WO2024131887A1 - 一种含卢比替定的药物组合物及其制备方法和应用 - Google Patents

一种含卢比替定的药物组合物及其制备方法和应用 Download PDF

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WO2024131887A1
WO2024131887A1 PCT/CN2023/140627 CN2023140627W WO2024131887A1 WO 2024131887 A1 WO2024131887 A1 WO 2024131887A1 CN 2023140627 W CN2023140627 W CN 2023140627W WO 2024131887 A1 WO2024131887 A1 WO 2024131887A1
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pharmaceutical composition
freeze
rubitidine
preparation
drying
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PCT/CN2023/140627
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English (en)
French (fr)
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李佳晗
李会芳
董悦
黄仰青
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博瑞生物医药（苏州）股份有限公司
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Publication of WO2024131887A1 publication Critical patent/WO2024131887A1/zh

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition containing rubitidine, and a preparation method and application thereof.
  • Lung cancer is a disease in which malignant (cancer) cells form in the lung tissue.
  • the two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • SCLC is a more aggressive type of lung cancer, with cancer cells that tend to grow quickly and metastasize more easily to other parts of the body.
  • the most common current treatment regimen involves giving either cisplatin or carboplatin and etoposide, however, patients are prone to developing resistance to chemotherapy and relapse.
  • Lubinectedin (CAS No.: 497871-47-3) is a derivative of the marine compound ET-736 isolated from the sea squirt Ecteinacidia turbinata. The hydrogen atoms in ET-736 are replaced by methoxy groups. The structure is shown below. In addition to its direct effect on cancer cells, Lubinectedin can also inhibit the transcription and production of certain cytokines in tumor-associated macrophages that are critical for tumor growth. Lubinectedin is suitable for the treatment of adult patients with SCLC whose disease has progressed during or after platinum chemotherapy.
  • rubitidine is a complex compound with limited solubility in water.
  • rubitidine has poor stability and will degrade rapidly at room temperature (25°C). It can only be stored for one month at 5°C, so it can only be stored at -20°C for a long time, which greatly limits the clinical application of rubitidine. Therefore, it is very necessary to develop a rubitidine formulation with good stability, stable efficacy and long-term storage.
  • the object of the present invention is to provide a pharmaceutical composition containing rubitidine.
  • the second object of the present invention is to provide a method for preparing a pharmaceutical composition containing rubitidine
  • the third object of the present invention is to provide a use of a pharmaceutical composition containing rubitidine in the preparation of an anti-tumor drug.
  • a first aspect of the present invention provides a pharmaceutical composition containing rubitidine, wherein the pharmaceutical composition is a freeze-dried composition, and the freeze-dried composition comprises: rubitidine, a buffer derived from an inorganic acid, and a support agent, wherein the buffer derived from an inorganic acid is selected from a combination of an inorganic acid and an inorganic acid salt or a combination of an inorganic acid and a base.
  • the buffering agent derived from an inorganic acid is selected from a combination of phosphoric acid and a phosphate, a combination of hydrochloric acid and an alkali, a combination of sulfuric acid and an alkali, a combination of phosphoric acid and an alkali, or a combination of phosphoric acid and a phosphate, a combination of hydrochloric acid and an alkali, a combination of sulfuric acid and an alkali, wherein the alkali is any one of sodium carbonate, potassium carbonate, NH4OH , lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium bicarbonate; wherein the phosphate comprises a hydrate of phosphate.
  • the buffer derived from an inorganic acid is selected from a combination of phosphoric acid and sodium dihydrogen phosphate, a combination of phosphoric acid and potassium dihydrogen phosphate, a combination of hydrochloric acid and sodium hydroxide, a combination of sulfuric acid and sodium hydroxide, a combination of phosphoric acid and sodium hydroxide, or a combination of phosphoric acid and sodium dihydrogen phosphate, a combination of phosphoric acid and potassium dihydrogen phosphate, a combination of hydrochloric acid and sodium hydroxide, and a combination of sulfuric acid and sodium hydroxide.
  • the buffering agent derived from an inorganic acid is selected from a combination of phosphoric acid and potassium dihydrogen phosphate, a combination of phosphoric acid and sodium dihydrogen phosphate, or a combination of phosphoric acid and potassium dihydrogen phosphate.
  • the proppant is a disaccharide selected from any one of sucrose, trehalose and lactose.
  • the proppant is sucrose.
  • the concentration of rubitidine is 0.4-0.6 mg/mL, and preferably, the concentration of rubitidine is 0.5 mg/mL.
  • the molar ratio of rubitidine to the proppant is 1:440 to 1:480, preferably, the molar ratio of rubitidine to the proppant is 1:450 to 1:470, more preferably, the molar ratio of rubitidine to the proppant is 1:455 to 1:465. Further preferably, the molar ratio of rubitidine to the proppant is 1:458.58.
  • the support agent is sucrose
  • the molar ratio of rubitidine to sucrose is 1:458.58, and the corresponding mass ratio is 1:200.
  • the pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5, preferably, the pH value of the original solution of the freeze-dried composition before freeze-drying is 3.5-4.5.
  • the pharmaceutical composition consists of rubitidine, phosphoric acid, potassium dihydrogen phosphate, sucrose, potassium hydroxide, and water.
  • concentration of rubitidine is 0.4-0.6 mg/mL
  • pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5.
  • each 80 mL pharmaceutical composition is as follows: .
  • the pharmaceutical composition consists of rubitidine, phosphoric acid, sodium dihydrogen phosphate, sucrose, and water.
  • concentration of rubitidine is 0.4-0.6 mg/mL
  • pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5.
  • each 80 mL pharmaceutical composition is as follows: .
  • the second aspect of the present invention provides a method for preparing a pharmaceutical composition containing rubitidine, which comprises mixing rubitidine, a buffer, a support and water, and adjusting the pH value to obtain the pharmaceutical composition.
  • a freeze-drying process is also included after adjusting the pH value.
  • the freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying.
  • the pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, and the vacuum degree is 0.05 to 0.5 mbar; the secondary drying temperature is -25 to 45°C, and the vacuum degree is 0.01 to 0.5 mbar.
  • the vacuum degree of the secondary drying is 0.05-0.5 mbar.
  • the time required for the pre-freezing is 0.5 to 8 hours
  • the time required for the primary drying (first drying) is 50 to 120 hours
  • the time required for the secondary drying (second drying) is 24 to 65 hours.
  • preparation method of the pharmaceutical composition can be selected from any one of the following three preparation methods:
  • step 1) mixing the solution obtained in step 1) with the solution obtained in step 2), and adjusting the pH value to obtain;
  • step 3 mixing the solution obtained in step 1) with the solution obtained in step 2), and adjusting the pH value to obtain the product.
  • the preparation method of the pharmaceutical composition also includes a freeze-drying process after adjusting the pH value, and the freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying; the pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, and the vacuum degree is 0.1 to 0.5 mbar; the secondary drying temperature is -25 to 25°C, and the vacuum degree is 0.01 to 0.5 mbar.
  • the vacuum degree of the secondary drying is 0.05-0.5 mbar.
  • the time required for the pre-freezing is 0.5 to 8 hours
  • the time required for the primary drying (first drying) is 35 to 50 hours
  • the time required for the secondary drying (second drying) is 28 hours.
  • the pre-freezing temperature is -40 to 5°C; and the primary drying temperature is -40 to -25°C.
  • the preparation method of the pharmaceutical composition also includes a freeze-drying process after adjusting the pH value, and the freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying; the pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, and the vacuum degree is 0.05-0.5mbar; the secondary drying temperature is -25 to 45°C, and the vacuum degree is 0.01-0.5mbar.
  • the vacuum degree of the secondary drying is 0.05-0.5 mbar.
  • the time required for the pre-freezing is 0.5 to 8 hours
  • the time required for the primary drying (first drying) is 50 to 120 hours
  • the time required for the secondary drying (second drying) is 24 to 65 hours.
  • the time required for the primary drying (first drying) is 50 to 100 hours
  • the time required for the secondary drying (second drying) is 24 to 46 hours.
  • the third aspect of the present invention provides use of a pharmaceutical composition containing rubitidine in the preparation of an anti-tumor drug.
  • auxiliary materials such as a buffer and a support agent
  • rubitidine as a pharmaceutical active ingredient maintains good stability during freeze-drying, and at the same time solves the problem of poor solubility of rubitidine in water, thereby obtaining a rubitidine pharmaceutical composition that meets the requirements of intravenous infusion and can be stably stored, and the pharmaceutical composition shows important application prospects in the preparation of anti-tumor drugs.
  • the present invention utilizes a combination of an inorganic acid and an inorganic acid salt or a combination of an inorganic acid and an alkali as a buffer, thereby ensuring that the active ingredient rubitidine can be completely dissolved during the preparation process of the pharmaceutical composition, and can ensure that the pH value of the pharmaceutical composition is stable during storage, without affecting the quality and stability of the active ingredient of the pharmaceutical composition, with a low impurity content, long-term storage, and an osmotic pressure that meets the requirements (260-330 mOsmol/kg) of intravenous drip drugs ( ⁇ 100 mL).
  • the preparation method of the pharmaceutical composition provided by the present invention is simple to operate, has low production cost, is conducive to large-scale production, and provides assistance for the large-scale application of pharmaceutical preparations.
  • the numerical range expressed using “numerical value A to numerical value B” or “numerical value A-numerical value B” means a range including the endpoints numerical values A and B.
  • the word “may” includes both performing a certain process and not performing a certain process.
  • references to “some specific/preferred embodiments”, “other specific/preferred embodiments”, “embodiments”, etc. mean that the specific elements (e.g., features, structures, properties and/or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments.
  • the elements may be combined in various embodiments in any suitable manner.
  • concentrations of phosphoric acid, sulfuric acid, hydrochloric acid, and sodium hydroxide used in the examples of the present invention are all 0.1 mol/L.
  • concentrations of phosphoric acid, sulfuric acid, hydrochloric acid, and sodium hydroxide used in the examples of the present invention are all 0.1 mol/L.
  • Rubitidine was used as the active ingredient, phosphoric acid/potassium dihydrogen phosphate combination was used as the buffer, phosphoric acid/potassium hydroxide was used as the pH adjuster, sucrose was used as the support agent, and water for injection was used as the solvent to prepare the rubitidine pre-lyophilization solution.
  • the specific composition and dosage of the prescription are shown in Table 1:
  • step 3 Take 8 g of sucrose and add it to the solution obtained in step 2. After stirring to dissolve, adjust the pH value to 4.0 ⁇ 0.2 with phosphoric acid solution or potassium hydroxide solution;
  • the above solution was freeze-dried to prepare a freeze-dried preparation, and the appearance, water content, and related substances were examined.
  • the freeze-drying in this example adopted the freeze-drying procedure 1 in Example 12.
  • the storage stability of the freeze-dried preparation under accelerated conditions 25°C, 60% RH was tested, and the results are shown in Table 2:
  • Rubitidine was used as the active ingredient, phosphoric acid/sodium dihydrogen phosphate combination was used as the buffer, phosphoric acid/sodium hydroxide was used as the pH value adjuster, sucrose was used as the support agent, and water for injection was used as the solvent to prepare the rubitidine pre-lyophilization solution.
  • the specific composition and dosage of the second prescription are shown in Table 3:
  • step 3 Take 8 g of sucrose and add it to the solution obtained in step 2. After stirring to dissolve, adjust the pH value to 4.0 ⁇ 0.2 with phosphoric acid solution or sodium hydroxide solution;
  • the above solution was freeze-dried to prepare a freeze-dried preparation, and the appearance, water content, and related substances were examined.
  • the freeze-drying in this example adopted the freeze-drying procedure 1 in Example 12.
  • the storage stability of the freeze-dried preparation under accelerated conditions 25°C, 60% RH was tested, and the results are shown in Table 4:
  • Rubitidine was used as the active ingredient, a hydrochloric acid/sodium hydroxide combination was used as a buffer, hydrochloric acid/sodium hydroxide was used as a pH adjuster, sucrose was used as a support agent, and water for injection was used as a solvent to prepare the rubitidine pre-lyophilization solution.
  • the specific composition and dosage of the three prescriptions are shown in Table 5:
  • step 3 Take 8 g of sucrose and add it to the solution obtained in step 2. After stirring to dissolve, adjust the pH value to 4.0 ⁇ 0.2 with hydrochloric acid solution or sodium hydroxide solution;
  • Rubitidine was used as an active ingredient, a sulfuric acid/sodium hydroxide combination was used as a buffer, sulfuric acid/sodium hydroxide was used as a pH adjuster, sucrose was used as a support, and water for injection was used as a solvent to prepare a rubitidine pre-lyophilized solution.
  • the specific composition and dosage of the fourth prescription are shown in Table 7:
  • step 3 Take 8 g of sucrose and add it to the solution obtained in step 2. After stirring to dissolve it, adjust the pH value to 4.0 ⁇ 0.2 with sulfuric acid solution or sodium hydroxide solution;
  • the above solution was freeze-dried to prepare a rubitidine freeze-dried preparation, and the appearance, moisture, and related substances were examined.
  • the freeze-drying in this example adopted the freeze-drying procedure 1 in Example 12.
  • the shelf stability of the freeze-dried preparation under accelerated conditions 25°C, 60% RH was tested, and the results are shown in Table 8:
  • step 3 Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and the pH of the resulting solution is 4.0 ⁇ 0.2;
  • the freeze drying in this embodiment is carried out using the following procedure: .
  • Rubitidine was used as the active ingredient, phosphoric acid/sodium dihydrogen phosphate combination was used as the buffer, sodium hydroxide was used as the pH adjuster, sucrose was used as the support agent, and water for injection was used as the solvent to prepare the rubitidine pre-lyophilization solution.
  • the specific composition and dosage of the sixth prescription are shown in Table 10:
  • step 3 Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and adjust the pH value to 4.0 ⁇ 0.2 with sodium hydroxide solution;
  • the freeze drying in this embodiment is carried out using the following procedure: .
  • Rubitidine was used as an active ingredient, phosphoric acid/potassium dihydrogen phosphate combination was used as a buffer, sodium hydroxide was used as a pH adjuster, sucrose was used as a support agent, and water for injection was used as a solvent to prepare a rubitidine pre-lyophilized solution.
  • the specific composition and dosage of the formula 7 are shown in Table 11:
  • step 3 Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and adjust the pH value to 4.0 ⁇ 0.2 with sodium hydroxide solution;
  • the above solution is freeze-dried to prepare a freeze-dried preparation.
  • the freeze drying in this embodiment is carried out using the following procedure: .
  • Rubitidine was used as the active ingredient, a phosphoric acid/sodium hydroxide combined buffer, sucrose as a support, phosphoric acid as a pH adjuster, and water for injection as a solvent to prepare a rubitidine pre-lyophilized solution.
  • the specific formula eight composition and dosage are shown in Table 12:
  • step 3 Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and adjust the pH value to 4.0 ⁇ 0.2 with phosphoric acid;
  • the above solution is further freeze-dried to prepare a lyophilized preparation.
  • the freeze drying in this embodiment is carried out using the following procedure: .
  • Rubitidine was used as the active ingredient, a phosphoric acid/sodium hydroxide combination was used as a buffer, sucrose was used as a support agent, and water for injection was used as a solvent to prepare the rubitidine pre-lyophilization solution.
  • the specific composition and dosage of the formula 9 are shown in Table 13:
  • step 3 Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and the pH of the resulting solution is 4.0 ⁇ 0.2;
  • the above solution is further freeze-dried to prepare a lyophilized preparation.
  • the freeze drying in this embodiment is carried out using the following procedure: .
  • Rubitidine was used as the active ingredient, a lactic acid/sodium hydroxide combination was used as a buffer, sucrose was used as a support agent, and water for injection was used as a solvent to prepare the rubitidine pre-lyophilization solution.
  • the specific formulation composition and dosage are shown in Table 14:
  • the above solution is further freeze-dried to prepare a lyophilized preparation.
  • the freeze drying in this embodiment is carried out using the following procedure: .
  • Example 10 Stability study of the lyophilized preparations obtained from Prescriptions 5 to 9 and Reference Example 1
  • Impurities A, B, and C are known specific impurities in the quality standard of the reference preparation.
  • Impurity A has an RRT of 0.78
  • impurity B has an RRT of 1.2
  • impurity C has an RRT of 2.0.
  • the reference example 1 uses a lactic acid/sodium hydroxide combination as a buffer, and the impurities of the rubitidine freeze-dried composition prepared after being placed at 40°C for 1 month increased from 0.20 to 0.49; the stability of the prescriptions 6 and 7 of the present invention is comparable to that of the reference example 1, the stability of the prescription 9 is slightly better than that of the reference example 1, and the stability of the prescriptions 5 and 8 is significantly better than that of the reference example 1. Overall, the stability effect of the prescriptions in the present invention is better than that of the reference example 1, and the stability of rubitidine during storage can be guaranteed.
  • step 3 Add the solution obtained in step 1 to the solution obtained in step 2, mix well, and adjust the pH value to 4.0 ⁇ 0.2 with phosphoric acid solution or potassium hydroxide solution.
  • step 3 Add the solution obtained in step 1 to the solution obtained in step 2, mix well, and adjust the pH value to 4.0 ⁇ 0.2 with phosphoric acid solution or potassium hydroxide solution;
  • the pre-lyophilized solution was prepared according to the formulation and preparation method of Example 1, and lyophilized according to the following three lyophilization procedures.
  • Tables 21 and 22 show that the preparations prepared by the three freeze-drying procedures had no significant changes in properties and related substances after being placed under accelerated conditions for 3 months, and no significant differences were observed between the groups. Among them, the moisture and appearance of freeze-drying procedure one were slightly better than those of the other two groups. In order to ensure better product quality, freeze-drying procedure one can be preferred.
  • the pre-lyophilized solution was prepared according to the prescription and preparation method of Example 5, and lyophilized according to the lyophilization procedure 4 in Table 23:
  • freeze-dried preparation obtained by freeze-drying procedure 4 was placed under accelerated conditions (40°C, 60°C) for 10 or 30 days, and the properties and related substances did not change significantly, and the moisture content was greatly reduced, so a freeze-dried preparation of better quality could be obtained.

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Abstract

一种含卢比替定的药物组合物及其制备方法和应用。该含卢比替定的药物组合物为冻干组合物，冻干组合物包含：卢比替定、来源于无机酸的缓冲剂、支撑剂。药物组合物活性成分卢比替定可以溶解完全，并能够保证药物组合物在储存过程中的pH值稳定，且不影响药物活性成分的质量和稳定性，杂质含量低，可以长久保存，在治疗癌症等相关疾病中表现出重要的应用前景。该药物组合物的制备方法操作简便，生产成本低，有利于规模化生产，为药物制剂的大范围应用提供帮助。

Description

一种含卢比替定的药物组合物及其制备方法和应用
本发明要求于2022年12月22日提交中国专利局、申请号为202211667008.4、发明名称为“一种含卢比替定的药物组合物及其制备方法和应用”的中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明属于医药领域，具体涉及一种含卢比替定的药物组合物及其制备方法和应用。
背景技术
肺癌是一种在肺组织中形成恶性(癌)细胞的疾病。肺癌的两种主要类型是小细胞肺癌(Small Cell Lung Cancer,SCLC)和非小细胞肺癌(Non Small Cell Lung Cancer,NSCLC)。诊断时，SCLC占所有肺癌的约13％-15％，然而，SCLC是更具侵袭性的肺癌类型，癌细胞往往快速生长并更容易转移到身体的其他部位。目前最常见的治疗方案包括给予顺铂或卡铂和依托泊苷治疗，然而，患者容易对化疗产生耐药性并复发。
卢比替定(Lurbinectedin，CAS No.:497871-47-3)是从海鞘Ecteinacidia turbinata中分离出的海洋化合物ET-736的衍生物，ET-736中的氢原子被甲氧基取代，结构如下所示。除了其对癌细胞的直接作用，卢比替定还能够抑制肿瘤相关巨噬细胞中某些对肿瘤生长至关重要的细胞因子的转录和产生。卢比替定适用于在铂化疗中或化疗后病情进展的SCLC成人患者的治疗。
然而，卢比替定是一种复杂的化合物，在水中溶解度有限，同时，卢比替定稳定性差，在室温(25℃)条件下会发生快速降解，在5℃冷藏仅能保存1个月，因此只能长期存储于-20℃，这极大地限制了卢比替定在临床上的应用。因此，开发一种稳定性好、药效稳定并且可长期储存的卢比替定制剂是非常必要的。
发明内容
本发明的目的在于提供一种含卢比替定的药物组合物。
本发明的第二个目的在于提供含卢比替定的药物组合物的制备方法；
本发明的第三个目的在于提供含卢比替定的药物组合物在制备抗肿瘤药物中的应用。
为实现上述目的，本发明的技术方案是：
本发明第一方面提供一种含卢比替定的药物组合物，所述药物组合物为冻干组合物，所述冻干组合物包含：卢比替定、来源于无机酸的缓冲剂、支撑剂，其中，所述来源于无机酸的缓冲剂选自无机酸和无机酸盐的组合或无机酸和碱的组合。
进一步的，所述来源于无机酸的缓冲剂选自磷酸和磷酸盐的组合、盐酸和碱的组合、硫酸和碱的组合、磷酸和碱的组合，或者，选自磷酸和磷酸盐的组合、盐酸和碱的组合、硫酸和碱的组合，其中，所述碱为碳酸钠、碳酸钾、NH4OH、氢氧化锂、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾中的任意一种；其中，所述磷酸盐包含磷酸盐的水合物。
优选的，所述来源于无机酸的缓冲剂选自磷酸和磷酸二氢钠的组合、磷酸和磷酸二氢钾的组合、盐酸和氢氧化钠的组合、硫酸和氢氧化钠的组合、磷酸和氢氧化钠的组合，或者，选自磷酸和磷酸二氢钠的组合、磷酸和磷酸二氢钾的组合、盐酸和氢氧化钠的组合、硫酸和氢氧化钠的组合。
更优选的，所述来源于无机酸的缓冲剂选自磷酸和磷酸二氢钾的组合、磷酸和磷酸二氢钠的组合，或者，选自磷酸和磷酸二氢钾的组合。
进一步的，在所述药物组合物中，所述支撑剂为二糖，选自蔗糖、海藻糖、乳糖中任意一种，优选的，所述支撑剂为蔗糖。
进一步的，在所述冻干组合物冻干前的原液中，卢比替定的浓度是0.4～0.6mg/mL，优选的，卢比替定浓度为0.5mg/mL。
进一步的，在所述药物组合物中，所述卢比替定与支撑剂的摩尔比是1：440～1：480，优选的，所述卢比替定与支撑剂的摩尔比是1：450～1：470，更优选的，所述卢比替定与支撑剂的摩尔比是1：455～1：465。进一步优选的，所述卢比替定与支撑剂的摩尔比为1:458.58。
优选的，在所述药物组合物中，所述支撑剂为蔗糖，所述卢比替丁与蔗糖的摩尔比为1:458.58，相应的质量比为1:200。
进一步的，在所述药物组合物中，所述冻干组合物冻干前原液的pH值为3～5，优选的，所述冻干组合物冻干前原液的pH值为3.5～4.5。
进一步的，所述药物组合物由卢比替定、磷酸、磷酸二氢钾、蔗糖、氢氧化钾、水组成，所述卢比替定的浓度为0.4～0.6mg/mL，冻干组合物冻干前原液的pH值为3～5。
进一步的，每80mL药物组合物各成分如下：

。
进一步的，所述药物组合物由卢比替定、磷酸、磷酸二氢钠、蔗糖、水组成，所述卢比替定的浓度为0.4～0.6mg/mL，冻干组合物冻干前原液的pH值为3～5。
进一步的，每80mL药物组合物各成分如下：

。
本发明第二方面提供含卢比替定的药物组合物的制备方法：将卢比替定、缓冲剂、支撑剂与水混合，调节pH值，即得。
进一步的，上述制备方法中，在调节pH值后还包括冻干程序。所述冻干程序分为三个阶段：预冻、一次干燥、二次干燥。所述预冻的温度为-50～5℃；所述一次干燥的温度为-40～-10℃，真空度为0.05-0.5mbar；所述二次干燥的温度为-25～45℃，真空度为0.01-0.5mbar。
优选的，所述二次干燥的真空度为0.05-0.5mbar。
进一步的，所述预冻所需时间为0.5～8h，所述一次干燥(第一次干燥)所需时间为50～120h，所述二次干燥(第二次干燥)所需时间为24～65h。
进一步的，所述药物组合物的制备方法可以选自以下三种制备方法中的任意一种：
制备方法一：
1)将卢比替定与无机酸混合；
2)加入水、碱/无机酸盐；
3)加入支撑剂，调节pH值，即得；
制备方法二：
1)将卢比替定与无机酸混合；
2)将碱/无机酸盐、支撑剂、水混合，调节pH值；
3)将步骤1)所得溶液与步骤2)所得溶液混合，调节pH值，即得；
制备方法三：
1)将无机酸、无机酸盐与卢比替定混合；
2)将支撑剂与水混合，调节pH值；
3)将步骤1)所得溶液与步骤2)所得溶液混合，调节pH值，即得。
进一步的，所述药物组合物的制备方法，在调节pH值后还包括冻干程序，所述冻干程序分为三个阶段：预冻、一次干燥、二次干燥；所述预冻的温度为-50～5℃；所述一次干燥的温度为-40～-10℃，真空度为0.1～0.5mbar；所述二次干燥的温度为-25～25℃，真空度为0.01～0.5mbar。
优选的，所述二次干燥的真空度为0.05-0.5mbar。
进一步的，所述预冻所需时间为0.5～8h，所述一次干燥(第一次干燥)所需时间为35～50h，所述二次干燥(第二次干燥)所需时间为28h。
优选的，所述预冻的温度为-40～5℃；所述一次干燥的温度为-40～-25℃。
进一步的，所述药物组合物的制备方法，在调节pH值后还包括冻干程序，所述冻干程序分为三个阶段：预冻、一次干燥、二次干燥；所述预冻的温度为-50～5℃；所述一次干燥的温度为-40～-10℃，真空度为0.05-0.5mbar；所述二次干燥的温度为-25～45℃，真空度为0.01-0.5mbar。
优选的，所述二次干燥的真空度为0.05-0.5mbar。
进一步的，所述预冻所需时间为0.5～8h，所述一次干燥(第一次干燥)所需时间为50～120h，所述二次干燥(第二次干燥)所需时间为24～65h。优选的，所述一次干燥(第一次干燥)所需时间为50～100h，所述二次干燥(第二次干燥)所需时间为24～46h。
本发明第三个方面提供含卢比替定的药物组合物在制备抗肿瘤药物中的应用。
本发明在提供的药物组合物中通过缓冲剂、支撑剂等辅料的选择，使作为药物活性成分的卢比替定在冻干中保持良好的稳定性，同时解决了卢比替定在水中溶解度差的问题，得到一种满足静脉滴注要求的、能稳定保存的卢比替定药物组合物，该药物组合物在制备抗肿瘤药物中表现出重要的应用前景。
本发明利用无机酸和无机酸盐的组合或无机酸和碱的组合作为缓冲剂，确保了药物组合物在制备过程中活性成分卢比替定可以溶解完全，并能够保证药物组合物在储存过程中的pH值稳定，且不影响药物活性成分的质量和稳定性，杂质含量低，可以长久保存，渗透压符合静脉滴注药物(≥100mL)的要求(260～330mOsmol/kg)。
本发明提供的药物组合物的制备方法操作简便，生产成本低，有利于规模化生产，为药物制剂的大范围应用提供帮助。
具体实施方案
以下对本发明的实施方式进行说明，但本发明不限定于此。本发明不限于以下说明的各构成，在发明请求保护的范围内可以进行各种变更，而适当组合不同实施方式、实施例中各自公开的技术手段而得到的实施方式、实施例也包含在本发明的技术范围中。
除非另有定义，本发明所用的技术和科学术语具有与本发明所属技术领域中的普通技术人员所通常理解的相同含义。
本发明中，“/”的含义为“和”或者“或”。
本说明书中，使用“数值A～数值B”或“数值A-数值B”表示的数值范围是指包含端点数值A、B的范围。
本说明书中，使用“可以”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。
如无特殊声明，本说明书中，未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售获得的常规产品。
本说明书中，所使用的单位均为国际标准单位，并且本发明中出现的数值、数值范围，均应当理解为包含了工业生产中所不可避免的系统性误差。
本说明书中，所提及的“一些具体/优选的实施方案”、“另一些具体/优选的实施方案”、“实施方案”等是指所描述的与该实施方案有关的特定要素(例如，特征、结构、性质和/或特性)包括在此处所述的至少一种实施方案中，并且可存在于其它实施方案中或者可不存在于其它实施方案中。另外，应理解，所述要素可以任何合适的方式组合在各种实施方案中。
本发明实施例中所用的磷酸、硫酸、盐酸、氢氧化钠的浓度均为0.1mol/L。例如，当使用0.1mol/L磷酸时，处方中若使用3.44mL磷酸，则理论上对应的摩尔数为0.344mmol，重量为0.344mmol×97.99g/mol＝33.71mg。
实施例1：处方一
以卢比替定为活性成分，采用磷酸/磷酸二氢钾组合为缓冲剂，磷酸/氢氧化钾为pH调节剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方一组成及用量如表1所示：
表1处方一信息
制备方法：
1、取33.71mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水加入药物溶液中，搅拌均匀后取544mg磷酸二氢钾加入药物溶液中，搅拌使其溶解；
3、取8g蔗糖加入步骤2所得溶液中，搅拌使其溶解后，用磷酸溶液或氢氧化钾溶液调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进行冷冻干燥制备成冻干制剂，考察外观、水分、有关物质。本实施例冷冻干燥采用实施例12中的冻干程序一。检测冻干制剂在加速条件下(25℃，60％RH)的放置稳定性，结果如表2所示：
表2处方一所得冻干制剂的稳定性研究

注：①“/”表示未检出或小于0.05％；
由表2可知，以磷酸和磷酸二氢钾的组合作为缓冲剂，活性成分卢比替定在溶液中溶解完全，冻干制备得到的冻干制剂，外观、水分、有关物质合格，冻干制剂在加速条件下稳定性较好，25℃，60％RH条件下放置3个月总杂基本不变，说明以磷酸二氢钾和磷酸组合物作为卢比替定制剂的缓冲剂可以提高卢比替定在储存过程中的稳定性。
实施例2：处方二
以卢比替定为活性成分，采用磷酸/磷酸二氢钠组合为缓冲剂，磷酸/氢氧化钠为pH值调节剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方二组成及用量如表3所示：
表3处方二信息
制备方法：
1、取33.71mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水加入药物溶液中，搅拌均匀后取480mg磷酸二氢钠加入药物溶液中，搅拌使其溶解；
3、取8g蔗糖加入步骤2所得溶液中，搅拌使其溶解后，用磷酸溶液或氢氧化钠溶液调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进行冷冻干燥制备成冻干制剂，考察外观、水分、有关物质。本实施例冷冻干燥采用实施例12中的冻干程序一。检测冻干后制剂在加速条件下(25℃，60％RH)的放置稳定性，结果如表4所示：
表4处方二所得冻干制剂的稳定性研究

注：①“/”表示未检出或小于0.05％；
由表4内容可知，以磷酸二氢钠和磷酸的组合作为缓冲剂，活性成分卢比替定在溶液中溶解完全，冻干制备得到的冻干制剂外观、水分、有关物质合格，冻干制剂在加速条件下稳定性较好，25℃，60％RH条件下放置3个月总杂由0.41到0.47，基本不变，说明磷酸二氢钠和磷酸组合物作为卢比替定制剂的缓冲剂可以提高卢比替定在储存过程中的稳定性。
实施例3：处方三
以卢比替定为活性成分，采用盐酸/氢氧化钠组合作为缓冲剂，盐酸/氢氧化钠为pH值调节剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方三组成及用量如表5所示：
表5处方三信息
制备方法：
1、取12.54mg盐酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水加入药物溶液中，搅拌均匀；
3、取8g蔗糖加入步骤2所得溶液中，搅拌使其溶解后，用盐酸溶液或氢氧化钠溶液调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进行冷冻干燥制备卢比替定冻干制剂。考察外观、水分、有关物质。本实施例冷冻干燥采用实施例12中的冻干程序一。检测冻干后制剂在加速条件(25℃，60％RH)下的放置稳定性，结果如表6所示：
表6处方三所得冻干制剂的稳定性研究

注：①“/”表示未检出或小于0.05％；
由表6内容可知，以盐酸和氢氧化钠的组合作为缓冲剂，活性成分卢比替定在溶液中溶解完全，冻干制备得到的冻干制剂，外观、水分、有关物质合格，冻干制剂在加速条件下稳定性较好，25℃，60％RH条件下放置3个月总杂由0.48到0.69，总杂变化较小，说明盐酸和氢氧化钠组合物作为卢比替定制剂的缓冲剂，可以保证卢比替定在储存过程中的稳定性。
实施例4：处方四
以卢比替定为活性成分，采用硫酸/氢氧化钠组合为缓冲剂，硫酸/氢氧化钠为pH值调节剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方四组成及用量如表7所示：
表7处方四信息
制备方法：
1、取33.71mg硫酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水加入药物溶液中，搅拌均匀；
3、取8g蔗糖加入步骤2所得溶液中，搅拌使其溶解后，用硫酸溶液或氢氧化钠溶液调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进行冷冻干燥制备卢比替定冻干制剂，考察外观、水分、有关物质。本实施例冷冻干燥采用实施例12中的冻干程序一。检测冻干后制剂在加速条件(25℃，60％RH)下的放置稳定性，结果如表8所示：
表8处方四所得冻干制剂的稳定性研究

注：①“/”表示未检出或小于0.05％。
由表8内容可知，以硫酸和氢氧化钠的组合作为缓冲剂，活性成分卢比替定在溶液中溶解完全，冻干制备得到的冻干制剂，外观、水分、有关物质合格，冻干制剂在加速条件下稳定性较好，25℃，60％RH条件下放置3个月总杂由0.67到0.89，总杂变化较小，说明硫酸和氢氧化钠组合物作为卢比替定制剂的缓冲剂，也可以保证卢比替定在储存过程中的稳定性。
实施例5：处方五
以卢比替定为活性成分，采用磷酸/磷酸二氢钠组合为缓冲剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方五组成及用量如表9所示：
表9处方五信息
制备方法：
1、取11.5mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水，加入8g蔗糖、294mg磷酸二氢钠，搅拌使其溶解；
3、将步骤1所得溶液全部加入步骤2所得溶液中，搅拌均匀，所得溶液pH为4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进行冷冻干燥制备卢比替定冻干制剂；
本实施例冷冻干燥采用如下程序进行：

。
实施例6：处方六
以卢比替定为活性成分，采用磷酸/磷酸二氢钠组合为缓冲剂，氢氧化钠为pH调节剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方六组成及用量如表10所示：
表10处方六信息
制备方法：
1、取33.71mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水，加入8g蔗糖、480mg磷酸二氢钠，搅拌使其溶解；
3、将步骤1所得溶液全部加入步骤2所得溶液中，搅拌均匀，用氢氧化钠溶液调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进行冷冻干燥制备卢比替定冻干制剂。
本实施例冷冻干燥采用如下程序进行：

。
实施例7：处方七
以卢比替定为活性成分，采用磷酸/磷酸二氢钾组合为缓冲剂，氢氧化钠为pH调节剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方七组成及用量如表11所示：
表11处方七信息
制备方法：
1、取23.71mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水，加入8g蔗糖、544mg磷酸二氢钾，搅拌使其溶解；
3、将步骤1所得溶液全部加入步骤2所得溶液中，搅拌均匀，用氢氧化钠溶液调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进行冷冻干燥制备成冻干制剂。
本实施例冷冻干燥采用如下程序进行：

。
实施例8：处方八
以卢比替定为活性成分，采用磷酸/氢氧化钠组合缓冲剂，蔗糖为支撑剂，磷酸为pH调节剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方八组成及用量如表12所示：
表12处方八信息
制备方法：
1、取127.1mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水，加入8g蔗糖、51mg氢氧化钠，搅拌使其溶解；
3、将步骤1所得溶液全部加入步骤2所得溶液中，搅拌均匀，用磷酸调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进一步冷冻干燥制备成冻干制剂。
本实施例冷冻干燥采用如下程序进行：

。
实施例9：处方九
以卢比替定为活性成分，采用磷酸/氢氧化钠组合为缓冲剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方九组成及用量如表13所示：
表13处方九信息
制备方法：
1、取139.1mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水，加入8g蔗糖、51mg氢氧化钠，搅拌使其溶解；
3、将步骤1所得溶液全部加入步骤2所得溶液中，搅拌均匀，所得溶液pH为4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进一步冷冻干燥制备成冻干制剂。
本实施例冷冻干燥采用如下程序进行：

。
参照例一
以卢比替定为活性成分，采用乳酸/氢氧化钠组合为缓冲剂，蔗糖为支撑剂，注射用水为溶剂制备卢比替定冻干前溶液，具体处方组成及用量如表14所示：
表14参照例一处方信息
制备方法：
1、取45mg乳酸，加入40mg芦比替定，搅拌使药物完全溶解，得药物溶液；
2、取70％注射用水，加入8g蔗糖，51mg氢氧化钠，176mg乳酸，搅拌使其溶解；
3、将步骤1所得溶液全部加入步骤2所得溶液中，搅拌均匀；
4、将上述溶液定至总重，灌装半加塞。
将上述溶液进一步冷冻干燥制备成冻干制剂。
本实施例冷冻干燥采用如下程序进行：

。
实施例10：处方五至处方九以及参照例一所得冻干制剂的稳定性研究
考察处方五至处方九以及参照例一所得冻干制剂的外观、水分及有关物质。检测冻干后制剂在加速条件(25℃/60％RH、40℃)下的放置稳定性，结果如表15所示：
表15处方五至九以及参照例一所得冻干制剂的稳定性研究

注：②杂质A、B、C属于参比制剂质量标准的已知特定杂质，杂质A为RRT0.78，杂质B为RRT1.2，杂质C为RRT2.0。
由表15内容可知，参照例一以乳酸/氢氧化钠组合为缓冲剂，制得的卢比替定冻干组合物在40℃放置1个月后，杂质由0.20增加到0.49；本发明中处方六和处方七的稳定性相较其相当，处方九的稳定性略优于参照例一，处方五和处方八的稳定性显著优于参照例一。整体来说，本发明中处方的稳定性效果要优于参照例一，可以保证卢比替定在储存过程中的稳定性。
实施例11：不同冻干前溶液制备方法
以处方一为例制备组合物，共设计三种不同的冻干前溶液制备方法：
●第一种制备方法：
具体参见实施例1。
●第二种制备方法：
1、取33.71mg磷酸，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取544mg磷酸二氢钾与8g蔗糖加入70％注射用水中，搅拌至完全溶解，采用磷酸溶液或氢氧化钾溶液调节pH值至4.0±0.2；
3、将步骤1所得的溶液加入到步骤2所得的溶液中，混合均匀，用磷酸溶液或氢氧化钾溶液调节pH值至4.0±0.2。
4、将上述溶液定至总重，灌装半加塞。
●第三种制备方法：
1、取33.71mg磷酸与544mg磷酸二氢钾，加入40mg卢比替定，搅拌使药物完全溶解，得药物溶液；
2、取8g蔗糖加入70％注射用水中，搅拌至完全溶解，采用磷酸溶液或氢氧化钾溶液调节pH值至4.0±0.2；
3、将步骤1所得的溶液加入到步骤2所得的溶液中，混合均匀，用磷酸溶液或氢氧化钾溶液调节pH值至4.0±0.2；
4、将上述溶液定至总重，灌装半加塞。
将上述三种溶液进行冷冻干燥，制备成冻干制剂，考察外观、水分、有关物质。检测冻干制剂在加速条件(25℃，60％RH)下的放置稳定性，结果如表16所示：
表16不同制备方法所得冻干制剂的稳定性研究
此外，还考察了冻干制剂外观，结果如表17所示：
表17不同制备方法所得冻干制剂的外观
由表16和表17内容可知，三种制备方法制备的制剂在加速条件下放置3个月，性状与有关物质均无明显变化，各组别间未见明显差异，其中，制备方法一的水分与外观略优于其余两组，为保证更好的产品质量，可以优选制备方法一作为冻干前溶液的制备方法。
实施例12：不同冻干程序
以实施例1的处方和制备方法制备冻干前溶液，分别以下列三种冻干程序进行冻干。
表18冻干程序一
表19冻干程序二
表20冻干程序三
考察外观、水分、有关物质。检测冻干制剂在加速条件(25℃，60％RH)下的 放置稳定性，结果如表21所示：
表21不同冻干程序所得冻干制剂的稳定性研究
此外，还考察了冻干制剂外观，结果如表22所示：
表22不同冻干程序所得冻干制剂的外观
表21和表22结果显示，三种冻干程序制备的制剂在加速条件下放置3个月，性状与有关物质均无明显变化，各组别间未见明显差异，其中，冻干程序一的水分与外观略优于其余两组，为保证更好的产品质量，可以优选冻干程序一。
实施例13：不同冻干程序
以实施例5的处方和制备方法制备冻干前溶液，以表23中的冻干程序四进行冻干：
表23冻干程序四
考察冻干程序四所得冻干制剂的外观、水分及有关物质，结果如表24所示：
表24冻干程序四所得冻干制剂的稳定性研究

注：①“/”表示未检出；②杂质A、B、C属于参比制剂质量标准的已知特定杂质，
杂质A为RRT0.78，杂质B为RRT1.2，杂质C为RRT2.0。
由表24可知，冻干程序四所得冻干制剂在加速条件(40℃、60℃)下放置10或30天，性状与有关物质均无明显变化，且水分大大降低，可以得到质量更好的冻干制剂。
以上已经描述了本公开的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。本文中所用术语的选择，旨在最好地解释各实施例的原理、实际应用或对市场中的技术的改进，或者使本技术领域的其它普通技术人员能理解本文披露的各实施例。

Claims (17)

  1. 一种含卢比替定的药物组合物，其特征在于，所述药物组合物为冻干组合物，所述冻干组合物包含：卢比替定、来源于无机酸的缓冲剂、支撑剂。
  2. 如权利要求1所述药物组合物，其特征在于，所述来源于无机酸的缓冲剂为无机酸和无机酸盐的组合或无机酸和碱的组合。
  3. 如权利要求2所述药物组合物，其特征在于，所述无机酸和无机酸盐的组合为磷酸和磷酸盐的组合；所述无机酸和碱的组合为盐酸和碱的组合、硫酸和碱的组合或磷酸和碱的组合。
  4. 如权利要求3所述药物组合物，其特征在于，所述碱为碳酸钠、碳酸钾、NH4OH、氢氧化锂、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾中任意一种。
  5. 如权利要求1所述药物组合物，其特征在于，所述支撑剂为二糖，选自蔗糖、海藻糖、乳糖中任意一种。
  6. 如权利要求1所述药物组合物，其特征在于，在所述冻干组合物冻干前的原液中，卢比替定的浓度是0.4～0.6mg/mL。
  7. 如权利要求1所述药物组合物，其特征在于，所述卢比替定与支撑剂的摩尔比是1：440～1：480。
  8. 如权利要求1所述药物组合物，其特征在于，所述冻干组合物冻干前原液的pH值为3～5。
  9. 如权利要求1所述药物组合物，其特征在于，所述药物组合物由卢比替定、磷酸、磷酸二氢钾、蔗糖、氢氧化钾、水组成，所述卢比替定的浓度为0.4～0.6mg/mL，冻干组合物冻干前原液的pH值为3～5。
  10. 如权利要求1所述药物组合物，其特征在于，所述药物组合物由卢比替定、磷酸、磷酸二氢钠、蔗糖、水组成，所述卢比替定的浓度为0.4～0.6mg/mL，冻干组合物冻干前原液的pH值为3～5。
  11. 如权利要求9所述药物组合物，其特征在于，每80mL药物组合物各成分如下：
  12. 如权利要求10所述药物组合物，其特征在于，每80mL药物组合物各成分如下：
  13. 如权利要求1～12任意一项所述药物组合物的制备方法，其特征在于，包括如下步骤：将卢比替定、来源于无机酸的缓冲剂、支撑剂与水混合，调节pH值，即得。
  14. 如权利要求13所述制备方法，其特征在于，是如下任意一种制备方法：
    制备方法一：
    1)将卢比替定与无机酸混合；
    2)加入水、碱/无机酸盐；
    3)加入支撑剂，调节pH值，即得；
    制备方法二：
    1)将卢比替定与无机酸混合；
    2)将碱/无机酸盐、支撑剂、水混合，调节pH值；
    3)将步骤1)所得溶液与步骤2)所得溶液混合，调节pH值，即得；
    制备方法三：
    1)将无机酸、无机酸盐与卢比替定混合；
    2)将支撑剂与水混合，调节pH值；
    3)将步骤1)所得溶液与步骤2)所得溶液混合，调节pH值，即得。
  15. 如权利要求13所述制备方法，其特征在于，在调节pH值后还包括冻干程序，所述冻干程序分为三个阶段：预冻、一次干燥、二次干燥；所述预冻的温度为-50～5℃；所述一次干燥的温度为-40～-10℃，真空度为0.1～0.5mbar；所述二次干燥的温度为-25～25℃，真空度为0.01～0.5mbar；优选的，所述二次干燥的真空度为0.05～0.5mbar。
  16. 如权利要求13所述制备方法，其特征在于，在调节pH值后还包括冻干程序，所述冻干程序分为三个阶段：预冻、一次干燥、二次干燥；所述预冻的温度为-50～5℃；所述一次干燥的温度为-40～-10℃，真空度为0.05～0.5mbar；所述二次干燥的温度为-25～45℃，真空度为0.01～0.5mbar；优选的，所述二次干燥的真空度为0.05～0.5mbar。
  17. 如权利要求1～12任一项所述药物组合物在制备抗肿瘤药物中的应用。
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