WO2022151940A1 - 一种稳定的帕妥珠单抗的药物组合物 - Google Patents
一种稳定的帕妥珠单抗的药物组合物 Download PDFInfo
- Publication number
- WO2022151940A1 WO2022151940A1 PCT/CN2021/140703 CN2021140703W WO2022151940A1 WO 2022151940 A1 WO2022151940 A1 WO 2022151940A1 CN 2021140703 W CN2021140703 W CN 2021140703W WO 2022151940 A1 WO2022151940 A1 WO 2022151940A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polysorbate
- pharmaceutical composition
- pertuzumab
- acid
- histidine
- Prior art date
Links
- 229960002087 pertuzumab Drugs 0.000 title claims abstract description 70
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 65
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims abstract description 21
- 229930182817 methionine Natural products 0.000 claims abstract description 21
- 229930006000 Sucrose Natural products 0.000 claims abstract description 17
- 239000003381 stabilizer Substances 0.000 claims abstract description 17
- 239000005720 sucrose Substances 0.000 claims abstract description 17
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims abstract description 14
- 229960003589 arginine hydrochloride Drugs 0.000 claims abstract description 14
- 239000004094 surface-active agent Substances 0.000 claims abstract description 13
- 239000000872 buffer Substances 0.000 claims abstract description 12
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 7
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 7
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 7
- 238000009472 formulation Methods 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 17
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 17
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 17
- 229940068977 polysorbate 20 Drugs 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 8
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 8
- 229920000053 polysorbate 80 Polymers 0.000 claims description 8
- 229940068968 polysorbate 80 Drugs 0.000 claims description 8
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 7
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 229920000136 polysorbate Polymers 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229950008882 polysorbate Drugs 0.000 claims description 6
- 238000001990 intravenous administration Methods 0.000 claims description 5
- -1 octyl glycoside Chemical class 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000001802 infusion Methods 0.000 claims description 3
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- 229920002642 Polysorbate 65 Polymers 0.000 claims description 2
- 229920002651 Polysorbate 85 Polymers 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000007983 Tris buffer Substances 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 229930182470 glycoside Natural products 0.000 claims description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- IZWSFJTYBVKZNK-UHFFFAOYSA-N lauryl sulfobetaine Chemical compound CCCCCCCCCCCC[N+](C)(C)CCCS([O-])(=O)=O IZWSFJTYBVKZNK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 2
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 claims description 2
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- 239000000843 powder Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 125000000185 sucrose group Chemical group 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 238000010255 intramuscular injection Methods 0.000 claims 1
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- 239000007929 subcutaneous injection Substances 0.000 claims 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 abstract description 15
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Classifications
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/812—Breast
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/828—Stomach
Definitions
- the invention belongs to the field of biotechnology, and in particular relates to a pharmaceutical composition of Pertuzumab containing methionine as an antioxidant.
- Pertuzumab is a new type of anti-HER2 monoclonal antibody, which was first launched in the United States in June 2012. It is mainly used in combination with trastuzumab for the treatment of patients with HER2-positive advanced metastatic breast cancer. By binding to HER2, Pertuzumab blocks the heterodimerization of HER2 with other receptors, thereby slowing tumor growth.
- Pertuzumab is a humanized monoclonal antibody that is currently listed by Roche It is a water injection preparation, and the marketed prescription contains Pertuzumab 30mg/mL, 120mM sucrose, 0.2mg/ml polysorbate 80, 20mM histidine-acetate buffer, pH 6.0. Among them, Pertuzumab is the main drug in the prescription; sucrose is a stabilizer; polysorbate 20 is a surfactant; histidine-acetic acid is a pH adjuster.
- Pertuzumab is unstable and undergoes various chemical and physical degradations.
- biomolecules Compared with traditionally synthesized small-molecule drugs, biomolecules have complex structures, such as primary, secondary, and tertiary structures.
- the structure of protein, especially the higher-order structure, is very fragile and prone to structural changes, such as denaturation, aggregation and precipitation. Maintaining the higher-order structure of antibodies is the most basic requirement for exerting their biological activity.
- These degradation products can have a great impact on the safety of biopharmaceuticals.
- some protein aggregates will stimulate the body's immune response, which will reduce the efficacy of biological drugs in mild cases, and even cause the death of patients in severe cases.
- CQA critical quality attribute
- the object of the present invention is to provide a stable Pertuzumab composition and use thereof, the composition prepared by the present invention can still maintain physical and chemical stability under the destruction of light or for a long time, compared with the existing Technology has been greatly improved.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- stabilizer is selected from sucrose, trehalose or arginine hydrochloride, preferably arginine hydrochloride;
- the pH of the formulation is 5.0-6.8, preferably the pH is 5.0-6.0.
- the concentration of Pertuzumab is 3-30 mg/ml.
- the concentration of Pertuzumab is 30-60 mg/ml.
- the concentration of methionine is 10-40 mM, preferably 20-40 mM.
- the concentration of the stabilizer is 100-140 mM, preferably 110-130 mM, more preferably 115-125 mM.
- the buffer is selected from the group consisting of glycine, acetic acid/acetate, succinic acid/succinate, citric acid/citrate, ascorbic acid/ascorbate, tartaric acid/tartrate, maleic acid /maleate, lactic acid/lactate, carbonic acid/bicarbonate, benzoic acid/benzoate, histidine, histidine/hydrochloric acid, histidine/acetic acid, phosphoric acid/phosphate or tris /tris hydrochloride, preferably histidine-hydrochloric acid, histidine-acetic acid, phosphoric acid/phosphate, more preferably histidine-hydrochloric acid, histidine-acetic acid.
- the concentration of the buffer is 10-30 mM, preferably 15-25 mM.
- the surfactants include, but are not limited to, polysorbates such as polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer, triton, sodium lauryl sulfate, sodium lauryl sulfate, sodium octyl glycoside, lauryl-sulfobetaine, polyethylene Diol or polypropylene glycol, preferably polysorbate 20 or polysorbate 80.
- polysorbates such as polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer, triton, sodium lauryl sulfate, sodium lauryl sulfate, sodium octyl glycoside, lauryl-sulfobetaine, polyethylene Diol or polypropylene glycol, preferably
- the concentration of the surfactant is 0.01-5 mg/ml, preferably 0.05-0.5 mg/ml.
- the pharmaceutical composition of the present invention further contains a pharmaceutically acceptable amount of a chelating agent including, but not limited to, aminopolycarboxylic acids, hydroxyaminocarboxylic acids, N-substituted glycines, citric acid, niacinamide, desferri Amines and deoxycholate salts and mixtures thereof, such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA) and their salts.
- EDTA ethylenediaminetetraacetic acid
- DTPA diethylenetriaminepentaacetic acid
- NDA nitrilotriacetic acid
- the chelating agent used in the present invention can exist in the form of free acid or free base or salt of the compound, and can also exist in the form of anhydrous, hydrate or other solvate of the compound or the corresponding salt.
- the pharmaceutical composition of the present invention further contains a pharmaceutically acceptable amount of a preservative, including but not limited to m-cresol, phenol, benzyl alcohol, benzalkonium chloride, phenoxyethanol, or methylparaben ester.
- a preservative including but not limited to m-cresol, phenol, benzyl alcohol, benzalkonium chloride, phenoxyethanol, or methylparaben ester.
- the pharmaceutical composition of the present invention contains the following components:
- pH is 5.0-6.0.
- the pharmaceutical composition of the present invention contains the following components:
- histidine-histidine hydrochloride or histidine-acetate buffer 15-25mM, preferably 20mM;
- pH is 5.0-6.0.
- the pharmaceutical composition of the present invention contains the following components:
- pH is 6.0.
- the pharmaceutical composition of the present invention can be a water injection preparation, a freeze-dried preparation, or a preparation form prepared from freeze-dried powder and water for injection through a dual-chamber cartridge, and can be subcutaneously injected (s.c.), Intravenous (i.v.), intravenous drip, intramuscular (i.m.) or other parenteral form of administration, preferably intravenous infusion.
- s.c. subcutaneously injected
- i.v. Intravenous
- intravenous drip intramuscular (i.m.) or other parenteral form of administration, preferably intravenous infusion.
- the pharmaceutical composition of the present invention may not require additional tonicity agents, such as tonicity agents such as sodium chloride, potassium chloride, etc., reduce the types of excipients.
- additional tonicity agents such as tonicity agents such as sodium chloride, potassium chloride, etc.
- composition of the present invention contains only one protein, Pertuzumab, to avoid potential stability risks caused by interaction between two or more proteins.
- the inventor found that when the concentration of methionine in the preparation of the present invention is lower than 5mM, the ability of methionine to improve the stability of the composition is significantly limited, and when the concentration of methionine is higher than 40mM, it is greater than the listed antibody drug When the methionine concentration is 5-40mM, the physical and chemical stability of the Pertuzumab composition can be significantly improved.
- the inventors have conducted in-depth research, conducted a large number of screenings on each component and content, and obtained the pharmaceutical composition of the present invention with better stability. It has good physical and chemical stability in phosphate/phosphoric acid, histidine-acetate, histidine-hydrochloric acid, among which histidine-acetate has the same effect as histidine-hydrochloric acid, and is better than phosphoric acid Salt/phosphoric acid; the stabilizer was screened, and it was determined that it had better stability in sucrose, trehalose and arginine hydrochloride, and the stability was better in arginine hydrochloride.
- the present invention also relates to the use of a medicament for the preparation of a HER2-positive tumor, preferably, the HER2-positive tumor is breast cancer or gastric cancer.
- composition of the present invention not only has good effects on appearance and visible foreign matter (all are colorless and clear liquid and no foreign matter), but also its physical stability and chemical stability are greatly improved, and it has a very good effect. Broad market application prospects.
- the SEC-HPLC purity test is mainly used to monitor the multimer (physical stability) of the sample, and the IEC-HPLC purity test is mainly used to monitor the main peak purity of the charge isomer (chemical stability).
- Detection instrument Agilent 1200 liquid chromatograph; SEC-HPLC column: TSK-gel G3000SW XL from TOSOH, Japan, 7.8 ⁇ 300mm; Mobile phase: 0.06mol/L potassium dihydrogen phosphate, 0.14mol/L potassium dihydrogen phosphate , 0.25mol/L potassium chloride, pH 6.2; flow rate: 0.5ml/min; column temperature: 30°C; running time: 30min; wavelength: 280nm.
- IEC-HPLC column Thermo Scientific ProPac WCX-10 (4 ⁇ 250mm), detection wavelength: 280nm, flow rate: 0.8ml/min, column temperature: 34°C, injection volume: 50 ⁇ l, gradient: 0min, 18% mobile phase B; 3min, 18% mobile phase B; 8min, 28% mobile phase B; 45min, 46.5% mobile phase B; 45.5min, 100% mobile phase B; 52.5min, 100% mobile phase B; 53min, 18% mobile phase B; 60 min, 18% mobile phase B.
- the SEC-HPLC detection and IEC-HPLC detection methods in the examples are implemented according to this method.
- Each formulation contained 30 mg/ml Pertuzumab, 120 mM sucrose, 20 mM histidine-HCl buffer, and 0.2 mg/ml polysorbate 20, pH 6.0.
- the dosage of each preparation excipient is shown in Table 1.
- High temperature test place the samples in a 40°C ⁇ 2°C incubator, and take samples for testing in the 2nd and 4th weeks respectively;
- Light test place the sample in a light box (25°C ⁇ 3°C, 4500Lx ⁇ 500Lx) for 10 days and take samples.
- Formulation 7 and Formulation 8 (aqueous injection form) both contained 120 mM sucrose, 0.2 mg/ml polysorbate 20, 20 mM histidine-acetate buffer, pH 6.0.
- the dosage of each preparation excipient is shown in Table 3.
- High temperature test place the sample in a 40°C ⁇ 2°C incubator, and take samples for testing in the second week;
- Light test place the sample in a light box (25°C ⁇ 3°C, 4500Lx ⁇ 500Lx) for 10 days and take samples.
- High temperature test place the sample in a 40°C ⁇ 2°C incubator, and take samples for testing in the second week;
- Light test place the sample in a light box (25°C ⁇ 3°C, 4500Lx ⁇ 500Lx) for 10 days and take samples.
- Each formulation contained 3 mg/ml Pertuzumab, 120 mM sucrose, 20 mM histidine-acetic acid, and 0.2 mg/ml polysorbate 20.
- the dosage of each preparation excipient is shown in Table 9.
- High temperature test place the sample in a 40°C ⁇ 2°C incubator, and take samples for testing in the second week;
- Light test place the sample in a light box (25°C ⁇ 3°C, 4500Lx ⁇ 500Lx) for 10 days and take samples.
- the pertuzumab composition of the present invention has lower polymer content and higher IEC-HPLC main peak purity, indicating its physical stability and chemical stability.
- the stability is good, especially between pH 5.0-6.0, the IEC-HPLC main peak purity of the Pertuzumab preparation of the present invention is better (for example, pH 6.0/5.0/6.8 after 2 weeks of high temperature, respectively : 63.7 ⁇ 0.1; 60.2 ⁇ 0.1; 54.6 ⁇ 0.2, respectively 66.4 ⁇ 0.4; 68.1 ⁇ 0.2; 60.1 ⁇ 0.5 after light damage), that is, its chemical stability effect is better.
- Each formulation contained 3 mg/ml Pertuzumab, 120 mM sucrose, and 20 mM histidine-acetate buffer, pH 6.0.
- the dosage of each preparation excipient is shown in Table 9.
- High temperature test place the sample in a 40°C ⁇ 2°C incubator, and take samples for testing in the second week;
- Light test place the sample in a light box (25°C ⁇ 3°C, 4500Lx ⁇ 500Lx) for 10 days and take samples.
- Formulations 18 and 19 both contained 30 mg/ml Pertuzumab, 0.2 mg/ml polysorbate 20, pH 6.0.
- the dosage of each formulation excipient is shown in Table 11.
- High temperature test place the sample in a 40°C ⁇ 2°C incubator, and take samples for testing in the second week;
- Light test place the sample in a light box (25°C ⁇ 3°C, 4500Lx ⁇ 500Lx) for 10 days and take samples.
- the pertuzumab composition of the present invention with sucrose and arginine hydrochloride as stabilizers has lower polymer content and higher IEC-HPLC main peak purity, It shows that the physical stability and chemical stability of the composition are good, wherein, compared with the Pertuzumab preparation of the present invention with sucrose as the stabilizer, the Pertuzumab of the present invention with arginine hydrochloride as the stabilizer
- the chemical stability of the inhibitor is better (the IEC-HPLC main peak is more pure, especially after light damage), and the physical stability is comparable.
- the pharmaceutical composition has better physical and/or chemical stability under the condition of pH 5.0-6.8, especially at 3 -30mg/ml Pertuzumab, 20-40mM methionine, 115-125mM sucrose or trehalose or arginine hydrochloride, 15-25mM histidine-histidine hydrochloride or histidine-acetate buffer, pH5 0-6.0, 0.05-0.5mg/ml polysorbate 20 and other conditions, the physical and/or chemical stability of the Pertuzumab composition under high temperature and light conditions is better.
- stabilizers such as sucrose/arginine hydrochloride/trehalose
- buffers such as histidine-hydrochloric acid, histidine-acetic acid
- phosphoric acid/phosphate phosphoric acid/phosphate
- surfactant such as polysorbate 20 or 80
Abstract
一种稳定的帕妥珠单抗药物组合物,所述组合物包括:(a)帕妥珠单抗3-60mg/ml;(b)蛋氨酸5-40mM;(c)稳定剂,所述稳定剂选自蔗糖、海藻糖或盐酸精氨酸;(d)表面活性剂;(e)缓冲液,中,所述组合物的pH为5.0-6.8。所述的药物组合物的稳定性有很大程度的提高,具有非常广阔的市场应用前景。
Description
本发明属于生物技术领域,具体涉及一种含有蛋氨酸为抗氧化剂的帕妥珠单抗的药物组合物。
帕妥珠单抗是一种新型的抗HER2单克隆抗体,于2012年6月首次在美国上市,主要和曲妥珠单抗联用用于治疗HER2阳性的晚期转移性乳腺癌患者。通过结合HER2,帕妥珠单抗阻滞了HER2与其他受体的杂二聚,从而减缓了肿瘤的生长。
帕妥珠单抗属于人源化单抗,目前已上市的罗氏(Roche)
为水针制剂,上市处方中含有帕妥珠单抗30mg/mL、120mM蔗糖、0.2mg/ml聚山梨酯80、20mM组氨酸-醋酸缓冲液,溶液pH 6.0。其中,处方中帕妥珠单抗为主药;蔗糖为稳定剂;聚山梨酯20为表面活性剂;组氨酸-醋酸为pH调节剂。
和大多数蛋白分子一样,帕妥珠单抗具有不稳定性,会经历多种化学和物理降解。和传统合成的小分子药物相比,生物分子具有复杂的结构,如一级、二级、三级等高级结构。而蛋白质的结构,特别是高级结构非常脆弱,容易发生结构变化,如变性(denaturation),聚集(aggregation)和沉淀(precipitation)。保持抗体的高级结构是发挥它们生物学活性的最基本要求。这些降解的产物会对生物制药的安全性产生很大的影响。特别是一些蛋白聚集物会激发人体的免疫反应,轻者会降低生物药物的疗效,重者甚至会造成病人的死亡。因此多聚体被认为是生物制药安全性的关键质量属性(critical quality attribute,CQA),直接影响到生物药的用药安全,这对于长期用药的产品如帕妥珠单抗尤为重要。抗体药物不仅仅需要在生产的时候能得到高纯度的产品,还要在运输、储存和使用过程中保持结构稳定。
因此,有必要开发一种新型帕妥珠单抗制剂以提高抗体的稳定性,从而提高产品质量的均一性和一致性,以及提高临床使用稳定性。
发明内容
本发明的目的在于提供一种稳定的帕妥珠单抗组合物及其用途,本发明制备的组合物在光照破坏下或较长的时间内仍能维持物理和化学稳定性,相比现有技术得到了很大程度的提高。
在一方面,本发明涉及一种药物组合物,其包括:
(a)帕妥珠单抗3-60mg/ml;
(b)蛋氨酸5-40mM;
(c)稳定剂,所述稳定剂选自蔗糖、海藻糖或盐酸精氨酸,优选盐酸精氨酸;
(d)表面活性剂;
(e)缓冲液;
其中,所述制剂的pH为5.0-6.8,优选pH为5.0-6.0。
在一实施方案中,所述帕妥珠单抗的浓度为3-30mg/ml。
在一实施方案中,所述帕妥珠单抗的浓度为30-60mg/ml。
在优选的实施方案中,所述蛋氨酸的浓度为10-40mM,优选20-40mM。
在优选的实施方案中,所述稳定剂的浓度为100-140mM,优选110-130mM,更优选115-125mM。
在优选的实施方案中,所述缓冲液选自甘氨酸、乙酸/乙酸盐、琥珀酸/琥珀酸盐、柠檬酸/柠檬酸盐、抗坏血酸/抗坏血酸盐、酒石酸/酒石酸盐、顺丁烯二酸/顺丁烯二酸盐、乳酸/乳酸盐、碳酸/碳酸氢盐、苯甲酸/苯甲酸盐、组氨酸、组氨酸/盐酸、组氨酸/醋酸、磷酸/磷酸盐或tris/tris盐酸盐,优选组氨酸-盐酸,组氨酸-醋酸、磷酸/磷酸盐,更优选组氨酸-盐酸,组氨酸-醋酸。
在优选的实施方案中,所述缓冲液的浓度为10-30mM,优选15-25mM。
在优选的实施方案中,所述表面活性剂包括但不限于聚山梨酯类,如聚山梨酯20、聚山梨酯21、聚山梨酯40、聚山梨酯60、聚山梨酯61、聚山梨酯65、聚山梨酯80、聚山梨酯81、聚山梨酯85、泊洛沙姆、triton、十二烷基硫酸钠、月桂硫酸钠、辛基糖苷钠、月桂基-磺基甜菜碱、聚乙二醇或聚丙二醇,优选聚山梨酯20或聚山梨酯80。
在优选的实施方案中,所述表面活性剂的浓度为0.01-5mg/ml,优选0.05-0.5mg/ml。
在一实施方案中,本发明的药物组合物进一步含有药学上可接受量的螯合剂,包括但不限于氨基多羧酸、羟基氨基羧酸、N-取代甘氨酸、柠檬酸、烟酰胺、去铁胺和去氧胆酸盐及其混合物,如乙二胺四乙酸(EDTA)、二乙三胺五乙酸(DTPA)、次氮基三乙酸(NTA)及它们的盐。本发明中使用的螯合剂可以是化合物的游离酸或者游离碱或者盐的形式存在,也可以是化合物或者相应盐的无水合物、水合物或者其它溶剂化物的形式存在。
在一实施方案中,本发明的药物组合物进一步含有药学上可接受量的防腐剂,包括但不限于间甲酚、苯酚、苯甲醇、苯扎氯铵、苯氧乙醇或对羟基苯甲酸甲酯。
在优选的实施方案中,本发明所述的药物组合物含有以下的成分:
(1)帕妥珠单抗 3-30mg/ml;
(2)蔗糖或海藻糖或盐酸精氨酸 115-125mM;
(3)聚山梨酯20 0.05-0.5mg/ml;
(4)组氨酸-盐酸或组氨酸-醋酸缓冲液 15-25mM;
(5)蛋氨酸 20-40mM;
其中,pH为5.0-6.0。
在优选的实施方案中,本发明所述的药物组合物含有以下的成分:
(1)帕妥珠单抗 3-30mg/ml;
(2)盐酸精氨酸 115-125mM,优选120mM;
(3)聚山梨酯20 0.05-0.5mg/ml;
(4)组氨酸-盐酸组氨酸或组氨酸-醋酸缓冲液 15-25mM,优选20mM;
(5)蛋氨酸 20-40mM;
其中,pH为5.0-6.0。
在优选的实施方案中,本发明所述的药物组合物含有以下的成分:
(1)帕妥珠单抗 30mg/ml;
(2)蔗糖或盐酸精氨酸 120mM;
(3)聚山梨酯20 0.2mg/ml;
(4)组氨酸-盐酸组氨酸或组氨酸-醋酸缓冲液 20mM;
(5)蛋氨酸 20mM;
其中,pH为6.0。
本发明的药物组合物可以是水针制剂、冻干制剂、或者由冻干粉末和注射用水通过双腔卡氏瓶(dual-chamber cartridge)配制得到的制剂形式,可以通过皮下注射(s.c.)、静脉注射(i.v.)、静脉滴注、肌肉注射(i.m.)或其它非肠胃(parenteral)形式给药,优选静脉滴注。
在一实施方案中,本发明的药物组合物可以不需要额外添加张力剂,这样的张力剂例如氯化钠、氯化钾等,减少了辅料的种类。
在一实施方案中,本发明组合物仅含有帕妥珠单抗一种蛋白质,以避免两种或两种以上蛋白之间互相影响导致的潜在的稳定性风险。
发明人经过大量的实验和数据筛选发现,当本发明制剂中蛋氨酸的浓度低于5mM时,蛋氨酸提高组合物稳定性的能力受到明显限制,当蛋氨酸的浓度高于40mM时,大于已上市抗体药物的常规用量,当蛋氨酸浓度在5-40mM时,能显著提高帕妥珠单抗组合物的物理和化学稳定性。
在本发明中,发明人经过了深入的研究,对各组分以及含量进行了大量的筛选,获得了稳定性更好的本发明的药物组合物,例如,对缓冲液进行了筛选,确定了在磷酸盐/磷酸、组氨酸-醋酸盐、组氨酸-盐酸中有较好的物理和化学稳定性,其中组氨酸-醋酸盐与组氨酸-盐酸效果相当,优于磷酸盐/磷酸;对稳定剂进行了筛选,确定了在蔗糖、海藻糖和盐酸精氨酸中 均有较好的稳定性,其中在盐酸精氨酸中稳定性更好。
在另一方面,本发明还涉及用于制备治疗HER2阳性的肿瘤的药物的用途,优选地,所述HER2阳性的肿瘤为乳腺癌或胃癌。
本发明的有益效果为:
本发明所述组合物不仅在外观、可见异物上等有较好的效果(均为无色澄明液体且无异物),而且其物理稳定性和化学稳定性均有很大程度的提高,具有非常广阔的市场应用前景。
SEC-HPLC纯度检测主要用于监测样品的多聚体(物理稳定性),IEC-HPLC纯度检测主要监测电荷异构体主峰纯度(化学稳定性)。
检测仪器:Agilent 1200液相色谱仪;SEC-HPLC色谱柱:日本TOSOH公司的TSK-gel G3000SW
XL,7.8×300mm;流动相:0.06mol/L磷酸氢二钾,0.14mol/L磷酸二氢钾,0.25mol/L氯化钾,pH 6.2;流速:0.5ml/min;柱温:30℃;运行时间:30min;波长:280nm。IEC-HPLC色谱柱:Thermo Scientific ProPac WCX-10(4×250mm),检测波长:280nm,流速:0.8ml/min,柱温:34℃,进样量:50μl,梯度:0min,18%流动相B;3min,18%流动相B;8min,28%流动相B;45min,46.5%流动相B;45.5min,100%流动相B;52.5min,100%流动相B;53min,18%流动相B;60min,18%流动相B。实施例中SEC-HPLC检测以及IEC-HPLC检测方法均按此方法实施。
以下通过实施例对本发明进一步进行说明。必须指出,这些实施例是用于说明本发明,而不应理解为对本发明的限制。
实施例1.不同浓度蛋氨酸对帕妥珠单抗组合物稳定性的影响
对比了不同浓度蛋氨酸(0-40mM)对帕妥珠单抗组合物在强降解条件下的保护作用。各个处方(水针剂型)均含有30mg/ml帕妥珠单抗、120mM蔗糖、20mM组氨酸-盐酸缓冲液和0.2mg/ml的聚山梨酯20,pH为6.0。各制剂辅料用量见表1。
表1.不同浓度蛋氨酸的帕妥珠制剂
注:“/”表示不含。
影响因素试验方案
将上述处方分别进行高温和光照破坏试验。
高温试验:将样品置于40℃±2℃恒温箱中,分别于第2周和第4周取样检测;
光照试验:将样品放置于光照箱(25℃±3℃,4500Lx±500Lx)中10天后取样。
将经过上述影响因素试验的样品进行外观、可见异物、SEC-HPLC和IEC-HPLC纯度检测。结果见表2。
表2.各个制剂经过高温和光照破坏后帕妥珠单抗外观/可见异物、聚合物含量和IEC-HPLC主峰纯度
*试验数据为平均值±标准偏差,重复3次。
上述结果表明,相较于不含蛋氨酸的帕妥珠单抗组合物,加入5-40mg/ml的蛋氨酸,在光照破坏和高温2周条件下均能降低多聚体含量(光照条件下多聚体含量降低更多),且能够在光照下提高IEC-HPLC主峰纯度,提高了帕妥珠单抗组合物的物理和化学稳定性,尤其是加入20-40mg/ml的蛋氨酸,更能明显提高帕妥珠单抗的物理及化学稳定性。
实施例2.不同浓度帕妥珠单抗对帕妥珠单抗组合物稳定性的影响
对比了不同浓度帕妥珠单抗(3mg/ml及60mg/ml)对帕妥珠单抗组合物稳定性的影响。制剂7和制剂8(水针剂型)均含有120mM蔗糖、0.2mg/ml的聚山梨酯20,20mM组氨酸-醋酸缓冲液,pH为6.0。各制剂辅料用量见表3。
表3.不同浓度帕妥珠单抗的制剂
影响因素试验方案
将上述处方分别进行高温和光照破坏试验。
高温试验:将样品置于40℃±2℃恒温箱中,于第2周取样检测;
光照试验:将样品放置于光照箱(25℃±3℃,4500Lx±500Lx)中10天后取样。
将经过上述影响因素试验的样品进行外观、可见异物、SEC-HPLC和IEC-HPLC纯度检测。结果见表4。
表4.制剂1-2经过高温和光照破坏后帕妥珠单抗外观/可见异物、多聚体含量和IEC-HPLC主峰纯度
上述结果表明,高温和光照破坏后,含有3mg/ml-60mg/ml的帕妥珠单抗的本发明的帕妥珠单抗制剂,其多聚体含量均较低,IEC-HPLC主峰纯度均较高,说明相应制剂的物理稳定性和化学稳定性均较好,低浓度的帕妥珠单抗制剂其物理稳定性和化学稳定性好于高浓度的帕妥珠单抗制剂。
实施例3.不同缓冲液对帕妥珠单抗组合物稳定性的影响
对比了不同缓冲溶液(组氨酸-醋酸及磷酸/磷酸盐缓冲液)对帕妥珠单抗组合物稳定性的影响。其中帕妥珠单抗浓度为3mg/ml。制剂9和10均含有120mM蔗糖和0.2mg/ml的聚山梨酯20,pH为6.0;各制剂辅料用量见表5。
表5.不同缓冲液的帕妥珠单抗制剂
影响因素试验方案
将上述处方分别进行高温和光照破坏试验。
高温试验:将样品置于40℃±2℃恒温箱中,于第2周取样检测;
光照试验:将样品放置于光照箱(25℃±3℃,4500Lx±500Lx)中10天后取样。
将经过上述影响因素试验的样品进行外观、可见异物、SEC-HPLC和IEC-HPLC纯度检测。结果见表6。
表6.制剂9和制剂10经过高温和光照破坏后帕妥珠单抗外观/可见异物、多聚体含量和IEC-HPLC主峰纯度
*试验数据为平均值±标准偏差,重复3次;N/A表示未进行实验
上述结果表明,含有磷酸/磷酸盐缓冲液和组氨酸-醋酸缓冲液的帕妥珠单抗组合物,多聚体含量均较低,IEC-HPLC主峰纯度均较高,说明相应的帕妥珠单抗组合物的物理和化学稳定性均较好,其中,使用组氨酸-醋酸缓冲液,高温和光照破坏后多聚体含量更少,物理稳定性更优。
实施例4.不同pH对帕妥珠单抗组合物稳定性的影响
对比了不同pH条件下对帕妥珠单抗组合物稳定性的影响。各个处方(水针剂型)均含有3mg/ml帕妥珠单抗、120mM蔗糖、20mM组氨酸-醋酸和0.2mg/ml的聚山梨酯20。各制剂辅料用量见表9。
表7.不同pH制剂的组成
影响因素试验方案
将上述处方分别进行高温和光照破坏试验。
高温试验:将样品置于40℃±2℃恒温箱中,于第2周取样检测;
光照试验:将样品放置于光照箱(25℃±3℃,4500Lx±500Lx)中10天后取样。
将经过上述影响因素试验的样品进行外观、可见异物、SEC-HPLC和IEC-HPLC纯度检测。结果见表8。
表8.各个制剂经过高温和光照破坏后帕妥珠单抗外观/可见异物、聚合物含量和IEC-HPLC主峰纯度
*试验数据为平均值±标准偏差,重复3次。
上述结果表明,在pH5.0-6.8条件下,本发明所述的帕妥珠单抗组合物的多聚体含量均较低,IEC-HPLC主峰纯度均较高,说明其物理稳定性和化学稳定性均较好,尤其是在pH5.0-6.0之间,本发明的帕妥珠单抗制剂的IEC-HPLC主峰纯度更好(例pH6.0/5.0/6.8的高温2周后分别为:63.7±0.1;60.2±0.1;54.6±0.2,光照破坏后分别为66.4±0.4;68.1±0.2;60.1±0.5),即其化学稳定性效果更好。
实施例5.不同表面活性剂对帕妥珠单抗组合物稳定性的影响
对比了在不同表面活性剂(聚山梨酯80及不同含量聚山梨酯20)对帕妥珠单抗组合物稳定性的影响。各个处方(水针剂型)均含有3mg/ml帕妥珠单抗、120mM的蔗糖和20mM组氨酸-醋酸缓冲液,pH为6.0。各制剂辅料用量见表9。
表9.不同表面活性剂的帕妥珠单抗组合物
影响因素试验方案
将上述处方分别进行高温和光照破坏试验。
高温试验:将样品置于40℃±2℃恒温箱中,分别于第2周取样检测;
光照试验:将样品放置于光照箱(25℃±3℃,4500Lx±500Lx)中10天后取样。
将经过上述影响因素试验的样品进行外观、可见异物、SEC-HPLC和IEC-HPLC纯度检测。结果见表10。
表10.各个制剂经过高温和光照破坏后帕妥珠单抗外观/可见异物、聚合物含量和IEC-HPLC主峰纯度
上述结果表明,在以不同含量聚山梨酯20及聚山梨酯80作为表面活性剂的帕妥珠单抗组合物中,其多聚体含量均较低,IEC-HPLC主峰纯度均较高,说明相应帕妥珠单抗组合物的物理稳定性和化学稳定性均较好。
实施例6.不同稳定剂对帕妥珠单抗组合物稳定性的影响
对比了不同稳定剂对帕妥珠单抗组合物的稳定性的影响。制剂18和19(水针制剂)均含有30mg/ml帕妥珠单抗、0.2mg/ml的聚山梨酯20,pH为6.0。各制剂辅料用量见表11。
表11.不同稳定剂的帕妥珠单抗组合物
影响因素试验方案
将上述处方分别进行高温和光照破坏试验。
高温试验:将样品置于40℃±2℃恒温箱中,于第2周取样检测;
光照试验:将样品放置于光照箱(25℃±3℃,4500Lx±500Lx)中10天后取样。
将经过上述影响因素试验的样品进行外观、可见异物、SEC-HPLC和IEC-HPLC纯度检测。结果见表12。
表12.各个制剂经过高温和光照破坏后帕妥珠单抗外观/可见异物、聚合物含量和IEC-HPLC主峰纯度
*试验数据为平均值±标准偏差,重复3次。
上述结果表明,经过高温和光照后,蔗糖和盐酸精氨酸为稳定剂的本发明所述的帕妥珠单抗组合物的多聚体含量均较低,IEC-HPLC主峰纯度均较高,说明组合物的物理稳定性和化学稳定性均较好,其中,相较于蔗糖为稳定剂的本发明的帕妥珠单抗制剂,盐酸精氨酸为稳定剂的本发明的帕妥珠单抗制剂化学稳定性更优(IEC-HPLC主峰纯度更高,尤其是光照破坏后),物理稳定性相当。
总结
发明人经过广泛深入的研究发现,特定浓度的蛋氨酸与帕妥珠单抗、稳定剂(例蔗糖/盐酸精氨酸/海藻糖)、缓冲剂(例组氨酸-盐酸、组氨酸-醋酸、磷酸/磷酸盐)、表面活性剂(例聚山梨酯20或80)组成的药物组合物在pH为5.0-6.8的条件下,具有较优的物理和/或化学稳定性,特别是在3-30mg/ml帕妥珠单抗,20-40mM的蛋氨酸、115-125mM蔗糖或海藻糖或盐酸精氨酸,15-25mM组氨酸-盐酸组氨酸或组氨酸-醋酸缓冲液,pH5.0-6.0,0.05-0.5mg/ml聚山梨酯20等条件下,帕妥珠单抗组合物在高温和光照条件下的物理和/或化学稳定性更优。
本领域技术人员会清楚,可以进行本发明的许多修改和变化而不背离其精神和范围。本文所述的具体实施方案仅通过实例的方式提供,并不意味着以任何方式限制。本发明的真正范围和精神通过所附权利要求书示出,说明书和实施例仅是示例性的。
Claims (10)
- 一种药物组合物,其特征在于,所述组合物包括:(a)帕妥珠单抗3-60mg/ml;(b)蛋氨酸5-40mM;(c)稳定剂,所述稳定剂选自蔗糖、海藻糖或盐酸精氨酸,优选盐酸精氨酸;(d)表面活性剂;(e)缓冲液;其中,所述制剂的pH为5.0-6.8,优选pH为5.0-6.0。
- 根据权利要求1所述的药物组合物,其特征在于,所述帕妥珠单抗的浓度为3-30mg/ml。
- 根据权利要求1或2所述的药物组合物,其特征在于,所述蛋氨酸的浓度为10-40mM,优选20-40mM。
- 根据权利要求1-3任一项所述的药物组合物,其特征在于,所述稳定剂的浓度为100-140mM,优选110-130mM,更优选115-125mM。
- 根据权利要求1-4任一项所述的药物组合物,其特征在于,所述缓冲液选自甘氨酸、乙酸/乙酸盐、琥珀酸/琥珀酸盐、柠檬酸/柠檬酸盐、抗坏血酸/抗坏血酸盐、酒石酸/酒石酸盐、顺丁烯二酸/顺丁烯二酸盐、乳酸/乳酸盐、碳酸/碳酸氢盐、苯甲酸/苯甲酸盐、组氨酸、组氨酸-盐酸、组氨酸-醋酸、磷酸/磷酸盐或tris/tris盐酸盐,优选组氨酸-盐酸,组氨酸-醋酸、磷酸/磷酸盐,更优选组氨酸-盐酸,组氨酸-醋酸。
- 根据权利要求1-5任一项所述的药物组合物,其特征在于,所述缓冲液的浓度为10-30mM,优选15-25mM。
- 根据权利要求1-6任一项所述的药物组合物,其特征在于,所述表面活性剂选自聚山梨酯20、聚山梨酯21、聚山梨酯40、聚山梨酯60、聚山梨酯61、聚山梨酯65、聚山梨酯80、聚山梨酯81、聚山梨酯85、泊洛沙姆、triton、十二烷基硫酸钠、月桂硫酸钠、辛基糖苷钠、月桂基-磺基甜菜碱、聚乙二醇、或聚丙二醇,优选聚山梨酯20或聚山梨酯80;所述表面活性剂的浓度为0.01-5mg/ml,优选0.05-0.5mg/ml。
- 权利要求1-8任一项所述的药物组合物为水针制剂、冻干制剂、或者由冻干粉末和注射用水通过双腔卡氏瓶配制得到的制剂形式,通过非肠胃形式给药,优选地,所述非肠胃形式为皮下注射、静脉注射、静脉滴注或肌肉注射,更优选静脉滴注。
- 权利要求1-9任一项所述的药物组合物在制备用于治疗HER2阳性的肿瘤的药物的用途,优选地,所述HER2阳性的肿瘤为乳腺癌或胃癌。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004091658A1 (en) * | 2003-04-04 | 2004-10-28 | Genentech, Inc. | High concentration antibody and protein formulations |
CN104302320A (zh) * | 2012-05-04 | 2015-01-21 | 诺华股份有限公司 | 冻干以及水性抗cd40抗体制剂 |
US20150343058A1 (en) * | 2012-12-21 | 2015-12-03 | Glenmark Pharmaceuticals S.A. | Antibody formulation |
WO2018179138A1 (ja) * | 2017-03-29 | 2018-10-04 | 持田製薬株式会社 | 抗体含有液体製剤 |
WO2020017901A1 (ko) * | 2018-07-19 | 2020-01-23 | (주)셀트리온 | 안정한 액체 약제학적 제제 |
US20200071352A1 (en) * | 2018-08-28 | 2020-03-05 | Arecor Limited | Stabilized antibody protein solutions |
CN110974958A (zh) * | 2019-12-25 | 2020-04-10 | 北京东方百泰生物科技有限公司 | 一种抗pd-l1单克隆抗体的注射制剂 |
-
2021
- 2021-01-15 CN CN202110052055.7A patent/CN114762727A/zh active Pending
- 2021-12-23 WO PCT/CN2021/140703 patent/WO2022151940A1/zh active Application Filing
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004091658A1 (en) * | 2003-04-04 | 2004-10-28 | Genentech, Inc. | High concentration antibody and protein formulations |
CN104302320A (zh) * | 2012-05-04 | 2015-01-21 | 诺华股份有限公司 | 冻干以及水性抗cd40抗体制剂 |
US20150343058A1 (en) * | 2012-12-21 | 2015-12-03 | Glenmark Pharmaceuticals S.A. | Antibody formulation |
WO2018179138A1 (ja) * | 2017-03-29 | 2018-10-04 | 持田製薬株式会社 | 抗体含有液体製剤 |
WO2020017901A1 (ko) * | 2018-07-19 | 2020-01-23 | (주)셀트리온 | 안정한 액체 약제학적 제제 |
US20200071352A1 (en) * | 2018-08-28 | 2020-03-05 | Arecor Limited | Stabilized antibody protein solutions |
CN110974958A (zh) * | 2019-12-25 | 2020-04-10 | 北京东方百泰生物科技有限公司 | 一种抗pd-l1单克隆抗体的注射制剂 |
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