WO2019080830A1 - 一种含有喹啉衍生物的药物组合物 - Google Patents

一种含有喹啉衍生物的药物组合物

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WO2019080830A1
WO2019080830A1 PCT/CN2018/111388 CN2018111388W WO2019080830A1 WO 2019080830 A1 WO2019080830 A1 WO 2019080830A1 CN 2018111388 W CN2018111388 W CN 2018111388W WO 2019080830 A1 WO2019080830 A1 WO 2019080830A1
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Prior art keywords
pharmaceutical composition
composition according
drying
lubricant
weight
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PCT/CN2018/111388
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English (en)
French (fr)
Inventor
张新华
王晨阳
张代美
白剑峰
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江苏恒瑞医药股份有限公司
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Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to US16/757,363 priority Critical patent/US11701349B2/en
Priority to UAA202002649A priority patent/UA125706C2/uk
Priority to CN201880040357.9A priority patent/CN110769825B/zh
Priority to EP18870455.5A priority patent/EP3701948A4/en
Priority to JP2020522733A priority patent/JP2021500363A/ja
Priority to KR1020207014599A priority patent/KR20200078561A/ko
Priority to BR112020007873-5A priority patent/BR112020007873A2/pt
Priority to RU2020115172A priority patent/RU2020115172A/ru
Priority to CA3079916A priority patent/CA3079916A1/en
Priority to MX2020004221A priority patent/MX2020004221A/es
Priority to AU2018357438A priority patent/AU2018357438A1/en
Publication of WO2019080830A1 publication Critical patent/WO2019080830A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a preparation of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano- A method of a pharmaceutical composition of 7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide or a pharmacologically acceptable salt thereof.
  • Protein kinases can be divided into two classes: protein tyrosine kinases and serine-threonine kinases. PTKs phosphorylate tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues. Tyrosine kinases can be further divided into receptor type and non-receptor type. At present, 90 tyrosine kinase-encoding genes have been identified in human genes, of which about 60 are receptor-type and about 30 are non-receptor-type.
  • CN102471312B discloses a small molecule receptor tyrosine kinase inhibitor (R, E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3- Cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide, the compound having the structure shown in formula I,
  • CN102933574B discloses maleate forms of the compounds of formula I which are advantageous in terms of solubility and bioavailability and pharmacokinetics relative to other salts and compounds of formula I.
  • CN103974949B discloses Form I crystals of the compound dimaleate salt of the formula I.
  • the crystal form has good crystal form stability and chemical stability and can be used for the preparation of a medicament for treating diseases associated with the EGFR receptor tyrosine kinase or the HER-2 receptor tyrosine kinase.
  • WO2017129087, WO2017129088 discloses (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinoline a pharmaceutical composition of -6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide or a pharmaceutically acceptable salt thereof, which comprises the steps of: preparing the active ingredient with a pharmaceutically acceptable The medicinal excipients are mixed, wet granulated, dried, tableted into tablets or filled into capsules. The pharmaceutical composition dissolves rapidly and the dissolution rate of the batch sample is uniform.
  • the present inventors have unexpectedly discovered that post-granulation drying is carried out by means of dynamic drying, and the dissolution of the resulting pharmaceutical composition can reach the level of the sample of the small test batch, and the dissolution between the batches is uniform.
  • the present invention provides an active ingredient (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-B
  • the wet agent is mixed with at least one pharmaceutical excipient selected from the group consisting of a disintegrant, a filler, a binder or a lubricant, and is dynamically dried, optionally mixed with a lubricant, and then tableted or filled. obtain.
  • the active ingredient is present in an amount ranging from 5 to 70%, preferably from 10 to 50%, based on the total weight of the pharmaceutical composition, and in particular embodiments may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50%, more preferably 20 to 40%.
  • the wetting agent of the present invention is selected from, but not limited to, at least one of ethanol, methanol, acetone, isopropanol, and water, preferably at least one selected from the group consisting of ethanol, methanol, and water, more preferably ethanol/water.
  • the ethanol/water ethanol content may be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99%, preferably 50 to 95%, more preferably 80 to 95%.
  • the material is dried by dynamic drying, i.e., by mechanical agitation in a drying vessel or by passing a dry gas stream through a drying vessel. Drying with stirring and fluidized drying are all such drying methods.
  • the dynamic drying of the present invention is selected from, but not limited to, agitation drying, fluidized drying, preferably fluidized drying.
  • the granulation mode of the present invention employs a high speed shear granulation process or a fluidized bed spray granulation process.
  • the high-speed shear granulation method of the present invention refers to adding the component to be granulated to a high-speed shearing wet granulator, and adding the binder liquid to the granulator under the dynamic condition of stirring mixing and high-speed shearing. Wet granulation is carried out.
  • the fluidized bed spray granulation of the present invention refers to adding the component to be granulated into a fluidized bed, introducing a gas into the fluidized bed to make the material in a fluidized state, and spraying the adhesive liquid into the fluidized bed. Granulation.
  • the disintegrating agent of the present invention is selected from one or more of low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone, preferably the disintegration.
  • the content of the agent is from 2 to 20% based on the total weight of the composition.
  • the filler of the present invention is selected from one or more of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch and lactose, and the content of the filler is about 5 ⁇ based on the total weight of the composition.
  • 80% can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 , 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 , 78, 79, 80%.
  • the binder of the present invention is preferably one or more of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, based on the total weight of the composition.
  • the content of the binder is about 0.5 to 15%, and may be 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 14,15%.
  • the lubricant of the present invention is selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal silica, based on the composition
  • the total weight of the lubricant is about 0.5 to 5%, and may be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0%.
  • the pharmacologically acceptable salt of 6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide may be selected from, but not limited to, hydrochloride, maleate, hydrobromide, Tosylate, mesylate, sulfate or ethanesulfonate, preferably maleate, more preferably dimaleate.
  • the pharmaceutical composition of the invention comprises:
  • a binder selected from at least one of polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose;
  • a lubricant selected from at least one of magnesium stearate and talc.
  • the dissolution rate (%) of the active ingredient in the pharmaceutical composition is 0.1 min in a 0.1 mol/L hydrochloric acid solution medium, 30 min. It can still reach 85% or higher, preferably 90% or higher.
  • the dissolution rate (%) of the active ingredient in the pharmaceutical composition reaches 50% or more at 15 minutes, and may be greater than or equal to 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95%.
  • the solid preparation dissolves quickly and completely, has good bioavailability, and has a simple preparation process and is suitable for process amplification.
  • the invention also provides a method of preparing the aforementioned pharmaceutical composition, comprising:
  • the parameters of the fluidized drying according to the present invention are: the fan flow rate is 5 to 15 m 3 /min, the inlet air temperature is 50 to 70 ° C, the material temperature is 20 to 55 ° C, and the drying time is 10 to 30 min.
  • the pharmaceutical composition prepared by the preparation method provided by the present invention has rapid dissolution and remarkable effect, and can be used for the treatment of cancer such as gastric cancer, lung cancer or breast cancer.
  • Compound A (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6 -yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide or a pharmaceutically acceptable salt thereof can be obtained by the method described in CN102471312B.
  • Figure 1 shows the dissolution profiles of the tablets of Example 1 and Comparative Example 1 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 2 shows the dissolution profiles of the tablets of Example 2 and Comparative Example 2 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 3 shows the dissolution profiles of the tablets of Example 3 and Comparative Example 3 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 4 shows the dissolution profiles of the tablets of Example 4 and Comparative Example 4 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 5 shows the dissolution profiles of the tablets of Example 5 and Comparative Example 5 in a 0.1 mol/L hydrochloric acid solution.
  • the dissolution rates of the tablets of Examples 1 to 5 were measured according to the second method of the Chinese Pharmacopoeia 2015 Edition, General Rules 0931. 900 mL of a 0.1 mol/L hydrochloric acid solution was used as a dissolution medium, and a dissolution test was performed at a paddle speed of 50 rpm at 37 ⁇ 0.5 °C. The results showed that the particles prepared in the dynamic drying process of Examples 1 to 5 were quickly and completely dissolved. The dissolution test results are shown in Table 2, and the dissolution curve comparison charts are shown in Figures 1 to 5.
  • the tablets of Comparative Examples 1 to 5 were subjected to dissolution measurement according to the second method of the Chinese Pharmacopoeia 2015 Edition, General Rules 0931. 900 ml of a 0.1 mol/L hydrochloric acid solution was used as a dissolution medium, and a dissolution test was performed at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that the dissolution rate of the tablet compound A of Comparative Examples 1 to 5 using the static drying process was significantly lower than that of the example tablets of the same formulation using the dynamic drying process.
  • the dissolution test results are shown in Table 4, and the dissolution curve comparison charts are shown in Figures 1 to 5.

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Abstract

本发明提供了一种含有喹啉衍生物的药物组合物。具体而言，本发明提供了一种制备含有(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受盐的药物组合物的方法，该制备方法适合于工业化大生产，所得样品具有溶出迅速且均一等特点。

Description

一种含有喹啉衍生物的药物组合物
本申请要求申请日为2017年10月24日的中国专利申请CN201711002771.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物制剂领域，具体涉及一种制备(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受盐的药物组合物的方法。
背景技术
蛋白激酶(PKs)可以分成两类：蛋白酪氨酸激酶和丝氨酸-苏氨酸激酶。PTKs可使蛋白质上的酪氨酸残基磷酸化，STKs可以磷酸化丝氨酸、苏氨酸残基。酪氨酸激酶又可以分为受体型和非受体型。目前，在人类基因中已有90种酪氨酸激酶编码基因被识别，其中约60种是受体型，约30种是非受体型。
CN102471312B公开了一种小分子受体酪氨酸激酶抑制剂(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺，该化合物具有式I所示的结构，
Figure PCTCN2018111388-appb-000001
CN102933574B公开了式I化合物的马来酸盐形式，其相对于其他盐和式I化合物本身在溶解度以及生物利用度和药代动力学方面更具优势。
CN103974949B公开了式I化合物二马来酸盐的I型结晶。该晶型具有良好的晶型稳定性和化学稳定性，可用于制备治疗与EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶有关的疾病的药物。
WO2017129087、WO2017129088公开了(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药学上可接受的盐的药物组合物，其制备方法包括：将活性成分与药学可接受的药用辅料混合，湿法制粒，干燥，压片制成片剂或灌装制成胶囊的步骤。该药物组合物溶出迅速，批次样品溶出速度均一。但将WO2017129087或WO2017129088的工艺进行放大实验时，所得样品的溶出速率明显低于相对应地小试批次样品，而且批次间药物制剂溶出速度也不均一。影响药物组合物溶出速度的原因是复杂的，处方中药物辅料的种类、比例、水分、颗粒的粒径、压片的速度及硬度等中的任意一种或多种都有可能影响到最终的溶出速度。因此提供一种放大后仍然保持所需要的溶出速度、且保持批次间均一性的药物组合物是非常困难的。
在制药领域，可用于样品干燥的方式很多，譬如常压干燥，减压干燥，喷雾干燥。沸腾干燥，冷冻干燥，红外干燥，微波干燥，吸湿干燥，等等。每一种干燥方式都具有其自身优点和缺点。在干燥方式选择时，技术人员通常会选择能耗低，简单易行的，例如减压干燥。在制剂研究的小试阶段，更倾向于利用减压干燥或常压鼓风干燥等。
本发明意外地发现利用动态干燥的方式进行制粒后干燥，所得药物组合物的溶出度能达到小试批次样品的水平，且批次间溶出度均一。
发明内容
本发明提供了一种含有活性成分(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受盐的药物组合物，该药物组合物由活性成分、润湿剂与任 选自崩解剂、填充剂、粘合剂或润滑剂中的至少一种药用辅料相混合制粒后动态干燥，任选与润滑剂总混后粒压片或灌装胶囊获得。
基于药物组合物的总重量，所述活性成分的含量范围为5～70％，优选10～50％，在具体实施方案中可以为10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50％，更优选为20～40％。
进一步地，本发明所述润湿剂选自但不限于乙醇、甲醇、丙酮、异丙醇、水中的至少一种，优选自乙醇、甲醇、水中的至少一种，更优选为乙醇/水，在一些实施方案中，乙醇/水中乙醇的含量可以为20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99％，优选为50～95％，更优选为80～95％。
在一些实施方案中，动态干燥，即通过干燥容器中机械搅拌或在干燥容器中通入干燥气流，使物料处于运动状态下得以干燥。边搅拌边干燥，流化干燥都属于这种干燥方式。本发明所述动态干燥选自但不限于搅拌干燥、流化干燥，优选为流化干燥。
在另一些实施方案中，本发明所述制粒方式采用高速剪切制粒法或流化床喷雾制粒法。
本发明所述高速剪切制粒法是指将待制粒组分加入到高速剪切湿法制粒机中，在搅拌混合和高速剪切的动态情况下，将粘合剂液体加入制粒机中进行湿法制粒。
本发明所述流化床喷雾制粒是指将待制粒组分加入到流化床中，在流化床中通入气体使物料处于流化状态，将粘合剂液体喷入流化床制粒。
本发明所述崩解剂选自低取代羟丙基纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮中的一种或多种，优选所述崩解剂的含量为基于组合物总重量的2～20％。
本发明所述填充剂选自微晶纤维素、磷酸氢钙、甘露醇、预胶化淀粉和乳糖中的一种或多种，基于组合物总重量，所述填充剂的含量约为5～80％，可以为5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80％。
本发明所述粘合剂优选羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素中的一种或多种，基于组合物总重量，所述粘合剂的含量约为0.5～15％，可以为0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15％。
本发明所述润滑剂选自滑石粉、硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、胶体二氧化硅中的一种或多种，基于组合物总重量，所述润滑剂的含量约为0.5～5％，可以为0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0％。
本发明所述(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺药理学上可接受盐可选自但不限于盐酸盐、马来酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐，优选马来酸盐，更优选二马来酸盐。
在优选实施方案中，本发明所述药物组合物包括：
1)2～20wt％的崩解剂，所述崩解剂为交联聚乙烯吡咯烷酮；
2)5～80wt％的填充剂，所述填充剂选自乳糖和微晶纤维素中的至少一种；
3)0.5～15wt％的粘合剂，所述粘合剂选自聚乙烯吡咯烷酮、羟丙基甲基纤维素及羟丙基纤维素中的至少一种；
4)0.5～5wt％的润滑剂，所述润滑剂选自硬脂酸镁和滑石粉中的至少一种。
在一些实施方案中，批次投料为公斤级(譬如1公斤)时，前述药物组合物在0.1mol/L盐酸溶液介质条件下，所述药物组合物中活性成分的溶出度(％)，30min仍可达到85％或更高，优选为90％或更高。进一步地，药物组合物中活性成分溶出度(％)，在15min达到50％或更高，可以大于或等于50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95％。该固体制剂溶出迅速且完全，具有良好的生物利用度，同时制备工艺简单，适合于工艺放大。
本发明还提供一种制备前述的药物组合物的方法，包括：
a)将活性成分(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受盐与任选自崩解剂、填充剂、粘合剂或润滑剂中至少一种药用辅料相混合；
b)加入润湿剂进行湿法制粒；
c)动态干燥，所述动态干燥优选为流化干燥；
d)加入润滑剂，总混后压片。
本发明所述流化干燥所设参数：风机流量5～15m 3/min，进风温度50～70℃，物料温度20～55℃，干燥时间10～30min。
通过本发明提供的制备方法制得的药物组合物溶出迅速，起效显著，可用于胃癌、肺癌或乳腺癌等癌症的治疗。
本发明所述药物辅料或试剂均可来自商业途径。化合物A：(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡 咯烷基-2-基)-丙烯酰胺或其可药用盐可以参照CN102471312B所述方法制备获得。
附图说明
图1显示实施例1和比较例1的片剂在0.1mol/L盐酸溶液中的溶出曲线。
图2显示实施例2和比较例2的片剂在0.1mol/L盐酸溶液中的溶出曲线。
图3显示实施例3和比较例3的片剂在0.1mol/L盐酸溶液中的溶出曲线。
图4显示实施例4和比较例4的片剂在0.1mol/L盐酸溶液中的溶出曲线。
图5显示实施例5和比较例5的片剂在0.1mol/L盐酸溶液中的溶出曲线。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1～5
以表1的处方比例，将(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺的马来酸盐(以下简称为化合物A)、乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮混合，分别以适量20wt％乙醇的水溶液、无水乙醇、93.75wt％乙醇的水溶液为润湿剂湿法制粒，将湿颗粒置于流化床中，设定风机流量5～15m 3/min，进风温度50～70℃，物料温度20～55℃，干燥时间10～30min。动态干燥至水分小于2％进行干整粒，加入处方量的硬脂酸镁，采用旋转总 混机进行混合。将得到的总混颗粒进行压片、包衣，制备成片剂。
表1
Figure PCTCN2018111388-appb-000002
单位：质量％。
实验例1：溶出实验
根据中国药典2015版四部通则0931第二法，对实施例1～5的片剂进行溶出度测定。使用900mL的0.1mol/L盐酸溶液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例1～5采用动态干燥工艺制备的颗粒，化合物A溶出迅速完全。溶出实验结果见表2，溶出曲线比较图见图1～图5。
表2
Figure PCTCN2018111388-appb-000003
比较例1～5
以表3的处方比例，将(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺的马来酸盐(以下简称为化合物A)、乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮混合，分别以适量20wt％乙醇的水溶液、无水乙醇、93.75wt％乙醇的水溶液为润湿剂湿法制粒，将湿颗粒加入鼓风干燥箱中，设定干燥温度为50～60℃，干燥60～180min，每30min翻动一次颗粒，静态干燥至水分小于2％进行干整粒，加入处方量的硬脂酸镁，采用旋转总混机进行混合。将得到的总混颗粒压片、包衣，制备成片剂。
表3
Figure PCTCN2018111388-appb-000004
Figure PCTCN2018111388-appb-000005
单位：质量％。
实验例2：溶出实验
根据中国药典2015版四部通则0931第二法，对比较例1～5的片剂进行溶出度测定。使用900ml的0.1mol/L盐酸溶液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，采用静态干燥工艺的比较例1～5的片剂化合物A溶出速度较采用动态干燥工艺的相同处方的实施例片剂明显更低。溶出实验结果见表4，溶出曲线比较图见图1～图5。
表4
Figure PCTCN2018111388-appb-000006
。

Claims (14)

  1. 一种含有活性成分(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受盐的药物组合物，其由活性成分、润湿剂与任选自崩解剂、填充剂、粘合剂或润滑剂中的至少一种药用辅料相混合制粒后动态干燥，任选与润滑剂混合后压片或灌装胶囊获得。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述润湿剂选自乙醇、甲醇、丙酮、异丙醇、水中的至少一种，优选自乙醇、甲醇、水中的至少一种。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，所述崩解剂选自低取代羟丙基纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮中的一种或多种，优选所述崩解剂的含量为基于组合物总重量的2～20％。
  4. 根据权利要求1或2所述的药物组合物，其特征在于，所述填充剂选自微晶纤维素、磷酸氢钙、甘露醇、预胶化淀粉和乳糖中的一种或多种，优选所述填充剂的含量为基于组合物总重量计的5～80％。
  5. 根据权利要求1或2所述的药物组合物，其特征在于，所述粘合剂优选羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素中的一种或多种，优选所述粘合剂的含量为基于组合物总重量计的0.5～15％。
  6. 根据权利要求1或2所述的药物组合物，其特征在于，所述润滑剂选自滑石粉、硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、胶体二氧化硅中的一种或多种，优选所述润滑剂的含量为基于组合物总重量计的0.5～5％。
  7. 根据权利要求1-6中任一项所述的药物组合物，其特征在于，所述动态干燥选自搅拌干燥、流化干燥，优选为流化干燥。
  8. 根据权利要求1-7中任一项所述的药物组合物，其特征在于，所述制粒方式采用高速剪切制粒法或流化床喷雾制粒法。
  9. 根据权利要求1-8中任一项所述的药物组合物，其特征在于，所述药理学上可接受盐为马来酸盐，优选二马来酸盐。
  10. 根据权利要求1-9中任一项所述的药物组合物，其特征在于，所述活性成分的含量为基于组合物总重量的5％～70％，优选10％～50％，更优选20～40％。
  11. 根据权利要求1-10中任一项所述的药物组合物，其特征在于，所述药物组合物包括：
    1)2～20wt％的崩解剂，所述崩解剂为交联聚乙烯吡咯烷酮；
    2)5～80wt％的填充剂，所述填充剂选自乳糖和微晶纤维素中的至少一种；
    3)0.5～15wt％的粘合剂，所述粘合剂选自聚乙烯吡咯烷酮、羟丙基甲基纤维素及羟丙基纤维素中的至少一种；
    4)0.5～5wt％的润滑剂，所述润滑剂选自硬脂酸镁和滑石粉中的至少一种。
  12. 根据权利要求1-11中任一项所述的药物组合物，其特征在于，在0.1mol/L盐酸溶液介质条件下，所述药物组合物中活性成分的溶出度(％)，30min达到85％或更高，优选为90％或更高。
  13. 一种制备权利要求1-11中任一项所述的药物组合物的方法，包括：
    a)将活性成分(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受盐与任选自崩解剂、填充剂、粘合剂或润滑剂中至少一种药用辅料相混合；
    b)加入润湿剂进行湿法制粒；
    c)动态干燥，所述动态干燥优选为流化干燥；
    d)加入润滑剂，总混后压片或灌装胶囊。
  14. 权利要求1-12中任一项所述的药物组合物或由权利要求13所述的方法制备的药物组合物在制备治疗癌症的药物中的用途；所述癌症优选胃癌、肺癌或乳腺癌。
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