WO2021078077A1 - 乙酰化艾曲波帕的新晶型及其制备方法 - Google Patents

乙酰化艾曲波帕的新晶型及其制备方法 Download PDF

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WO2021078077A1
WO2021078077A1 PCT/CN2020/121711 CN2020121711W WO2021078077A1 WO 2021078077 A1 WO2021078077 A1 WO 2021078077A1 CN 2020121711 W CN2020121711 W CN 2020121711W WO 2021078077 A1 WO2021078077 A1 WO 2021078077A1
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crystal form
eltrombopag
acetylated
ray powder
pharmaceutical composition
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PCT/CN2020/121711
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English (en)
French (fr)
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张鹏伟
黄河
廖伟龙
李英龙
寇景平
林碧悦
陈勇
王仲清
罗忠华
黄芳芳
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广东东阳光药业有限公司
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Priority to CN202080060760.5A priority Critical patent/CN114341113A/zh
Publication of WO2021078077A1 publication Critical patent/WO2021078077A1/zh

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms

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  • the invention belongs to the field of medicinal chemistry, and relates to a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • Eltrombopag olamine is a thrombopoietin receptor agonist used to treat certain conditions that cause thrombocytopenia.
  • the structure of Eltrombopag diethanolamine salt is shown in the following formula (1).
  • Eltrombopag has a food effect
  • acetylated Eltrombopag is a prodrug of Eltrombopag and can be used to overcome the food effect of Eltrombopag.
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is conducive to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
  • the present invention obtains a new crystal form of the compound through a large number of experimental studies on the prodrug of Eltrombopag: acetylated Eltrombopag, which has good stability, good release in the animal body, and simple preparation process Easy to operate and other superior properties.
  • the invention provides a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • the crystal form has good stability and good release in animals, and the preparation method of the crystal form is simple and easy to operate.
  • the present invention provides a new crystal form of acetylated Eltrombopag: crystal form A.
  • the new crystal form was studied, and it was found that the crystal form A has good properties in terms of stability, release in vivo, etc., and can be used in the production of pharmaceutical preparations.
  • the crystal form A is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 4.6, 7.3, 9.2, 9.8, 16.8 and 25.9.
  • the differential scanning calorimetry (DSC) of the crystal form A has an endothermic peak at 168-170°C, and also has an endothermic peak at 210-212°C.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form A and pharmaceutically acceptable auxiliary materials or excipients.
  • the pharmaceutical composition contains acetylated Eltrombopag, wherein at least 80% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form A.
  • the pharmaceutical composition or preparation can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy, and patients with chronic hepatitis C that are ineffective in the treatment of glucocorticoid drugs or immunoglobulin.
  • ITP chronic idiopathic thrombocytopenic purpura
  • the present invention also provides a method for preparing the acetylated Eltrombopag crystal form A.
  • a method for preparing acetylated Eltrombopag crystal form A includes: mixing acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding the solution dropwise to the anti-solvent, stirring to precipitate crystals, collecting the crystals, and removing the solvent, The crystal form A is obtained.
  • the crystal form A provided by the present invention has good stability and is beneficial to operations in storage, transfer, and production processes, and can be released well in animals and can be used to prepare preparations.
  • an object of the present invention is to provide a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • the crystal form has good stability and release in animals, and the preparation method of the crystal form is simple and easy to operate.
  • the present invention provides a new crystal form of acetylated Eltrombopag: crystal form A.
  • the new crystal form of the present invention was studied, and it was found that the crystal form A has good properties in terms of stability, release in the body, etc., and can be used in the production of pharmaceutical preparations.
  • the crystal form A is characterized in that, by an X-ray powder diffractometer using Cu-K ⁇ radiation, it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 4.6, 7.3, 9.2, 9.8, 16.8 and 25.9.
  • the crystal form A has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 13.5, 14.7, 23.8, 24.4 , 25.4, 26.6 and 27.3.
  • the crystal form A has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 13.5, 21.2, 23.8, 24.4 , 25.4, 26.6 and 27.3.
  • the crystal form A has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 4.6, 7.3, 9.2, 9.8 , 13.5, 14.7, 16.8, 23.8, 24.4, 25.4, 25.9, 26.6 and 27.3.
  • the crystal form A has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 4.6, 7.3, 9.2, 9.8 , 13.5, 21.2, 16.8, 23.8, 24.4, 25.4, 25.9, 26.6 and 27.3.
  • the X-ray powder diffraction pattern of acetylated Eltrombopag Form A is shown in Figure 1, wherein the relative intensity of the peak at 4.6 degrees 2 ⁇ is greater than 70%, or greater than 80%, or More than 90%, or more than 99%.
  • the crystal form A has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.
  • the differential scanning calorimetry (DSC) of the crystalline form A has an endothermic peak at 168-170°C, and also has an endothermic peak at 210-212°C.
  • the crystalline form A has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.
  • the crystalline form A has a thermogravimetric analysis curve (TGA) showing that there is a weight loss between 30°C and 160°C, and the weight loss is about 1.03%.
  • TGA thermogravimetric analysis curve
  • the crystal form A has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.
  • TGA pattern thermogravimetric analysis curve
  • the acetylated Eltrombopag crystal form A has a purity of at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%.
  • the new acetylated eltrombopag crystal form of the present invention namely acetylated eltrombopag crystal form A, can be used to treat certain diseases that cause thrombocytopenia, such as glucocorticoid drugs and immunoglobulin that are ineffective. Or thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy, thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • ITP chronic idiopathic thrombocytopenic purpura
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form A and pharmaceutically acceptable excipients or excipients.
  • a therapeutically effective amount of acetylated Eltrombopag crystalline form A is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation.
  • the pharmaceutical composition or preparation may be well-known in the pharmaceutical field. Way to prepare.
  • the pharmaceutical composition or preparation can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy, and patients with chronic hepatitis C that are ineffective in the treatment of glucocorticoid drugs or immunoglobulin.
  • ITP chronic idiopathic thrombocytopenic purpura
  • a pharmaceutical composition contains acetylated Eltrombopag, wherein at least 80% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form A. In some embodiments, a pharmaceutical composition contains acetylated Eltrombopag, wherein at least 90% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form A. In some embodiments, a pharmaceutical composition contains acetylated Eltrombopag, wherein at least 95% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form A.
  • a pharmaceutical composition contains acetylated Eltrombopag, wherein at least 97% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form A. In some embodiments, a pharmaceutical composition contains acetylated Eltrombopag, wherein at least 99% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form A.
  • the content of the crystal form A is at least 0.1%-10% of the total weight of the composition. In some embodiments, in the pharmaceutical composition, the content of the crystal form A is at least 0.1%-1% of the total weight of the composition. In some embodiments, in the pharmaceutical composition, the content of the crystal form A is at least 1%-3% of the total weight of the composition. In some embodiments, in the pharmaceutical composition, the content of the crystal form A is at least 3%-5% of the total weight of the composition. In some embodiments, in the pharmaceutical composition, the content of the crystal form A is at least 5%-8% of the total weight of the composition. In some embodiments, in the pharmaceutical composition, the content of the crystal form A is at least 5%-10% of the total weight of the composition. In some embodiments, in the pharmaceutical composition, the content of the crystal form A is at least 1% or 5% of the total weight of the composition.
  • the pharmaceutical composition containing acetylated Eltrombopag crystal form A of the present invention can be used to prepare chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoid drugs, immunoglobulin treatment is invalid or after splenectomy ) Thrombocytopenia in patients, as well as thrombocytopenia in patients with chronic hepatitis C, and pharmaceutical preparations for severe aplastic anemia that do not respond to immunosuppressive therapy.
  • ITP chronic idiopathic thrombocytopenic purpura
  • the pharmaceutical composition of the present invention containing acetylated Eltrombopag crystal form A can be used to treat chronic idiopathic thrombocytopenic purpura (ITP ) Thrombocytopenia in patients, thrombocytopenia in patients with chronic hepatitis C, and methods for severe aplastic anemia that do not respond to immunosuppressive therapy.
  • ITP chronic idiopathic thrombocytopenic purpura
  • the crystal form A provided by the present invention has no patents or literature reports.
  • the inventors of the present invention have broken through this problem through research and found a new crystal form suitable for development.
  • the new crystal form has better stability and A more stable crystal form is of great significance for improving the quality of drugs.
  • the crystal form A provided by the present invention has good stability, is not easy to deliquesce under high humidity conditions, is convenient for long-term storage and placement of drugs, and can be released well in animals.
  • the crystal form provided by the present invention has good stability, significant process purification effect, can well avoid crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and drug efficacy, and has strong economic value.
  • the present invention proposes a method for preparing the aforementioned acetylated Eltrombopag crystal form A.
  • a method for preparing acetylated Eltrombopag crystal form A includes: mixing acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding the solution to the anti-solvent, stirring to precipitate crystals, collecting the crystals, and removing the solvent to obtain Form A.
  • a method for preparing acetylated Eltrombopag crystal form A includes: mixing acetylated Eltrombopag with tetrahydrofuran, and after the dissolution is complete, adding the solution dropwise to a single anti-solvent to precipitate crystals, The crystals are collected and the solvent is removed to obtain crystal form A.
  • the anti-solvent is at least one of ethyl formate, butyl formate, ethyl acetate, dimethyl carbonate, acetonitrile, and toluene.
  • mass-volume ratio of the acetylated Eltrombopag to tetrahydrofuran is 1:3 to 1:10; more preferably 1:4 to 1 :6.
  • the “crystal form” of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention
  • the “crystal form” of should be understood as falling within the protection scope of the present invention.
  • the present invention tests various parameters on a sample containing a certain "crystal form” that is substantially pure and carries out the determination of the crystal form. Characterization and identification.
  • the differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different, and the experimental error or the value of the difference may be less than or equal to 10°C, or less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than It is equal to 1°C, so the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the mass unit is grams and the volume unit is milliliters.
  • RH means relative humidity
  • Figure 1 X-ray powder diffraction (XRPD) pattern of acetylated Eltrombopag Form A.
  • FIG. 1 Differential scanning calorimetry (DSC) graph of acetylated Eltrombopag Form A.
  • FIG. 3 Thermogravimetric analysis (TGA) graph of acetylated Eltrombopag Form A.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • AUC is the abbreviation of "Area under curve", which means the area under the curve.
  • Cmax is the abbreviation of "Concentration”, which means the peak concentration.
  • SD represents the coefficient of variation.
  • the obtained crystal was detected by XPRD and confirmed to be acetylated Eltrombopag Form A; its X-ray powder diffraction pattern was basically consistent with Figure 1, its DSC spectrum was basically consistent with Figure 2, and its TGA spectrum was basically consistent with Figure 3.
  • Example 4 Beagle dog pharmacokinetic test of acetylated Eltrombopag crystal form A
  • test instrument In the present invention, the test instrument and method
  • the X-ray powder diffraction (XRPD) pattern was collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of the X-ray confinement on the sample, is 10mm. Using ⁇ - ⁇ Continuous scanning mode, to obtain an effective 2 ⁇ range of 3° ⁇ 40°.
  • the DSC measurement was performed in TA Instruments TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between room temperature and 300°C at a heating rate of 10°C/min. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA Universal Analysis.
  • the TGA measurement was performed in TA Instruments TM model Q500.
  • the operation step is to peel the empty crucible, take about 10 mg of solid sample, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/min between room temperature and 300°C under nitrogen purge, and record the spectrum.

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Abstract

乙酰化艾曲波帕的新晶型及其制备方法，属于药物化学领域。所述晶型具有较好的稳定性有利于储存、转移、生产工艺中操作，其能够在动物体内能良好释放，可以用于制备成制剂。

Description

乙酰化艾曲波帕的新晶型及其制备方法 技术领域
本发明属于药物化学领域，涉及乙酰化艾曲波帕的新晶型及其制备方法。
背景技术
艾曲波帕二乙醇胺盐(Eltrombopag olamine)，CAS：496775-62-3，是一种血小板生成素受体激动剂，用于治疗导致血小板减少的某些病症。艾曲波帕二乙醇胺盐结构如下式(1)所示。
Figure PCTCN2020121711-appb-000001
乙酰化艾曲波帕，结构如下式(2)所示。
Figure PCTCN2020121711-appb-000002
艾曲波帕具有食物效应，乙酰化艾曲波帕是艾曲波帕的前药，可用于克服艾曲波帕的食物效应。
药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一药物的不同晶型在外观、流动性、溶解度、储存稳定性、生物利用度等理化性质方面可能会有显著不同，可能存在极大差异，会对药物的储存转移、应用、稳定性、疗效等产生不同的影响；为了得到有效的利于生产或利于药物制剂的晶型，需要对药物的结晶行为进行全面的考察，以得到满足生产要求的晶型。
本发明通过对艾曲波帕的前药：乙酰化艾曲波帕进行大量实验研究，得到了该化合物的新晶型，该新晶型具有稳定性好，在动物体内释放良好，制备工艺简单易操作等优越性质。
发明内容
发明概述
本发明提供了一种乙酰化艾曲波帕新晶型及其制备方法，该晶型具有良好的稳定性及在动物体内释放良好，该晶型的制备方法简单易操作。
根据本发明的一个方面，本发明提供了乙酰化艾曲波帕的新晶型：晶型A。
对所述新晶型进行研究，发现晶型A在稳定性、体内释放等方面具有良好的性能，可用于制备药物制剂生产中。
所述晶型A的特征在于，通过使用Cu-Kα辐射的X射线粉末衍射仪，其在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：4.6,7.3,9.2,9.8,16.8和25.9。
所述晶型A的差示扫描量热曲线(DSC)在168-170℃具有吸热峰，在210-212℃也具有吸热峰。
本发明的还提供了包含治疗有效量的乙酰化艾曲波帕晶型A和药学上可接受的辅料或赋形剂的药物组合物。所述药物组合物，含有乙酰化艾曲波帕，其中至少80％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型A。
所述药物组合物或制剂可以用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血等疾病。
本发明还提出了一种制备所述的乙酰化艾曲波帕晶型A的方法。
一种制备乙酰化艾曲波帕晶型A的方法包括：将乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将溶液滴加到反溶剂中，搅拌析出晶体，收集晶体，除去溶剂，得到晶型A。
本发明提供的晶型A，具有较好的稳定性有利于储存、转移、生产工艺中操作，其在动物体内能够良好释放，可以用于制备成制剂。
发明详述
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提供乙酰化艾曲波帕新晶型及其制备方法，该晶型具有良好的稳定性及在动物体内释放良好，该晶型的制备方法简单易操作。
根据本发明的一个方面，本发明提供了乙酰化艾曲波帕的新晶型：晶型A。
对本发明所述新晶型进行研究，发现晶型A在稳定性、体内释放等方面具有良好的性能，可用于制备药物制剂生产中。
晶型A的特征在于，通过使用Cu-Kα辐射的X射线粉末衍射仪，其在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：4.6,7.3,9.2,9.8,16.8和25.9。
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型A在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：13.5,14.7,23.8,24.4,25.4,26.6和27.3。
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型A在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：13.5,21.2,23.8,24.4,25.4,26.6和27.3。
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型A在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：4.6,7.3,9.2,9.8,13.5,14.7,16.8,23.8,24.4,25.4,25.9,26.6和27.3。
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型A在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：4.6,7.3,9.2,9.8,13.5,21.2,16.8,23.8,24.4,25.4,25.9,26.6和27.3。
在一些实施例中，乙酰化艾曲波帕晶型A的X-射线粉末衍射图如图1所示，其中，在2θ为4.6度的峰的相对强度大于70％，或大于80％，或大于90％，或大于99％。
在一些实施例中，所述晶型A具有基本上如图1所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施例中，所述晶型A的差示扫描量热曲线(DSC)在168-170℃具有吸热峰，在210-212℃也具有吸热峰。
在一些实施例中，所述晶型A具有如图2所示的差示扫描量热曲线(DSC图谱)。
在一些实施例中，所述晶型A具有热重分析曲线(TGA)显示在30℃-160℃间有失重，失重量约为1.03％。
在一些实施例中，所述晶型A具有基本上如图3所示的热重分析曲线(TGA图谱)。
所述乙酰化艾曲波帕晶型A，晶型A的纯度至少70％，或至少80％，或至少90％，或至少95％，或至少99％。
本发明所述的乙酰化艾曲波帕新晶型，即乙酰化艾曲波帕晶型A，可用于治疗导致血小板减少的某些病症，如经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血等症状。
本发明的另一个目的在于提供包含治疗有效量的乙酰化艾曲波帕晶型A和药学上可接受的辅料或赋形剂的药物组合物。一般是将治疗有效量的乙酰化艾曲波帕晶型A与一种或多种药用辅料混合或接触制成药物组合物或制剂，该药物组合物或制剂可以是以制药领域中熟知的方式进行制备的。所述药物组合物或制剂可以用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血等疾病。
在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，其中至少80％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型A。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，其中至少90％的乙 酰化艾曲波帕为所述乙酰化艾曲波帕晶型A。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，其中至少95％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型A。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，其中至少97％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型A。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，其中至少99％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型A。
所述药物组合物中，所述晶型A含量至少为组合物的总重量的0.1％-10％。在一些实施方式中，所述药物组合物中，所述晶型A含量至少为组合物的总重量的0.1％-1％。在一些实施方式中，所述药物组合物中，所述晶型A含量至少为组合物的总重量的1％-3％。在一些实施方式中，所述药物组合物中，所述晶型A含量至少为组合物的总重量的3％-5％。在一些实施方式中，所述药物组合物中，所述晶型A含量至少为组合物的总重量的5％-8％。在一些实施方式中，所述药物组合物中，所述晶型A含量至少为组合物的总重量的5％-10％。在一些实施方式中，所述药物组合物中，所述晶型A含量至少为组合物的总重量的1％或5％。
本发明所述的含有乙酰化艾曲波帕晶型A的药物组合物，可用于制备经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血的药物制剂。本发明所述的含有乙酰化艾曲波帕晶型A的药物组合物，可用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血的方法中。
本发明的有益效果为：
本发明提供的晶型A，目前尚无专利或文献报道，本发明的发明人经过研究，突破了这一难题，找到了适合开发的新晶型，该新晶型具有稳定性更好，而更稳定的晶型对于提高药物质量具有重要意义。
本发明提供的晶型A，具有良好的稳定性，不易在高湿条件下潮解，方便药物长期贮存放置，在动物体内也能很好的释放。本发明提供的晶型稳定性好，工艺提纯效果显著，能很好的避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变，具有很强的经济价值。
根据本发明的第二方面，本发明提出了一种制备前面所述的乙酰化艾曲波帕晶型A的方法。
一种制备乙酰化艾曲波帕晶型A的方法包括：将乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将溶液加入到反溶剂中，搅拌析出晶体，收集晶体，除去溶剂，得到晶型A。在一些实施方式中，一种制备乙酰化艾曲波帕晶型A的方法包括：乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将溶液滴加到单一的反溶剂中，析出晶体，收集晶体，除去溶剂，得到晶型A。
所述反溶剂为甲酸乙酯、甲酸丁酯、乙酸乙酯、碳酸二甲酯、乙腈、甲苯中的至少一种。质量以克(g)计算，溶剂体积以毫升(mL)计算时，所述乙酰化艾曲波帕与四氢呋喃的质量体积比为1:3～1:10；更优选地为1:4～1:6。
本发明所述“晶型”可以以0.0001％-100％存在于样品中，因此，只要样品中含有即使痕量例如大于0.0001％，大于0.001％，大于0.001％或者大于0.01％的本发明所述的“晶型”都应当理解为落入本发明的保护范围内。为把本发明所述的“晶型”的各种参数描述得更清楚，本发明通过对含基本上纯净的某种“晶型”时的样品进行测试各种参数并对所述晶型进行表征和鉴别。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。基于公开的数值，每一个数字的数值有可能会出现1％，2％，或5％等差异。
所述晶型的差示扫描量热测定(DSC)有实验误差，并受样品的干燥程度有轻微影响，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于10℃，或小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
在本发明中，计算质量体积比时，质量单位为克，体积单位为毫升。
在本发明中“RH”为相对湿度。
附图说明
图1：乙酰化艾曲波帕的晶型A的X-射线粉末衍射(XRPD)图。
图2：乙酰化艾曲波帕的晶型A的差示扫描量热(DSC)曲线图。
图3：乙酰化艾曲波帕的晶型A的热重分析(TGA)曲线图。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
为了使本领域的技术人员更好的理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
本发明中，AUC是“Area under curve”的缩写，表示曲线下面积。
本发明中，Cmax是“Concentration”的缩写，表示达峰浓度。
本发明中，SD表示变异系数。
实施例1乙酰化艾曲波帕晶型A的制备方法
将10g的乙酰化艾曲波帕加入到四氢呋喃(30ml)中，加热至40℃搅拌得到澄清溶液后，再将该溶液滴加至120mL甲酸乙酯中进行溶析结晶反应。搅拌析出黄色固态产品，搅拌12小时。抽滤并置于干燥箱内50℃真空干燥至恒重，得到黄色粉末5.65g；经XPRD检测，确认为乙酰化艾曲波帕晶型A；其X射线粉 末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。
实施例2乙酰化艾曲波帕晶型A的制备方法
将2.4g的乙酰化艾曲波帕加入到四氢呋喃(12ml)中，加热至40℃搅拌得到澄清溶液后，再将该溶液滴加至60mL甲酸乙酯中进行溶析结晶反应。搅拌析出黄色固态产品，搅拌3小时。抽滤并置于干燥箱内50℃真空干燥至恒重，得到黄色粉末1.46g。所得晶体经XPRD检测，确认为乙酰化艾曲波帕晶型A；其X射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。
实施例3乙酰化艾曲波帕晶型A的稳定性实验
取乙酰化艾曲波帕晶型A样品敞口分别放置于60℃(温度偏差±2℃)/75％相对湿度、25℃/60％相对湿度/4500勒克斯、25℃/92.5％相对湿度条件，10天后取样测XRPD，实验结果如下表1。
表1晶型A稳定性研究
Figure PCTCN2020121711-appb-000003
上述结果显示：60℃(温度偏差±2℃)/75％相对湿度、25℃/60％相对湿度/4500勒克斯、25℃/92.5％相对湿度条件分别放置10天后，晶型不变，稳定性良好。
实施例4乙酰化艾曲波帕晶型A的比格犬药代动力学试验
取晶型A少量样品，与环糊精，微晶纤维素，甘露醇、聚维酮、羧甲基淀粉钠、硬脂酸镁混合后，制成胶囊。采用胶囊这种形式给试验动物给药。在试验时间点采取动物血样分析血药浓度，完成药代动力学试验，实验结果如下表2。
表2晶型A药代动力学实验结果
Figure PCTCN2020121711-appb-000004
上述结果显示：乙酰化艾曲波帕可以在动物体内达成释放。且乙酰化艾曲波帕晶型A体内吸收与艾曲 波帕二乙醇胺盐相比，Mean结果相近，SD值更小，说明本发明的晶型A与艾曲波帕乙醇胺盐在动物体内释放接近，但变异系列更小，误差更小。
本发明中，测试仪器及方法
(1)粉末X-射线衍射(XRPD)研究
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα1
Figure PCTCN2020121711-appb-000005
1.540598；Kα2
Figure PCTCN2020121711-appb-000006
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm.采用θ-θ连续扫描模式，得到3°～40°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0168°的扫描步长在3～40°2θ范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。
采用上述条件，分别对实施例制备的晶型进行XRPD检测。
(2)差示扫描量热法(DSC)分析
DSC测量在TA Instruments TM型号Q2000中用密封盘装置进行。将样品(约1～3mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在室温到300℃之间以10℃/min的加热速率收集数据。以吸热峰向下进行绘图,数据用TA Universal Analysis分析和展示。
(3)热重分析(TGA)分析
TGA测量在TA Instruments TM型号Q500中进行。操作步骤为空坩埚去皮，取固体样品约10mg、于去皮空坩埚内，铺匀即可。待仪器运行稳定后，在氮气吹扫下，室温到300℃之间以10℃/min的加热速率收集数据，记录图谱。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (11)

  1. 乙酰化艾曲波帕晶型A，其特征在于，使用Cu-Kα辐射，以2θ(误差±0.2度)表示的X射线粉末衍射光谱，其中，晶型A的X-射线粉末衍射图中在2θ为4.6,7.3,9.2,9.8,16.8和25.9度的位置有衍射峰。
  2. 权利要求1所述的晶型，其中，晶型A的X-射线粉末衍射图中在2θ为13.5,14.7,23.8,24.4,25.4,26.6和27.3度的位置有衍射峰；或晶型A的X-射线粉末衍射图中在2θ为4.6,7.3,9.2,9.8,13.5,14.7,16.8,23.8,24.4,25.4,25.9,26.6和27.3度的位置有衍射峰；或晶型A的X-射线粉末衍射图中在2θ为13.5,21.2,23.8,24.4,25.4,26.6和27.3度的位置有衍射峰；或晶型A的X-射线粉末衍射图中在2θ为4.6,7.3,9.2,9.8,13.5,21.2,16.8,23.8,24.4,25.4,25.9,26.6和27.3度的位置有衍射峰；或晶型A的X-射线粉末衍射图如图1所示。
  3. 权利要求1所述的乙酰化艾曲波帕晶型A，其中晶型A的热重分析曲线显示在30℃-160℃间有失重。
  4. 权利要求1所述的乙酰化艾曲波帕晶型A，其中晶型A的热重分析曲线显示在30℃-160℃间有失重，失重量约为1.03％。
  5. 权利要求1所述的乙酰化艾曲波帕晶型A，其中晶型A的纯度至少70％。
  6. 一种制备权利要求1-5任一所述的乙酰化艾曲波帕晶型A的方法，包括：乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将溶液滴加到反溶剂中，搅拌析出晶体，收集晶体，除去溶剂，得到晶型A；其中，所述反溶剂为甲酸乙酯、甲酸丁酯、乙酸乙酯、碳酸二甲酯、乙腈、甲苯中的至少一种。
  7. 根据权利要求6所述的方法，其特征在于所述乙酰化艾曲波帕与四氢呋喃的质量体积比为1:3～1:10。
  8. 一种药物组合物，包含治疗有效量的权利要求1-5任一所述的晶型A及药学上可接受的辅料。
  9. 权利要求8所述的药物组合物，其中，至少80％的乙酰化艾曲波帕为晶型A。
  10. 权利要求8或9所述的药物组合物，其特征在于，所述晶型A含量至少为组合物的总重量的0.1％-10％。
  11. 权利要求1-5任一所述的晶型A或权利要求8-10任一所述的药物组合物在制备治疗血小板减少症的药物中的用途。
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