the present invention may contain a buffering agent to maintain the desired pH for stabilizing trastuzumab or an antigen-binding fragment thereof.
  • buffer refers to a neutralizing material that minimizes the change in pH by acid or alkali, and in one embodiment, the buffering agent is histidine, phosphoric acid, citric acid, maleic acid, tartaric acid, succinic acid, citrate, acetate , Carbonate and salts thereof, but are not limited thereto.
  • the buffering agent is histidine. In one embodiment, the buffering agent is 1 to 100 mM histidine. The concentration of histidine is, for example, 1 to 80 mM, 1 to 70 mM, 1 to 60 mM, 1 to 50 mM, 1 to 40 mM, 1 to 30 mM, 2 to 80 mM, 2 to 70 mM, 2 To 60 mM, 2 to 50 mM, 2 to 40 mM, 2 to 30 mM, 2 to 25 mM, 3 to 80 mM, 3 to 70 mM, 3 to 60 mM, 3 to 50 mM, 3 to 40 mM, 3 To 30 mM, 3 to 25 mM, 4 to 80 mM, 4 to 70 mM, 4 to 60 mM, 4 to 50 mM, 4 to 40 mM, 4 to 30 mM, 4 to 25 mM, 5 to 80 mM, 5 To 70 mM, 5 to 60 mM, 5 to 60 m
  • the histidine may be in the form of histidine and its conjugate acid.
  • the conjugate acid may be histidine HCl.
  • the ratio of histidine and its conjugate acid may vary depending on the pH of the selected agent. For example, when the pH of the formulation is 5.5 ⁇ 0.2, the concentration ratio of histidine and histidine HCl monohydrate may be about 1: 6.
  • Stabilizers, buffering agents, and surfactants as defined above may be different.
  • the trastuzumab or antigen-binding fragment thereof may be stabilized.
  • the liquid formulation may be a stable liquid pharmaceutical formulation.
  • stabilization means that trastuzumab or an antigen-binding fragment thereof substantially retains its physical stability, chemical stability and / or biological activity before and after administration, during further manufacturing processes, storage or storage. Physical stability, chemical stability and / or biological activity can be assessed by commonly known methods.
  • the trastuzumab or antigen-binding fragment thereof has no signs of any aggregation, precipitation and / or denaturation upon visual inspection for color and / or transparency or as measured by ultraviolet (UV) light scattering or size exclusion chromatography. If not visible, it retains physical stability within the pharmaceutical formulation.
  • UV ultraviolet
  • “Stability” can be measured for a selected period of time at a selected temperature.
  • a stable formulation is one in which no significant change is observed at 2-8 ° C. for 12 months or longer.
  • a stable formulation is one that does not exhibit significant changes at 2-8 ° C. for 18 months or longer.
  • a stable formulation is one where no significant change is observed for 3 months or longer at 23-27 ° C.
  • a stable formulation is one where no significant changes are observed for 6 months or longer at 23-27 ° C.
  • a stable formulation is one where no significant change is observed at 23-27 ° C. for 12 months or longer.
  • a stable formulation is one where no significant change is observed at 23-27 ° C. for 18 months or longer.
  • Stability criteria for antibody formulations are as follows. When measured by SE-HPLC, the antibody monomer is 10% or less, for example, 5% or less, or 2.5% or less relative to the initial monomer amount. For example, when measuring low molecular weight (LMW) species by SE-HPLC, the change in the amount of the low molecular weight species is less than 10%, less than 5%, or less than 2.5% relative to its initial amount. It may have.
  • LMW low molecular weight
  • the change in the amount of the high molecular weight species is 10% or less, 5% or less, or 2.5% or less relative to its initial amount. It may have.
  • the concentration of the formulation, and the pH may have a change of 0% or less, ⁇ 5% or less, or ⁇ 2.5% or less relative to the initial value.
  • the antibody potency can be within 60 to 140%, or 80 to 120%, of the control or standard antibody.
  • the trastuzumab or antigen-binding fragment thereof retains chemical stability within the pharmaceutical agent when it is chemically stable at a predetermined time that appears to still retain biological activity. Chemical stability can be assessed by detecting and quantifying the chemically modified form of trastuzumab. Chemical modification includes size modification or charge change. The charge change can be, for example, a charge change that occurs as a result of deamidation.
  • the size modification is size exclusion chromatography (SE-HPLC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary electrophoresis-sodium dodecyl sulfate, CE-SDS ) Analysis, and substrate-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS).
  • charge changes can be evaluated by ion exchange chromatography (IEC), and imaged capillary isoelectric focusing (icIEF).
  • Activity can be determined through HER2 receptor binding assay.
  • the HER2 receptor binding assay can be performed by an enzyme-linked immunosorbent assay (ELISA).
  • ELISA analysis measures the ratio (%) of trastuzumab binding to the HER2 receptor.
  • ELISA can be performed using the Her2 ELISA kit (R & D system). After reacting with the trastuzumab sample and the HER2 receptor on the ELISA substrate, the binding degree can be determined by measuring the absorbance at 450 nm to obtain a relative binding rate (%).
  • the trastuzumab or antigen-binding fragment thereof retains biological activity in the pharmaceutical agent when the trastuzumab or antigen-binding fragment thereof is biologically active for its intended purpose.
  • the biological activity is, for example, within about 30%, about 20%, about 10% or within an analysis error of the biological activity of the trastuzumab or antigen-binding fragment thereof in the pharmaceutical agent at the time of manufacture of the pharmaceutical agent. If present, retain biological activity.
  • the biological activity can be determined, for example, in antigen binding assays.
  • the biological activity may be, for example, antigen binding activity.
  • Stabilization is temperature stress, for example, 1 to 4 or 8 weeks at 40 ° C, freeze-thaw stress, for example, 5 repetitions of cycles at -70 ° C freezing and thawing at room temperature, or stirring stress,
  • it can be evaluated by measuring the% HMW,% monomer and / or% LMW using SE-HPLC by applying a rotational force of 400 rpm for 72 hours in a stirrer.
  • the liquid formulations of the present invention may have less ⁇ % HMW, ⁇ % monomer and / or ⁇ % LMW values compared to Herceptin®.
  • the liquid formulation provided herein has a change in% HMW measured when stored at 40 ° C for 4 weeks at 40 ° C when the antibody content is 120 mg / ml (pH 5.5), that is,% HMW at week 4 of storage- Week 0% HMW value is about 5% or less, about 3% or less, about 2% or less, about 1.5% or less, about 1.3% or less, about 0.1 to about 5%, about 0.5 to about 3%, about 0.5 to About 2%, about 0.5 to about 1.5%, about 0.7 to about 1.3%, and also about 0.8 to about 1.2%.
  • the "week 0" indicates the initial time of storage.
  • the liquid formulation provided herein is thawed by maintaining the liquid composition at -70 ⁇ 10 ° C for 18 hours, and then standing at room temperature for 1 hour when the antibody content is 120 mg / ml (pH 5.5).
  • the change amount of% HMW measured by conventional SEC is about 2% or less, about 1.5% or less, about 1.0% or less, about 0.5% or less, about 0.1% or less, about 0.05% or less, or about 0.01% or less, about 0.001% or less, about 0.1 to about 1%, about 0.01 to about 1%, about 0.001 to about 1%, about -0.05 to about 0.05%, about -0.04 to about 0.05%, about -0.03 to About 0.05%, about -0.02% to about 0.05%, or about -0.01 to about 0.05%.
  • the liquid composition provided in the present specification is an antibody content of 120 mg / ml (pH 5.5), the liquid composition is maintained at -70 ⁇ 10 ° C for 18 hours, and then left to stand at room temperature for 1 hour to thaw. After repeated 5 times, 0.4 mL of the sample is injected into a 96-month plate, the 96-well plate is mounted on a microscope MFI 5200 (Protein Simple) instrument, and an autosampler aspirates the sample, followed by flow cell flow.
  • MFI 5200 Protein Simple
  • the obtained particles may be 200 to 1,200, 210 to 1,100, 200 to 310, 210 to 310, or 220 to 310 particles having a size of 25 ⁇ m or more.
  • the liquid formulation may be for subcutaneous or intravenous injection.
  • the liquid formulation may further include an aqueous carrier suitable for injection.
  • the aqueous carrier may be a safe and non-toxic pharmaceutically acceptable drug when administered to humans.
  • the aqueous carrier includes, but is not limited to, sterile water, for example, sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), sterile saline solution, Ringer's solution, and dextrose.
  • the liquid formulation of the present invention may have an appropriate range of osmolality upon subcutaneous or intravenous injection.
  • Osmolarity may be, for example, 200 to 400 mOsm / kg, 250 to 380 mOsm / kg, or 270 to 360 mOsm / kg.
  • the osmolarity concentration can be appropriately adjusted to minimize pain that may occur during administration.
  • the liquid formulation of the present invention may have an appropriate range of viscosity when subcutaneously or intravenously injected.
  • the viscosity for example, 0.5 to 50 cp, can be appropriately adjusted to minimize pain that may occur upon administration.
  • the liquid formulation of the present invention may include a hyaluronidase enzyme.
  • the amount of the hyaluronidase enzyme may vary depending on the hyaluronidase enzyme used.
  • the amount of hyaluronidase enzyme can be an amount sufficient to increase the dispersion and absorption of an anti-HER2 antibody, e.g., trastuzumab or an antigen binding fragment thereof, administered together.
  • the amount of hyaluronidase enzyme can be 150 U / ml or more.
  • An effective amount of hyaluronidase enzyme is, for example, about 1,000 to 16,000 U / ml, where the amount corresponds to about 0.01 mg to 0.16 mg based on 100,000 U / mg of estimated specific activity.
  • the concentration of the hyaluronidase enzyme may be about 1,500 to 12,000 U / ml, or about 2,000 to 12,000 U / ml. This amount corresponds to the amount of hyaluronidase enzyme added to the formulation.
  • the amount of hyaluronidase enzyme measured in the final formulation can vary within a specific range.
  • the ratio (w / w) of hyaluronidase enzyme to anti-HER2 antibody is 1: 5,00 to 1: 100,000, 1: 1,000 to 1: 50,000, 1: 1,000 to 1: 30,000, 1: 1,000 to 1: 20,000, 1: 1,000 to 1: 15,000, 1: 1,000 to 1: 13,000, 1: 1,000 to 1: 12,000, 1: 1,000 to 1: 10,000, 1: 1,000 to 1: 8,000, 1: 4,000 to 1: 5,000, Or about 1: 6,000.
  • the hyaluronidase enzyme may be derived from an animal, bacterial, or human sample or prepared by recombinant DNA technology.
  • the hyaluronidase enzyme may be soluble hyaluronidase glycoproteins (sHASEGPs). These soluble hyaluronidase glycoproteins can be administered together with the agent or separately. The addition of the soluble hyaluronidase glycoprotein can facilitate the subcutaneous administration of the therapeutic drug.
  • soluble hyaluronidase glycoprotein By rapidly depolymerizing hyaluronan (HA) in the extracellular space, the soluble hyaluronidase glycoprotein lowers the viscosity of the interstitium, increasing hydraulic conductance, making it easier for large volumes to subcutaneous tissue. Make it administered comfortably.
  • the increased hydraulic conductivity induced by soluble hyaluronidase glycoproteins through reduced interstitial viscosity can result in better dispersion, thereby increasing the systemic bioavailability of the subcutaneously administered therapeutic drug.
  • the hyaluronidase enzyme may be licensed for use in humans in any one or more countries.
  • the hyaluronidase enzyme may be, for example, Hylase TM , Dessau, Hyalase TM , EU approved, Vitrase TM , Hydase TM , Amphadase TM , or Hylenex TM , licensed in the United States.
  • the hyaluronidase enzyme may be a human hyaluronidase enzyme such as PH20 or rHuPH20. Recombinant human PH20 (rHuPH20) is a member of the neutral and acid-active ⁇ -1,4 glycosyl hydrolase family.
  • rHuPH20 depolymerizes hyaluronan by hydrolysis of a ⁇ -1,4 bond between the C1 position of N-acetyl glucosamine and the C4 position of glucuronic acid.
  • rHuPH20 may be a truncated deletion variant without amino acid at the carboxy terminal required for lipid attachment developed by Halozyme.
  • the trastuzumab or antigen-binding fragment thereof is 2 to 300 mg / mL
  • the stabilizer is a combination of trehalose and methionine
  • the buffering agent is histidine
  • the surfactant is 0.1 to Provided is a liquid formulation that is 0.9 w / v% surfactant.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • the stabilizer is a combination of 1 to 20 w / v% trehalose and 1 to 20 mM methionine, and the buffering agent is 10 to 50 mM histidine.
  • the concentration of the trehalose is 2 to 20w / v%, 4 to 20w / v%, 6 to 20w / v%, 1 to 18w / v%, 1 to 15w / v%, 1 to 12w / v%, 1 to 10w / v%, 2 to 18w / v%, 2 to 15w / v%, 2 to 12w / v%, 2 to 10w / v%, 4 to 18w / v%, 4 to 15w / v%, 4 to 12w / v% or 4 to 10 w / v%.
  • the concentration of the methionine is 1 to 20 mM, 2 to 20 mM, 5 to 20 mM, 8 to 20 mM, 1 to 18 mM, 2 to 18 mM, 5 to 18 mM, 1 to 15 mM, 2 to 15 mM, 5 to 15 mM, 8 to 15 mM, 1 to 12 mM, 2 to 12 mM, 5 to 12 mM, or 8 to 12 mM.
  • the histidine may be 10 to 45 mM, 10 to 40 mM, 10 to 35 mM, 10 to 30 mM, 15 to 25 mM, or 18 to 22 mM.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant has a concentration of 0.1 w / v% or more, for example, 0.1 to 1.0 w / v%, 0.1 to 0.9 w / v%, 0.15 to 0.85 w / v%, 0.1 to 0.8 w / v%, 0.2 To 0.8 w / v%, 0.2 to 0.85 w / v%, 0.15 to 0.8 w / v%, 0.2 to 0.6 w / v%, 0.2 to 0.4 w / v%, 0.3 to 0.5 w / v%, 0.1 to 0.3 It can be w / v%, 0.6 to 1.0w / v%, 0.7 to 0.9w / v%, 0.2w / v% ⁇ 5%, 0.4w / v% ⁇ 5%, or 0.8w / v% ⁇ 5% have.
  • One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 80 to 160 mg / ml thereof; (b) 1 to 20 mM methionine and 1 to 15 (w / v)% trehalose as stabilizers; And (c) 1 to 50 mM histidine as a buffering agent, and 0.1 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 80 to 160 mg / ml thereof; (b) 1 to 20 mM methionine and 1 to 15 (w / v)% trehalose as stabilizers; And (c) 1 to 40 mM histidine as a buffering agent, and 0.1 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 100 to 140 mg / ml thereof; (b) 3 to 18 mM of methionine and 2 to 13 (w / v)% of trehalose as stabilizers; And (c) 10-30 mM histidine as a buffering agent, and 0.1 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment 110 to 130 mg / ml thereof; (b) 5 to 15 mM methionine as stabilizer and 4 to 12 (w / v)% trehalose; And (c) 15 to 25 mM histidine as a buffering agent, and 0.1 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment 110 to 130 mg / ml thereof; (b) 8 to 12 mM methionine and 6 to 10 (w / v)% threonyl as stabilizers; And (c) 16 to 24 mM histidine as a buffering agent, and 0.1 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 80 to 160 mg / ml thereof; (b) 1 to 20 mM methionine and 1 to 15 (w / v)% trehalose as stabilizers; And (c) 1 to 50 mM histidine as a buffering agent, and 0.1 to 0.3 w / v%, 0.3 to 0.5 w / v%, or 0.7 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 80 to 160 mg / ml thereof; (b) 1 to 20 mM methionine and 1 to 15 (w / v)% trehalose as stabilizers; And (c) 1 to 40 mM histidine as a buffering agent, and 0.1 to 0.3 w / v%, 0.3 to 0.5 w / v%, or 0.7 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 100 to 140 mg / ml thereof; (b) 3 to 18 mM of methionine and 2 to 13 (w / v)% of trehalose as stabilizers; And (c) 10-30 mM histidine as a buffering agent, and 0.1-0.3 w / v%, 0.3-0.5 w / v%, or 0.7-0.9 w / v% surfactant as surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment 110 to 130 mg / ml thereof; (b) 5 to 15 mM methionine as stabilizer and 4 to 12 (w / v)% trehalose; And (c) 15 to 25 mM histidine as a buffering agent, and 0.1 to 0.3 w / v%, 0.3 to 0.5 w / v%, or 0.7 to 0.9 w / v% surfactant as surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment 110 to 130 mg / ml thereof; (b) 8 to 12 mM methionine and 6 to 10 (w / v)% threonyl as stabilizers; And (c) 16 to 24 mM histidine as a buffering agent, and 0.1 to 0.3 w / v%, 0.3 to 0.5 w / v%, or 0.7 to 0.9 w / v% surfactant as a surfactant.
  • the formulation may be pH 5.5 ⁇ 0.2.
  • the surfactant may be poloxamer 188, PS20 or PS80.
  • the surfactant may be poloxamer 188 or PS20.
  • One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment thereof 120 mg / ml ⁇ 5%; (b) 10 mM ⁇ 5% methionine as stabilizer and 8% (w / v)% ⁇ 5% trehalose; And (c) 20 mM ⁇ 5% histidine as a buffering agent, and 0.4 w / v% ⁇ 5%, or 0.8 w / v% ⁇ 5% poloxamer 188 or PS20 as surfactant.
  • ⁇ 5% indicates that there is a variation of “ ⁇ 5%” with respect to the basic amount.
  • the liquid formulation may be pH 5.5 ⁇ 0.2.
  • the histidine may include histidine and its conjugate acid, for example, histidine HCl.
  • the buffering agent may include only histidine and its conjugate acid.
  • the formulation may not contain surfactants other than the surfactant.
  • Another aspect of the present invention adding a stabilizer and a buffering agent to the solvent to prepare a mixed solution; Adding 0.1 w / v% or more surfactant to the mixed solution; And adding trastuzumab to the solution to which the surfactant has been added.
  • the surfactant may be poloxamer 188 or PS20.

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Abstract

L'invention concerne une formulation liquide comprenant : du trastuzumab ou un fragment de liaison à l'antigène de celui-ci ; un stabilisant ; et un tampon, et contenant une concentration élevée d'un tensioactif. L'invention concerne également un procédé de préparation associé.
PCT/KR2019/012077 2018-09-18 2019-09-18 Formulation liquide stabilisante de trastuzumab contenant une concentration élevée de tensioactif Ceased WO2020060192A1 (fr)

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PCT/KR2019/012056 Ceased WO2020060183A1 (fr) 2018-09-18 2019-09-18 Formation de liquide pour stabiliser un anticorps de trastuzumab

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CN113827718A (zh) * 2020-06-24 2021-12-24 上海宝济药业有限公司 一种含有透明质酸酶的制剂及其应用
CN113855798A (zh) * 2021-09-30 2021-12-31 佛山汉腾生物科技有限公司 抗cd20的抗体制剂
WO2023100095A1 (fr) * 2021-11-30 2023-06-08 Enzene Biosciences Limited Composition comprenant un anticorps her2, formulation et son procédé de préparation
WO2024022414A1 (fr) * 2022-07-29 2024-02-01 舒泰神（北京）生物制药股份有限公司 Préparation d'anticorps monoclonal à haute concentration et son utilisation
CN118526603A (zh) * 2024-01-16 2024-08-23 上海复星医药产业发展有限公司 一种含抗体药物偶联物的药物组合物及其应用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113827718A (zh) * 2020-06-24 2021-12-24 上海宝济药业有限公司 一种含有透明质酸酶的制剂及其应用
CN113855798A (zh) * 2021-09-30 2021-12-31 佛山汉腾生物科技有限公司 抗cd20的抗体制剂
WO2023100095A1 (fr) * 2021-11-30 2023-06-08 Enzene Biosciences Limited Composition comprenant un anticorps her2, formulation et son procédé de préparation
WO2024022414A1 (fr) * 2022-07-29 2024-02-01 舒泰神（北京）生物制药股份有限公司 Préparation d'anticorps monoclonal à haute concentration et son utilisation
CN118526603A (zh) * 2024-01-16 2024-08-23 上海复星医药产业发展有限公司 一种含抗体药物偶联物的药物组合物及其应用

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