WO2016045570A2 - 一种针对血管内皮生长因子的人源化抗体的药物组合物 - Google Patents

一种针对血管内皮生长因子的人源化抗体的药物组合物 Download PDF

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WO2016045570A2
WO2016045570A2 PCT/CN2015/090224 CN2015090224W WO2016045570A2 WO 2016045570 A2 WO2016045570 A2 WO 2016045570A2 CN 2015090224 W CN2015090224 W CN 2015090224W WO 2016045570 A2 WO2016045570 A2 WO 2016045570A2
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mass
pharmaceutical composition
volume concentration
cancer
concentration
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WO2016045570A3 (zh
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程艳菊
赵伟
张来芳
郭莹莹
曹宇虹
恽丽红
季剑芸
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正大天晴药业集团股份有限公司
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  • the invention relates to a pharmaceutical composition for humanized antibodies against vascular endothelial growth factor, belonging to the field of medicinal chemical industry.
  • Bevacizumab is a humanized monoclonal antibody developed by Roche that inhibits vascular endothelial growth factor (VEGF) and is used to treat various metastatic cancers, for example, in combination with 5-fluorouracil. Chemotherapy is indicated for the treatment of patients with metastatic colorectal cancer.
  • the clinically applied dosage form of bevacizumab is Bevacizumab Injection (Avastin), which has been marketed in the United States, Europe, and China.
  • Avastin is a sterile solution for intravenous injection, pH 5.9 ⁇ 6.3, colorless to slightly brownish opal to clear liquid, concentration of 25mg / mL, there are two specifications of 100mg and 400mg, respectively, the corresponding volume is 4mL and 16mL, no preservatives, packaged in disposable vials.
  • composition of the adjuvant in Avastin is as follows: ⁇ , ⁇ -trehalose dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous sodium hydrogen phosphate, Tween 20 and sterile water for injection.
  • Avastin is widely used clinically, the stability of Avastin is not ideal, and the growth of polymers and degradants is remarkable during accelerated experiments and long-term storage, especially for polymers.
  • High molecular weight polymers entering the body are prone to immunogenicity and pose a potential risk to clinical use; while low or inactive degradants can affect product activity. Therefore, there is an urgent need to develop a more stable bevacizumab pharmaceutical composition to effectively reduce the risk of bevacizumab, improve its efficacy, and enable the composition to meet the requirements of large-scale production and long-term storage. .
  • One of the objects of the present invention is to provide a pharmaceutical composition of bevacizumab which has good stability.
  • Another object of the invention is to provide the use of a pharmaceutical composition of said bevacizumab.
  • the present invention provides a pharmaceutical composition of bevacizumab comprising bevacizumab, a buffer, an osmotic pressure adjusting agent and water; wherein the buffer comprises phosphoric acid and a phosphate buffer, and a second buffer; the second buffer is selected from the group consisting of a combination of citric acid and citrate, or a combination of acetic acid and acetate; the osmotic pressure adjusting agent is selected from the group consisting of Mannitol and/or sodium chloride; the pH of the composition is from 4.5 to 5.9.
  • the water For water for injection.
  • the present inventors have surprisingly found that accelerated and long-term stability experiments are carried out by using a combination of a phosphoric acid and/or a phosphate buffer and a second buffer as a buffer system, and using mannitol and/or sodium chloride as an osmotic regulator.
  • the amount of polymer impurities and degradant impurities formed by the pharmaceutical composition of the present invention is significantly lower than that of Avastin using only sodium phosphate buffer and ⁇ , ⁇ -trehalose as an osmotic regulator.
  • the stability of the composition is significantly improved.
  • polymer impurity refers to a polymer produced by the reaction of bevacizumab due to the interaction of amino acid residues on the peptide chain;
  • degradation impurity means bevacizumab A product having a smaller molecular weight than bevacizumab produced in a reaction such as amide or peptide chain cleavage.
  • the concentration referred to in the present invention refers to the mass to volume concentration, wherein the unit of mass is mg and the unit of volume is mL.
  • the salt described in the present invention includes the salt itself and a hydrate of the salt.
  • bevacizumab as described in the present invention includes not only the active ingredient bevacizumab itself in Avastin developed by Roche, but also other shells developed by any company. Bevacizumab biosimilar.
  • phosphate buffer refers to a phosphate buffer formed by a combination of a pharmaceutically acceptable salt of phosphoric acid or a hydrate thereof, wherein the pharmaceutically acceptable salts of the phosphate include, but are not limited to, various inorganic acids of phosphoric acid.
  • a salt or an organic acid salt such as disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, diammonium phosphate, ammonium dihydrogen phosphate or ammonium phosphate or a variety; as an example of a specific phosphate buffer, which may include dipotassium hydrogen phosphate or a hydrate thereof, a combination with potassium dihydrogen phosphate or a hydrate thereof; disodium hydrogen phosphate or a hydrate thereof, and phosphoric acid A combination of sodium dihydrogen or a hydrate thereof.
  • the phosphate buffer of the present invention comprises disodium hydrogen phosphate or a hydrate thereof, in combination with sodium dihydrogen phosphate or a hydrate thereof.
  • the hydrate of disodium hydrogen phosphate includes, but is not limited to, one or more of disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate heptahydrate or disodium hydrogen phosphate dodecahydrate; the hydrate of sodium dihydrogen phosphate includes but not It is limited to sodium dihydrogen phosphate monohydrate and/or sodium dihydrogen phosphate dihydrate.
  • the "tannic acid” as used in the present invention includes citric acid itself and a hydrate of citric acid, such as citric acid monohydrate; the "cartrate” includes various pharmaceutically acceptable phthalic acids. a mineral acid salt or an organic acid salt or a hydrate thereof, including but not limited to potassium citrate or a hydrate thereof, sodium citrate or a hydrate thereof; preferably, the citrate is sodium citrate or two Hydrated sodium citrate.
  • the "acetate” of the present invention includes various pharmaceutically acceptable inorganic or organic acid salts of acetic acid or hydrates thereof, including but not limited to potassium acetate or a hydrate thereof, sodium acetate or a hydrate thereof; Preferably, the acetate is sodium acetate or sodium acetate trihydrate.
  • the mass and volume concentration of the bevacizumab It is 10 to 40 mg/mL.
  • the osmotic pressure adjusting agent has a mass volume concentration of 0.1 to 200 mg/mL.
  • the pharmaceutical composition of bevacizumab of the present invention further comprises Tween 20 having a mass volume concentration of 0.1 to 10 mg/mL.
  • the pharmaceutical composition of bevacizumab of the present invention comprises:
  • osmotic pressure adjusting agent is selected from the group consisting of mannitol and/or sodium chloride;
  • the second buffering agent is selected from the group consisting of a combination of citric acid and sodium citrate, or a combination of acetic acid and sodium acetate;
  • the pharmaceutical composition has a pH of 4.5 to 5.9.
  • the “sodium phosphate buffer” described in the present invention is a buffer formed by a combination of disodium hydrogen phosphate or a hydrate thereof, and sodium dihydrogen phosphate or a hydrate thereof.
  • sodium phosphate buffer of the present invention may also be a phosphate buffer formed by a combination of other phosphoric acid or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the phosphate pharmaceutically acceptable salt includes, but is not limited to, phosphoric acid.
  • inorganic or organic acid salts such as disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate or ammonium phosphate
  • dipotassium hydrogen phosphate and potassium dihydrogen phosphate are a combination of dipotassium hydrogen phosphate and potassium dihydrogen phosphate, and combinations using other phosphoric acid or a pharmaceutically acceptable salt thereof or a hydrate thereof are still within the scope of the present invention.
  • sodium decanoate of the present invention may also be other phthalates or hydrates thereof including, but not limited to, various inorganic or organic acid salts of citric acid, such as potassium citrate.
  • sodium acetate of the present invention may also be other acetates or hydrates thereof, including but not limited to various inorganic or organic acid salts of acetic acid, such as potassium acetate.
  • bevacizumab in addition to the Avastin developed by Roche, encompasses the bevacizumab biosimilar developed by any other company.
  • the bevacizumab has a mass volume concentration of 20 to 30 mg/mL, more preferably about 25 mg/mL.
  • the osmotic pressure adjusting agent has a mass volume concentration of 1 to 50 mg/mL, more preferably about 4.7 to 25 mg/mL.
  • the mass concentration of the Tween 20 is preferably 0.2 to 2 mg/mL, more preferably about 0.4 mg/mL.
  • the pharmaceutical composition of bevacizumab has a pH of 4.9 to 5.5, more preferably a pH of about 5.2.
  • a pH of about 5.2 indicates a pH of 5.2 ⁇ 5%, preferably a pH of 5.2 ⁇ 2%, more preferably a pH of 5.2 ⁇ 1%.
  • the pharmaceutical composition comprises:
  • Tween 20 having a mass to volume concentration of about 0.4 mg/mL;
  • osmotic pressure adjusting agent is selected from the group consisting of mannitol and/or sodium chloride;
  • the second buffering agent is selected from the group consisting of a combination of citric acid and sodium citrate, or a combination of acetic acid and sodium acetate; the pharmaceutical composition has a pH of about 5.2.
  • the pharmaceutical composition comprises:
  • the second buffering agent is selected from the group consisting of a combination of citric acid and sodium citrate, or a combination of acetic acid and sodium acetate; the pharmaceutical composition has a pH of about 5.2.
  • the pharmaceutical composition comprises:
  • the second buffering agent is selected from the group consisting of a combination of citric acid and sodium citrate, or a combination of acetic acid and sodium acetate; the pharmaceutical composition has a pH of about 5.2.
  • the pharmaceutical composition comprises:
  • Tween 20 having a mass to volume concentration of about 0.4 mg/mL
  • a buffer system consisting of a sodium phosphate buffer and a second buffer
  • the second buffering agent is selected from the group consisting of a combination of citric acid and sodium citrate, or a combination of acetic acid and sodium acetate; the pharmaceutical composition has a pH of about 5.2.
  • the pharmaceutical composition comprises:
  • pH of the pharmaceutical composition is about 5.2.
  • the pharmaceutical composition comprises:
  • pH of the pharmaceutical composition is about 5.2.
  • the pharmaceutical composition comprises:
  • pH of the pharmaceutical composition is about 5.2.
  • the pharmaceutical composition comprises:
  • Tween 20 having a mass volume concentration of about 0.4 mg/mL;
  • pH of the pharmaceutical composition is about 5.2.
  • the present invention provides the use of the pharmaceutical composition of bevacizumab as a VEGF receptor tyrosine kinase inhibitor in the preparation of a pharmaceutical preparation, in particular in the preparation of a medicament for the treatment of a hyperproliferative disease Use in a formulation; preferably, the pharmaceutical formulation is a sterile solution for injection.
  • the hyperproliferative diseases include brain tumors (preferably glioblastoma), lung cancer (preferably non-small cell lung cancer), epidermal squamous cell carcinoma, bladder cancer, pancreatic cancer, breast cancer, ovarian cancer, Cervical cancer, endometrial cancer, colorectal cancer, renal cell carcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin's lymphoma, liver cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, glial More preferably, the hyperproliferative disease is colorectal cancer, non-small cell lung cancer, glioblastoma, renal cell carcinoma or cervical cancer.
  • the present invention provides a method for treating a hyperproliferative disease, the method comprising administering a pharmaceutical composition according to the present invention to a recipient in an effective dose, the receptor being an animal or a human;
  • the hyperproliferative Diseases include brain tumors (preferably glioblastoma), lung cancer (preferably non-small cell lung cancer), epidermal squamous cell carcinoma, bladder cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer, renal cells
  • the hyperproliferative disease is colorectal cancer, non-small cell lung cancer, glioblastoma, renal cell carcinoma or cervical cancer.
  • the present invention provides a pharmaceutical composition of bevacizumab which has a markedly improved stability compared to Avastin. It can be used to treat hyperproliferative diseases to effectively reduce the risk of bevacizumab administration, improve its efficacy, and enable the composition to meet the requirements of large-scale production and long-term storage.
  • Preparation method According to the above formula, a blank solution containing bevacizumab was prepared, and the pH was 5.2. The purified Bevacizum single antigen solution was replaced with a blank solution 6 times to prepare a solution of the above formula, sterilized and filtered, aseptically packaged, and visually inspected, and the bevacizumab injection of the present example was obtained.
  • Preparation method According to the above formula, a blank solution containing bevacizumab was prepared, and the pH was 5.2. The purified Bevacizum single antigen solution was replaced with a blank solution 6 times to prepare a solution of the above formula, sterilized and filtered, aseptically packaged, and visually inspected, and the bevacizumab injection of the present example was obtained.
  • Preparation method According to the above formula, a blank solution containing bevacizumab was prepared, and the pH was 5.2. The purified Bevacizum single antigen solution was replaced with a blank solution 6 times to prepare a solution of the above formula, sterilized and filtered, aseptically packaged, and visually inspected, and the bevacizumab injection of the present example was obtained.
  • Preparation method According to the above formula, a blank solution containing bevacizumab was prepared, and the pH was 5.2. The purified Bevacizum single antigen solution was replaced with a blank solution 6 times to prepare a solution of the above formula, sterilized and filtered, aseptically packaged, and visually inspected, and the bevacizumab injection of the present example was obtained.
  • Preparation method According to the above formula, a blank solution containing bevacizumab was prepared, and the pH was 6.1. The purified Bevacizum single antigen solution was replaced with a blank solution 6 times to prepare a solution of the above formula, and the solution was sterile-filtered, aseptically packaged, and visually inspected to obtain a comparative example of bevacizumab injection. .
  • the bevacizumab injection samples prepared in the methods of Examples 1 to 4 and Comparative Example 1 were placed in a constant temperature environment at 25 ° C, and were sampled and tested in January, January, February, March, and June, using molecular sieves.
  • the purity of the bevacizumab and the change in impurities were examined by Size-Exclusion chromatography (SEC) to evaluate the stability of the pharmaceutical composition of the present invention.
  • the bevacizumab injection samples prepared in the methods of Examples 1 to 4 and Comparative Example 1 were stored at 2 to 8 ° C, and were sampled and tested in 0, March, June, September, and December.
  • the purity of the bevacizumab and the change in impurities were examined by Size-Exclusion chromatography (SEC) to evaluate the stability of the pharmaceutical composition of the present invention.
  • Molecular sieve chromatography (SEC) determination method using TSKgel G3000 SWXL molecular sieve column, 20mmol / L Na 2 HPO 4 +200mmol / L NaCl, pH 7.4 buffer as the mobile phase for elution, detection wavelength of 280nm. Under the chromatographic conditions, the order of the peaks is the polymer peak, the main peak, and the degradation peak. The percentage of polymer, main peak and degradant was calculated by area normalization method. The results are shown in Table 2.
  • Example 1 - 4 The obtained bevacizumab injection sample was placed at 2-8 °C for 12 months, the polymer increased by only 0.2-0.5%, the degradation product only increased by 0.06-0.12%, and the main peak decreased by only 0.4-0.6%.
  • the above results show that the bevacizumab injection samples obtained in Examples 1 to 4 of the present invention are relatively stable, while the bevacizumab injection sample obtained in Comparative Example 1 has poor stability, and the bevacizumab injection of the present invention is inferior. The stability of the liquid is significantly improved.

Abstract

本发明涉及一种针对血管内皮生长因子的人源化抗体的药物组合物，其包括贝伐珠单抗、缓冲剂、渗透压调节剂及水；所述缓冲剂包括磷酸和/或磷酸盐类缓冲剂，及第二缓冲剂；所述第二缓冲剂选自枸橼酸和枸橼酸盐的组合，或者醋酸和醋酸盐的组合；所述渗透压调节剂选自甘露醇和/或氯化钠；所述组合物的pH为4.5～5.9。本发明所述的药物组合物具有良好的稳定性。

Description

一种针对血管内皮生长因子的人源化抗体的药物组合物 技术领域
本发明涉及一种针对血管内皮生长因子的人源化抗体的药物组合物，属于医药化工领域。
背景技术
贝伐珠单抗(Bevacizumab)是罗氏公司开发的一种人源化单克隆抗体，可抑制血管内皮生长因子(VEGF)，用于治疗各类转移性癌症，例如联合以5-氟尿嘧啶为基础的化疗适用于转移性结直肠癌患者的治疗。贝伐珠单抗临床上应用的剂型为贝伐珠单抗注射液(Bevacizumab Injection，商品名安维汀(Avastin))，目前已在美国、欧洲、中国等多地上市。
安维汀为静脉注射用无菌溶液，pH为5.9～6.3，无色至略带棕色的乳光至澄明液体，浓度为25mg/mL，有100mg和400mg两种规格，分别对应的体积分别为4mL和16mL，不含防腐剂，以一次性小瓶包装。
安维汀中辅料组成如下：α,α-海藻糖二水合物，磷酸二氢钠一水合物，无水磷酸氢二钠，吐温20和无菌注射用水。
尽管安维汀在临床上应用广泛，然而安维汀的稳定性不理想，在加速实验和长期存放的过程中聚合物和降解物增长明显，尤其是聚合物显著增长。高分子量的聚合物进入体内易产生免疫原性，对临床使用安全存在潜在风险；同时活性低或无活性的降解物会影响产品的活性。因此，亟需开发稳定性更好的贝伐珠单抗药物组合物，以有效降低贝伐珠单抗的用药风险，提高其疗效，并使该组合物能满足大规模生产和长期储藏的要求。
发明内容
本发明的目的之一在于提供一种贝伐珠单抗的药物组合物，所述贝伐珠单抗的药物组合物具有良好的稳定性。
本发明的另一目的在于提供所述贝伐珠单抗的药物组合物的应用。
为实现上述目的，本发明提供一种贝伐珠单抗的药物组合物，所述组合物包括贝伐珠单抗、缓冲剂、渗透压调节剂及水；其中，所述缓冲剂包括磷酸和/或磷酸盐类缓冲剂，及第二缓冲剂；所述第二缓冲剂选自枸橼酸和枸橼酸盐的组合，或者醋酸和醋酸盐的组合；所述渗透压调节剂选自甘露醇和/或氯化钠；所述组合物的pH为4.5～5.9。优选地，所述水 为注射用水。
本发明出人意料的发现，通过将磷酸和/或磷酸盐类缓冲剂及第二缓冲剂的组合作为缓冲体系，以及采用甘露醇和/或氯化钠作为渗透压调节剂，在加速及长期稳定性实验中，与仅采用磷酸钠缓冲剂以及采用α,α-海藻糖作为渗透压调节剂的安维汀相比，本发明药物组合物所形成的聚合物杂质和降解物杂质的量明显降低，所述组合物的稳定性显著提高。上述的“聚合物杂质”是指贝伐珠单抗由于肽链上的氨基酸残基相互作用，发生聚合而产生的聚合物；所述的“降解物杂质”是指贝伐珠单抗经脱酰胺或肽链断裂等反应中产生的比贝伐珠单抗分子量小的产物。
除特别声明外，本发明中所述的浓度指质量体积浓度，其中质量的单位为mg，体积的单位为mL。本发明中所述的盐包括盐本身及盐的水合物。
本领域技术人员应该知晓本发明中所述的“贝伐珠单抗”(bevacizumab)不仅包括罗氏公司开发的安维汀中的活性成分贝伐珠单抗本身，还涵盖其他任何公司开发的贝伐珠单抗生物类似物(bevacizumab biosimilar)。
本发明所述“磷酸盐类缓冲剂”是指磷酸药学上可接受盐或其水合物的组合形成的磷酸盐类缓冲剂，其中磷酸药学上可接受盐包括但不限于磷酸的各种无机酸盐或有机酸盐，例如磷酸氢二钠、磷酸二氢钠、磷酸钠、磷酸氢二钾、磷酸二氢钾、磷酸钾、磷酸氢二铵、磷酸二氢铵或磷酸铵中的一种或多种；作为具体的磷酸盐类缓冲剂的例子，其可包括磷酸氢二钾或其水合物，与磷酸二氢钾或其水合物形成的组合；磷酸氢二钠或其水合物，与磷酸二氢钠或其水合物形成的组合。优选地，本发明所述的磷酸盐缓冲剂包括磷酸氢二钠或其水合物，与磷酸二氢钠或其水合物形成的组合。磷酸氢二钠的水合物包括但不限于二水合磷酸氢二钠、七水合磷酸氢二钠或十二水合磷酸氢二钠中的一种或多种；磷酸二氢钠的水合物包括但不限于一水合磷酸二氢钠和/或二水合磷酸二氢钠。
本发明所述的“枸橼酸”包括枸橼酸本身以及枸橼酸的水合物，例如一水合枸橼酸；所述“枸橼酸盐”包括枸橼酸的药学上可接受的各种无机酸盐或有机酸盐或其水合物，包括但不限于枸橼酸钾或其水合物、枸橼酸钠或其水合物；优选地，所述枸橼酸盐为枸橼酸钠或二水合枸橼酸钠。
本发明所述的“醋酸盐”包括醋酸的药学上可接受的各种无机酸盐或有机酸盐或其水合物，包括但不限于醋酸钾或其水合物、醋酸钠或其水合物；优选地，所述醋酸盐为醋酸钠或三水合醋酸钠。
优选地，在本发明所述贝伐珠单抗的药物组合物中，所述贝伐珠单抗的质量体积浓度 为10～40mg/mL。
优选地，在本发明所述贝伐珠单抗的药物组合物中，所述渗透压调节剂的质量体积浓度为0.1～200mg/mL。
优选地，本发明所述贝伐珠单抗的药物组合物还包括质量体积浓度为0.1～10mg/mL的吐温20。
特别优选地，本发明所述贝伐珠单抗的药物组合物包括：
(a)质量体积浓度为10～40mg/mL的贝伐珠单抗；
(b)质量体积浓度为0.1～200mg/mL的渗透压调节剂；
(c)质量体积浓度为0.1～10mg/mL的吐温20，及
(d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
其中，渗透压调节剂选自甘露醇和/或氯化钠；
其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；
其中，所述药物组合物的pH值为4.5～5.9。
本发明中所述的“磷酸钠缓冲剂”为磷酸氢二钠或其水合物，与磷酸二氢钠或其水合物的组合形成的缓冲剂。
应当理解，本发明的“磷酸钠缓冲剂”还可以是其他的磷酸或其药学上可接受盐或其水合物的组合形成的磷酸盐缓冲剂，其中磷酸药学上可接受盐包括但不限于磷酸的各种无机酸盐或有机酸盐，例如磷酸氢二钠、磷酸二氢钠、磷酸钠、磷酸氢二钾、磷酸二氢钾、磷酸钾、磷酸氢二铵、磷酸二氢铵或磷酸铵中的一种或多种，具体的例子有磷酸氢二钾和磷酸二氢钾的组合，使用其他的磷酸或其药学上可接受盐或其水合物的组合仍属于本发明保护的范围。
应当理解，本发明的枸橼酸钠也可以是其他枸橼酸盐或其水合物，包括但不限于枸橼酸的各种无机酸盐或有机酸盐，例如枸橼酸钾。
应当理解，本发明的醋酸钠也可以是其他醋酸盐或其水合物，包括但不限于醋酸的各种无机酸盐或有机酸盐，例如醋酸钾。
应该理解，“贝伐珠单抗(bevacizumab)”的定义，除了指罗氏公司开发的安维汀(Avastin)外，还涵盖其他任何公司开发的贝伐珠单抗生物类似物(bevacizumab biosimilar)。
优选地，在本发明所述的贝伐珠单抗的药物组合物中，所述贝伐珠单抗的质量体积浓度为20～30mg/mL，更优选为约25mg/mL。
优选地，在本发明所述的贝伐珠单抗的药物组合物中，所述渗透压调节剂的质量体积浓度为1～50mg/mL，更优选为约4.7～25mg/mL。
优选地，在本发明所述的贝伐珠单抗的药物组合物中，所述吐温20的质量体积浓度优选为0.2～2mg/mL，更优选为约0.4mg/mL。
优选地，在本发明所述的贝伐珠单抗的药物组合物中，所述贝伐珠单抗的药物组合物的pH值为4.9～5.5，更优选pH值为约5.2。
除特别声明外，本发明中的“约”是指在所给定的具体数值范围±5％范围内波动，优选在±2％范围内波动，更优选在±1％范围内波动。例如pH值为约5.2表示pH为5.2±5％，优选pH为5.2±2％，更优选pH为5.2±1％。
在本发明的一个具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约4.7～25mg/mL的渗透压调节剂；
(c)质量体积浓度约0.4mg/mL的吐温20；及
(d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
其中，渗透压调节剂选自甘露醇和/或氯化钠；
其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药物组合物的pH值为约5.2。
在本发明的又一个具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约25mg/mL的甘露醇；
(c)质量体积浓度约0.4mg/mL的吐温20，及
(d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药物组合物的pH值为约5.2。
在本发明的再一个具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约9mg/mL的氯化钠；
(c)质量体积浓度约0.4mg/mL的吐温20，及
(d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系，
其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药物组合物的pH值为约5.2。
在本发明的还一个具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约12mg/mL的甘露醇；
(c)质量体积浓度约4.7mg/mL的氯化钠；
(d)质量体积浓度约0.4mg/mL的吐温20，及
(e)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药物组合物的pH值为约5.2。
在本发明的一个更加具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约25mg/mL的甘露醇；
(c)质量体积浓度约0.4mg/mL的吐温20；
(d)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
(e)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
(f)质量体积浓度约1.725mg/mL的三水合醋酸钠，及
(g)质量体积浓度约0.02mg/mL的醋酸；
其中，所述药物组合物的pH值为约5.2。
在本发明的又一个更加具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约25mg/mL的甘露醇；
(c)质量体积浓度约0.4mg/mL的吐温20；
(d)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
(e)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
(f)质量体积浓度约1.21mg/mL的一水合枸橼酸，及
(g)质量体积浓度约0.68mg/mL的二水合枸橼酸钠；
其中，所述药物组合物的pH值为约5.2。
在本发明的再一个更加具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约9mg/mL的氯化钠；
(c)质量体积浓度约0.4mg/mL的吐温20；
(d)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
(e)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
(f)质量体积浓度约1.21mg/mL的一水合枸橼酸，及
(g)质量体积浓度约0.68mg/mL的二水合枸橼酸钠，
其中，所述药物组合物的pH值为约5.2。
在本发明的还一个更加具体实施方案中，所述药物组合物包括：
(a)质量体积浓度约25mg/mL的贝伐珠单抗；
(b)质量体积浓度约12mg/mL的甘露醇；
(c)质量体积浓度约4.7mg/mL的氯化钠；
(d)质量体积浓度约0.4mg/mL的吐温20；
(e)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
(f)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
(g)质量体积浓度约1.21mg/mL的一水合枸橼酸，及
(h)质量体积浓度约0.68mg/mL的二水合枸橼酸钠；
其中，所述药物组合物的pH值为约5.2。
另一方面，本发明提供所述贝伐珠单抗的药物组合物在作为VEGF受体酪氨酸激酶抑制剂在制备药物制剂中的应用，特别是在制备用于治疗过度增殖性疾病的药物制剂中的应用；优选地，所述药物制剂为注射用无菌溶液。
优选地，其中所述的过度增殖性疾病包括脑瘤(优选为成胶质细胞瘤)、肺癌(优选为非小细胞肺癌)、表皮鳞癌、膀胱癌、胰腺癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、结直肠癌、肾细胞癌、食管腺癌、食管鳞状细胞癌、非霍奇金淋巴瘤、肝癌、皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤及鼻咽癌中的一种或多种；更优选地，所述的过度增殖性疾病为结直肠癌、非小细胞肺癌、成胶质细胞瘤、肾细胞癌或宫颈癌。
本发明提供一种治疗过度增殖性疾病的方法，所述方法包括将本发明所述的药物组合物以有效剂量给予受体，所述受体为动物或人类；优选地，所述过度增殖性疾病包括脑瘤 (优选为成胶质细胞瘤)、肺癌(优选为非小细胞肺癌)、表皮鳞癌、膀胱癌、胰腺癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、结直肠癌、肾细胞癌、食管腺癌、食管鳞状细胞癌、非霍奇金淋巴瘤、肝癌、皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤及鼻咽癌中的一种或多种；更优选地，所述的过度增殖性疾病为结直肠癌、非小细胞肺癌、成胶质细胞瘤、肾细胞癌或宫颈癌。
综上可知，本发明提供了一种贝伐珠单抗的药物组合物，与安维汀相比，其稳定性显著提高。其可用于治疗过度增殖性疾病，以有效降低贝伐珠单抗的用药风险，提高其疗效，并使该组合物能满足大规模生产和长期储藏的要求。
具体实施方式
下面结合具体实施例对本发明进行进一步的描述，然而，本发明中这些实施例仅用于阐明而不限制本发明的范围。同样，本发明不限于本文描述的任何具体优选的实施方案。本领域技术人员应该理解，对本发明技术特征所作的等同替换，或相应的改进，仍属于本发明的保护范围之内。
实施例1贝伐珠单抗注射液的制备
配方：
Figure PCTCN2015090224-appb-000001
制备方法：按照上述配方，配制不含贝伐珠单抗的空白溶液，pH值为5.2。将纯化后的贝伐珠单抗原液，采用空白溶液置换6次，制成上述配方的溶液，除菌过滤，无菌分装，视检合格，得本实施例贝伐珠单抗注射液。
实施例2贝伐珠单抗注射液的制备
配方：
Figure PCTCN2015090224-appb-000002
Figure PCTCN2015090224-appb-000003
制备方法：按照上述配方，配制不含贝伐珠单抗的空白溶液，pH值为5.2。将纯化后的贝伐珠单抗原液，采用空白溶液置换6次，制成上述配方的溶液，除菌过滤，无菌分装，视检合格，得本实施例贝伐珠单抗注射液。
实施例3贝伐珠单抗注射液的制备
配方：
Figure PCTCN2015090224-appb-000004
制备方法：按照上述配方，配制不含贝伐珠单抗的空白溶液，pH值为5.2。将纯化后的贝伐珠单抗原液，采用空白溶液置换6次，制成上述配方的溶液，除菌过滤，无菌分装，视检合格，得本实施例贝伐珠单抗注射液。
实施例4贝伐珠单抗注射液的制备
配方：
Figure PCTCN2015090224-appb-000005
Figure PCTCN2015090224-appb-000006
制备方法：按照上述配方，配制不含贝伐珠单抗的空白溶液，pH值为5.2。将纯化后的贝伐珠单抗原液，采用空白溶液置换6次，制成上述配方的溶液，除菌过滤，无菌分装，视检合格，得本实施例贝伐珠单抗注射液。
对比例1与
Figure PCTCN2015090224-appb-000007
相同处方的贝伐珠单抗注射液的制备
处方：
Figure PCTCN2015090224-appb-000008
制备方法：按照上述配方，配制不含贝伐珠单抗的空白溶液，pH值为6.1。将纯化后的贝伐珠单抗原液，采用空白溶液置换6次，制成上述配方的溶液，除菌过滤，无菌分装，视检合格，即得对比例1贝伐珠单抗注射液。
实施例5贝伐珠单抗注射液的高温加热稳定性
将实施例1～4及对比例1方法制得的贝伐珠单抗注射液样品置在25℃恒温环境中，于0月、1月、2月、3月、6月取样检测，利用分子筛色谱(Size-Exclusion chromatography，SEC)考察贝伐珠单抗纯度及杂质的变化，以评价本发明药物组合物的稳定性。
分子筛色谱(SEC)测定方法：采用TSKgel G3000 SWXL分子筛色谱柱，以20mmol/L Na2HPO4+200mmol/L NaCl，pH为7.4的缓冲液为流动相进行洗脱，检测波长为280nm。该色谱条件下出峰先后顺序依次为聚合物峰、主峰、降解物峰。按面积归一化法计算聚合物、主峰和降解物的百分含量，结果见表1。
表1贝伐珠单抗纯度变化情况
Figure PCTCN2015090224-appb-000009
从表1中可以看出，对比例1所得贝伐珠单抗注射液样品在25℃放置6月后聚合物增长5.1％，降解物增长0.73％，主峰下降5.8％，而实施例1～4所得贝伐珠单抗注射液样品在25℃放置6月后聚合物仅增长1.5～1.8％，降解物仅增长0.16～0.42％，主峰仅下降1.7～2.2％。上述结果表明，本发明实施例1～4所得贝伐珠单抗注射液样品均较稳定，而对比例1所得贝伐珠单抗注射液样品的稳定性较差，本发明的贝伐珠单抗注射液的稳定性显著提高。
实施例6贝伐珠单抗注射液的长期稳定性
将实施例1～4及对比例1方法制得的贝伐珠单抗注射液样品在2～8℃条件下保存，于0月、3月、6月、9月、12月取样检测，利用分子筛色谱(Size-Exclusion chromatography，SEC)考察贝伐珠单抗纯度及杂质的变化，以评价本发明药物组合物的稳定性。
分子筛色谱(SEC)测定方法：采用TSKgel G3000 SWXL分子筛色谱柱，以20mmol/L Na2HPO4+200mmol/L NaCl，pH为7.4的缓冲液为流动相进行洗脱，检测波长为280nm。该色谱条件下出峰先后顺序依次为聚合物峰、主峰、降解物峰。按面积归一化法计算聚合物、主峰和降解物的百分含量，结果见表2。
表2贝伐珠单抗纯度变化情况
Figure PCTCN2015090224-appb-000010
从表2中可以看出，对比例1所得贝伐珠单抗注射液样品在2～8℃放置12月聚合物增长2.5％，降解物增长0.38％，主峰下降2.9％，而实施例1～4所得贝伐珠单抗注射液样品在2～8℃放置12月聚合物仅增长0.2～0.5％，降解物仅增长0.06～0.12％，主峰仅下降0.4～0.6％。上述结果表明，本发明实施例1～4所得贝伐珠单抗注射液样品较稳定，而对比例1所得贝伐珠单抗注射液样品稳定性较差，本发明的贝伐珠单抗注射液的稳定性显著提高。

Claims (20)

  1. 一种贝伐珠单抗的药物组合物，所述组合物包括贝伐珠单抗、缓冲剂、渗透压调节剂及水；其中，
    所述缓冲剂包括磷酸和/或磷酸盐类缓冲剂，及第二缓冲剂；
    所述第二缓冲剂选自枸橼酸和枸橼酸盐的组合，或者醋酸和醋酸盐的组合；
    所述渗透压调节剂选自甘露醇和/或氯化钠；
    所述组合物的pH为4.5～5.9；
    优选地，所述水为注射用水。
  2. 根据权利要求1所述的药物组合物，其中，所述贝伐珠单抗的质量体积浓度为10～40mg/mL。
  3. 根据权利要求1所述的药物组合物，其中，所述渗透压调节剂的质量体积浓度为0.1～200mg/mL。
  4. 根据权利要求1～3中任一项所述的药物组合物，其中，所述组合物还包括质量体积浓度为0.1～10mg/mL的吐温20。
  5. 根据权利要求1所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度为10～40mg/mL的贝伐珠单抗；
    (b)质量体积浓度为0.1～200mg/mL的渗透压调节剂；
    (c)质量体积浓度为0.1～10mg/mL的吐温20，及
    (d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
    其中，渗透压调节剂选自甘露醇和/或氯化钠；
    其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；
    其中，所述药物组合物的pH值为4.5～5.9。
  6. 根据权利要求5所述的药物组合物，其中，所述贝伐珠单抗的质量体积浓度为20～30mg/mL，优选为约25mg/mL。
  7. 根据权利要求5所述的药物组合物，其中，所述渗透压调节剂的质量体积浓度为1～50mg/mL，优选为约4.7～25mg/mL。
  8. 根据权利要求5所述的药物组合物，其中，所述吐温20的质量体积浓度优选为0.2～2mg/mL，优选为约0.4mg/mL。
  9. 根据权利要求5所述的药物组合物，其中，贝伐珠单抗的药物组合物的pH值为 4.9～5.5；优选pH值为约5.2。
  10. 根据权利要求5所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约4.7～25mg/mL的渗透压调节剂；
    (c)质量体积浓度约0.4mg/mL的吐温20；及
    (d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
    其中，渗透压调节剂选自甘露醇和/或氯化钠；
    第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药物组合物的pH值为约5.2。
  11. 根据权利要求10所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约25mg/mL的甘露醇；
    (c)质量体积浓度约0.4mg/mL的吐温20，及
    (d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
    其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药物组合物的pH值为约5.2。
  12. 根据权利要求10所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约9mg/mL的氯化钠；
    (c)质量体积浓度约0.4mg/mL的吐温20，及
    (d)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系，
    其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药物组合物的pH值为约5.2。
  13. 根据权利要求10所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约12mg/mL的甘露醇；
    (c)质量体积浓度约4.7mg/mL的氯化钠；
    (d)质量体积浓度约0.4mg/mL的吐温20，及
    (e)磷酸钠缓冲剂和第二缓冲剂组成的缓冲体系；
    其中，第二缓冲剂选自枸橼酸和枸橼酸钠的组合，或者醋酸和醋酸钠的组合；所述药 物组合物的pH值为约5.2。
  14. 根据权利要求10所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约25mg/mL的甘露醇；
    (c)质量体积浓度约0.4mg/mL的吐温20；
    (d)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
    (e)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
    (f)质量体积浓度约1.725mg/mL的三水合醋酸钠，及
    (g)质量体积浓度约0.02mg/mL的醋酸；
    其中，所述药物组合物的pH值为约5.2。
  15. 根据权利要求10所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约25mg/mL的甘露醇；
    (c)质量体积浓度约0.4mg/mL的吐温20；
    (d)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
    (e)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
    (f)质量体积浓度约1.21mg/mL的一水合枸橼酸，及
    (g)质量体积浓度约0.68mg/mL的二水合枸橼酸钠；
    其中，所述药物组合物的pH值为约5.2。
  16. 根据权利要求10所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约9mg/mL的氯化钠；
    (c)质量体积浓度约0.4mg/mL的吐温20；
    (d)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
    (e)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
    (f)质量体积浓度约1.21mg/mL的一水合枸橼酸，及
    (g)质量体积浓度约0.68mg/mL的二水合枸橼酸钠；
    其中，所述药物组合物的pH值为约5.2。
  17. 根据权利要求10所述的药物组合物，其中，所述药物组合物包括：
    (a)质量体积浓度约25mg/mL的贝伐珠单抗；
    (b)质量体积浓度约12mg/mL的甘露醇；
    (c)质量体积浓度约4.7mg/mL的氯化钠；
    (d)质量体积浓度约0.4mg/mL的吐温20；
    (e)质量体积浓度约0.48mg/mL的一水合磷酸二氢钠；
    (f)质量体积浓度约3.75mg/mL的十二水合磷酸氢二钠；
    (g)质量体积浓度约1.21mg/mL的一水合枸橼酸，及
    (h)质量体积浓度约0.68mg/mL的二水合枸橼酸钠；
    其中，所述药物组合物的pH值为约5.2。
  18. 权利要求1～17中任一项所述的药物组合物在作为VEGF受体酪氨酸激酶抑制剂制备药物制剂中的应用，特别是在制备用于治疗过度增殖性疾病的药物制剂中的应用；优选地，所述药物制剂为注射用无菌溶液。
  19. 根据权利要求18所述的应用，其中，所述的过度增殖性疾病包括成胶质细胞瘤、非小细胞肺癌、表皮鳞癌、膀胱癌、胰腺癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、结直肠癌、肾细胞癌、食管腺癌、食管鳞状细胞癌、非霍奇金淋巴瘤、肝癌、皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤及鼻咽癌中的一种或多种；更优选地，所述的过度增殖性疾病为结直肠癌、非小细胞肺癌、成胶质细胞瘤、肾细胞癌或宫颈癌。
  20. 一种治疗过度增殖性疾病的方法，所述方法包括将权利要求1～17中任一项所述的要求药物组合物以有效剂量给予受体，所述受体为动物或人类；优选地，所述过度增殖性疾病包括成胶质细胞瘤、非小细胞肺癌、表皮鳞癌、膀胱癌、胰腺癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、结直肠癌、肾细胞癌、食管腺癌、食管鳞状细胞癌、非霍奇金淋巴瘤、肝癌、皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤及鼻咽癌中的一种或多种；更优选地，所述的过度增殖性疾病为结直肠癌、非小细胞肺癌、成胶质细胞瘤、肾细胞癌或宫颈癌。
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