WO2021204188A1 - 优替德隆半水合物单晶及其制备方法与应用 - Google Patents

优替德隆半水合物单晶及其制备方法与应用 Download PDF

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WO2021204188A1
WO2021204188A1 PCT/CN2021/085903 CN2021085903W WO2021204188A1 WO 2021204188 A1 WO2021204188 A1 WO 2021204188A1 CN 2021085903 W CN2021085903 W CN 2021085903W WO 2021204188 A1 WO2021204188 A1 WO 2021204188A1
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crystal
utidelone
hemihydrate
pharmaceutical composition
preparation
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PCT/CN2021/085903
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English (en)
French (fr)
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唐莉
孔日祥
邱荣国
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北京华昊中天生物医药股份有限公司
成都华昊中天药业有限公司
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Priority to CN202180006310.2A priority Critical patent/CN114727994B/zh
Priority to JP2022538911A priority patent/JP2023509871A/ja
Priority to EP21783766.5A priority patent/EP4062912B1/en
Priority to PL21783766.5T priority patent/PL4062912T3/pl
Priority to US17/757,979 priority patent/US20230041956A1/en
Publication of WO2021204188A1 publication Critical patent/WO2021204188A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to 4S,7R,8S,9S,13Z,16S-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[E-1-methyl-2-(2 -Methyl-1,3-thiazol-4-yl)-prop1-en-2-yl]-hexadecyloxacyclo-13-ene-2,6-ketolactone (ie Utidrolone, utidelone) hemihydrate crystals, preparation method thereof, and use for preparing pharmaceutical compositions, especially for preparing anti-tumor drugs.
  • Utidrolone is an epothilone compound.
  • Epothilone is a 16-membered macrolide natural cytotoxic compound produced by the metabolism of microbial myxobacteria. It has a similar mechanism of action with paclitaxel, which has obvious anti-tumor activity. They induce tubulin polymerization to form an ultra-stable state. , Inhibit the depolymerization of microtubules, hinder mitosis, prevent tumor cell reproduction, and lead to apoptosis. Epothilone shows strong anti-tumor activity in p-glycoprotein-expressing multidrug resistant tumor cell lines, and has better water solubility than paclitaxel. Epothilone is superior to paclitaxel in many aspects and is considered to be a newer product of paclitaxel.
  • Utidrolone is a member of the epothilone family, and the compound is chemically named 4S,7R,8S,9S,13Z,16S-4,8-dihydroxy-5,5,7,9,13-pentamethyl
  • Base-16-[E-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)-prop1-en-2-yl]-hexadecyloxane-13- En-2,6-ketolactone has the following structural formula:
  • Utidelon can be used to treat gastrointestinal tumors such as breast cancer, lung cancer, bowel cancer and gastric cancer, gynecological tumors such as ovarian cancer and cervical cancer, head and neck squamous cell carcinoma, esophageal cancer, pancreatic cancer, cholangiocarcinoma, skin cancer, and brain cancer And solid tumors such as liver cancer.
  • gastrointestinal tumors such as breast cancer, lung cancer, bowel cancer and gastric cancer
  • gynecological tumors such as ovarian cancer and cervical cancer, head and neck squamous cell carcinoma, esophageal cancer, pancreatic cancer, cholangiocarcinoma, skin cancer, and brain cancer
  • solid tumors such as liver cancer.
  • Different crystal forms of the same drug may have significant differences in hygroscopicity, stability, and bioavailability, which may affect the efficacy of the drug. Carrying out crystal form research is very important for the development of the pharmaceutical composition application of Utidrolone.
  • a crystal form of Utidrolone with extremely high stability is provided.
  • the present invention provides a single crystal of Utidrolone, which is a hemihydrate crystal form (hemihydrate crystal, crystal form A).
  • the X-ray diffraction pattern is shown in Figure 1, and the DSC is shown in Figure 6, and the single crystal diffraction The figure is shown in Figure 8.
  • the present invention provides a method for preparing Utidrolone hemihydrate crystals.
  • the preparation method includes dissolving Utidelone in a solvent, standing at 2-25° C. or stirring, and then crystallizing.
  • the solvent is a mixed liquid of n-heptane and tetrahydrofuran or a mixed liquid of dichloromethane and n-heptane. High-purity single crystals can be obtained by this mixed solvent.
  • the preparation method is described as follows: Weigh 3.0 mg of the starting sample of Utidrolone compound into a 3 mL glass bottle, add 0.2 mL of the mixed solvent of the system listed in Table 1 below, and vortex After proper sonication, it was observed that the solid sample was completely dissolved. Subsequently, the above 3mL glass bottle was capped and sealed, and allowed to stand at room temperature. After 5 days, white needle-like solids or flake crystal samples were precipitated in the system. According to XRPD detection, the crystal form of the compound prepared by the preparation method is a hemihydrate crystal form, that is, a hemihydrate crystal form of 4 Utidrolone molecules containing 2 water molecules.
  • the X-ray powder diffraction pattern of the crystal form A is basically the same as that of FIG. 1.
  • the crystalline euteideron hemihydrate of the present invention is a single long flaky crystal.
  • the single crystal X-ray diffraction characterization results show that the crystal belongs to the triclinic crystal system, the P1 space group, and its single crystal.
  • the experimental details of the crystalline structure, resultant solution and refinement parameters of Utidrolone hemihydrate are listed in Table 2.
  • the crystal structure is an asymmetric structural unit, and the asymmetric structural unit of the crystal is composed of four Utidelone molecules (crystallographically independent) and two water molecules, which means that the crystal is a hemihydrate of the compound Utidelone Things.
  • the single crystal structure data successfully confirmed the stereochemical structure of the compound Utidrolone.
  • the absolute configuration of the chiral center in the molecule is ⁇ C3(S), C6(R), C7(S), C8(S), C16 (S).
  • the DSC (differential scanning calorimetry) study of the crystallinity of Utide shows that hemihydrate has two characteristic signals in DSC.
  • the first relatively broad endothermic signal at 50-110°C is due to Utide Polyuron hemihydrate is dehydrated to form an anhydrous form.
  • the second relatively sharp endothermic peak at 122 ⁇ 3°C is due to the melting of the substance ( Figure 4).
  • the anhydrous crystallinity of Utidelone has only one characteristic signal in DSC, which is a relatively sharp endothermic peak at 122 ⁇ 3°C due to the melting of the substance (Figure 5).
  • the present invention relates to the crystallinity of Utidelone, which is characterized by infrared (IR) spectroscopy.
  • the measurement is carried out with 10-20 mg of Utidelone hemihydrate in 300 mg of potassium bromide.
  • the crystal form of Utidelone hemihydrate has absorption bands at wavenumber IR(KBr)vmax 3506, 2968, 2938, 2901, 1726, 1680, 1456, 1246, 971 cm -1.
  • the semi-hydrated crystal form of Utidrolone provided by the present invention has good high-temperature stability and high-humidity stability, and is beneficial to maintain its specific physical properties under storage and production conditions.
  • Crystalline Utidelone has stronger high-humidity stability than powdered Utidelone. Under high-humidity conditions, the semi-hydrated crystals are very stable and the water content does not change significantly. Moreover, the crystallinity Utidrolone also has stronger high temperature stability. It can be stored at 60°C for more than 1 year, and stored at 40°C for more than 3 years without material changes, and it is stable for long-term storage at high temperatures.
  • Crystal A is determined to be the most stable crystal, which is stable for a long time under normal storage conditions and is chemically stable.
  • the present invention provides the use of at least one crystal form of Utidelone in a pharmaceutical composition.
  • another aspect of the present invention relates to the use of Utidrolone to prepare a pharmaceutical composition for the treatment of diseases, the pharmaceutical composition comprising crystalline Utidrolone hemihydrate Crystals, the present invention further provides the pharmaceutical composition including a parenteral injection combination, an oral preparation: a capsule or a tablet pharmaceutical combination, including 10-50 mg of the compound in polymorphic form.
  • the pharmaceutical composition of the present invention is provided in a polymorphic form of the crystalline Utidelone in an effective amount for mammals, especially for humans. It is preferably used to prepare a pharmaceutical composition for the treatment of cancer.
  • Figure 1 is the X powder diffraction pattern of Utidelone hemihydrate crystal
  • Figure 2 is the X powder diffraction pattern of the anhydrate crystal of Utidrolone
  • Figure 3 is an X powder diffraction spectrum of a mixed crystal of Utidrolone
  • Figure 4 is a DSC chart of crystalline Utidelone hemihydrate
  • Figure 5 is a DSC chart of crystalline Utidelone anhydrate
  • Figure 6 is the IR absorption spectrum of Utidelone hemihydrate
  • Figure 7 is the IR absorption spectrum of Utidelone anhydrate crystals
  • Figure 8 Single crystal diffraction pattern of Utidrolone compound.
  • the resulting crystal is 0.5 hemihydrate crystal (A), which is a single crystal lattice.
  • the diffraction pattern of Utidelone single crystal is shown in Fig. 8.
  • Table 2 Test data and structure refinement parameters for crystal structure analysis of Utidelone hemihydrate
  • Stability test The stability test of semi-hydrated crystals is carried out under the following conditions:
  • Storage condition 1 2 ⁇ 25°C, stored in a sealed state for more than 3 years, confirmed by NMR, HPLC, X-ray powder diffraction and infrared spectroscopy, the semi-hydrated crystal remains stable (the content is unchanged, there is no degradation of impurities, no appearance And changes in physical and chemical properties).
  • Storage condition 2 25°C, 60% ⁇ 10%RH, unsealed storage for more than 3 days. After the sample is kept at 25°C for 1 year, the performance is confirmed by NMR, HPLC, X-ray powder diffraction and infrared spectroscopy. Stable and consistent (no change in content, no degradation of impurities, no changes in appearance and physical and chemical properties).
  • Storage condition 3 Stored in a sealed state at 40°C for more than 2 years. It is confirmed by NMR, HPLC, X-ray powder diffraction and infrared spectroscopy that the product remains stable and consistent (the content has no change, no degradation impurities, no appearance and physical and chemical properties) Changes).
  • Storage condition 4 Stored at 60°C for more than 1 year, confirmed by NMR, HPLC, X-ray powder diffraction and infrared spectroscopy, the products are stable and consistent (no content change, no degradation of impurities, no changes in appearance and physical and chemical properties) .
  • the semi-hydrated crystal sample obtained in Example 1 was placed under the conditions of relative humidity of 90% ⁇ 5% for 10 days, and samples were taken on the 5th and 10th days.
  • the sample was stable: there was no significant change in content, no degradation of impurities, no appearance and The change of physical and chemical properties, the moisture content is basically unchanged.
  • the anhydrous crystal samples were placed under the conditions of 90% ⁇ 5% relative humidity for 10 days, and samples were taken on the 5th and 10th days. The moisture content increased and the moisture absorption was obvious.
  • the hemihydrate crystal sample obtained in Example 1 was placed in a light box and placed for 10 days under the condition of an illuminance of 4500lx ⁇ 500lx.
  • the sample is stable: there is no obvious change in the content, no degradation of impurities, no changes in appearance and physical and chemical properties, and the moisture content is basically unchanged.
  • Example 5 The solubility test of Utidrolone hemihydrate crystal showed good solubility.
  • the hemihydrate crystal sample obtained in Example 1 was placed in a 0.1N hydrochloric acid solution, and the sample was stable: no obvious degradation impurities were generated. Solubility>5mg/ml.
  • the self-emulsifying solution has good stability, no obvious degradation impurities are observed, and it can be completely dissolved In 100ml of water, the solubility is good, and no solids will precipitate within 1 hour.
  • crystalline Utidelone composition can be used to prepare a pharmaceutical composition for treating solid tumors such as breast cancer, intestinal cancer, liver cancer, gastric cancer, and lung cancer, and has excellent curative effect.
  • MRT was 4.5 ⁇ 0.8h and 5.1 ⁇ 0.7h
  • plasma clearance rate CL is 9.2 ⁇ 2.7L/h/m2 and 8.9 ⁇ 3.9L/h/m2, respectively
  • apparent volume of distribution is 114.0 ⁇ 35.2L/m2 and 109.1 ⁇ 62.6L/m2, respectively.

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Abstract

优替德隆的多晶型，具体涉及优替德隆的半水合晶型(A)及其制备方法以及使用结晶性优替德隆用于制备药物组合物的应用，特别是用于制备抑制哺乳动物尤其是人类肿瘤生长、治疗实体瘤的药物组合物的应用。提供的晶型稳定、耐受高温和高湿且制备方法多样简单，并适合新药产业化生产。

Description

优替德隆半水合物单晶及其制备方法与应用 技术领域
本发明涉及4S,7R,8S,9S,13Z,16S-4,8-二羟基-5,5,7,9,13-五甲基-16-[E-1-甲基-2-(2-甲基-1,3-噻唑-4-基)-丙1-烯-2-基]-十六烷氧杂环-13-烯-2,6-酮内酯(即优替德隆，utidelone)的半水合晶体及其制备方法以及用于制备药物组合物的用途，特别是用于制备抗肿瘤药物的用途。
技术背景
优替德隆为埃坡霉素(epothilone)类化合物。埃坡霉素是由微生物粘细菌代谢产生的一类16元大环内酯类天然细胞毒化合物，与有明显抗肿瘤活性的紫杉醇具有相似的作用机制，它们诱导微管蛋白聚合形成超稳定态，抑制微管解聚，阻碍有丝分裂，阻止肿瘤细胞繁殖，进而导致细胞凋亡。埃坡霉素在p-糖蛋白表达型的多药耐药性肿瘤细胞系中显示很强的抗肿瘤活性，而且比紫杉醇有更好的水溶性。埃博霉素在许多方面优于紫杉醇，被认为是紫杉醇的更新换代产品。
优替德隆作为埃博霉素家族的一员，该化合物化学命名为4S,7R,8S,9S,13Z,16S-4,8-二羟基-5,5,7,9,13-五甲基-16-[E-1-甲基-2-(2-甲基-1,3-噻唑-4-基)-丙1-烯-2-基]-十六烷氧杂环-13-烯-2,6-酮内酯，具有如下结构式：
Figure PCTCN2021085903-appb-000001
优替德隆可用于治疗乳腺癌、肺癌、肠癌和胃癌等消化道肿瘤、卵巢癌和宫颈癌等妇科肿瘤、头颈部鳞癌、食管癌、胰腺癌、胆管癌、皮肤癌、脑癌以及肝癌等实体瘤。同一药物不同的晶型，其吸湿性、稳定性以及生物利用度等方面可能会存在明显差异，从而影响药物的疗效。开展晶型研究，对开发优替德隆的药物组合物应用至关重要。迄今为止，未有优替德隆相关晶型报道。
发明内容
本发明在一方面，提供了优替德隆的一种稳定性极高的晶体晶型。本发明提供了优替德隆的一种单晶，其为半水合物的晶型(半水合物晶体，晶型A)，X-ray衍射图谱见图1，DSC见图6，单晶衍射图见图8。
本发明在另一方面提供了优替德隆半水合物晶体的制备方法。该制备方法包括将优替德隆溶解在溶剂中，置于2-25℃静置或搅拌后结晶。所述溶剂为正庚烷和四氢呋喃的混合液或二氯甲烷和正庚烷的混合液。通过该混合溶剂可获得高纯度的单晶。
根据本发明的一个具体实施方式，将制备方法说明如下：称取3.0mg优替德隆化合物起始样品置于3mL玻璃瓶内，加入0.2mL下表1列出的体系的混合溶剂，涡旋并适当超声后，观察到固体样品完全溶解。随后将上述3mL玻璃瓶加盖密封，于室温下静置。5天后体系中均析出白色针状 固体、或片状晶体样品。经XRPD检测，通过该制备方法下制备的化合物晶型为半水合物晶型，即4个优替德隆分子含2个水分子的半水合化合物晶型。所述的晶型A，其X-射线粉末衍射图基本与图1一致。通过X衍射结构分析，本发明的结晶性优替德隆半水合物为单一的长片状晶体，单晶X-射线衍射表征结果显示：该晶体属三斜晶系，P1空间群，其单胞参数为：{
Figure PCTCN2021085903-appb-000002
α＝81.3294(4)o,β＝86.3641(4)o,γ＝86.6019(5)o,
Figure PCTCN2021085903-appb-000003
}，Z值为4。优替德隆半水合物的结晶结构、结果解法和精修参数的试验细节列于表2。
所述晶体结构为不对称结构单元，该晶体的不对称结构单元由四个优替德隆分子(晶体学独立)和两个水分子构成，即表明该晶体为化合物优替德隆的半水合物。
单晶结构数据成功确证了化合物优替德隆的立体化学结构，其分子中手性中心的绝对构型为{C3(S),C6(R),C7(S),C8(S),C16(S)。
结晶性优替德隆通过DSC(示差扫描量热法)研究表明，半水合物在DSC有2个特征信号，第一个在50-110℃间的相对宽广的吸热信号是由于优替德隆半水合物脱水形成无水形式。第二个在122±3℃间的相对尖锐的吸热峰是由于物质的融化(图4)。而无水合物结晶性优替德隆在DSC只有1个特征信号，为在122±3℃间的相对尖锐的吸热峰由于物质的融化(图5)。
本发明是关于结晶性优替德隆，通过红外(IR)光谱表征。测量采用10-20mg优替德隆半水合物在300mg溴化钾中进行。根据图6的IR光谱表征，半水合物优替德隆晶型在波数IR(KBr)vmax 3506，2968，2938， 2901，1726，1680，1456，1246，971cm -1处具有吸收带。
本发明提供的优替德隆半水合晶型，具有良好的高温稳定性和高湿稳定性，有益于在存储和生产条件下保持其特定的物理性质。
结晶性优替德隆较粉末性优替德隆具有更强的高湿稳定性，在高湿条件下，半水合晶体非常稳定，含水量无明显变化。且结晶性优替德隆也具有更强的高温稳定性，60℃保存1年以上，40℃保存3年以上都不发生物质变化，高温下长期保存稳定。
晶体A被确定为最稳定的晶体，该晶体在正常储备条件下能长期稳定，且化学上稳定。
本发明在另一方面提供了至少一种优替德隆晶型在药物组合物中的应用。
基于优替德隆的抗肿瘤药物性能，本发明的另一方面是有关是使用优替德隆制备治疗疾病用的药物组合物，所述药物组合物包括结晶性优替德隆的半水合物晶体，本发明进一步提供了所述药物组合物在包括一种非肠道给药的注射液组合，一种口服制剂：胶囊或片剂的药物组合，包括10-50mg的多晶型形式化合物。提供所述的对哺乳动物，尤其是对人类有治疗效果的有效量的本发明药物组合物，结晶性优替德隆的多晶型形式。优选用于制备治疗癌症的药物组合物。
附图说明
图1为优替德隆半水合物晶体的X粉末衍射图谱；
图2为优替德隆的无水合物晶体的X粉末衍射图谱；
图3为优替德隆的混合晶体的X粉末衍射谱图；
图4为结晶性优替德隆半水合物的DSC图；
图5为结晶性优替德隆无水合物的DSC图；
图6是优替德隆半水合物的IR吸收图谱；
图7是优替德隆无水合物晶体的IR吸收图谱；
图8优替德隆化合物的单晶衍射图。
具体实施方式
实施例
以下实施例用于进一步详细说明本发明的结晶性优替德隆及其制备方法，本发明内容并不局限于这些实施例。
【实施例1】
将100mg优替德隆置于一100ml玻璃瓶内，加入6ml四氢呋喃/正庚烷(1:5，v/v)的混合溶剂，涡旋、超声、混合均匀，观察样品完全溶解。然后将该玻璃瓶加盖密封，于室温下放置，5天后可以观察到长片状单晶样品，收集晶体，然后通过真空抽滤，过滤后用30-35％乙醇溶液洗涤晶体。再将晶体置于干燥箱内干燥至含水量在1.8-3％。根据X射线衍射图数据表明(图1)，生成的晶体为0.5半水合晶体(A)，为单一晶格。优替德隆单晶衍射图见图8。
表2：优替德隆半水合物结晶结构分析的试验数据与结构精修参数
Figure PCTCN2021085903-appb-000004
表3：优替德隆半水合物的X射线粉末衍射结果
Figure PCTCN2021085903-appb-000005
Figure PCTCN2021085903-appb-000006
X-衍射图谱见图1.
【实施例2】
将干燥的优替德隆7.5克固体用100％乙醇20mL/g浓度溶解后，采用0.2um膜无菌过滤，滤液在搅拌下，缓慢加入40％水后，加入少量晶种后继续搅拌30分钟。然后将其余的水加入到溶液中至乙醇浓度为50％。在搅拌过程中，利用冷却水浴，使结晶溶液温度至4℃，继续搅拌2-12小时。将晶体真空抽滤，随后迅速用4℃的冷却30％乙醇水溶液进行洗涤，然后在真空干燥箱中干燥48小时。获得产品6g。该产品的X射线衍射图见图2，其主要特征峰反射角2θ约在12.4,17.5,20.4,21.6,23.8,24.8,25.8,33.9处， 与半水合晶体不同。
【实施例3】优替德隆半水合晶体在高温下测试稳定
稳定性试验：通过在以下条件进行半水合晶体的稳定性试验：
储存条件1：2～25℃，密封状态下储存3年以上，经NMR，HPLC，X射线粉末衍射和红外光谱分析等证实，半水合晶体保持稳定(含量无变化，无降解杂质产生，无外观和理化性质的改变)。
储存条件2：25℃，60％±10％RH下，非密封保存3天以上，样品继续在25℃保存1年后，经NMR，HPLC，X射线粉末衍射和红外光谱分析等证实，性能保持稳定一致(含量无变化，无降解杂质产生，无外观和理化性质的改变)。
储存条件3：40℃密封状态下储存2年以上，经NMR，HPLC，X射线粉末衍射和红外光谱分析等证实，产品均保持稳定一致(含量无变化，无降解杂质产生，无外观和理化性质的改变)。
储存条件4：60℃储存1年以上，经NMR，HPLC，X射线粉末衍射和红外光谱分析等证实，产品均保持稳定一致(含量无变化，无降解杂质产生，无外观和理化性质的改变)。
【实施例4】优替德隆半水合晶体在高湿、强光下测试稳定
将实施例1所得半水合晶体样品置于相对湿度90％±5％条件下放置10天，于第5天和第10天取样，样品稳定：含量无明显变化，无降解杂质产生，无外观和理化性质的改变，水分含量也基本不变。
而无水晶体样品置于相对湿度90％±5％条件下放置10天，于第5天和第10天取样，水分含量增加，吸湿明显。
将实施例1所得半水合晶体样品置于光照箱内，于光照度为4500lx±500lx的条件下放置10天。样品稳定：含量无明显变化，无降解杂质产生，无外观和理化性质的改变，水分含量也基本不变。
【实施例5】优替德隆半水合晶体溶解度测试，具有良好的溶解度。将实施例1所得半水合晶体样品置于0.1N盐酸溶液中，样品稳定：无明显降解杂质产生。溶解度>5mg/ml。
Figure PCTCN2021085903-appb-000007
约25mg实施例1所得半水合晶体样品在10％乙醇,5％丙二醇,45％蓖麻油,40％玉米油形成的自乳化溶液具有良好的稳定性，未观测到明显的降解杂质，可完全溶解在100ml的的水中，溶解度良好，1小时内不会析出固体物。
【实施例6】半水合晶体结晶性优替德隆药物组合物静脉给药的PK研究
本实施例充分说明结晶性优替德隆组合物，可以用于制备治疗乳腺癌、肠癌、肝癌、胃癌、肺癌等实体瘤的药物组合物，其疗效优。
将结晶性优替德隆(晶型A或含有晶型A的混合晶体)用50％v/v无水乙醇(USP)，30％v/v丙二醇(USP)和20％v/v聚氧乙烯蓖麻油(Cremophor EL或ELP)增溶剂进行制备优替德隆注射液。产品含水量低，稳定性高。
受试者静脉滴注优替德隆40mg/m2，每天1次，连续5天，第1天和第5天给药后血浆中优替德隆的消除半衰期t1/2分别是8.6±0.1h和8.2±1.1h，MRT分别为4.5±0.8h和5.1±0.7h，第1天和第5天给药后的AUC(0-24)分别为4178.3±1008.5h·ng/mL和4547.4±1628.1h·ng/mL；血浆清除率CL分别是9.2±2.7L/h/m2和8.9±3.9L/h/m2；表观分布容积分别是114.0±35.2L/m2和109.1±62.6L/m2。所有参数首次和末次间的差异均没有统计学意义，说明连续给药40mg/m2后，药物在体内没有蓄积和诱导代谢加快，优替德隆在体内的代谢处置没有发生变化。

Claims (9)

  1. 优替德隆的半水合物晶体(A)，该晶体为单晶，其不对称结构单元是由四个优替德隆(晶体学独立1)和两个水分子构成半水合晶型。
  2. 根据权利要求1所述的晶体，该晶体的单晶衍射图如图8所示。
  3. 优替德隆的半水合物晶体(A)，该晶体为单晶，其X射线粉末衍射图在反射角2θ约为6.1，7.2，12.1，12.7，14.4，15.5，17.2，18.3，18.6，19.0，20.1，20.4，21.3，23.5，24.4，25.6，26.1，29.1，33.4处具有特征峰。
  4. 根据权利要求3所述的半水合物晶体(A)，该晶体的X-射线粉末衍射图谱如图1所示。
  5. 根据权利要求1-4任一项所述的半水合物晶体(A)，其中所述单晶为长片状晶体，该晶体属三斜晶系，P1空间群，单胞参数为：{
    Figure PCTCN2021085903-appb-100001
    Figure PCTCN2021085903-appb-100002
    α＝81.3294(4)°,β＝86.3641(4)°,γ＝86.6019(5)°,
    Figure PCTCN2021085903-appb-100003
    }，Z值为4。
  6. 根据权利要求1-5中任一项的晶型，其特征在于使用DSC热分析时，在10℃/分钟加热速度下，在122±3℃出现吸热峰。
  7. 一种制备优替德隆的半水合物晶体(A)的方法，所述方法可利用混合溶剂四氢呋喃/正庚烷为1:5或二氯甲烷/正庚烷为1:10而获得。
  8. 一种药物组合物，所述药物组合物包含权利要求1-6任何一项所述的优替德隆的晶体和药学上可接受的赋形剂。
  9. 如权利要求8所述的药物组合物，其特征在于该药物组合物用于治疗哺乳动物，尤其是人类的实体肿瘤。
PCT/CN2021/085903 2020-04-08 2021-04-08 优替德隆半水合物单晶及其制备方法与应用 WO2021204188A1 (zh)

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