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WO2018184540A1 - 包含组氨酸缓冲体系的英夫利西单抗组合物 - Google Patents

包含组氨酸缓冲体系的英夫利西单抗组合物 Download PDF

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Publication number
WO2018184540A1
WO2018184540A1 PCT/CN2018/081806 CN2018081806W WO2018184540A1 WO 2018184540 A1 WO2018184540 A1 WO 2018184540A1 CN 2018081806 W CN2018081806 W CN 2018081806W WO 2018184540 A1 WO2018184540 A1 WO 2018184540A1
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Prior art keywords
pharmaceutical composition
polysorbate
acid
concentration
infliximab
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English (en)
French (fr)
Inventor
方伟杰
钱慈
王海彬
郑洪健
高栋
白骅
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Zhejiang Hisun Pharmaceutical Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
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Application filed by Zhejiang Hisun Pharmaceutical Co Ltd filed Critical Zhejiang Hisun Pharmaceutical Co Ltd
Priority to EP18780466.1A priority Critical patent/EP3607969A4/en
Publication of WO2018184540A1 publication Critical patent/WO2018184540A1/zh
Anticipated expiration legal-status Critical
Priority to CONC2019/0011300A priority patent/CO2019011300A2/es
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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
    • A61K39/39533—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
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • 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
    • 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
    • A61K47/26—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
    • 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
    • A61K9/14—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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the invention belongs to the field of pharmacy, and in particular relates to an infliximab composition comprising a histidine buffer system.
  • Infliximab (CAS #170277-31-3) is a human-mouse chimeric monoclonal antibody that blocks the binding of TNF- ⁇ to its cell surface receptor by specifically binding to TNF- ⁇ in humans. The biological activity of TNF- ⁇ is broken, which ultimately reduces the inflammatory response and reduces the activation of osteoclasts, achieving the purpose of controlling and alleviating symptoms. Infliximab can be used to treat rheumatoid arthritis, psoriasis, mandatory spondylitis, ulcerative colitis and Crohn's disease.
  • infliximab is not sufficiently stable, and a variety of chemical and physical degradations occur, especially in high-grade structures, which are prone to structural changes such as denaturation, aggregation, and precipitation. These degraded or unstable products can have a major impact on the safety of biopharmaceuticals. In particular, some protein aggregates will stimulate the body's immune response, and lighter people will reduce the efficacy of biopharmaceuticals, and even severely cause death. Multimers are therefore considered to be a key quality attribute (CQA) for biopharmaceutical safety, directly affecting the safety of infliximab.
  • CQA key quality attribute
  • Antibody drugs not only require high-purity products at the time of production, but also maintain structural stability during transportation, storage, and use.
  • CN104159614A discloses an improved liquid formulation comprising a suitable amount of a suitable buffer, one or more suitable stabilizers, and other excipients optionally selected from suitable surfactants and tonicity agents.
  • CN103402540A relates to a non-aqueous high concentration suspension comprising a carrier comprising a water delivery set and a viscosity reducing agent and an antibody formulated with an excipient.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising infliximab, a histidine buffer system, a structure protectant, and a surfactant,
  • the concentration of infliximab in the composition is about 5-40 mg/ml
  • the concentration of histidine in the histidine buffer system is about 1-200 mM
  • the concentration of the structure protecting agent is about 0-
  • the concentration of the surfactant is about 0.01-1 mg/ml at 100 mg/ml.
  • the concentration of the infliximab in the pharmaceutical composition is between about 5 and 20 mg/ml.
  • the concentration of the histidine in the pharmaceutical composition is from about 5 to 75 mM, preferably from about 25 to 45 mM, such as about 25, 30, 35, 40, 45 mM.
  • the structural protectant in the pharmaceutical composition is selected from the group consisting of sucrose, trehalose, and combinations thereof, wherein the concentration of the structural protectant is from about 10 to 75 mg/ml, preferably from about 10 to 50 mg/ml. .
  • the concentration of the surfactant in the pharmaceutical composition is from about 0.025 to 0.4 mg/ml, preferably from about 0.025 to 0.1 mg/ml.
  • the surfactant is selected from the group consisting of polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, poly Sorbate 81, polysorbate 85, poloxamer, triton, sodium lauryl sulfate, sodium lauryl sulfate, sodium octyl glycoside, lauryl-sulfobetaine, polyethylene glycol, polypropylene glycol, and combinations thereof
  • polysorbate 80 is selected from the group consisting of polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, poly Sorbate 81, polysorbate 85, poloxamer, triton, sodium lauryl sulfate, sodium lauryl sulfate, sodium octyl glycoside, lauryl-sulfobetaine, polyethylene glycol, polypropylene glycol, and combinations thereof
  • the pharmaceutical composition has a pH of from about 4.0 to 9.0, preferably from about 4.5 to 8.0, more preferably from about 5.2 to 7.2.
  • the pharmaceutical composition of the invention comprises:
  • the pH is about 5.2-7.2.
  • the present invention relates to a method of preventing or treating a human autoimmune-related disease, the method comprising administering to a subject in need thereof a pharmaceutical composition of the present invention.
  • the invention also relates to the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a human autoimmune related disease.
  • the present invention also relates to a pharmaceutical composition for preventing or treating a human autoimmune-related disease.
  • the human autoimmune related diseases include, but are not limited to, rheumatoid arthritis, psoriasis, juvenile idiopathic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, Plaque psoriasis, etc.
  • composition optionally includes an antioxidant covering the case with or without an antioxidant.
  • Infliximab which is used herein, is commercially available and has a CAS number of 170277-31-3, for example, available from Zhejiang Hisun Pharmaceutical Co., Ltd.
  • histidine buffer or "histidine buffer system” means a buffer system obtained by combining histidine with an acid which is optionally present for pH adjustment such as hydrochloric acid, acetic acid, sulfuric acid or the like.
  • an acid which is optionally present for pH adjustment
  • histidine buffer system in characterizing the histidine buffer system in a formulation, the sum of the concentrations of histidine therein, including its free and ionized forms, is typically used.
  • histidine buffers include, but are not limited to, histidine/hydrochloric acid, histidine/acetic acid, histidine/sulfuric acid, and the like.
  • a preferred histidine buffer of the invention is a histidine/hydrochloric acid buffer.
  • carbohydrate includes monosaccharides, disaccharides, oligosaccharides and polysaccharides.
  • examples of carbohydrates include, but are not limited to, fructose, glucose, sucrose, trehalose, mannose, lactose, mannose, maltose, sorbose, dextran, dextrin, cyclodextrin, hydroxyethyl starch, or combinations thereof.
  • amino acid includes amino acids and/or pharmaceutically acceptable salts thereof.
  • amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine Acid, lysine, methionine, phenylalanine, valine, serine, threonine, tryptophan, tyrosine, proline or a combination thereof.
  • “Pharmaceutically acceptable salt” refers to a salt formed with a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids.
  • a salt formed with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid
  • a salt formed with an organic acid such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, Propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, nicotinic acid, pamoic acid, picric acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid, citric acid, tartaric acid,
  • Lyophilized means a drying technique in which a solution formulation is frozen to a solid state at a lower temperature, and then the water therein is sublimed directly to a gaseous state without a liquid state, and finally the material is dehydrated. Lyophilization includes, but is not limited to, freezing, primary drying, and secondary drying.
  • a histidine buffer system is included in the pharmaceutical composition of the present invention.
  • the stability of the infliximab-containing pharmaceutical composition comprising the histidine buffer system is greatly improved compared to the phosphate buffer system used in the prior art.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising infliximab, a histidine buffer system, a structure protectant, and a surfactant.
  • the concentration of infliximab in the pharmaceutical composition is between about 5 and 40 mg/ml, preferably between about 5 and 20 mg/ml.
  • examples of the histidine buffer system include, but are not limited to, histidine/hydrochloric acid, histidine/acetic acid, histidine/sulfuric acid, and the like, preferably a histidine/hydrochloric acid buffer.
  • concentration of histidine of the histidine buffer system in the pharmaceutical composition is from about 1 to 200 mM, preferably from about 5 to 75 mM, more preferably from about 25 to 45 mM, such as from about 25, 30, 35, 40, 45 mM.
  • the pharmaceutical compositions of the present invention may comprise a structural protectant.
  • the structure protectant can be used to stabilize the structure of the active ingredient in the pharmaceutical composition, providing protection properties at normal temperature and in a lyophilized state.
  • Carbohydrates and amino acids are stabilizers for commonly used protein drugs. It also acts as a cryoprotectant and a desiccant to protect the protein from denaturation that may occur during lyophilization.
  • the structural protectant is a carbohydrate, an amino acid, or a combination thereof.
  • the structural protectant is selected from the group consisting of sucrose, trehalose, and combinations thereof, more preferably sucrose.
  • the concentration of the structural protectant is from about 0 to 100 mg/ml, preferably from about 10 to 75 mg/ml, more preferably from about 10 to 50 mg/ml, such as about 25 mg/ml.
  • the pharmaceutical preparation of the present invention may further comprise a surfactant.
  • a surfactant is a substance that changes (usually reduces) the surface tension of a liquid or the interfacial tension between two phases.
  • Surfactants are amphiphilic and contain hydrophilic groups and lipophilic groups. Examples of surfactants include, but are not limited to, polysorbates, poloxamers, tritons, sodium lauryl sulfate, sodium lauryl sulfate, sodium octyl glycoside, lauryl-sulfobetaine, polyethylene glycol, Polypropylene glycol or a mixture thereof.
  • Polysorbate surfactants which can be used include polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81. Polysorbate 85 or a mixture thereof, preferably polysorbate 80.
  • the concentration of the surfactant may range from about 0.01 to 1 mg/ml, preferably from about 0.025 to 0.4 mg/ml, and most preferably from about 0.025 to 0.1 mg/ml.
  • the pharmaceutical preparation of the present invention may optionally contain an antioxidant which inhibits oxidation of the pharmaceutical preparation, improves the stability of the drug and contributes to prolonging the storage period.
  • antioxidants include, but are not limited to, ascorbic acid, tryptophan, methionine, glutathione, sodium thiosulfate, catalase, or mixtures thereof.
  • the pharmaceutical composition of the present invention may optionally contain a chelating agent which, in combination with a metal ion which readily catalyzes the oxidation of the protein, thereby enhancing its stability, including but not limited to aminopolycarboxylic acid, hydroxyaminocarboxylic acid, N-substituted glycine, citric acid, nicotinamide, deferoxamine and deoxycholate and mixtures thereof, such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid ( NTA) and their salts.
  • the chelating agent used may be in the form of the free acid, the free base or the salt, or it may be in the form of an anhydrate, hydrate or other solvate of the compound or the corresponding salt.
  • the pharmaceutical preparation of the present invention may also optionally contain a preservative which inhibits the growth and reproduction of microorganisms including, but not limited to, m-cresol, phenol, benzyl alcohol, benzalkonium chloride, phenoxyethanol, p-hydroxybenzene. Methyl formate and mixtures thereof.
  • a preservative which inhibits the growth and reproduction of microorganisms including, but not limited to, m-cresol, phenol, benzyl alcohol, benzalkonium chloride, phenoxyethanol, p-hydroxybenzene. Methyl formate and mixtures thereof.
  • a suitable pH is from about 4.0 to 9.0, preferably from about 4.5 to 8.0, more preferably from about 5.2 to 7.2, such as about 5.7, 6.7.
  • the pharmaceutical composition of the present invention may not require an additional addition of a tonicity agent such as sodium chloride, potassium chloride or the like.
  • a pharmaceutical composition is formulated based on an aqueous solution or water such as water for injection.
  • the invention provides a pharmaceutical composition comprising:
  • the pH is about 5.2-7.2.
  • the pharmaceutical composition of the present invention may be in the form of a water-needle preparation, a lyophilized preparation, or a preparation prepared from a lyophilized powder and water for injection through a dual-chamber cartridge, which may be administered by subcutaneous injection (sc), Intravenous (iv), intramuscular (im) or other parenteral administration.
  • sc subcutaneous injection
  • iv Intravenous
  • im intramuscular
  • im intramuscular
  • the present invention greatly improves the stability of the pharmaceutical composition and its lyophilized preparation, especially under high temperature and light conditions, by using histidine as a buffer system of infliximab, and can stably store for a long time in a lyophilized state.
  • the infliximab pharmaceutical composition solution was prepared by using water for injection, and the product was freeze-dried.
  • the freeze-drying process is shown in Table 1.
  • the preparations before and after lyophilization were subjected to high temperature and light tests, respectively.
  • High temperature test The sample is placed in an incubator at 40 ° C ⁇ 2 ° C, and samples are taken at week 1 and 2 or weeks 2 and 4, respectively;
  • Light test The sample was placed in a light box (5 ° C ⁇ 3 ° C, 4500 Lx ⁇ 500 Lx) and sampled 10 days later.
  • Infliximab provided by Zhejiang Hairong Pharmaceutical Co., Ltd.
  • Trehalose purchased from Linyuan, Japan
  • Polysorbate 80 available from JT Baker
  • SEC-HPLC column TSK-GEL G3000SWXL from Japan TOSOH Co., Ltd., 7.8 ⁇ 300 mm; mobile phase: 0.02 mol/L sodium dihydrogen phosphate, 0.2 mol/L sodium chloride buffer, 10% acetonitrile, pH 7.0; 0.5 ml/min; column temperature: 30 ° C; running time: 30 min; wavelength: 280 nm.
  • Formulation 1 and Formulation 2 in Table 1 were lyophilized.
  • Test data is mean ⁇ standard deviation, repeated 3 times, the same below.
  • the multimer content is often used to indicate the stability of the formulation, and the higher the polymer content, the worse the formulation stability.
  • the results in Table 3 show that the use of histidine (Formulation 2) instead of phosphate (Formulation 1) as a buffer has a significant improvement in the stability of the aqueous needle preparation and a small amount of multimer.
  • the stability of the formulation under lyophilization conditions was better than that of the aqueous needle formulation, and the stability of the lyophilized formulation 2 was better.
  • compositions of Pharmaceutical Compositions Formulations 3-4 are shown in Table 4.
  • the particle size of the monoclonal antibody in aqueous solution was investigated using dynamic light scattering (Malvin Zetasizer Nano-ZS ZEN3600) (Table 5).
  • the average particle size of the phosphate-containing preparation 3 was larger than that of the histidine-containing preparation 4, indicating that the interaction of the monoclonal antibody in the histidine solution was weak, and it was less likely to collide to form a multimer, and the stability was good.
  • Formulation 3 and Formulation 4 were lyophilized according to the freeze-drying procedure of Table 1.
  • the stability of the lyophilized formulation at high temperature (40 ° C ⁇ 2 ° C, 2 weeks, 4 weeks) and light (5 ° C ⁇ 3 ° C, 4500 Lx ⁇ 500 Lx, 10 days) was compared (Table 6).
  • the lyophilized formulation 4 formulated in histidine buffer had a lower polymer content, i.e., higher stability, than the lyophilized formulation 3 formulated in phosphate buffer.
  • each of the infliximab-resistant pharmaceutical compositions was prepared according to Table 7, wherein the pH was adjusted with hydrochloric acid.
  • Formulations 5-8 were lyophilized using the lyophilization process of Table 1. After lyophilization, high temperature (40 ⁇ 2 ° C) and light (5 ° C ⁇ 3 ° C, 4500 Lx ⁇ 500 Lx, 10 days) test were carried out.
  • the lyophilized preparations are white block solid after being subjected to high temperature or light, and are dissolved in a colorless clear liquid without visible foreign matter.
  • the polymer content of the preparations 5-8 was measured by SEC-HPLC after the end of the test, and the results are shown in Table 8.
  • This example compares the effect of a structural protectant on the stability of an infliximab pharmaceutical composition.
  • Each of the infliximab medicinal compositions (Formulations 9-11) was prepared according to Table 9, and lyophilized using the lyophilization process of Table 1. After lyophilization, high temperature (40 ⁇ 2 ° C) and light (4500 ⁇ 500 Lx) tests were performed.
  • the lyophilized preparations are white block solid after being subjected to high temperature or light, and are dissolved in a colorless clear liquid without visible foreign matter.
  • the polymer content of Formulation 9-11 was measured by SEC-HPLC after the end of the test, and the results are shown in Table 10.
  • This example compares the effect of surfactant concentration on the stability of infliximab pharmaceutical compositions.
  • Each of the infliximab medicinal compositions (Formulations 12-14) was prepared according to Table 11, and Formulations 12-14 were lyophilized using the lyophilization process of Table 1. After lyophilization, high temperature (40 ⁇ 2 ° C) and light (4500 ⁇ 500 Lx) tests were performed.
  • the lyophilized preparations are white block solid after being subjected to high temperature or light, and are dissolved in a colorless clear liquid without visible foreign matter.
  • the polymer content of the preparations 12-14 was measured by SEC-HPLC after the end of the test, and the results are shown in Table 12.
  • the polysorbate 80 has a concentration increase of 0.025-0.4 mg/ml, especially 0.025-0.1 mg/ml, and the increase of the polymer content is not obvious, and the stability of the infliximab pharmaceutical composition is stable. All are within acceptable limits.
  • the infliximab medicinal composition (Formulations 15-21) was prepared according to Table 13, and subjected to a high temperature (40 ⁇ 2 ° C) and light (4500 ⁇ 500 Lx) test.

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Abstract

提供一种药物组合物，其包含英夫利西单抗、组氨酸缓冲体系、结构保护剂和表面活性剂，其中所述组氨酸缓冲体系中组氨酸的浓度为约1-200 mM。

Description

包含组氨酸缓冲体系的英夫利西单抗组合物
本申请要求2017年4月7日提交的题为“包含组氨酸缓冲体系的英夫利西单抗组合物”的第201710224525.7号中国专利申请的优先权。该申请的内容整体援引加入本文。
技术领域
本发明属于药学领域，具体涉及一种包含组氨酸缓冲体系的英夫利西单抗组合物。
背景技术
英夫利西单抗(infliximab,CAS#170277-31-3)是一种人鼠嵌合单抗，其通过特异性结合人体内的TNF-α，阻止TNF-α与其细胞表面受体结合，从而阻断了TNF-α的生物学活性，最终减轻炎症反应并减少破骨细胞激活，达到控制并缓解症状的目的。英夫利西单抗可用于治疗类风湿性关节炎、银屑病、强制性脊柱炎、溃疡性结肠炎和克罗恩氏病等。
但是，英夫利西单抗稳定性不够，会发生多种化学和物理降解，尤其是高级结构非常脆弱，容易发生结构变化，如变性、聚集和沉淀。这些降解或不稳定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(CQA)，直接影响到英夫利西单抗的用药安全。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。
CN104159614A公开了改进的液体制剂，其包含在合适的缓冲剂、一种或更多种合适的稳定剂以及其他任选地选自合适的表面活性剂和张力剂的赋形剂中的合适量的治疗性蛋白。CN103402540A涉及一种非水性高浓度混悬剂，其包含含有输水集和降粘剂的载体和用赋形剂配制的抗体。
发明内容
在一方面，本发明涉及一种药物组合物，其包含英夫利西单抗、组氨酸缓冲体系、结构保护剂和表面活性剂，
其中所述组合物中英夫利西单抗的浓度为约5-40mg/ml，所述组氨酸缓冲体系中组氨酸的浓度为约1-200mM，所述结构保护剂的浓度为约0-100mg/ml，所述表面活性剂的浓度为约0.01-1mg/ml。
在一优选实施方案中，药物组合物中所述英夫利西单抗的浓度为约5-20mg/ml。
在另一优选实施方案中，药物组合物中所述组氨酸的浓度为约5-75mM，优选约25-45mM，例如约25、30、35、40、45mM。
在另一优选实施方案中，药物组合物中所述结构保护剂选自蔗糖、海藻糖及其组合，其中所述结构保护剂的浓度为约10-75mg/ml，优选约10-50mg/ml。
在又一优选实施方案中，药物组合物中所述表面活性剂的浓度为约0.025-0.4mg/ml，优选约0.025-0.1mg/ml。
在还一实施方案中，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、聚丙二醇及其组合，优选聚山梨酯80。
在一实施方案中，所述药物组合物的pH值为约4.0-9.0，优选约4.5-8.0，更优选约5.2-7.2。
在优选的实施方案中，本发明的药物组合物包含：
Figure PCTCN2018081806-appb-000001
pH为约5.2-7.2。
在又一方面，本发明涉及一种预防或治疗人类自身免疫相关疾病的方法，所述方法包括向有此需要的个体给药本发明的药物组合物。
在还一方面，本发明还涉及本发明的药物组合物在制备用于预防或治疗人类自身免疫相关疾病的药物中的用途。
在还一方面，本发明还涉及用于预防或治疗人类自身免疫相关疾病的药物组合物。
在一实施方案中，所述人类自身免疫相关疾病包括但不限于类风湿性关节炎、银屑病、幼年特发性关节炎、强直性脊柱炎、克罗恩氏病、溃疡性结肠炎、斑块状银屑病等。
具体实施方式
一般定义和术语
除非另有说明，本文所用的术语和短语具有下文所列的含义。特定的术语或短语在没有特别定义的情况下不应该认为是不确定的或不清楚的，而应该按照本领域技术人员通常理解的含义进行解释。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
表述“包含”或与其同义的类似表述“包括”、“含有”和“具有”等是开放性的，不排除额外的未列举的元素、步骤或成分。表述“由…组成”排除未指明的任何元素、步骤或成分。表述“基本上由…组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，表述“包含”涵盖表述“基本上由…组成”和“由…组成”。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，组合物任选地包含抗氧化剂涵盖包含或者不包含抗氧化剂的情况。
除非另有说明，本文的百分比、份数等都按重量计。
本文所使用的英夫利西单抗(infliximab)是可商购的，其CAS号为170277-31-3，例如可获得自浙江海正药业股份有限公司。
术语“组氨酸缓冲液”或“组氨酸缓冲体系”表示组氨酸与任选存在的用 于调节pH的酸如盐酸、醋酸、硫酸等组合得到的缓冲体系。在表征制剂中的组氨酸缓冲体系时，通常使用的是其中的组氨酸的浓度的总和，包括其游离和电离形式。组氨酸缓冲液的实例包括但不限于组氨酸/盐酸、组氨酸/醋酸、组氨酸/硫酸等。本发明优选的组氨酸缓冲液是组氨酸/盐酸缓冲液。
术语“碳水化合物”包括单糖、二糖、低聚糖和多糖。碳水化合物的实例包括但不限于果糖、葡萄糖、蔗糖、海藻糖、甘露糖、乳糖、甘露糖、麦芽糖、山梨糖、葡聚糖、糊精、环糊精、羟乙基淀粉或其组合。
术语“氨基酸”包括氨基酸和/或其药学上可接受的盐。氨基酸的实例包括但不限于丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸或其组合。
“药学上可接受的盐”是指与药学上可接受的无毒的碱或酸，包括无机或有机碱和无机或有机酸形成的盐。例如与以下无机酸形成的盐：例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸；或者与以下有机酸形成的盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、烟酸、扑酸、苦味酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸或抗坏血酸。
术语“冻干”表示将溶液制剂在较低的温度下冻结成固态，然后在真空下使其中的水分不经液态直接升华成气态，最终使物料脱水的干燥技术。冻干包括但不限于冷冻、一次干燥和二次干燥。
药物组合物和给药
本发明的药物组合物中包含组氨酸缓冲体系。与现有技术中使用的磷酸盐缓冲体系相比，包含组氨酸缓冲体系的英夫利西单抗药物组合物的稳定性大大提高。
具体地，本发明提供一种药物组合物，其包含英夫利西单抗、组氨酸缓冲体系、结构保护剂和表面活性剂。
在一实施方案中，药物组合物中的英夫利西单抗的浓度为约5-40 mg/ml，优选约5-20mg/ml。
在本发明的制剂中，组氨酸缓冲体系的实例包括但不限于组氨酸/盐酸、组氨酸/醋酸、组氨酸/硫酸等，优选为组氨酸/盐酸缓冲液。在一实施方案中，药物组合物中组氨酸缓冲体系的组氨酸的浓度为约1-200mM，优选约5-75mM，更优选约25-45mM，例如约25、30、35、40、45mM。
本发明的药物组合物可以包含结构保护剂。结构保护剂可以用于稳定药物组合物中活性成分的结构，在常温和冻干状态下提供保护性能。碳水化合物和氨基酸为常用的蛋白质药物的稳定剂。其还可作为冷冻保护剂和干燥保护剂，保护蛋白质在冻干过程中可能发生的变性。在一实施方案中，结构保护剂为碳水化合物、氨基酸或其组合。在优选的实施方案中，结构保护剂选自选自蔗糖、海藻糖及其组合，更优选为蔗糖。结构保护剂的浓度为约0-100mg/ml，优选约10-75mg/ml，更优选约10-50mg/ml，例如约25mg/ml。
本发明的药物制剂还可以包含表面活性剂。表面活性剂为能改变(通常降低)液体表面张力或两相间界面张力的物质。表面活性剂具有两亲性，含有亲水基团和亲油基团。表面活性剂的实例包括但不限于聚山梨酯类、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、聚丙二醇或它们的混合物。可以使用的聚山梨酯类表面活性剂有聚山梨酯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或其混合物，优选聚山梨酯80。在本发明的药物组合物中，表面活性剂的浓度可以为约0.01-1mg/ml，优选约0.025-0.4mg/ml，最优选约0.025-0.1mg/ml。
本发明的药物制剂可以任选地包含抗氧化剂，抗氧剂可以抑制药物制剂的氧化，提高药物的稳定性并有助于延长储存期。抗氧剂的实例包括但不限于抗坏血酸、色氨酸、蛋氨酸、谷胱甘肽、硫代硫酸钠、过氧化氢酶或其混合物。
根据需要，本发明的药物组合物可以任选地包含螯合剂，螯合剂可以结合容易催化蛋白发生氧化的金属离子，从而提高其稳定性，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，例如乙二胺四乙酸(EDTA)、二乙三胺五乙酸 (DTPA)、次氮基三乙酸(NTA)及它们的盐。所用的螯合剂可以游离酸、游离碱或盐的形式存在，也可以化合物或相应盐的无水合物、水合物或者其它溶剂化物的形式存在。
本发明的药物制剂也可以任选地包含防腐剂，防腐剂可以抑制微生物的生长和繁殖，其包括但不限于间甲酚、苯酚、苯甲醇、苯扎氯铵、苯氧乙醇、对羟基苯甲酸甲酯及其混合物。
pH的选择对于组合物的稳定性而言很关键，pH的选择应使得对应的活性物质保持稳定。此外，pH的选择还应当使得药物组合物中的其他成分能够保持其物理和化学性质，例如不会降解。作为优选的实施方案，适合的pH值为约4.0-9.0，优选约4.5-8.0，更优选约5.2-7.2，例如约5.7、6.7。
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。
在本发明中，基于含水溶液或水例如注射用水配制药物组合物。
在具体的实施方案中，本发明提供一种药物组合物，其包含：
Figure PCTCN2018081806-appb-000002
pH为约5.2-7.2。
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.)、肌肉注射(i.m.)或其它非肠胃形式给药。
有益效果
本发明通过选用组氨酸作为英夫利西单抗的缓冲体系，大大提高了药物组合物及其冻干制剂特别是在高温和光照条件下的稳定性，在冻干状态下能够稳定地长期存储。
实施例
以下通过实施例对本发明进一步进行说明。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。在本文中，除非另外指明或者明显不适合，包括百分比在内的比例均按重量计。“/”表示不含或者未检测到。
制备
用注射用水配制英夫利西单抗药物组合物溶液，将产品进行冻干，冻干工艺见表1。
表1.英夫利西单抗冻干工艺
Figure PCTCN2018081806-appb-000003
对冻干前后的制剂分别进行高温和光照试验。
高温试验：将样品置于40℃±2℃恒温箱中，分别于第1周和2周或者第2周和第4周取样检测；
光照试验：将样品放置于光照箱(5℃±3℃，4500Lx±500Lx)中，10天后取样。
试剂和检测仪器
试剂：
英夫利西单抗，由浙江海正药业股份有限公司提供
组氨酸，购自JT Baker
蔗糖，购自Merck KGaA
海藻糖，购自日本林原
盐酸精氨酸，购自JT Baker
聚山梨酯80，购自JT Baker
仪器：
Agilent 1200液相色谱仪，购自美国Agilent公司
SEC-HPLC色谱柱：日本TOSOH公司的TSK-GEL G3000SWXL，7.8×300mm；流动相：0.02mol/L磷酸二氢钠、0.2mol/L氯化钠缓冲液、10％乙腈，pH 7.0；流速：0.5ml/min；柱温：30℃；运行时间：30min；波长：280nm。
马尔文Zetasizer Nano-ZS ZEN3600动态光散射仪，购自马尔文。
实施例1
本实施例比较了目前市售的处方(制剂1)和使用组氨酸缓冲液代替磷酸缓冲液(制剂2)对英夫利西单抗药物组合物稳定性的影响(表2)。
表2.药物组合物的组成
Figure PCTCN2018081806-appb-000004
将表格1中的制剂1和制剂2冻干。
对制剂1-2进行外观、可见异物检测，用SEC-HPLC检测多聚体含量，结果见表3。
表3.制剂1和制剂2经过高温和光照后外观/可见异物和多聚体含量
Figure PCTCN2018081806-appb-000005
Figure PCTCN2018081806-appb-000006
*试验数据为平均值±标准偏差，重复3次，下同。
多聚体含量常用来表示制剂的稳定性，多聚体含量越高，说明制剂稳定性越差。表3的结果表明，使用组氨酸(制剂2)代替磷酸盐(制剂1)作为缓冲液，水针制剂的稳定性有显著提升，多聚体含量较少。在冻干条件下制剂的稳定性均好于水针制剂的稳定性，且冻干制剂2的稳定性更好。
实施例2
本实施例比较了缓冲液种类对英夫利西单抗药物组合物的稳定性的影响。药物组合物的组成配方制剂3-4如表4所示。
表4.药物组合物的组成
Figure PCTCN2018081806-appb-000007
英夫利西单抗在水溶液中粒径大小比较
使用动态光散射技术(马尔文Zetasizer Nano-ZS ZEN3600)对两制剂在水溶液中的单抗粒径进行研究(表5)。含磷酸盐的制剂3的平均粒径大于含有组氨酸的制剂4，说明在组氨酸溶液中单抗相互作用较弱，较不易发生碰撞形成多聚体，稳定性较好。
表5.制剂3-4在水溶液中的粒径大小
序号 粒径(nm)
制剂3 20.14
制剂4 18.75
将制剂3和制剂4按照表1的冻干工艺冻干。比较冻干制剂在高温(40℃±2℃，2周、4周)和光照(5℃±3℃，4500Lx±500Lx，10天)条件下的稳定性(表6)。
表6.冻干制剂3和制剂4经过高温和光照后外观/可见异物和多聚体含量
Figure PCTCN2018081806-appb-000008
经过高温或光照后，相比以磷酸盐缓冲液配制的冻干制剂3，以组氨酸缓冲液配制的冻干制剂4具有更低的多聚体含量，即更高的稳定性。
实施例3.
在本实施例中，按表7配制各英夫利西单抗药物组合物(制剂5-8)，其中pH采用盐酸进行调节。将制剂5-8用表1的冻干工艺冻干。冻干后进行高温(40±2℃)和光照(5℃±3℃，4500Lx±500Lx，10天)试验。
表7.药物组合物的组成
Figure PCTCN2018081806-appb-000009
冻干制剂经受高温或光照后外观均为白色块状固体，溶解后为无色澄明液体，无可见异物。试验结束后用SEC-HPLC检测制剂5-8的多聚体含 量，结果如表8所示。
表8.制剂5-8经过高温和光照后多聚体含量(％)
序号 0时 40℃2周 40℃4周 光照10天
制剂5 0.91±0.02 1.30±0.02 1.38±0.04 0.98±0.03
制剂6 0.91±0.04 1.23±0.02 1.28±0.03 0.98±0.03
制剂7 0.82±0.02 1.12±0.03 1.17±0.02 0.90±0.02
制剂8 0.79±0.01 1.01±0.06 1.10±0.04 0.82±0.02
从表8可知，经过40℃高温后，pH越高，多聚体含量增加越明显。但在pH为4.7时制剂酸度较大，容易在注射时发生疼痛。在光照条件下，不同pH制剂的多聚体含量增加都不明显。
实施例4.
本实施例比较结构保护剂对英夫利西单抗药物组合物稳定性的影响。按表9配制各英夫利西单抗药物组合物(制剂9-11)，用表1的冻干工艺冻干。冻干后进行高温(40±2℃)和光照(4500±500Lx)试验。
表9.药物组合物的组成
Figure PCTCN2018081806-appb-000010
冻干制剂经受高温或光照后外观均为白色块状固体，溶解后为无色澄明液体，无可见异物。试验结束后用SEC-HPLC检测制剂9-11的多聚体含量，结果见表10。
表10.制剂9-11经过高温和光照后多聚体含量(％)
序号 0时 40℃2周 40℃4周 光照10天
制剂9 0.91±0.02 1.30±0.02 1.38±0.04 0.98±0.03
制剂10 1.05±0.00 1.11±0.03 1.17±0.02 1.13±0.03
制剂11 1.19±0.01 1.99±0.12 2.28±0.11 1.38±0.04
从表10可知，经过高温或光照试验后，蔗糖和海藻糖对于英夫利西单 抗药物组合物的稳定作用相当(制剂9、10多聚体含量增加均不明显)，均优于盐酸精氨酸的稳定作用。
实施例5.
本实施例比较表面活性剂浓度对英夫利西单抗药物组合物稳定性的影响。按表11配制各英夫利西单抗药物组合物(制剂12-14)，将制剂12-14用表1的冻干工艺冻干。冻干后进行高温(40±2℃)和光照(4500±500Lx)试验。
表11.药物组合物的组成
Figure PCTCN2018081806-appb-000011
冻干制剂经受高温或光照后外观均为白色块状固体，溶解后为无色澄明液体，无可见异物。试验结束后用SEC-HPLC检测制剂12-14的多聚体含量，结果见表12。
表12.制剂12-14经过高温和光照后多聚体含量(％)
序号 0时 40℃2周 40℃4周 光照10天
制剂12 0.91±0.02 1.30±0.02 1.38±0.04 0.98±0.03
制剂13 1.11±0.08 1.02±0.07 1.10±0.04 1.08±0.02
制剂14 1.03±0.03 1.74±0.15 1.81±0.04 1.12±0.02
从表12可知，聚山梨酯80在浓度为0.025-0.4mg/ml，特别是0.025-0.1mg/ml的范围内，多聚体含量增加都不明显，英夫利西单抗药物组合物的稳定性都在可接受范围内。
实施例6.
本实施例比较了不同浓度组氨酸缓冲体系对英夫利西单抗药物组合物稳定性的影响。按表13配制英夫利西单抗药物组合物(制剂15-21)，进行高温(40±2℃)和光照(4500±500Lx)试验。
表13.药物组合物的组成
Figure PCTCN2018081806-appb-000012
试验结束后进行了外观/可见异物检测，并用SEC-HPLC检测多聚体含量，结果见表14。
如表14所示，随着组氨酸浓度的上升，在高温条件下，多聚体含量先逐渐下降(制剂15-19)，随后又逐渐上升(制剂20-21)。在光照条件下制剂的稳定性对组氨酸的浓度变化更敏感，随组氨酸浓度的升高，制剂15-17的多聚体含量逐渐降低，制剂18-20的多聚体含量逐渐上升。此外，制剂19-21在经过高温2周或光照以后颜色有加深，且部分样品出现了肉眼可见异物。在测试的制剂中，制剂16-18，特别是制剂17的稳定性结果特别优异。
表14.制剂15-21经过高温和光照后多聚体含量(％)
Figure PCTCN2018081806-appb-000013
除非另有说明，本说明书(包括权利要求书)中使用的所有表示成分、细胞培养、处理条件等的量的数字应当理解为在所有条件下受到术语“约”的修饰。因此，除非另有相反的说明，数值参数为近似值，并且可以根据通过本发明试图获得的期望特性而变化。除非另有说明，一系列元素之前的术语“至少”应当理解为指该系列中的每个元素。本领域技术人员会认识到或者能够利用不超过常规实验确定本文所述的本发明的具体实施方案的许多等同物。所附权利要求书意图涵盖这类等同物。
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 (9)

  1. 一种药物组合物，其包含英夫利西单抗、组氨酸缓冲体系、结构保护剂和表面活性剂，
    其中所述组合物中英夫利西单抗的浓度为5-40mg/ml，所述组氨酸缓冲体系中组氨酸的浓度为1-200mM，所述结构保护剂的浓度为0-100mg/ml，所述表面活性剂的浓度为0.01-1mg/ml。
  2. 权利要求1的药物组合物，其特征在于，所述英夫利西单抗的浓度为5-20mg/ml。
  3. 权利要求1或2的药物组合物，其特征在于，所述组氨酸的浓度为5-75mM，优选25-45mM，更优选45mM。
  4. 权利要求1-3中任一项的药物组合物，其特征在于，所述结构保护剂选自蔗糖、海藻糖及其组合，其中所述结构保护剂的浓度为10-75mg/ml，优选10-50mg/ml。
  5. 权利要求1-4中任一项的药物组合物，其特征在于，所述表面活性剂的浓度为0.025-0.4mg/ml，优选0.025-0.1mg/ml。
  6. 权利要求5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、聚丙二醇及其组合，优选聚山梨酯80。
  7. 权利要求1-6中任一项的药物组合物，其特征在于，所述药物组合物的pH值为4.0-9.0，优选4.5-8.0，更优选5.2-7.2。
  8. 根据权利要求1-7中任一项的药物组合物在制备用于预防或治疗人类自身免疫相关疾病的药物中的用途。
  9. 根据权利要求8的用途，其特征在于，所述疾病包括类风湿性关节炎、银屑病、幼年特发性关节炎、强直性脊柱炎、克罗恩氏病、溃疡性结肠炎、斑块状银屑病。
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