WO2021096278A1 - Composition en phase liquide pour médicament à base d'anticorps - Google Patents

Composition en phase liquide pour médicament à base d'anticorps Download PDF

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WO2021096278A1
WO2021096278A1 PCT/KR2020/015969 KR2020015969W WO2021096278A1 WO 2021096278 A1 WO2021096278 A1 WO 2021096278A1 KR 2020015969 W KR2020015969 W KR 2020015969W WO 2021096278 A1 WO2021096278 A1 WO 2021096278A1
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histidine
pharmaceutical composition
composition according
less
antibody
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PCT/KR2020/015969
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English (en)
Korean (ko)
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강정훈
정소윤
남명주
오인영
김인애
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삼성바이오에피스 주식회사
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Publication of WO2021096278A1 publication Critical patent/WO2021096278A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—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
    • 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
    • A61K9/0012—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 [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin

Definitions

  • the present invention relates to a liquid composition for antibody pharmaceuticals showing excellent stability.
  • Antibodies which are active ingredients of antibody drugs, are obtained by removing impurities such as DNA, cells, and other proteins through the purification process.
  • impurities such as DNA, cells, and other proteins
  • highly purified antibodies are obtained by removing components that can maintain the folded state in a thermodynamically stable form. It may be sensitive to processes such as enzymatic chemical degradation and aggregation.
  • antibody destabilization There are two types of antibody destabilization: chemical types, including changes in covalent bonds, and physical types, including modifications of the three-dimensional spatial structure. Chemical types can include, for example, hydrolysis, oxidation, deamidation, disulfide modification and racemization of antibodies, and physical types include aggregation, adsorption of the antibody, and unfolding that causes a decrease in the activity of the antibody. May be included.
  • the antibody may be modified by physical factors such as surface adsorption and shear, or the activity may be reduced or structural modifications may occur due to modification, oxidation or aggregation of the antibody.
  • the present invention is an anti-Her2 antibody; And it provides a pharmaceutical composition comprising two or more kinds of amino acids, and does not contain acetate.
  • the present invention also provides a pharmaceutical composition comprising an anti-Her2 antibody and two or more amino acids, does not contain acetate, and maintains or improves stability under high temperature storage conditions, freezing/thawing conditions, or stirring conditions.
  • FIG. 1 shows the result of confirming the change in the content of HMW (High Molecular Weight Species) at 40° C. ⁇ 2° C. through size exclusion chromatography (SEC) analysis for the candidate formulation of Example 1.
  • SEC size exclusion chromatography
  • FIG. 2 shows the results of confirming the change in the content of the pertuzumab antibody monomer at 40° C. ⁇ 2° C. through size exclusion chromatography (SEC) analysis for the candidate formulation of Example 1.
  • SEC size exclusion chromatography
  • FIG. 3 shows the results of confirming the change in the content of LMW (Low Molecular Weight Species) at 40° C. ⁇ 2° C. through size exclusion chromatography (SEC) analysis for the candidate formulation of Example 1.
  • SEC size exclusion chromatography
  • FIG. 4 shows the results of confirming the change in the content of HMW at 40° C. ⁇ 2° C. through size exclusion chromatography (SEC) analysis for the candidate formulation of Example 2.
  • SEC size exclusion chromatography
  • Example 5 shows the results of confirming the change in the content of the pertuzumab antibody monomer at 40° C. ⁇ 2° C. through size exclusion chromatography (SEC) analysis for the candidate formulation of Example 2.
  • Example 7 shows the results of confirming the change in the content of HMW under the conditions of 5 cycles of freezing/thawing through size exclusion chromatography (SEC) analysis of the candidate formulation of Example 2.
  • FIG. 15 shows the results of confirming the change in the content of the pertuzumab antibody monomer at 40° C. ⁇ 2° C. through size exclusion chromatography (SEC) analysis for the candidate formulation of Example 4.
  • SEC size exclusion chromatography
  • the present invention anti-Her2 antibody; And to a pharmaceutical composition comprising two or more amino acids and not including acetate.
  • the "formulation" or “pharmaceutical composition” means a mixture or combination of an anti-Her2 antibody, which is an active ingredient capable of exerting a biological effect, and one or more inactive ingredients suitable for therapeutic administration.
  • the formulation may contain one or more pharmaceutically acceptable additional components such that the anti-Her2 antibody stably exhibits activity.
  • the formulation contains two or more amino acids, sugars or sugar alcohols.
  • the "pharmaceutical” (in some cases, “pharmaceutical” or “pharmaceutical”) formulation according to the present invention means a formulation suitable for administration of an antibody so that the desired pharmacological activity can be exhibited without side effects within the scope of medical judgment. I can.
  • the amino acid may be used as a buffer to maintain the pH in a formulation containing an anti-Her2 antibody, or may function as a stabilizer since it may affect the stability of the antibody.
  • the amino acid may be bonded to an antibody, for example, hydrogen bonded, polar bonded, or non-polar bonded.
  • a polar amino acid, a non-polar amino acid, a hydrophilic amino acid and/or a hydrophobic amino acid may be combined to include two or more amino acids.
  • the amino acid may include two or more, for example, two, three, four, five, or more.
  • the pharmaceutical formulation may contain two kinds of amino acids or three kinds of amino acids.
  • the amino acids are, for example, two or more selected from the group consisting of histidine, methionine, cysteine, arginine, glycine, proline, lysine, glutamic acid, isoleucine, phenylalanine, tyrosine, and aspartic acid, for example two , 3, 4, 5 or more amino acids may be included, but are not limited thereto.
  • the amino acid may further include one or more amino acids other than i) histidine and ii) histidine.
  • the amino acid is histidine-methionine, histidine-glycine, histidine-cysteine, histidine-arginine, histidine-proline, histidine-lysine, histidine-glutamic acid, histidine-isoleucine, histidine-phenylalanine, histidine-tyrosine, Histidine-aspartic acid, histidine-methionine-glycine, histidine-methionine-arginine, histidine-methionine-proline, histidine-methionine-lysine, histidine-methionine-glutamic acid, histidine-methionine-isoleucine, histidine-methionine-phenylalanine , Histidine-methionine-tyrosine, or histidine-methionine-aspartic acid.
  • the histidine may be included in a buffer for maintaining the pH in the formulation, or may be included as a stabilizer for maintaining stability by minimizing changes to the anti-Her2 antibody.
  • histidine may be included in the form of a weak acid and a conjugate base or a mixture of a weak base and a conjugate acid.
  • histidine and histidine derivatives such as histidine salts, may be included, for example, histidine chloride, histidine phosphate, or histidine sulfate. Can include.
  • the formulation according to the present invention does not contain histidine acetate.
  • the formulation according to the present invention may include, for example, histidine-HCl, specifically histidine and histidine monohydrochloride monohydrate.
  • the formulation of the present invention may have a pH of 5.0 to 6.5, specifically, 5.0 to 6.0, and more specifically 5.5 to 6.0.
  • the pH may be about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.5.
  • Amino acids other than histidine may be polar, non-polar, hydrophilic and/or hydrophobic amino acids.
  • Amino acids other than histidine may be selected from the group consisting of, for example, methionine, cysteine, arginine, glycine, proline, lysine, glutamic acid, isoleucine, phenylalanine, tyrosine, and aspartic acid.
  • Amino acids other than histidine may be one or more selected from the group containing methionine, arginine, and glycine. According to a specific embodiment of the present invention, it was confirmed that the formulation containing methionine has high stability under high temperature stress conditions, freezing/thawing conditions, or stirring conditions. Moreover, it was confirmed that methionine can function as an antioxidant.
  • EDTA ethylenediaminetetraacetic acid
  • amino acids other than histidine or amino acids other than histidine and EDTA may be included at the same time.
  • the formulation according to the invention does not contain acetate.
  • “Not including” includes “substantially not including”.
  • “Not including” or “substantially not including” means that acetate is considered a component that does not favor or does not affect the stabilization of the anti-Her2 antibody in the formulation according to the present invention, and is excluded from the component of the formulation. it means.
  • the sugar or sugar alcohol includes the form of a polyol containing a plurality of hydroxyl groups.
  • the sugar or sugar alcohol may function as a stabilizer or tonicity agent in the formulation.
  • the sugar or sugar alcohol is, for example, glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol, melibiose, meletithose, raffinose.
  • Mannotriose, stachiose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, iso-maltulose may be selected from the group consisting of.
  • the anti-Her2 antibody exhibited stability under high temperature storage conditions, freeze-thaw conditions, or agitation conditions of the antibody in the formulation containing sucrose, sorbitol or trehalose.
  • the formulation may contain, for example:
  • Histidine-HCl glycine, methionine
  • Histidine-HCl glycine, lysine
  • Histidine-HCl glycine, glutamic acid
  • Histidine-HCl glycine, isoleucine
  • Histidine-HCl glycine, phenylalanine
  • Histidine-HCl glycine, tyrosine
  • Histidine-HCl glycine, aspartic acid.
  • the formulation according to the present invention includes (1) histidine-HCl including histidine and histidine monohydrochloride monohydrate, sucrose, methionine, (2) histidine-HCl, sorbitol including histidine and histidine monohydrochloride monohydrate. , Methionine, (3) histidine-HCl including histidine and histidine monohydrochloride monohydrate, trehalose, methionine, (4) histidine-HCl including histidine and histidine monohydrochloride monohydrate, arginine, methionine or (5) ) Histidine and histidine monohydrochloride monohydrate, including histidine-HCl, glycine, and methionine.
  • the molar ratio of sugar or sugar alcohol: anti-Her2 antibody in the formulation according to the present invention may be, for example, 500:1 to 700:1.
  • the molar ratio calculates the molar amount of the anti-Her2 antibody by considering the molecular weight of the anti-Her2 antibody as about 150 kDa, and the known molecular weight of the sugar or sugar alcohol (e.g., sucrose 342.3 g/mol, sorbitol 182.2 g/mol) In consideration of, after calculating the molar amount, the ratio of the molar amount of sugar or sugar alcohol to the molar amount of the anti-Her2 antibody can be calculated and confirmed.
  • the molar ratio of the sugar or sugar alcohol: anti-Her2 antibody may be 500:1 to 700:1, specifically 510:1 to 690:1, or 540:1 to 690:1.
  • the molar ratio of the sugar or sugar alcohol: anti-Her2 antibody is about 500:1, about 501:1, about 502:1, about 503:1, about 504:1, about 505:1, about 506:1, about 507 :1, about 508:1, about 509:1, about 510:1, about 511:1, about 512:1, about 513:1, about 514:1, about 515:1, about 516:1, about 517 :1, about 518:1, about 519:1, about 520:1, about 521:1, about 522:1, about 523:1, about 524:1, about 525:1, about 526:1, about 527 :1, about 528:1, about 529:1, about 530:1, about 531:1, about 532:1, about 533:1, about 534:1, about 535:1, about 536:1, about
  • the formulation according to the present invention may comprise histidine and a salt thereof, for example, histidine: histidine monohydrochloride monohydrate in a molar ratio of 0.2 to 3.0:1.
  • Histidine: Histidine monohydrochloride monohydrate about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5 , About 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0 Value may also be included).
  • the molar ratio calculates the molar amount of histidine taking into account the known molecular weight of histidine, e.g. L-histidine (e.g., 155.2 g/mol histidine), and the known molecular weight of histidine monohydrochloride monohydrate (e.g., 209.6 g/mol) mol), the molar amount is calculated, and then the ratio of the molar amount of histidine monohydrochloride monohydrate to the molar amount of histidine can be calculated and confirmed.
  • L-histidine e.g., 155.2 g/mol histidine
  • histidine monohydrochloride monohydrate e.g., 209.6 g/mol
  • the formulation according to the present invention may contain histidine at a concentration of 5 mM to 50 mM, for example 10 mM to 40 mM, 15 mM to 35 mM, or 20 mM to 30 mM.
  • the histidine is about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM , About 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about 35 mM,
  • the formulation includes, for example, 5 mM to 30 mM of amino acids other than histidine selected from the group consisting of methionine, cysteine, arginine, glycine, proline, lysine, glutamic acid, isoleucine, phenylalanine, tyrosine, and aspartic acid. It can be included in concentration. Amino acids other than histidine may be included in a concentration of 5 mM to 30 mM, for example, 7 mM to 20 mM, or 9 mM to 15 mM.
  • the formulation contains 50 mM amino acids other than histidine selected from the group consisting of, for example, methionine, cysteine, arginine, glycine, proline, lysine, glutamic acid, isoleucine, phenylalanine, tyrosine, and aspartic acid.
  • amino acids other than histidine are 50 mM to 150 mM, 60 mM to 140 mM, 70 mM to 135 mM, 80 mM to 135 mM, 90 mM to 135 mM, 100 mM to 140 mM, or 100 mM to 135 mM. It can be included in the concentration of.
  • the amino acid other than histidine is about 50 mM, about 51 mM, about 52 mM, about 53 mM, about 54 mM, about 55 mM, about 55 mM, about 56 mM, about 57 mM, about 58 mM, about 59 mM, about 60 mM, about 61 mM, about 62 mM, about 63 mM, about 64 mM, about 65 mM, about 66 mM, about 67 mM, about 68 mM, about 69 mM, about 70 mM, about 71 mM , About 72 mM, about 73 mM, about 74 mM, about 75 mM, about 76 mM, about 77 mM, about 78 mM, about 79 mM, about 80 mM, about 81 mM, about 82 mM, about 83 mM, about 84 mM, about 85 mM, about
  • the molar ratio of the anti-Her2 antibody: amino acids other than histidine may be 1:10 to 1:100, for example, 1:20 to 1:80, or 1:30 to 1:70.
  • the molar ratio of the anti-Her2 antibody: amino acids other than histidine is about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16 , About 1:17, about 1:18, about 1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26 , About 1:27, about 1:28, about 1:29, about 1:30, about 1:31, about 1:32, about 1:33, about 1:34, about 1:35, about 1:36 , About 1:37, about 1:38, about 1:39, about 1:40, about 1:41, about 1:42, about 1:43, about 1:44, about 1:45, about 1:46 , About 1:47, about 1:48, about 1:49, about 1:50, about 1:51
  • the molar ratio of amino acids other than histidine: anti-Her2 antibody may be 300:1 to 450:1, specifically 330:1 to 420:1, or 350:1 to 400:1.
  • the molar ratio of amino acids other than histidine: anti-Her2 antibody is about 300:1, about 301:1, about 302:1, about 303:1, about 304:1, about 305:1, about 306:1, about 307 :1, about 308:1, about 309:1, about 310:1, about 311:1, about 312:1, about 313:1, about 314:1, about 315:1, about 316:1, about 317 :1, about 318:1, about 319:1, about 320:1, about 321:1, about 322:1, about 323:1, about 324:1, about 325:1, about 326:1, about 327 :1, about 328:1, about 329:1, about 330:1, about 331:1, about 332:1, about 333:1, about 334:1, about 335:1, about 335
  • the molar ratio of amino acids other than histidine: anti-Her2 antibody may be 500:1 to 700:1, specifically 510:1 to 690:1, or 540:1 to 690:1.
  • the molar ratio of amino acids other than histidine: anti-Her2 antibody is about 500:1, about 501:1, about 502:1, about 503:1, about 504:1, about 505:1, about 506:1, about 507 :1, about 508:1, about 509:1, about 510:1, about 511:1, about 512:1, about 513:1, about 514:1, about 515:1, about 516:1, about 517 :1, about 518:1, about 519:1, about 520:1, about 521:1, about 522:1, about 523:1, about 524:1, about 525:1, about 526:1, about 527 :1, about 528:1, about 529:1, about 530:1, about 531:1, about 532:1, about 533:1, about 534:1, about 535:1, about
  • the calculation for the molar ratio is the same as described above.
  • the molar amount of the anti-Her2 antibody is calculated by considering the molecular weight of the anti-Her2 antibody as about 150 kDa, and the molar amount is calculated by considering the known molecular weight of amino acids other than histidine, and then amino acids other than histidine are calculated based on the molar amount of the anti-Her2 antibody. It can be checked by calculating the ratio of the molar amount.
  • the formulation may contain 50 mM to 150 mM sugar or sugar alcohol.
  • the sugar or sugar alcohol is 50 mM to 150 mM, 60 mM to 140 mM, 70 mM to 135 mM, 80 mM to 135 mM, 90 mM to 135 mM, 100 mM to 140 mM, or 100 mM to 135 mM It can be included in the concentration of.
  • the sugar or sugar alcohol is about 50 mM, about 51 mM, about 52 mM, about 53 mM, about 54 mM, about 55 mM, about 55 mM, about 56 mM, about 57 mM, about 58 mM, about 59 mM, about 60 mM, about 61 mM, about 62 mM, about 63 mM, about 64 mM, about 65 mM, about 66 mM, about 67 mM, about 68 mM, about 69 mM, about 70 mM, about 71 mM , About 72 mM, about 73 mM, about 74 mM, about 75 mM, about 76 mM, about 77 mM, about 78 mM, about 79 mM, about 80 mM, about 81 mM, about 82 mM, about 83 mM, about 84 mM, about 85 mM, about 80 m
  • concentration ranges of 5 to 50 mM, 50 mM to 150 mM, and 5 mM to 30 mM it can be understood that the formulation of the present invention includes all of any concentrations within each range.
  • the formulation may further include a bulking agent, a viscosity modifier, a stabilizer, a surfactant, an antioxidant, or a tonicity agent.
  • the formulation according to the present invention may include, for example, polysorbate, poloxamer, sodium dodecyl sulfate (SDS), sodium laurel sulfate (SLS), and the like.
  • the polysorbate is polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85 or its It may contain a mixture.
  • the formulation according to the present invention may comprise a polysorbate, for example polysorbate 20.
  • the formulation according to the present invention may comprise a polysorbate in a concentration of 0.01 to 0.1% (w/v) or 0.02 to 0.08% (w/v).
  • Formulations according to the invention are about 0.01% (w/v), about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v) , About 0.06% (w/v), about 0.07% (w/v), or about 0.08% (w/v) (values between listed values may also be included).
  • the anti-Her2 antibody may be, for example, pertuzumab.
  • Pertuzumab herein is a monoclonal antibody that targets HER2 and is marketed as Perjeta®.
  • Pertuzumab binds to region II of the extracellular matrix domain of the HER2 receptor and inhibits the formation of dimers, thereby inhibiting the receptor-mediated signaling pathway.
  • ErbB2 also known as HER2/neu, is the second member of the EGFR family and exhibits biological functions by forming a heterodimer with the other three members of the EGFR family, EGFR/HER1, HER3 and HER4.
  • the neu gene encoding ErbB2 was first isolated from rat neuroblastoma.
  • the homologous gene of the neu gene in human somatic cells is located on chromosome 17q21.1.
  • the encoded product is ErbB2, consisting of 1255 amino acids having a molecular weight of approximately 185 kDa, and the 720 to 987 amino acid positions belong to the tyrosine kinase active domain.
  • ErbB2 is dependent on the PI3K and MAPK signaling pathways, can reduce the expression of cyclin D and c-myc, and decreases the expression of the cyclin-dependent kinase (cdk) inhibitor p27kipl, inducing cell proliferation by inhibiting cdk2 activity. do.
  • Antibody means a protein capable of neutralizing, blocking, inhibiting, eliminating, reducing or interfering with a biological activity.
  • monoclonal antibody is meant an antibody molecule of single molecular composition obtained from a population of substantially the same antibody, ie the individual antibodies occupying the population are identical except for possible naturally occurring mutations that may be present in trace amounts.
  • Monoclonal antibodies are highly specific, so they are directed against a single antigenic site and exhibit a single binding specificity and affinity for a particular epitope.
  • the antibody includes not only the complete antibody form, but also the antigen-binding fragment of the antibody.
  • a complete antibody is a tetrameric protein of about 150 kDa with two full-length light chains and two full-length heavy chains, each of which is linked to a heavy chain by a disulfide bond.
  • Antigen-binding fragments or antibody fragments of an antibody may include Fab, F(ab'), F(ab')2, Fv, or an epitope-binding fragment thereof.
  • Fab is a structure having a variable region of a light and heavy chain, a constant region of a light chain, and a first constant region (CH1) of a heavy chain, and has one antigen-binding site.
  • F(ab') differs from Fab in that it has a hinge region containing one or more cysteine residues at the C-terminus of the heavy chain CH1 domain.
  • F(ab')2 antibodies are produced by disulfide bonds between cysteine residues in the hinge region of F(ab').
  • Fv fragments are antibody fragments that contain a complete antibody recognition and binding site.
  • the double-chain Fv (two-chain Fv) is a non-covalent bond where the heavy chain variable region and the light chain variable region are connected, and the single-chain Fv (scFv) is generally a heavy chain variable region and a light chain variable region through a peptide linker. It is connected by this covalent bond.
  • Heavy chain may refer to the heavy chain of an IgG antibody, and refers to both a full-length heavy chain including a variable region domain VH and three constant region domains CH1, CH2 and CH3 for conferring specificity to an antigen, and fragments thereof.
  • light chain as used herein may mean the light chain of an IgG antibody, and all of the full-length light chain including the variable region domain VL and the constant region domain CL for conferring specificity to the antigen and fragments thereof it means.
  • Variable domain refers to the light and heavy chain portions of an antibody molecule comprising the amino acid sequences of the complementarity determining regions (CDRs; ie, CDR1, CDR2, and CDR3), and framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • VH refers to the variable domain of the heavy chain.
  • VL refers to the variable domain of the light chain.
  • CDR complementarity determining region
  • the “skeletal region” (FR) is a variable domain residue other than a CDR residue.
  • Each variable domain typically has 4 FRs identified as FR1, FR2, FR3 and FR4.
  • the heavy chain constant region has gamma ( ⁇ ), mu ( ⁇ ), alpha ( ⁇ ), delta ( ⁇ ) and epsilon ( ⁇ ) types, and has subclasses of gamma 1 ( ⁇ 1), gamma 2 ( ⁇ 2), and gamma 3 ( ⁇ 3). ), gamma4( ⁇ 4), alpha1( ⁇ 1) and alpha2( ⁇ 2).
  • the constant region of the light chain has kappa ( ⁇ ) and lambda ( ⁇ ) types.
  • Epitope refers to a determinant to which an antibody can specifically bind. Epitopes are usually composed of a group of chemically active surface molecules, such as amino acids or sugar side chains, and generally have specific three-dimensional structural characteristics as well as specific charge characteristics.
  • Monoclonal antibodies refer to antibodies obtained from a population of substantially homogeneous antibodies, i.e., those that are identical except for possible naturally occurring mutations in which the individual antibodies occupying the population may be present in trace amounts. Monoclonal antibodies are highly specific and are thus directed against a single antigenic site.
  • a non-human (eg murine) antibody in its “humanized” form is a chimeric antibody that contains a minimal sequence derived from a non-human immunoglobulin.
  • Humanized antibodies are those of a non-human species (donor antibody), such as a mouse, rat, rabbit or non-human primate, that retain the desired specificity, affinity and ability of the hypervariable region residues of the recipient. It is a replaced human immunoglobulin (receptor antibody).
  • the heavy chain CDR, light chain CDR, VH and VL sequences of Pertuzumab according to the present invention are described in US7862817B2 or US7537931B2, which documents can be incorporated by reference.
  • unpaired cysteine variants of pertuzumab or VHS extension variants of pertuzumab including acidic variants or disulfide-reducing variants of pertuzumab may be included, and US8652474B2 or US9181346B2, acidic
  • the unpaired cysteine variants of Pertuzumab, including variants or disulfide reducing variants are described in US9815904B2, US9969811B, and VHS extension variants of Pertuzumab in US7560111B2, US8241630B2 or US7879325B2, respectively, This document may also be incorporated by reference.
  • Preparation of an anti-Her2 antibody involves a conventional antibody preparation method, e.g., inserting a nucleic acid encoding a pertuzumab antibody into a replicable vector, transfecting the vector into cells, and then culturing the cells and culturing them. It can be prepared through a method of recovering the antibody from the cell.
  • a method for preparing a Pertuzumab antibody is specifically described in US 7879325 or US 8241630, and the document can be incorporated by reference.
  • Perturb comprising a sequence that is 85% or more, specifically 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, or 100% identical to the sequence Zumab antibodies may be included.
  • the identity of the sequences can be determined by comparing two sequences that are optimally aligned, and additions or deletions (i.e., gaps) compared to a reference sequence (not including additions or deletions) for optimal alignment of the two sequences. It may include.
  • Identity is expressed as a percentage, and the percentage determines the number of positions in which the same nucleic acid base or amino acid residue appears in both sequences to generate the number of matched positions, and the number of matched positions is divided by the total number of positions, and the It can be calculated by multiplying the result by 100.
  • the percent sequence identity can be determined, for example, using the Needle program, the BLOSUM62 matrix program, and the like.
  • the anti-Her2 antibody may be included in an amount effective for effective treatment or prevention of a disease. Accordingly, the anti-Her2 antibody may be included in a concentration of 20 mg/ml to 150 mg/ml. In the formulation according to the present invention, the anti-Her2 antibody may be 25 mg/ml to 130 mg/ml, 30 mg/ml to 110 mg/ml, or 40 mg/ml to 100 mg/ml.
  • the anti-Her2 antibody is about 20 mg/ml, about 21 mg/ml, about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 mg/ml, about 26 mg/ml, About 27 mg/ml, about 28 mg/ml, about 29 mg/ml, about 30 mg/ml, about 31 mg/ml, about 32 mg/ml, about 33 mg/ml, about 34 mg/ml, about 35 mg/ml, about 36 mg/ml, about 37 mg/ml, about 38 mg/ml, about 39 mg/ml, about 40 mg/ml, about 41 mg/ml, about 42 mg/ml, about 43 mg/ ml, about 44 mg/ml, about 45 mg/ml, about 46 mg/ml, about 47 mg/ml, about 48 mg/ml, about 49 mg/ml, about 50 mg/ml, about 51 mg/ml, About 52 mg/ml, about 53 mg/ml, about 54 mg/ml, about
  • the present invention may be a formulation for IV administration containing an anti-Her2 antibody at a concentration of 20 mg/ml to 30 mg/ml.
  • an anti-Her2 antibody at a concentration of 20 mg/ml to 30 mg/ml.
  • the present invention relates to a formulation containing an anti-Her2 antibody and two or more amino acids, no acetate, and maintaining or improving stability under high temperature storage conditions, freezing/thawing conditions, or stirring conditions.
  • the formulation according to the present invention may further contain sugar or sugar alcohol.
  • the sugar or sugar alcohol is, for example, glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol, melibiose, meletithose, raffinose.
  • Mannotriose, stachiose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, iso-maltulose may be selected from the group consisting of.
  • the anti-Her2 antibody exhibited stability under high temperature storage conditions, freeze-thaw conditions, or agitation conditions of the antibody in the formulation containing sucrose, sorbitol or trehalose.
  • a “stable” formulation is one that maintains the physical stability, chemical stability or biological activity of the anti-Her2 antibody from mechanical stress, thermal stress, or stress resulting from freezing and thawing, at a selected temperature for a selected period of time, for example about 5 ⁇ At least about 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks at 3°C, about 25 ⁇ 2°C or about 40 ⁇ 2°C , 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 Stable for a period of weeks or longer, or after freezing (eg -20°C or -70°C) and thawing, eg, after freezing and thawing in 1, 2, 3, 4, 5, or more cycles Or, it means that it is stable under agitation stress conditions, for example, 100 rpm or more, 200 rpm or more, 300 rpm
  • Assessment of aggregation formation e.g., using size exclusion chromatography or measuring turbidity and/or visual inspection), cation exchange chromatography, evaluation of charge heterogeneity using image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis, amino- Terminal or carboxy-terminal sequence analysis, mass spectrometric analysis, SDS-PAGE analysis comparing reduced and intact antibodies, peptide map (e.g., trypsin or LYS-C) analysis, or biological activity or antigen of the antibody Stability can be evaluated through various methods including evaluation of binding function and the like.
  • image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis evaluation of charge heterogeneity using image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis
  • amino- Terminal or carboxy-terminal sequence analysis e.g., mass spectrometric analysis
  • SDS-PAGE analysis comparing reduced and intact antibodies
  • UV light scattering or size exclusion chromatography SEC
  • the antibody is not modified by cleavage or bond formation, it may mean that the antibody remains chemically stable. Chemical stability can be ascertained by detecting and quantifying the chemically modified form of the antibody.
  • the biological activity of the antibody by antigen binding assay or neutralization assay is about 70% to about 150%, about 80% to about 125%, or about 90% to about 110% of the antibody biological activity at the time of preparation of the formulation
  • the biological activity is It can mean keeping.
  • the biological activity of the antibody under certain conditions and times is 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% of the antibody biological activity at the time of preparation of the formulation, If it is 105%, 110%, 115%, 120% or 125%, biological activity can be maintained.
  • the biological activity of an anti-Her2 antibody can be ascertained, for example, through the level of Her2 binding. Specifically, the biological activity of the anti-Her2 antibody can be measured through Receptor-Binding Activity (RBA).
  • RBA Receptor-Binding Activity
  • the Her2 binding level measured by confirming the receptor binding activity under storage conditions of 40°C ⁇ 2°C for 8 weeks in the formulation according to the present invention may be, for example, 92% or more, specifically 92 to 97%.
  • the Her2 binding level measured by confirming the receptor-binding activity under storage conditions of 40°C ⁇ 2°C for 12 weeks may be, for example, 90% or more, specifically 90 to 95%.
  • the Her2 binding level measured by confirming the receptor binding activity under storage conditions of 5°C ⁇ 3°C for 8 weeks in the formulation according to the present invention may be, for example, 97% or more, specifically 97 to 99%.
  • the Her2 binding level measured by confirming the receptor binding activity in the formulation of -70 ⁇ 10° C. 1 cycle or more, for example 5 cycles of freeze/thaw cycle in the formulation according to the present invention is, for example, 97 % Or more, specifically 97 to 99%.
  • the stability of the antibody in the formulation can be determined by identifying aggregation or fragment levels in the formulation. It can be determined by measuring whether a high molecular weight product (HMW) and/or a low molecular weight species (LMW) are formed in the formulation. The content of the high molecular weight product and/or the low molecular weight product in the formulation can be measured under certain temperature conditions. The content of the high molecular weight product and/or the low molecular weight product can be measured by size exclusion HPLC (SE-HPLC).
  • HMW high molecular weight product
  • LMW low molecular weight species
  • the stability of the antibody in the formulation can be determined by measuring whether a high molecular weight product (HMW) is formed in the formulation.
  • HMW high molecular weight product
  • the amount of change in HMW in the formulation can be measured under specific temperature conditions, and the HMW can be measured by size exclusion HPLC (SE-HPLC).
  • the% content of HMW measured by size exclusion HPLC was 6.0% or less, 5.0% or less, 4.0% or less, 3.0% or less, 2.0% or less, 1.0% or less, 0.9% or less, 0.8% It may be 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less.
  • the HMW measured by size exclusion HPLC (SE-HPLC) at 40° C. ⁇ 2° C. for 1 week or more in the formulation according to the present invention may be 0.5% or less.
  • the% of HMW content measured through size exclusion HPLC (SE-HPLC) in the formulation under storage conditions at a temperature of 40° C. ⁇ 2° C. for 1 week is, for example, 0.27% or less, specifically 0.16 to 0.27%.
  • the content% of HMW measured through size exclusion HPLC (SE-HPLC) in the formulation under storage conditions at a temperature of 40°C ⁇ 2°C for 2 weeks may be, for example, 0.33% or less, specifically 0.17 to 0.33%.
  • the content% of HMW measured through size exclusion HPLC (SE-HPLC) in the formulation under storage conditions at a temperature of 40°C ⁇ 2°C for 4 weeks may be, for example, 0.4% or less, specifically 0.20 to 0.4%.
  • the content% of HMW measured through size exclusion HPLC (SE-HPLC) in the formulation under storage conditions at a temperature of 40°C ⁇ 2°C for 8 weeks may be, for example, 0.48% or less, and specifically 0.24 to 0.48%.
  • the HMW content% measured through size exclusion HPLC (SE-HPLC) in the formulation at a temperature of 40° C. ⁇ 2° C. for 1 week storage conditions is, for example, 0.2% or less, specifically 0.15 to 0.2%.
  • the content% of HMW measured through size exclusion HPLC (SE-HPLC) in the formulation at a temperature of 40°C ⁇ 2°C for 2 weeks storage may be, for example, 0.25% or less, specifically 0.2 to 0.25%.
  • the content% of HMW measured through size exclusion HPLC (SE-HPLC) in the formulation under storage conditions at a temperature of 40°C ⁇ 2°C for 8 weeks may be, for example, 0.5% or less, specifically 0.35 to 0.5%.
  • the content% of HMW measured through size exclusion HPLC (SE-HPLC) in the formulation under storage conditions at a temperature of 40°C ⁇ 2°C for 12 weeks may be, for example, 0.6% or less, and specifically 0.35 to 0.6%.
  • HMW measured by size exclusion HPLC (SE-HPLC) in the formulation of 1 cycle or more freeze/thaw cycle is 2.0% or less, 1.0% or less, 0.9% or less, 0.8% or less, 0.7% Or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.25% or less, 0.2% or less, 0.15% or less, or 0.1% or less.
  • HMW measured through size exclusion HPLC (SE-HPLC) under 400 rpm stirring conditions may be 0.25% or less, 0.2% or less, 0.15% or less, or 0.1% or less.
  • the% content of HMW measured via size exclusion HPLC (SE-HPLC) in the formulation of 1 cycle or more, eg 5 cycles of freeze/thaw cycles is, for example, 2.0 % Or less, 1.0% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.25% or less, 0.2% or less, specifically 0.1 to 0.2% I can.
  • the content% of HMW measured by size exclusion HPLC (SE-HPLC) in the formulation at 400 rpm stirring conditions is, for example, 2.0% or less, 1.0% or less, 0.9% or less, 0.8% or less, 0.7% It may be less than, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.25% or less, specifically 0.15 to 0.25%.
  • the content% of the antibody monomer in the formulation may be 96% or more, 97% or more, 98% or more, 99% or more, or 100%.
  • the content of the antibody monomer may be 96% or more, 97% or more, 98% or more, 99% or more, or 100%.
  • the percentage of the IgG content in the formulation measured by CE-SDS (Capillary electrophoresis with sodium dodecylsulfate) at 40°C ⁇ 2°C for 8 weeks is, for example, 90% or more, specifically 90% to 93%.
  • the amount of IgG in the formulation measured through CE-SDS at 40° C. ⁇ 2° C. for 12 weeks may be, for example, 87% or more, and specifically 87% to 89%.
  • the% of the IgG content in the formulation measured through CE-SDS at a temperature of 5°C ⁇ 3°C for 8 weeks may be, for example, 95% or more, specifically 95% to 97%.
  • the percentage of the IgG content in the formulation measured through CE-SDS under conditions of 5°C ⁇ 3°C for 12 weeks may be, for example, 94% or more, and specifically 94% to 95%.
  • the percentage of IgG content measured through CE-SDS in the formulation of 1 cycle or more, eg, 5 cycles of freeze/thaw cycle is, for example, 95% or more, specifically It may be 95% to 97%.
  • the stability of the antibody in the formulation can be determined by measuring whether a variant in the antibody is formed.
  • the variant may mean, for example, an antibody having an amino acid sequence different from that of the main antibody, and may include substitution, deletion, and/or addition of amino acids at a specific position within or adjacent to the amino acid sequence of the antibody.
  • the variant may include a change in charge due to modification of the antibody, and may be, for example, a charge variant.
  • Charged variants can be acidic and have low pI values compared to unmodified antibodies. Acidic variants can be produced when they have a negative charge or lose a positive charge than the main antibody.
  • the charge variant may exhibit basicity compared to an unmodified antibody and may have a high pI value. Basic variants can be produced if they have a positive charge or lose a negative charge than the main antibody.
  • These charge variants can occur by oxidation of antibodies, deamidation, processing of the C-terminus of the lysine residue, formation of pyroglutamate at the N-terminus, and non-enzymatic glycosylation.
  • the charge variants may be separated by ion exchange chromatography, for example, cation exchange chromatography to separate proteins according to charge, or charge heterogeneity may be confirmed by image capillary isoelectric focusing (icIEF).
  • the content% of acidic variant or basic variant measured by cation exchange HPLC during the period is 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 19% or less, It may be 18% or less, 17% or less, 15% or less, or 10% or less.
  • icIEF Imaged Capillary Isoelectric Focusing
  • the content% of the acidic variant may be 70% or less under conditions of 1 week or more.
  • the content% of the acidic variant in the formulation measured by icIEF at a temperature of 40° C. ⁇ 2° C. for 2 weeks storage may be, for example, 45% or less, and specifically 44.0 to 44.5%.
  • the content% of the acidic variant in the formulation measured by icIEF at a temperature of 40°C ⁇ 2°C for 4 weeks storage may be, for example, 53% or less, specifically 50 to 53%.
  • the content% of the acidic variant in the formulation measured by icIEF at a temperature of 40°C ⁇ 2°C for 8 weeks storage may be, for example, 65% or less, specifically 60 to 65%.
  • the content% of the acidic variant in the formulation measured by icIEF at a temperature of 40°C ⁇ 2°C for 12 weeks storage may be, for example, 70% or less, specifically 65 to 70%.
  • the content% of acidic variant or basic variant in the formulation of 1 cycle or more of freeze/thaw cycle is 20% or less, 18% or less, 17% or less, 15% or less, 10% or less, 5% or less, 4% Or less, 3% or less, 2% or less, and 1% or less.
  • the content% of acidic variant or basic variant in the formulation under 400 rpm stirring conditions is 20% or less, 18% or less, 17% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% It is less than or equal to 1%.
  • the content% of the acidic variant in the formulation under the conditions of -70 °C ⁇ 10 °C freeze/thaw 5 cycles is, for example, 38% or less, specifically 36 to It could be 38%.
  • the formulation according to the present invention can be evaluated as stable for at least 1 month, at least 2 months, at least 3 months, or at least 6 months at 5°C ⁇ 3°C or more, particularly 40°C ⁇ 2°C.
  • the formulation according to the present invention can be evaluated as stable after freezing and thawing at -70°C ⁇ 10°C, freezing and thawing at -70 ⁇ 10°C for 24 hours, and then thawing at room temperature for 90 minutes Including, the cycle may be repeated 1-5 times, and maintained for 72 hours at a temperature of -70 ⁇ 10°C in the fifth cycle.
  • it can be evaluated as stable after stirring under the stirring conditions of 400 rpm.
  • the anti-Her2 antibody may be included in a therapeutically effective amount.
  • Effective amount refers to an amount necessary or sufficient to bind to region II of the extracellular matrix domain of the HER2 receptor to inhibit the formation of dimers, thereby inhibiting receptor-mediated signaling pathways. For example, it is the amount necessary to prevent or treat various morphological symptoms of conditions associated with dimer formation of HER2.
  • the symptom is cancer, it may be an amount necessary for reducing the number of cancer cells, reducing the size of the tumor, inhibiting invasion of cancer cells, inhibiting tumor metastasis, inhibiting tumor growth, or reducing symptoms of cancer.
  • An effective amount can prolong the survival period without disease progression, increase the overall survival period, or ameliorate adverse symptoms caused by cancer.
  • the effective amount may vary depending on the subject's height, weight, type or severity of the disease.
  • An effective amount can be determined and administered to a subject. As well as divided doses, it may be administered daily or continuously in alternating doses. The dose may be increased or decreased proportionally depending on the purpose of treatment, drugs used in combination, and the like.
  • Treatment includes the reduction or relief of one or more symptoms associated with or caused by the condition, disorder or disease being treated.
  • treatment can reduce one or more symptoms of the disorder or can completely eliminate the disorder.
  • the level of administration of the anti-Her2 antibody can vary in an amount effective for the desired therapeutic response through the patient, without toxicity to the patient. Dosage is the activity of the anti-Her2 antibody in the formulation, route of administration, time of administration, duration of treatment, other drugs and/or compounds in combination, age, sex, weight, symptoms, general health condition, and previous medical history of the patient to be treated. It can be determined through various factors including.
  • Anti-Her2 antibodies can be administered in combination with other Her2 target antibodies or chemotherapeutic agents. Concomitant administration includes co-administration and sequential administration using separate formulations or single pharmaceutical formulations. Other Her2 target antibodies or chemotherapeutic agents may be administered before or after administration of the anti-Her2 antibody. Other Her2 target antibodies or chemotherapeutic agents can be administered concurrently with administration of the anti-Her2 antibody.
  • Her2 target antibodies may be antibodies that bind to HER2 and inhibit the growth of cancer cells that overexpress HER2, and may be, for example, trastzumab (Herceptin®).
  • Chemotherapeutic agents are compounds useful in the treatment of cancer, such as anthracyclines, alkylating agents (e.g., mitomycin C), alkyl sulfonates, aziridines, ethylenimine, methylmelamine, nitrogen mustard, nitrosourea, antibiotics. , Antimetabolites, folic acid analogs (e.g., dihydrofolate reductase inhibitors such as methotrexate), purine analogs, pyrimidine analogs, enzymes, podophyllotoxin, or platinum-containing agents, and the like.
  • alkylating agents e.g., mitomycin C
  • alkyl sulfonates e.g., aziridines, ethylenimine, methylmelamine, nitrogen mustard, nitrosourea, antibiotics.
  • Antimetabolites folic acid analogs (e.g., dihydrofolate reductase inhibitors such as methotrexate), purine analogs
  • Antibody dosages can generally be from about 0.1 mg/kg to about 50 mg/kg. When administering a chemotherapeutic agent, it is usually administered at a known dosage, or a lower amount of the antibody may be administered due to side effects resulting from the administration of the chemotherapeutic agent or the combined action of drugs.
  • the dosing schedule and preparation for the chemotherapeutic agent can be used according to the manufacturer's instructions, or can be determined experimentally by a skilled person.
  • compositions are administered to a patient by, for example, intravenous administration, intramuscular, intraperitoneal, cerebrospinal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, topical, or inhalation routes. It is preferred to administer intravenously, intramuscularly or subcutaneously, and the pharmaceutical formulation of the present invention may be administered intravenously.
  • Syringes for subcutaneous administration Injection devices (eg INJECT-EASETM and GENJECTTM devices); Syringe pens (eg GENPENTM); Needleless devices (eg MEDIJECTORTM and BIOJECTORTM);
  • a subcutaneous patch delivery system can be used.
  • Articles of manufacture may include bottles, vials (eg double chamber vials), syringes (eg double chamber syringes) or tubular containers.
  • the container can be made of glass or plastic.
  • the container contains the formulation of the present invention, and instructions for use may be indicated on the container or on a label affixed to the container.
  • the article of manufacture may further include package inserts indicating instructions for further configuration and use, such as other buffers, diluents, fillers, needles, and syringes.
  • Pertuzumab antibody formulation was prepared as in Table 1. With regard to the sequence of the Pertuzumab antibody, reference may be made to the specific antibody sequence described in US7862817B2 or US7537931B2. Regarding the acidic variant of Pertuzumab, US8652474B2 or US9181346B2, the unpaired cysteine variants of Pertuzumab including the acidic variant or the reducing disulfide variant are US9815904B2, US9969811B, VHS extension variants of Pertuzumab (VHS extension variants). For more information, reference may be made to US7560111B2, US8241630B2 or US7879325B2.
  • Pertuzumab antibody was concentrated to 36 mg/mL or more, and pH 4.0-5.0 acetate (acetate), pH 5.0-6.0 histidine-HCl, pH 6.0-7.0 phosphate (phosphate) was used in the concentrated DS (drug substance). , Divided into 3 times at 3, 5, and 10 hour intervals and dialyzed in a 2-8°C cold chamber, pH 4.0-5.0 acetate (acetate), pH 5.0-6.0 histidine-HCl, pH 6.0- Exchange was carried out with each of 7.0 phosphates (phosphates).
  • the pH range of the sample was selected according to the intrinsic characteristics of the three components, and Samples 3 and 4 were the same as pH 5.0, and Samples 6 and 7 were the same as pH 6.0, and the average value was described by repeating three experiments.
  • the commercially available control drug Perjeta® contains histidine-acetate, and the average value was recorded by repeating three experiments.
  • Example 1-1 The sample of Table 1 prepared in Example 1-1 was filled into a vial by 0.5 mL, and samples were placed in a chamber for 1 week, 2 weeks, and 4 weeks in a 40°C ⁇ 2°C stability chamber. -in), and chamber-out the sample at each time point.
  • SE-HPLC Size Exclusion High Performance Liquid Chromatography: Tosoh Bioscience
  • HMW High molecular weight species
  • monomer and LMW high molecular weight species
  • monomers monomers
  • LMW Low molecular weight species
  • Example 1-2 it was confirmed that the composition containing histidine-HCl at pH 5.0-6.0 has better stability than the composition containing acetate or phosphate, and exhibits equivalent or higher stability compared to Perjeta®. .
  • a pertuzumab formulation according to Table 3 was prepared in the same manner as in Example 1-1.
  • Example 1-2 in order to further study the formulations containing histidine-HCl of Samples 4 to 6, which were effective in terms of %HMW, the same pH as Perjeta® was fixed to 6.0, and as an additional component, a predetermined concentration of sugar, The stability of the composition comprising a sugar alcohol or a second amino acid was compared.
  • the other composition was the same, but histidine-HCl was replaced with succinate (succinate), and the results were compared.
  • Samples 1, 6, and Perjeta® were of the same composition except that succinate, histidine-HCl, and histidine-acetate were included, and the average value was confirmed by performing 3 repeated experiments.
  • 1 week, 2 By confirming the experimental results up to weeks, 4 weeks and 8 weeks, it was attempted to confirm a little more long-term stability.
  • Example 2-1 The sample of Table 3 prepared in Example 2-1 was filled into a vial with 0.5 mL each, and samples for 1 week, 2 weeks, 4 weeks, and 8 weeks in a 40°C ⁇ 2°C stability chamber were each timed. Chamber-out at the point. Using SE-HPLC, HMW, monomer and LMW ratios were analyzed for each sample under the conditions of 40° C. ⁇ 2° C. initial, 1 week, 2 weeks, 4 weeks and 8 weeks. The analysis results are shown in Table 4 and FIGS. 4 to 6.
  • samples 6 to 10 containing sucrose, trehalose, sorbitol, arginine, and glycine along with histidine-HCl had less %HMW compared to Perjeta®, and thus were more stable.
  • samples 6 to 10 containing sucrose, trehalose, sorbitol, arginine, and glycine along with histidine-HCl had less %HMW compared to Perjeta®, and thus were more stable.
  • samples 6 to 10 containing sucrose, trehalose, sorbitol, arginine, and glycine along with histidine-HCl had less %HMW compared to Perjeta®, and thus were more stable.
  • Example 7 A formulation according to Table 7 was prepared in the same manner as in Example 1-1. Among the additional ingredients having good effects in Example 2, the concentration of sucrose, sorbitol, and glycine was changed, and methionine, a third amino acid, was added thereto to confirm the formulation stability. The samples were subjected to 3 repeated experiments to confirm the result as an average value, and compared with the Perjeta® experimental value of Example 2.
  • Table 8 shows the concentrations of L-histidine and L-histidine monohydrochloride monohydrate contained in the sample containing 20 mM histidine-HCl to adjust the pH to 5.5, 6.0, and 6.5, respectively.
  • Example 3-1 The sample of Table 7 prepared in Example 3-1 was filled into a vial with 0.5 mL each, and samples for 1 week, 2 weeks, 4 weeks, and 8 weeks were each time in a 40°C ⁇ 2°C stability chamber. Chamber-out at the point. Using SE-HPLC, HMW, monomer and LMW ratios were analyzed for each sample under the conditions of 40° C. ⁇ 2° C. initial, 1 week, 2 weeks, 4 weeks and 8 weeks. The analysis results are shown in Table 9 and FIGS. 9 to 11.
  • HMW, monomer and LMW ratios were analyzed for each sample of Table 12 under the conditions of 40°C ⁇ 2°C initial, 1 week, 2 weeks, 4 weeks and 8 weeks. The analysis results are shown in Table 13 and FIGS. 14 to 16.
  • Sample 13 (Example 3) were confirmed to be more stable due to less %HMW, and among them, 3 than Sample 10 (Example 2), Sample 3 (Example 3) and Sample 8 (Example 3) containing two kinds of amino acids. It was confirmed that Sample 13 (Example 3) containing species of amino acids had the least %HMW and was the most stable.
  • Sample 13 (Example 3) were confirmed to be more stable due to less %HMW, and among them, 3 than Sample 10 (Example 2), Sample 3 (Example 3) and Sample 8 (Example 3) containing two kinds of amino acids. It was confirmed that Sample 13 (Example 3) containing species of amino acids had the least %HMW and was the most stable.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un anticorps anti-Her2 et présentant une excellente stabilité.
PCT/KR2020/015969 2019-11-15 2020-11-13 Composition en phase liquide pour médicament à base d'anticorps WO2021096278A1 (fr)

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WO2023202685A1 (fr) * 2022-04-22 2023-10-26 Eirgenix, Inc. Compositions pharmaceutiques contenant un anticorps anti-her2 pour administration sous-cutanée

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KR20130041374A (ko) * 2009-07-31 2013-04-24 에프. 호프만-라 로슈 아게 피하용 항-에이치이알2 항체 제형
WO2018187057A1 (fr) * 2017-04-06 2018-10-11 Regeneron Pharmaceuticals, Inc. Formulation stable d'anticorps
KR20190088081A (ko) * 2016-12-16 2019-07-25 삼성바이오에피스 주식회사 안정한 액상의 항-c5 항체 조성물
KR20190104554A (ko) * 2017-01-17 2019-09-10 제넨테크, 인크. 피하 her 2 항체 제형

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KR20130041374A (ko) * 2009-07-31 2013-04-24 에프. 호프만-라 로슈 아게 피하용 항-에이치이알2 항체 제형
KR20190088081A (ko) * 2016-12-16 2019-07-25 삼성바이오에피스 주식회사 안정한 액상의 항-c5 항체 조성물
KR20190104554A (ko) * 2017-01-17 2019-09-10 제넨테크, 인크. 피하 her 2 항체 제형
WO2018187057A1 (fr) * 2017-04-06 2018-10-11 Regeneron Pharmaceuticals, Inc. Formulation stable d'anticorps

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KRISTINA KEMTER, JENS ALTRICHTER, ROLAND DERWAND, THOMAS KRIEHUBER, EVA REINAUER, MARTIN SCHOLZ: "Amino Acid-Based Advanced Liquid Formulation Development for Highly Concentrated Therapeutic Antibodies Balances Physical and Chemical Stability and Low Viscosity", BIOTECHNOLOGY JOURNAL, WILEY-VCH VERLAG, WEINHEIM, DE, vol. 13, no. 7, 1 July 2018 (2018-07-01), DE, pages 1700523, XP055494715, ISSN: 1860-6768, DOI: 10.1002/biot.201700523 *
ROBERT J FALCONER, CHERRINE CHAN, KAREN HUGHES, TRENT P MUNRO: "Stabilization of a monoclonal antibody during purification and formulation by addition of basic amino acid excipients", JOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, PUBLISHED FOR THE SOCIETY OF CHEMICAL INDUSTRY BY BLACKWELL SCIENTIFIC PUBLICATIONS, vol. 86, no. 7, 7 July 2011 (2011-07-07), pages 942 - 948, XP055076799, ISSN: 02682575, DOI: 10.1002/jctb.2657 *

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