WO2015090162A1 - 一种含有阿达木单抗的药物组合物 - Google Patents

一种含有阿达木单抗的药物组合物 Download PDF

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WO2015090162A1
WO2015090162A1 PCT/CN2014/093722 CN2014093722W WO2015090162A1 WO 2015090162 A1 WO2015090162 A1 WO 2015090162A1 CN 2014093722 W CN2014093722 W CN 2014093722W WO 2015090162 A1 WO2015090162 A1 WO 2015090162A1
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pharmaceutical composition
polysorbate
adalimumab
acid
formulation
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French (fr)
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方伟杰
王海彬
黄春辉
裘敏虹
王诏
郑洪健
应跃斌
白骅
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Zhejiang Hisun Pharmaceutical Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
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Priority to MX2016007878A priority Critical patent/MX386298B/es
Priority to RU2016125159A priority patent/RU2664736C2/ru
Priority to EP14871536.0A priority patent/EP3085385B1/en
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—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
    • 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
    • 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

Definitions

  • the invention belongs to the field of biotechnology, and in particular relates to a pharmaceutical composition containing adalimumab.
  • Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by joint synovitis. Prolonged recurrent episodes of synovitis can lead to destruction of cartilage and bone in the joints, joint dysfunction, and even disability.
  • Vasculitis lesions involve various organs of the body, so this disease is also known as rheumatoid disease.
  • About 80% of patients have an onset age of 20 to 45 years old, with young adults as the ratio of male to female, and the ratio of male to female is 1:2 to 4.
  • Tumor necrosis factor- ⁇ is a cytokine that directly kills tumor cells without significant toxicity to normal cells. It is mainly produced by synovial macrophages, which stimulates synovial fibroblast proliferation, secretes interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokines and matrix. Effector molecules such as metalloproteinases and prostaglandins play an extremely important role in the pathogenesis of RA. At present, TNF- ⁇ antagonists are the most effective drugs for the treatment of RA and other similar diseases, mainly etanercept, infliximab and adalimumab.
  • Adalimumab blocks the biological activity of TNF- ⁇ by specifically binding to TNF- ⁇ in humans, preventing TNF- ⁇ from binding to its cell surface receptors, ultimately reducing inflammation and reducing osteoclast activation. Achieve control and relieve symptoms and signs. Its marketing not only provides a new treatment strategy for patients with rheumatoid arthritis, but also because of its intractable active rheumatoid arthritis that is ineffective or intolerant to other anti-rheumatic drugs. Ankylosing spondylitis is also effective, and has the characteristics of rapid effect, high curative effect, good safety and good tolerance. The clinical value is very large, and the market prospect is quite good. The current adalimumab product on the market is produced by Abbott.
  • Adalimumab belongs to the whole source of monoclonal antibody, and “all-human” means that there is no difference between the antibody immunoglobulin IgG produced by the human body itself.
  • the human body randomly produces a variety of antibodies to protect against various foreign pathogens.
  • it since it is a randomly generated antibody, it also uses an autoantigen as an antibody to be attacked.
  • antibodies that attack themselves are eliminated by the immune system before they have mature functions. Therefore, in short, antibodies against human antigens are generally not produced in humans. Therefore, early therapeutic antibodies are often produced in mice. Due to differences in protein species, the time remaining in the human body is shortened, the efficacy is also affected, and there is a certain risk of allergies.
  • phage display technology screens randomly generated antibody precursors from healthy human donor B cells to identify a human antibody produced by human B cells, but specifically binds to TNF. - ⁇ , that is . in other words, It is a fully human TNF- ⁇ antibody that is searched for bypassing the human body's own review and elimination mechanism, which not only effectively antagonizes human TNF- ⁇ , but also greatly reduces immune rejection.
  • Adalimumab preparations currently on the market It is a water needle preparation containing adalimumab 50 mg/mL, sodium chloride 6.16 mg/mL, sodium citrate 0.35 mg/mL, citric acid 1.3 mg/mL, dihydrogen phosphate dihydrogen phosphate 0.86 mg/mL, Disodium hydrogen phosphate dihydrate 1.53 mg / mL, mannitol 12 mg / mL, polysorbate 801 mg / mL, solution pH 5.2.
  • adalimumab is an active ingredient
  • sodium chloride is an isotonic agent
  • citrate and phosphate are buffers
  • mannitol is structurally stable
  • polysorbate 80 is a surfactant.
  • the formulation is less stable and has significant degradation under long-term and accelerated test conditions, particularly the production of more impurities such as aggregates and insoluble particles.
  • Polymers and insoluble particles are considered to be important quality safety attributes (CQA) for biopharmaceutical safety, directly affecting the safety of adalimumab, especially their immunogenicity, which is long-term use. Products such as adalimumab are particularly important.
  • CN201080030083.9 discloses a pharmaceutical preparation of adalimumab which does not contain sodium chloride and which contains a high concentration (>20 mg/ml) of a polyol such as mannitol, which is commercially available.
  • the formulation has higher stability under high temperature conditions.
  • adalimumab is unstable and undergoes a variety of chemical and physical degradations.
  • biomolecules Compared with traditional synthetic small molecule drugs, biomolecules have complex structures such as primary, secondary, and tertiary structures.
  • the structure of proteins, especially high-grade structures, is very fragile and prone to structural changes such as denaturation, aggregation and precipitation.
  • Keep the antibody high Grade structures are the most basic requirements for exerting their biological activities.
  • These degradation products 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.
  • Antibody drugs not only require high-purity products at the time of production, but also maintain structural stability during transportation, storage, and use.
  • the present invention provides a pharmaceutical composition containing adalimumab which maintains the physical and chemical stability of the pharmaceutical composition for a prolonged period of time and which has viscosity and osmotic pressure which are highly suitable for subcutaneous administration. .
  • the present invention provides a pharmaceutical composition
  • adalimumab and a structural protectant.
  • concentration of adalimumab in the composition is from 1 to 200 mg/ml, preferably from 10 to 100 mg/ml, more preferably 50 mg/ml.
  • the structural protectant is selected from the group consisting of sucrose or trehalose, preferably sucrose, and the concentration of the structure protectant is from 1 to 200 mg/ml, preferably from 10 to 100 mg/ml.
  • the inventors have surprisingly found that the use of isotonic sucrose or trehalose as a structural protectant provides a substantial increase in the physical and chemical stability of the resulting composition compared to the prior art.
  • the pharmaceutical composition of the present invention does not contain sodium chloride.
  • the present inventors have surprisingly found that the stability of the adalimumab preparation containing no sodium chloride is significantly higher than that of the adalimumab preparation containing sodium chloride after the isotonic sucrose or trehalose is selected as the structural protective agent. stability.
  • compositions of the present invention further comprise surfactants including, but not limited to, polysorbates such as polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate Ester 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85 or mixtures thereof, poloxamer, triton, sodium lauryl sulfate, sodium lauryl sulfate, octyl Sodium glycosides, lauryl-sulfobetaine, polyethylene glycol, polypropylene glycol, or mixtures thereof, preferably polysorbate 80.
  • the concentration of the surfactant is from 0.01 to 10 mg/ml, preferably from 0.1 to 2 mg/ml, more preferably 1 mg/ml.
  • the pharmaceutical composition of the present invention further comprises a buffer including, but not limited to, glycine, acetic acid/acetate, succinic acid/succinate, citric acid/citrate, ascorbic acid/ascorbate, tartaric acid/tartrate, butenene Diacid/maleate, lactic acid/lactate, carbonic acid/bicarbonate, benzoic acid/benzoate, histidine, Phosphate/phosphate or tris/tris hydrochloride, preferably a combination of citric acid/citrate and carbonic acid/bicarbonate.
  • the buffer added thereto provides a pH of the composition of the invention of from 4.0 to 9.0, preferably from 4.5 to 8.0, more preferably 5.2.
  • compositions of the present invention further comprise a pharmaceutically acceptable amount of an antioxidant, including but not limited to ascorbic acid, tryptophan, methionine, glutathione, sodium thiosulfate or catalase.
  • an antioxidant including but not limited to ascorbic acid, tryptophan, methionine, glutathione, sodium thiosulfate or catalase.
  • compositions of the present invention further comprise a pharmaceutically acceptable amount of a chelating agent, including but not limited to aminopolycarboxylic acids, hydroxyaminocarboxylic acids, N-substituted glycines, citric acid, nicotinamide, deferoxamine, and deoxycholic acid. Salts and mixtures thereof, such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), and salts thereof.
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • NDA nitrilotriacetic acid
  • the chelating agent used in the present invention may be present in the form of the free acid or free base or salt of the compound, or may be in the form of an anhydrate, hydrate or other solvate of the compound or the corresponding salt.
  • compositions of the present invention further comprise a pharmaceutically acceptable amount of a preservative including, but not limited to, m-cresol, phenol, benzyl alcohol, benzalkonium chloride, phenoxyethanol or methylparaben.
  • a preservative including, but not limited to, m-cresol, phenol, benzyl alcohol, benzalkonium chloride, phenoxyethanol or methylparaben.
  • the adalimumab in the pharmaceutical composition of the present invention maintains solubility and stability over a wide pH range, suitably pH values of 4.0 to 9.0, preferably 4.5 to 8.0, more preferably 5.2.
  • the pharmaceutical composition of the present invention contains the following ingredients:
  • composition has a pH of 5.2.
  • 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 pharmaceutical composition of the present invention can be used for the preparation of a medicament for treating human autoimmune-related diseases, including rheumatoid arthritis, psoriasis, juvenile idiopathic arthritis, Ankylosing spondylitis, Crohn's disease (Crohn’s disease), ulcerative colitis, plaque psoriasis, and the like.
  • human autoimmune-related diseases including rheumatoid arthritis, psoriasis, juvenile idiopathic arthritis, Ankylosing spondylitis, Crohn's disease (Crohn’s disease), ulcerative colitis, plaque psoriasis, and the like.
  • the invention greatly improves the stability of the pharmaceutical composition by using iso-osmolal sucrose or trehalose as a structural protection agent of adalimumab, especially in the freeze-thaw experiment, high temperature and light damage, showing higher Stability, so it has a very broad market application prospects.
  • Figure 1 is a SEC-HPLC overlay of Formulations 1-4 after freeze-thaw.
  • the inventors have conducted a large number of experimental studies and surprisingly found that in a pharmaceutical composition containing adalimumab, an isotonic sucrose or trehalose is used as a structural protective agent for adalimumab, which can greatly improve the pharmaceutical composition.
  • the stability has a very broad market application prospect.
  • SEC-HPLC is an analytical method that utilizes the relative relationship between the pore size of the gel pores and the size of the analyzed sample.
  • the larger molecular weight molecules in the sample are completely excluded due to their inability to enter the gel pores and can only pass through the column between the porous gel particles, so they are first eluted from the column by the mobile phase. Molecules with smaller molecular weights can enter the pores of the gel, which are more strongly retained in the column and are not easily eluted, thereby achieving separation of solute molecules of different sizes.
  • the analysis of biopharmaceuticals is mainly used to measure the content of aggregates, mainly in the loss of monomer content and the increase in polymer content.
  • Formulation 1 is a marketed product Formulation 2;
  • Formulation 2 is a preparation containing a high concentration of mannitol without sodium chloride;
  • Formulation 3 is a preparation prepared by using sucrose of equimolar osmotic pressure instead of mannitol of Formulation 1;
  • Formulation 4 is sucrose using equimolar osmotic pressure A formulation prepared in place of the mannitol of Formulation 2.
  • Formulations 1-4 of 0.85 ml/syringe were prepared according to the concentrations of the respective formulation components in Table 1 for stability studies. The appearance and SEC-HPLC purity and impurity polymer content test results at 0 are shown in Table 2.
  • High temperature test The sample was placed in a 40 ° C incubator and tested at 2 weeks and 4 weeks later.
  • Freeze-thaw test frozen at -20 °C for 5 hours, 4 °C for 10 hours, repeated freeze-thaw 8 times.
  • the corresponding polymer contents are Formulation 1 > Formulation 3 > Formulation 2 > Formulation 4, respectively.
  • the above experimental data show that the use of sucrose instead of mannitol can increase the stability of the adalimumab preparation regardless of whether or not the adalimumab preparation contains sodium chloride.
  • the high concentration (50 mg/ml) adalimumab formulation 2 containing mannitol as a structural protectant had a SEC-HPLC purity even lower than that of the formulation without any structural protective agent after freeze-thaw destruction.
  • Example 3 Preparation of low concentration (1 mg/ml) and high concentration (100 mg/ml) adalimumab preparations of sucrose and trehalose as structure protectants
  • This example designed and formulated formulations 12-15 containing low concentrations (1 mg/ml) and high concentrations (100 mg/ml) of adalimumab (Table 7) for verification of sucrose and trehalose as structures.
  • the protective agent is capable of formulating low and high concentrations of adalimumab preparations. These preparations do not contain sodium chloride, the other components are: 0.35mg / ml sodium citrate, 1.3mg / ml citric acid, 0.86mg / ml sodium dihydrogen phosphate, 1.53mg / ml disodium hydrogen phosphate, 1mg /ml polysorbate 80, solution pH 5.2.
  • Example 4 Preparation of adalimumab preparations of different pH values of sucrose and trehalose as structure protectants
  • This example designed and formulated formulation prescriptions 16-29 containing adalimumab formulations of different pH values (pH 4.5-8.0, Table 8). None of these preparations contained sodium chloride. The other components were: 50 mg/ml adalimumab, 0.35 mg/ml sodium citrate, 1.3 mg/ml citric acid, 0.86 mg/ml sodium dihydrogen phosphate, 1.53. Mg/ml disodium hydrogen phosphate, 1 mg/ml polysorbate 80.
  • This example designed and formulated adalimumab formulation 30-35 with various concentrations of sucrose or trehalose as a structural protectant (Table 9). None of these formulations contain sodium chloride.
  • the other components in the formulation are: 50 mg/ml adalimumab, 0.35 mg/ml sodium citrate, 1.3 mg/ml citric acid, 0.86 mg/ml sodium dihydrogen phosphate. 1.53 mg/ml disodium hydrogen phosphate, 1 mg/ml polysorbate 80.
  • Example 6 Preparation of Adalimumab Formulation with Different Polysorbate 80 Contents of Sucrose or Trehalose as Structure Protecting Agent
  • This example designed and formulated formulation formulations 36-45 containing adalimumab formulations at various concentrations of polysorbate 80 (Table 10). None of these formulations contain sodium chloride. The other components in the formulation are: 50 mg/ml adalimumab, 0.35 mg/ml sodium citrate, 1.3 mg/ml citric acid, 0.86 mg/ml sodium dihydrogen phosphate. , 1.53 mg / ml disodium hydrogen phosphate, pH 5.2.

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Abstract

一种含有阿达木单抗和结构保护剂的药物组合物，其中结构保护剂选自蔗糖或海藻糖，所述药物组合物的稳定性高。

Description

一种含有阿达木单抗的药物组合物 技术领域
本发明属于生物技术领域，具体涉及一种含有阿达木单抗的药物组合物。
背景技术
类风湿性关节炎(rheumatoid arthritis，RA)是一种以关节滑膜炎为特征的慢性全身性自身免疫性疾病。滑膜炎持久反复发作，可导致关节内软骨和骨的破坏，关节功能障碍，甚至残废。血管炎病变累及全身各个器官，故本病又称为类风湿病。约80％患者的发病年龄在20～45岁，以青壮年为多，男女之比为1∶2～4。全世界光关节炎患者有3.55亿人。在亚洲地区，每6个人中就有1人在一生的某个阶段患上关节炎这种世界头号致残性疾病。目前，估计中国大陆的关节炎病人有1亿以上，而且人数还在不断增加。而目前我国患类风湿关节炎的人数达600万左右。
肿瘤坏死因子-α(tumor necrosis factor，TNF-α)是一种能够直接杀伤肿瘤细胞而对正常细胞无明显毒性的细胞因子。它主要由滑膜巨噬细胞产生，能刺激滑膜成纤维细胞增生，分泌白细胞介素6(IL-6)，粒细胞-巨噬细胞集落刺激因子(GM-CSF)、趋化因子以及基质金属蛋白酶和前列腺素等效应分子，在RA的发病中起着极其重要的作用。目前TNF-α拮抗剂是最有效的治疗RA及其他类似疾病的药物，主要有依那西普(etanercept)、英夫利西单抗(infliximab)和阿达木单抗(adalimumab)等。
阿达木单抗是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体征的目的。它的上市不仅为类风湿性关节炎患者提供了一种新的治疗策略，而且因其对经其它抗类风湿药物治疗无效或不能耐受这些药物治疗的顽固性活动性类风湿性关节炎及强直性脊柱炎亦有效，并具有显效快、疗效高、安全性和耐受性好等特点，临床价值甚大，市场前景颇佳。目前市场上的阿达木单抗产品商品为美国雅培公司(Abbott)生产的
Figure PCTCN2014093722-appb-000001
，于2002年获得批准上市，其经FDA批准的适应症有：中-重度类风湿性关节炎、中-重幼年型类风湿性关节炎、银屑病、强制性脊柱炎和中-重度克罗恩氏病等。
阿达木单抗属于全人源单抗，“全人源”就是指与人体自身产生的抗体免疫球蛋 白IgG没有什么差别。一般来说，人体会随机产生各种抗体，用来防御各种外来的病原。然而，既然是随机产生的抗体，也会把自身抗原当作攻击对象的抗体。往往这种会攻击自身的抗体在具有成熟的功能之前就被免疫系统消除掉，因此，简单地说，人体内一般产生不了抗人抗原的抗体。所以，早期的治疗用抗体往往是在鼠体内产生的，因蛋白来源的属种差异，在人体内存在的时间缩短，疗效也受到影响，且有一定过敏风险。现在虽然可以通过与人的抗体部分组合而减少鼠来源成分的比例，但是鼠源蛋白的影响并不能完全消除。而美国雅培公司通过噬菌体表达技术，将来自健康的人类捐献者的B细胞中随机生成的抗体前体进行筛选，找出了一种由人类B细胞生成的人类抗体，但是能特异性地结合TNF-α，也就是
Figure PCTCN2014093722-appb-000002
。换句话说，
Figure PCTCN2014093722-appb-000003
是绕过人体自身审查消除机制而搜寻到的全人源TNF-α抗体，不仅能够有效拮抗人类的TNF-α，而且极大地减少了免疫排斥反应。
目前已上市的阿达木单抗制剂
Figure PCTCN2014093722-appb-000004
为水针制剂，含有阿达木单抗50mg/mL，氯化钠6.16mg/mL，枸橼酸钠0.35mg/mL，枸橼酸1.3mg/mL，二水磷酸二氢钠0.86mg/mL，二水磷酸氢二钠1.53mg/mL，甘露醇12mg/mL，聚山梨醇酯801mg/mL，溶液pH 5.2。其中，阿达木单抗为有效成分，氯化钠为等渗剂，枸橼酸盐和磷酸盐为缓冲剂，甘露醇为结构稳定性，聚山梨醇酯80为表面活性剂。
已发现上市的
Figure PCTCN2014093722-appb-000005
制剂较不稳定，在长期和加速试验条件下有显著的降解，特别是产生较多的杂质如聚合物(aggregates)及不溶性微粒(insoluble particles)。而聚合物及不溶性微粒被认为是生物制药安全性非常重要的质量参数(critical quality attribute，CQA)，直接影响到阿达木单抗的用药安全，特别是它们的免疫原性，这对于长期用药的产品如阿达木单抗尤为重要。
CN201080030083.9公开了一种不含氯化钠而含有高浓度(>20mg/ml)多元醇如甘露醇的阿达木单抗药物制剂，该制剂相比已上市的
Figure PCTCN2014093722-appb-000006
制剂在高温条件下具有更高的稳定性。
和大多数蛋白分子一样，阿达木单抗具有不稳定性，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。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，本领域尚需提供一种稳定的阿达木单抗的药物组合物。
发明内容
本发明提供了一种含有阿达木单抗的药物组合物，该组合物在较长的时间内仍能维持药物组合物的物理和化学稳定性，并且具有非常适合于皮下施用的粘度和渗透压。
具体的，本发明提供了一种药物组合物，其含有阿达木单抗及结构保护剂。其中，所述组合物中阿达木单抗的浓度为1-200mg/ml，优选10-100mg/ml，更优选50mg/ml。所述结构保护剂选自蔗糖或海藻糖，优选蔗糖，所述结构保护剂的浓度为1-200mg/ml，优选10-100mg/ml。本发明人惊讶的发现，选用等渗透压的蔗糖或海藻糖作为结构保护剂，所得组合物的物理和化学稳定性相比现有技术得到了很大程度的提高。
进一步的，本发明所述的药物组合物不含氯化钠。本发明人惊讶的发现，选用等渗透压的蔗糖或海藻糖作为结构保护剂后，不含氯化钠的阿达木单抗制剂的稳定性显著高于含有氯化钠的阿达木单抗制剂的稳定性。
本发明的药物组合物进一步含有表面活性剂，包括但不限于聚山梨醇酯类，如聚山梨醇酯20、聚山梨醇酯21、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯61、聚山梨醇酯65、聚山梨醇酯80、聚山梨醇酯81、聚山梨醇酯85或其混合物，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，优选聚山梨醇酯80。所述表面活性剂的浓度为0.01-10mg/ml，优选0.1-2mg/ml，更优选1mg/ml。
本发明的药物组合物进一步含有缓冲液，包括但不限于甘氨酸、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、 磷酸/磷酸盐或tris/tris盐酸盐，优选柠檬酸/柠檬酸盐和碳酸/碳酸氢盐的组合。其中加入的缓冲液使得本发明组合物的pH值为4.0-9.0，优选4.5-8.0，更优选5.2。
本发明的药物组合物进一步含有药学上可接受量的抗氧化剂，包括但不限于抗坏血酸、色氨酸、蛋氨酸、谷胱甘肽、硫代硫酸钠或过氧化氢酶。
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化合物的游离酸或者游离碱或者盐的形式存在，也可以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。
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。
本发明药物组合物中的阿达木单抗在较宽的pH值范围内可以保持溶解和稳定性，适合的pH值为4.0-9.0，优选4.5-8.0，更优选5.2。
优选的，本发明所述的药物组合物含有如下的成分：
(1)阿达木单抗          50mg/ml
(2)蔗糖                83mg/ml，或海藻糖          91.7mg/ml
(3)吐温80              1mg/ml
(4)柠檬酸              1.3mg/ml
(5)柠檬酸钠            0.35mg/ml
(6)磷酸二氢钠          0.86mg/ml
(7)磷酸氢二钠          1.53mg/ml
其中所述组合物的pH为5.2。
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(parenteral)形式给药。
本发明的药物组合物可用于制备治疗人类自身免疫相关疾病的药物，这些疾病包括类风湿性关节炎(rheumatoid arthritis)、银屑病(psoriasis)、幼年特发性关节炎(juvenile idiopathic arthritis)、强直性脊柱炎(ankylosing spondylitis)、克罗恩氏病 (Crohn’s disease)、溃疡性结肠炎(ulcerative colitis)、斑块状银屑病(plaque psoriasis)等。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
本发明的有益效果为：
本发明通过选用等渗透压的蔗糖或海藻糖作为阿达木单抗的结构保护剂，大大提高了药物组合物的稳定性，特别是在冻融实验、高温和光照破坏时，显示出更高的稳定性，因此具有非常广阔的市场应用前景。
附图说明
图1为制剂1-4经过冻融后的SEC-HPLC重叠图。
具体实施方式
本发明人经过大量的实验研究，惊喜的发现，在含有阿达木单抗的药物组合物中，使用等渗透压的蔗糖或海藻糖作为阿达木单抗的结构保护剂，可大大提高药物组合物的稳定性，具有非常广阔的市场应用前景。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1稳定性研究(一)
生物制药在生产、运输、储备和使用过程中会经历各种破坏条件，如高温、光照和冻融。为了确保安全，它们必须能够保持结构的完整，特别是高级结构的完整。生物药物的聚合物(aggregates)以及不溶性微粒(particles)是引起生物药物免疫反应的非常关键的因素。生物药物的外观也是一个非常重要的指标。各国药典规定生 物药物必须不含可见异物，因为生物药物中微粒的存在与否以及含量的多少直接关系到生物药物的安全性，它们被认为是造成生物药物免疫反应的最主要因素之一。
SEC-HPLC是一种利用凝胶孔隙的孔径大小与分析样品的尺寸大小的相对关系而进行分离的分析方法。样品中分子量较大的分子由于不能进入凝胶孔洞而完全被排阻，只能沿多孔凝胶粒子之间的空隙通过色谱柱，因此最先从柱中被流动相洗脱出来。而分子量较小的分子可以进入凝胶孔洞，在柱中受到更强的滞留(retention)，不易被洗脱出来，从而达到不同大小的溶质分子的分离。对于生物药的分析主要用于测量聚合物(aggregates)的含量，主要体现在单体含量的损失和聚合物含量的增加。
本实施例设计了几个制剂处方1-4(见表1)。其中制剂1为上市产品
Figure PCTCN2014093722-appb-000007
制剂；制剂2为含有高浓度甘露醇而不含氯化钠的制剂；制剂3为使用等摩尔渗透压的蔗糖代替制剂1的甘露醇所配制的制剂；制剂4为使用等摩尔渗透压的蔗糖代替制剂2的甘露醇所配制的制剂。
表1 各个制剂中所含组分的量(阿达木单抗浓度为50mg/ml)
Figure PCTCN2014093722-appb-000008
按照表1中各制剂组分的浓度配制得到0.85ml/syringe的制剂1-4进行稳定性研究。0时外观和SEC-HPLC纯度及杂质聚合物含量检测结果见表2。
表2 处方检测结果(0时)
Figure PCTCN2014093722-appb-000009
注：SEC-HPLC纯度(％)和聚合物含量(％)的值为平均值±标准偏差，下同。
影响因素试验方案(制剂1-4)
将根据表1制备得到的制剂1-4各3组样品分别进行高温、光照以及冻融破坏试验，试验条件如下：
高温试验：将样品放置于40℃恒温箱中，于2周，4周后检测。
光照试验：25℃、600W/m2(相当于110000Lx)放置4小时后检测。
冻融试验：-20℃冻存5小时、4℃融化10小时，反复冻融8次检测。
将经过上述影响因素试验的样品进行外观可见异物和SEC-HPLC纯度检测(检测仪器：Agilent 1200液相色谱仪；色谱柱：日本TOSOH公司的TSK-GEL G3000SWXL，7.8×300mm；流动相：0.2M氯化钠，0.02M磷酸钠缓冲液，pH 7.4；流速：0.5ml/min；柱温：25℃；运行时间：30min；波长：280nm)。
影响因素试验结果
高温试验
将根据表1制备得到的制剂1-4各3组样品置于40℃恒温箱中，于2周、4周进行外观和SEC-HPLC纯度检测，结果见表3。
表3 处方检测结果(40℃，2周，4周)
Figure PCTCN2014093722-appb-000010
肉眼观察高温试验后各制剂样品的外观与可见异物。高温试验2周后，制剂1和制剂3出现少量可见异物，而制剂2和制剂4无变化；高温试验4周后，制剂1和制剂3出现大量白点，而制剂2和制剂4在4周后分别仅有1支出现少量白点。相对应的SEC-HPLC数据也显示，含有蔗糖为保护剂的制剂2和制剂4经过破坏后聚合物含量分别低于相应的以甘露醇为保护剂的制剂1和制剂3(表3)。以上实验 数据表明，使用结构保护剂代替氯化钠能显著提高阿达木单抗制剂在高温条件下的稳定性，而且，含有蔗糖作为结构保护剂的制剂(制剂4)的稳定性显著高于含有甘露醇作为结构保护剂的制剂(制剂2)。
光照试验
将根据表1制备得到的制剂1-4各3组样品于25℃、600W/m2下光照4小时后，进行外观和SEC-HPLC检测。结果见表4。
表4 处方检测结果(25℃、600W/m2，4小时)
Figure PCTCN2014093722-appb-000011
所有制剂都出现不同程度的白点，但制剂4的三个样品中仅有1个出现疑似白点，明显优于其他制剂，制剂2有2个样品出现疑似白点，制剂1和制剂3最差，三个样品中都出现了白点。SEC-HPLC纯度的趋势也较一致，上市
Figure PCTCN2014093722-appb-000012
制剂(制剂1)最差，纯度只有约69.19％，制剂3用等渗的蔗糖代替甘露醇后，其纯度上升至约71.77％；不含氯化钠的制剂2的SEC-HPLC纯度为75.45％，而不含氯化钠的制剂4使用等渗的蔗糖代替甘露醇后，其稳定性得到了进一步的增强，SEC-HPLC纯度达到82.21％。相应的聚合物含量分别是制剂1>制剂3>制剂2>制剂4。以上实验数据表明，无论阿达木单抗制剂中是否含有氯化钠，使用蔗糖代替甘露醇都能增加阿达木单抗制剂的稳定性。
冻融试验
将根据表1制备得到的制剂1-4各3组样品于-20℃冻存5小时、4℃融化10小时，反复冻融8次破坏后，进行外观和SEC-HPLC检测，结果见表5和图1。
表5 处方检测结果(-20℃冻存5小时、4℃融化10小时，反复冻融8次)
Figure PCTCN2014093722-appb-000013
结果显示，经过8次冻融破坏后，制剂4的外观和SEC-HPLC纯度均优于制剂1和3，而制剂2发生了非常显著的变化，产生了可见悬浮物，乳光现象比较严重，SEC-HPLC纯度下降、聚合物上升也非常明显。这说明制剂2使用甘露醇代替氯化钠后不但不能保护阿达木单抗免受冻融破坏，反而会促进其降解。制剂4选用等渗透压的蔗糖作为结构保护剂，其冻融试验结果明显优于甘露醇。
实施例2稳定性研究(二)
本实施例设计了几个制剂处方5-11，同时结合实施例1中制剂2和制剂4的实验结果，比较了在不同阿达木单抗浓度下，甘露醇，蔗糖和海藻糖对制剂冻融稳定性的影响，其中这些制剂都不含氯化钠，制剂中其它组分为：0.35mg/ml枸橼酸钠，1.3mg/ml枸橼酸，0.86mg/ml磷酸二氢钠，1.53mg/ml磷酸氢二钠，1mg/ml聚山梨醇酯80，溶液pH值为5.2。将这些制剂处方于-20℃冻存5小时、4℃融化10小时，反复冻融8次后进行SEC-HPLC纯度和聚合物含量检测。结果见表6。
表6 不同阿达木单抗浓度下甘露醇，蔗糖和海藻糖对制剂冻融稳定性的影响
Figure PCTCN2014093722-appb-000014
根据表6的结果可知，无论是高浓度(50mg/ml)的阿达木单抗制剂还是低浓度(10mg/ml)的阿达木单抗制剂，选用等摩尔浓度的蔗糖或海藻糖作为结构保护剂，在冻融试验的稳定性方面均明显优于甘露醇。在1mg/ml阿达木单抗浓度的实验条件下，具有相同质量浓度的蔗糖在冻融试验的稳定性方面也明显优于甘露醇(制剂10和制剂11)。其中，含甘露醇作为结构保护剂的高浓度(50mg/ml)阿达木单抗制剂2在冻融破坏后SEC-HPLC纯度甚至低于不含任何结构保护剂的制剂9。
实施例3：蔗糖和海藻糖作为结构保护剂的低浓度(1mg/ml)和高浓度(100mg/ml)阿达木单抗制剂的制备
本实施例设计并配制了制剂处方12-15，分别含有低浓度(1mg/ml)和高浓度(100mg/ml)阿达木单抗的制剂(表7)，用于验证蔗糖和海藻糖作为结构保护剂能够配制低浓度和高浓度的阿达木单抗制剂。这些制剂都不含氯化钠，其它组分为：0.35mg/ml枸橼酸钠，1.3mg/ml枸橼酸，0.86mg/ml磷酸二氢钠，1.53mg/ml磷酸氢二钠，1mg/ml聚山梨醇酯80，溶液pH值为5.2。
表7 蔗糖和海藻糖作为结构保护剂的含有高浓度和低浓度阿达木单抗的制剂
Figure PCTCN2014093722-appb-000015
实施例4：蔗糖和海藻糖作为结构保护剂的不同pH值的阿达木单抗制剂的制备
本实施例设计并配制了制剂处方16-29，分别含有不同pH值的阿达木单抗制剂(pH 4.5-8.0，表8)。其中这些制剂都不含氯化钠，其它组分为：50mg/ml阿达木单抗，0.35mg/ml枸橼酸钠，1.3mg/ml枸橼酸，0.86mg/ml磷酸二氢钠，1.53mg/ml磷酸氢二钠，1mg/ml聚山梨醇酯80。
表8 蔗糖和海藻糖作为结构保护剂的不同pH的阿达木单抗浓度制剂
Figure PCTCN2014093722-appb-000016
实施例5：不同蔗糖和海藻糖浓度的阿达木单抗制剂的制备
本实施例设计并配制了不同浓度的蔗糖或海藻糖作为结构保护剂的阿达木单抗制剂30-35(表9)。其中这些制剂都不含氯化钠，制剂中其它组分为：50mg/ml阿达木单抗，0.35mg/ml枸橼酸钠，1.3mg/ml枸橼酸，0.86mg/ml磷酸二氢钠，1.53mg/ml磷酸氢二钠，1mg/ml聚山梨醇酯80。
表9 不同浓度蔗糖或海藻糖作为结构保护剂的阿达木单抗浓度制剂
Figure PCTCN2014093722-appb-000017
实施例6：蔗糖或海藻糖作为结构保护剂不同聚山梨醇酯80含量的阿达木单抗制剂的制备
本实施例设计并配制了制剂处方36-45，分别含有不同浓度的聚山梨醇酯80的阿达木单抗制剂(表10)。其中这些制剂都不含氯化钠，制剂中其它组分为：50mg/ml阿达木单抗，0.35mg/ml枸橼酸钠，1.3mg/ml枸橼酸，0.86mg/ml磷酸二氢钠，1.53mg/ml磷酸氢二钠，pH5.2。
表10 不同浓度的聚山梨醇酯80的含蔗糖或海藻糖的阿达木单抗制剂
Figure PCTCN2014093722-appb-000018

Claims (10)

  1. 一种药物组合物，含有阿达木单抗和结构保护剂，其特征在于，所述结构保护剂选自蔗糖或海藻糖。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物不含氯化钠。
  3. 根据根据权利要求1或2所述的药物组合物，其特征在于，所述阿达木单抗的浓度为1-200mg/ml，优选10-100mg/ml，更优选50mg/ml。
  4. 根据根据权利要求1-3任一项所述的药物组合物，其特征在于，所述蔗糖或海藻糖的浓度为1-200mg/ml，优选10-100mg/ml。
  5. 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述药物组合物进一步含有表面活性剂，其浓度范围为0.01-10mg/ml，优选0.1-2mg/ml，更优选1mg/ml。
  6. 根据权利要求5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醇酯20、聚山梨醇酯21、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯61、聚山梨醇酯65、聚山梨醇酯80、聚山梨醇酯81、聚山梨醇酯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、或它们的混合物，优选聚山梨醇酯80。
  7. 根据权利要求1-6任一项所述的药物组合物，其特征在于，所述药物组合物进一步含有缓冲液，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、磷酸/磷酸盐或tris/tris盐酸盐，优选柠檬酸/柠檬酸盐和碳酸/碳酸氢盐的组合。
  8. 根据根据权利要求1-7任一项所述的药物组合物，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。
  9. 一种药物组合物，其特征在于，所述组合物含有以下组分：
    Figure PCTCN2014093722-appb-100001
    Figure PCTCN2014093722-appb-100002
    其中所述组合物的pH为5.2。
  10. 权利要求1-9任一项所述的药物组合物在制备用于治疗人类自身免疫相关疾病的药物中的用途。
PCT/CN2014/093722 2013-12-16 2014-12-12 一种含有阿达木单抗的药物组合物 Ceased WO2015090162A1 (zh)

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