WO2015185013A1 - 包含喹啉衍生物或其盐的药物组合物及其制备方法 - Google Patents

包含喹啉衍生物或其盐的药物组合物及其制备方法 Download PDF

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WO2015185013A1
WO2015185013A1 PCT/CN2015/080868 CN2015080868W WO2015185013A1 WO 2015185013 A1 WO2015185013 A1 WO 2015185013A1 CN 2015080868 W CN2015080868 W CN 2015080868W WO 2015185013 A1 WO2015185013 A1 WO 2015185013A1
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pharmaceutical composition
formula
compound
weight
mannitol
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PCT/CN2015/080868
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English (en)
French (fr)
Inventor
王善春
王训强
顾红梅
董平
徐宏江
何雄雄
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正大天晴药业集团股份有限公司
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Priority to CN201580026809.4A priority Critical patent/CN106456625A/zh
Publication of WO2015185013A1 publication Critical patent/WO2015185013A1/zh
Priority to HK17104983.2A priority patent/HK1231377A1/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
    • A61K31/435—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
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • 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
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition comprising a quinoline derivative or a salt thereof and a process for the preparation thereof; in particular, the present invention relates to 1-[[[4-(4-fluoro-2-methyl-1H-oxime) A pharmaceutical composition of -5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine or a salt thereof and a process for the preparation thereof;
  • Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues and play an important role in signal transduction in cells. They are involved in the regulation, signaling and development of normal cells, as well as in tumor cells. Proliferation, differentiation, migration and apoptosis are closely related. Many receptor tyrosine kinases are involved in tumor formation and can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor depending on their extracellular domain structure. Body (VEGFR), fibroblast growth factor receptor (FGFR), and the like.
  • EGFR epidermal growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • FGFR fibroblast growth factor receptor
  • VEGFR1 vascular endothelial growth factor receptor
  • VEGFR2 vascular endothelial growth factor receptor
  • VEGFR3 stem cell factor receptor
  • platelet-derived growth factor receptor vascular endothelial growth factor receptor
  • It is an object of the present invention to find a stable pharmaceutical composition comprising a compound of formula I suitable for clinical use.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof as an active ingredient and at least one pharmaceutically acceptable excipient, wherein The weight of the pharmaceutical composition contains 0-3% by weight of water.
  • the pharmaceutical composition described above is a pharmaceutical composition for treating a tumor in a patient, the patient comprising a mammal, preferably a human; the tumor is selected from the group consisting of colorectal cancer, non-small cell lung cancer, kidney cancer, liver cancer, Breast or gastrointestinal stromal tumors.
  • the above pharmaceutical compositions contain from 0.2 mg to 100 mg of a compound of formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof, on a unit dosage basis; in some embodiments, the above pharmaceutical composition is in unit doses On the basis of 0.5 mg to 30 mg of the compound of the formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some embodiments, the above-mentioned drug group
  • the compound comprises from 1 mg to 20 mg of a compound of formula I or a pharmaceutically acceptable salt thereof and/or hydrate thereof on a unit dosage basis; in some embodiments, the above pharmaceutical composition contains from 4 mg to 16 mg of formula I on a unit dosage basis.
  • the above pharmaceutical composition contains 8 mg to 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof, on a unit dosage basis; In some embodiments, the above pharmaceutical composition contains 10 mg to 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof, on a unit dosage basis; in some embodiments, the above pharmaceutical composition is in unit doses
  • the base contains from 10 mg to 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof. In the present invention, for example, for a tablet or capsule, "containing 12 mg of the compound of the formula I on a unit dosage basis" means that 12 mg of the formula I is contained per tablet or capsule per capsule. Compound.
  • the above pharmaceutical composition contains 0-2.5% by weight of water; in some embodiments, the above pharmaceutical composition contains 0-2% by weight of water; in some embodiments, the above pharmaceutical composition contains 0. - 1.5% by weight of water.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, and/or a hydrate thereof is the only active ingredient.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof and/or hydrate thereof is present in an amount from 0.5% to 20%; in some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, and/or hydrate thereof
  • the content of the compound is from 1% to 10%; in some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof and/or hydrate thereof is present in an amount from 2% to 8%; in some embodiments, the compound of formula I or The pharmaceutically acceptable salt and/or hydrate thereof is contained in an amount of from 3.5% to 6%.
  • the pharmaceutical composition of the present invention comprises a compound of Formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof as an active ingredient, at least one filler, at least one disintegrant, and at least one lubricant Wherein 0 to 3% by weight of water is contained based on the weight of the pharmaceutical composition.
  • the filler comprises, but is not limited to, a mixture of one or more of lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose; in some embodiments, the filler is selected from the group consisting of lactose a mixture of one or more of starch, pregelatinized starch, microcrystalline cellulose, mannitol; preferably, the filler is selected from one or a mixture of lactose, microcrystalline cellulose, mannitol Further preferably, the filler is selected from the group consisting of microcrystalline cellulose and/or mannitol.
  • the disintegrants include, but are not limited to, low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, dry starch, sodium carboxymethyl starch, hydroxypropyl starch, polysorbate 80, a mixture of one or more of sodium alginate; in some embodiments, the disintegrant is selected from one of low substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone or Mixtures of several; preferably, the disintegrant is selected from the group consisting of low substituted hydroxypropyl cellulose and/or crospovidone.
  • the lubricants include, but are not limited to, polyethylene glycol, magnesium stearate, stearic acid, calcium stearate, talc, microsilica gel, hydrogenated castor oil, glyceryl behenate, sodium lauryl sulfate. a mixture of one or more of magnesium lauryl sulfate; in some embodiments, the lubricant is selected from the group consisting of polyethylene glycol, magnesium stearate, hydrogenated castor oil, glyceryl behenate One or a mixture of several; preferably, the lubricant is magnesium stearate.
  • the filler is present in an amount of from 30% to 99%; preferably, the filler is present in an amount from 50% to 96%; more preferably, the filler is present in an amount from 85% to 96%.
  • the disintegrant is present in an amount of from 0.5% to 10%; preferably, the disintegrant is present in an amount from 1% to 6%; more preferably, the disintegrant is present in an amount from 2% to 4% .
  • the lubricant is present in an amount from 0% to 5%; preferably, the lubricant is present in an amount from 0.1% to 2%; more preferably, the lubricant is present in an amount from 0.1% to 1%.
  • the pharmaceutical composition may further contain a binder, a sweetener, a colorant, and the like.
  • binders include, but are not limited to, povidone, starch syrup, dextrin, powdered sugar, syrup, microcrystalline cellulose, cellulose derivatives (eg, hypromellose, methylcellulose, carboxymethyl) Cellulose sodium, ethyl cellulose), sodium alginate, polyethylene glycol, magnesium aluminum silicate.
  • Sweet Examples of flavoring agents include, but are not limited to, stevioside, aspartame.
  • colorants include, but are not limited to, titanium dioxide, iron oxide red, iron oxide yellow.
  • the pharmaceutical compositions of the present invention comprise: a hydrochloride salt of a compound of Formula I and/or a hydrate thereof, mannitol, microcrystalline cellulose, low substituted hydroxypropylcellulose, and magnesium stearate, characterized It consists in containing 0-3% by weight of water.
  • the pharmaceutical compositions of the present invention comprise: a compound of the formula I dihydrochloride, mannitol, microcrystalline cellulose, low substituted hydroxypropyl cellulose, and magnesium stearate, characterized by containing 0-3 % by weight of water.
  • the pharmaceutical compositions of the present invention comprise: 2% to 8% of the compound dihydrochloride salt of Formula I, 25% to 45% mannitol, 25% to 70% microcrystalline cellulose, 1%- 5% of low-substituted hydroxypropylcellulose and 0.1% to 1% of magnesium stearate, characterized by containing 0-3% by weight of water.
  • the pharmaceutical compositions of the present invention comprise: 3% to 6% of the compound of the formula I dihydrochloride, from 30% to 40% of mannitol, from 50% to 65% of microcrystalline cellulose, 1.5% - 4% low-substituted hydroxypropylcellulose and 0.1%-1% magnesium stearate, characterized by containing 0-3% by weight of water.
  • the present invention provides the use of the above pharmaceutical composition for the preparation of a medicament for inhibiting the activity of a receptor tyrosine kinase; preferably for use in the preparation of a medicament for treating a tumor; further preferably for preparation in preparation Use in the treatment of colorectal cancer, non-small cell lung cancer, kidney cancer, liver cancer, breast cancer or gastrointestinal stromal tumors.
  • the present invention provides a method of preparing the above pharmaceutical composition, characterized in that the method comprises the following steps:
  • step b) treating the disintegrant, the moisture content of the filler obtained in step a) to ⁇ 1.5% by weight of each excipient;
  • step b) mixing and sieving the components obtained in step b) and step c);
  • step d) mixing the mixture obtained in step d) with a lubricant.
  • the above step b) can be carried out, for example, by a conventional drying method, including but not limited to a normal pressure of 50 ° C to 120 ° C, drying for 0.5 h to 4 h; or a vacuum of 40 ° C to 100 ° C, drying for 0.5 h to 4 h; or 70 ° C, flow. Dry. It is preferably dried at a normal pressure of 105 ° C for 2 hours so that the moisture does not exceed 1.5% (based on the weight of each excipient).
  • a conventional drying method including but not limited to a normal pressure of 50 ° C to 120 ° C, drying for 0.5 h to 4 h; or a vacuum of 40 ° C to 100 ° C, drying for 0.5 h to 4 h; or 70 ° C, flow. Dry. It is preferably dried at a normal pressure of 105 ° C for 2 hours so that the moisture does not exceed 1.5% (based on the weight of each excipient).
  • the compound of the formula I in the above step c), or a pharmaceutically acceptable salt thereof and/or a hydrate thereof should have a moisture content of less than 2%, preferably ⁇ 1.5% (based on a compound of the formula I or a pharmaceutically acceptable salt thereof and/or a hydrate thereof the weight of).
  • it may further comprise: detecting the moisture of the mixture obtained in step e), the moisture content of which should be no greater than 3.0%, preferably no greater than 2.0%, further preferably no greater than 1.5%.
  • the mixture obtained in step e) can be further compressed into tablets or filled into a capsule shell.
  • Certain specific embodiments of the present invention provide a process for the preparation of a capsule comprising a compound of the formula I, wherein the moisture content is ⁇ 3%, the method comprising the steps of:
  • the low-substituted hydroxypropyl cellulose and the microcrystalline cellulose and mannitol obtained in the step a) are respectively dried at 105 ° C to a moisture content of ⁇ 1.5% by weight of each excipient;
  • step b) mixing and sieving the mannitol, the low-substituted hydroxypropylcellulose obtained in the step b) and the dihydrochloride salt of the compound of the formula I obtained in the step c); and then, the microcrystalline fiber obtained in the step b) Mixing and sieving;
  • step d) mixing the mixture obtained in step d) with magnesium stearate;
  • step f) The mixture obtained in step e) is filled into a capsule.
  • the capsules can be further packaged in cold aluminum.
  • step a) may, for example, pass through a sieve of 0.8 mm;
  • step c) may, for example, pass through a sieve of 80 mesh;
  • step d) may, for example, pass through a sieve of 0.8 mm; for uniform mixing, for example, a method of shear mixing may be employed.
  • the water content of the compound dihydrochloride of the formula I in the above step c) should be less than 2%, preferably ⁇ 1.5% (based on the weight of the compound dihydrochloride of the formula I).
  • the pharmaceutically acceptable salt includes, but is not limited to, an acid addition salt formed with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like; or with an organic acid such as acetic acid, trifluoroacetic acid, or C.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like
  • an organic acid such as acetic acid, trifluoroacetic acid, or C.
  • Acid caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid , mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, An acid addition salt formed by trimethylacetic acid, salicylic acid or the like.
  • the pharmaceutically acceptable salt is a hydrochloride salt; in some embodiments, is a crystalline form of the hydrochloride salt; in certain specific embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof Is the dihydrochloride salt form of the compound of formula I; in certain specific embodiments, is the crystalline form of the dihydrochloride salt.
  • the crystalline form of the hydrochloride salt of the compound of formula I includes, but is not limited to, the crystals of type A, B and C disclosed in Chinese Patent Application No. CN 102344438 A, wherein the crystals of type A and B are substantially free of water of crystallization and other solvents.
  • Crystallization, Form C crystal is a crystal containing two water of crystallization.
  • the crystalline form of the dihydrochloride salt of Compound I is Form A crystal.
  • the pharmaceutical composition of the present invention comprises an intermediate prepared in the course of preparing a pharmaceutical composition, for example, a prepared mixture of step d) or step e).
  • the pharmaceutical composition is an oral solid pharmaceutical composition including, but not limited to, powders, granules, tablets, capsules or pills.
  • the oral solid pharmaceutical composition is a capsule.
  • the oral solid pharmaceutical composition is a hard capsule.
  • the excipients include but not limited to fillers, disintegrants, and lubricants
  • the excipients have a moisture content of ⁇ 1.5%, based on the weight of the excipient.
  • the pharmaceutically acceptable excipients include, but are not limited to, fillers, absorbents, binders, disintegrants, lubricants, and the like.
  • Fillers include starch, lactose, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.;
  • binders include cellulose derivatives (eg, hyprothenol) Cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose), sodium alginate, polyethylene glycol, magnesium aluminum silicate, povidone, microcrystalline cellulose, starch slurry, dextrin, Powdered sugar, syrup, etc.; disintegrants include croscarmellose sodium, crospovidone, dry starch, sodium carboxymethyl starch, hydroxypropyl starch, polysorbate 80, sodium alginate, low-substituted hydroxypropyl Base cellulose, etc
  • the percentages are calculated on the basis of the weight of the pharmaceutical composition unless otherwise specified.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, during storage, will produce certain impurities, such as impurity A; Some impurities will increase in content, such as impurities B, C. These impurities will affect the purity of the drug, reduce the quality of the drug and further affect the clinical use of the drug.
  • impurities A, B, and C are as follows:
  • the present invention can control the production or growth of impurities A, B, C and other impurities by controlling the content of moisture in the pharmaceutical composition during storage. Improving the purity of the active ingredients in the pharmaceutical composition, improving the quality of the product, improving the efficacy of the drug, and reducing the toxic side effects of the drug are beneficial to the clinical application of the drug.
  • the method for preparing a pharmaceutical composition provided by the invention is simple and easy, and the obtained medicine has good stability.
  • the compound dihydrochloride of the formula I is dissolved in 4 times by weight of water, and the aqueous solution of the compound dihydrochloride of the formula I is separately added to various auxiliary powders to prepare a soft material; the soft material is sieved through a 20 mesh sieve.
  • the granules were dried under reduced pressure at 40 ° C; the obtained dry granules were allowed to stand in a sealed, light-shielded, 60 ° C environment for 10 days, and the stability of the compound dihydrochloride of the formula I was examined by using the properties and the total amount of impurities as an index.
  • the total amount of impurities was determined by HPLC method, and the test results are shown in Table 1.
  • the compound dihydrochloride of the formula I is an off-white powder before the test, the total amount of impurities is 0.78%; when dissolved in 4 times the amount of water, the solution is rapid, the solution is a pale yellow liquid, and the viscosity is large.
  • the resulting pharmaceutical composition has poor stability, mainly manifested in: the color is deepened, and the related substances are significantly increased.
  • the obtained mixed powder was allowed to stand in a sealed, light-shielded, 60 ° C environment for 10 days, and the stability of the compound dihydrochloride of the formula I was examined in terms of properties and total amount of impurities.
  • the total amount of impurities was determined by HPLC method, and the test results are shown in Table 2.
  • the compound dihydrochloride salt of the formula I was an off-white powder before the test, and the total amount of impurities was 0.78%.
  • Formulations 1-4 were prepared according to the prescriptions and preparation processes of Tables 3 and 4, and were tested at high temperature (40 ° C for 10 days, 40 ° C for 10 days) and high humidity (25 ° C, relative humidity of 75% ⁇ 5%). The total amount of impurities was determined by HPLC, and the test results are shown in Table 5.
  • Example 4 The capsules of the specification of 12 mg/granules in Example 4 were packaged in double aluminum and placed under accelerated test conditions (temperature 40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%), respectively, at 1 month, 2 months, Samples were taken at 3 months and the impurity content of the samples was analyzed by HPLC.
  • the capsules of the specification of 12 mg/granules in Example 4 were packaged in double aluminum, placed under long-term test conditions (temperature 25 ° C ⁇ 2 ° C, relative humidity 60% ⁇ 10%), sampled at 3 months, and subjected to HPLC. The method analyzes the impurity content of the sample.

Abstract

本发明提供了一种包含喹啉衍生物或其盐的药物组合物及其制备方法。本发明涉及 1-［［［4-（4-氟-2-甲基-1H-吲哚-5-基）氧基-6-甲氧基喹啉-7-基］氧基］甲基］环丙胺或其盐的药物组合物及其制备方法。本发明所提供的水分含量≤3％的药物组合物在储存过程中具有良好的稳定性。

Description

包含喹啉衍生物或其盐的药物组合物及其制备方法 技术领域
本发明涉及一种包含喹啉衍生物或其盐的药物组合物及其制备方法；具体而言，本发明涉及1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺或其盐的药物组合物及其制备方法；属于医药技术领域。
背景技术
酪氨酸激酶是一组催化蛋白质酪氨酸残基磷酸化的酶，在细胞内的信号转导中起着重要的作用，它参与正常细胞的调节、信号传递和发育，也与肿瘤细胞的增殖、分化、迁移和凋亡密切相关。许多受体酪氨酸激酶都与肿瘤的形成相关，根据其细胞外区域结构的不同可分为表皮生长因子受体(EGFR)、血小板衍化生长因子受体(PDGFR)、血管内皮细胞生长因子受体(VEGFR)、成纤维细胞生长因子受体(FGFR)等。
国际专利申请WO2008112407在实施例24中公开了化合物1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺及其制备方法，它的结构式如式Ⅰ所示：
Figure PCTCN2015080868-appb-000001
它是一个多靶点的受体酪氨酸激酶抑制剂，能抑制血管内皮细胞生长因子受体(VEGFR1、VEGFR2/KDR和VEGFR3)、干细胞因子受体、血小板源生长因子受体等激酶活性，抑制VEGFR2介导的下游信号转导，从而抑制肿瘤新生血管生成。
本发明的目的在于寻找一种稳定的、适于临床使用的包含式I化合物的药物组合物。
发明内容
第一方面，本发明提供了一种药物组合物，其特征在于包含式I化合物或其可药用盐和/或其水合物作为活性成分以及至少一种药学上可接受的辅料，其中基于该药物组合物的重量含有0-3％重量的水。
在一些实施方案中，上述药物组合物为治疗患者肿瘤的药物组合物，所述的患者包括哺乳动物，优选人；所述的肿瘤选自结直肠癌、非小细胞肺癌、肾癌、肝癌、乳腺癌或胃肠道间质瘤。
在一些实施方案中，上述药物组合物以单位剂量为基础含有0.2mg-100mg的式I化合物或其可药用盐和/或其水合物；在一些实施方案中，上述药物组合物以单位剂量为基础含有0.5mg-30mg的式I化合物或其可药用盐和/或其水合物；在一些实施方案中，上述药物组 合物以单位剂量为基础含有1mg-20mg的式I化合物或其可药用盐和/或其水合物；在一些实施方案中，上述药物组合物以单位剂量为基础含有4mg-16mg的式I化合物或其可药用盐和/或其水合物；在一些实施方案中，上述药物组合物以单位剂量为基础含有8mg-16mg的式I化合物或其可药用盐和/或其水合物；在一些实施方案中，上述药物组合物以单位剂量为基础含有10mg-16mg的式I化合物或其可药用盐和/或其水合物；在一些实施方案中，上述药物组合物以单位剂量为基础含有10mg-14mg的式I化合物或其可药用盐和/或其水合物。在本发明中，例如，对于片剂或胶囊剂而言，“以单位剂量为基础含有12mg的式I化合物”意味着最终制成的每片片剂或每颗胶囊剂中含有12mg的式I化合物。
在一些实施方案中，上述药物组合物含有0-2.5％重量的水；在一些实施方案中，上述药物组合物含有0-2％重量的水；在一些实施方案中，上述药物组合物含有0-1.5％重量的水。
在一些实施方案中，式I化合物或其可药用盐和/或其水合物是唯一的活性成分。
在一些实施方案中，式I化合物或其可药用盐和/或其水合物的含量为0.5％-20％；在一些实施方案中，式I化合物或其可药用盐和/或其水合物的含量为1％-10％；在一些实施方案中，式I化合物或其可药用盐和/或其水合物的含量为2％-8％；在一些实施方案中，式I化合物或其可药用盐和/或其水合物的含量为3.5％-6％。
在一些实施方案中，本发明的药物组合物包含式I化合物或其可药用盐和/或其水合物作为活性成分、至少一种填充剂、至少一种崩解剂和至少一种润滑剂，其中基于该药物组合物的重量含有0-3％重量的水。
其中，所述的填充剂包括但不限于乳糖、淀粉、预胶化淀粉、甘露醇、微晶纤维素、葡萄糖中的一种或几种的混合物；在一些实施方案中，填充剂选自乳糖、淀粉、预胶化淀粉、微晶纤维素、甘露醇中的一种或几种的混合物；优选地，填充剂选自乳糖、微晶纤维素、甘露醇中的一种或几种的混合物；进一步优选地，填充剂选自微晶纤维素和/或甘露醇。
所述的崩解剂包括但不限于低取代羟丙基纤维素、交联羧甲纤维素钠、交联聚维酮、干淀粉、羧甲淀粉钠、羟丙基淀粉、聚山梨酯80、海藻酸钠中的一种或几种的混合物；在一些实施方案中，崩解剂选自低取代羟丙基纤维素、交联羧甲纤维素钠、交联聚维酮中的一种或几种的混合物；优选地，崩解剂选自低取代羟丙基纤维素和/或交联聚维酮。
所述的润滑剂包括但不限于聚乙二醇、硬脂酸镁、硬脂酸、硬脂酸钙、滑石粉、微粉硅胶、氢化蓖麻油、山嵛酸甘油酯、十二烷基硫酸钠、十二烷基硫酸镁中的一种或几种的混合物；在一些实施方案中，所述的润滑剂选自聚乙二醇、硬脂酸镁、氢化蓖麻油、山嵛酸甘油酯中的一种或几种的混合物；优选地，润滑剂为硬脂酸镁。
在一些实施方案中，所述填充剂的含量为30％-99％；优选地，填充剂的含量为50％-96％；更优选地，填充剂的含量为85％-96％。在一些实施方案中，所述崩解剂的含量为0.5％-10％；优选地，崩解剂的含量为1％-6％；更优选地，崩解剂的含量为2％-4％。在一些实施方案中，所述润滑剂的含量为0-5％；优选地，润滑剂的含量为0.1％-2％；更优选地，润滑剂的含量为0.1％-1％。
所述的药物组合物可进一步含有粘合剂、甜味剂、着色剂等。其中粘合剂的实例包括但不限于聚维酮、淀粉浆、糊精、糖粉、糖浆、微晶纤维素、纤维素衍生物(例如羟丙甲纤维素、甲基纤维素、羧甲基纤维素钠、乙基纤维素)、海藻酸钠、聚乙二醇、硅酸镁铝。甜 味剂的实例包括但不限于甜菊甙、阿斯巴坦。着色剂的实例包括但不限于二氧化钛、氧化铁红、氧化铁黄。
在一些实施方案中，本发明的药物组合物含有：式I化合物盐酸盐和/或其水合物、甘露醇、微晶纤维素、低取代羟丙基纤维素和硬脂酸镁，其特征在于含有0-3％重量的水。
在一些实施方案中，本发明的药物组合物含有：式I化合物二盐酸盐、甘露醇、微晶纤维素、低取代羟丙基纤维素和硬脂酸镁，其特征在于含有0-3％重量的水。
在一些实施方案中，本发明的药物组合物含有：2％-8％式I化合物二盐酸盐、25％-45％的甘露醇、25％-70％的微晶纤维素、1％-5％的低取代羟丙基纤维素和0.1％-1％的硬脂酸镁，其特征在于含有0-3％重量的水。
在一些实施方式中，本发明的药物组合物含有：3％-6％式I化合物二盐酸盐、30％-40％的甘露醇、50％-65％的微晶纤维素、1.5％-4％的低取代羟丙基纤维素和0.1％-1％的硬脂酸镁，其特征在于含有0-3％重量的水。
第二方面，本发明提供了上述药物组合物在制备用于抑制受体酪氨酸激酶的活性的药物中的用途；优选在制备用于治疗肿瘤的药物中的用途；进一步优选在制备用于治疗结直肠癌、非小细胞肺癌、肾癌、肝癌、乳腺癌或胃肠道间质瘤的药物中的用途。
第三方面，本发明提供了上述药物组合物的制备方法，其特征在于该方法包括以下步骤：
a)将填充剂过筛；
b)将崩解剂、步骤a)中得到的填充剂的水分含量分别处理至占各辅料重量的≤1.5％；
c)将式I化合物或其可药用盐和/或其水合物粉碎、过筛；
d)将步骤b)和步骤c)中所得的组分混合、过筛；
e)将步骤d)中得到的混合物与润滑剂混合。
上述步骤b)中可通过例如常规的干燥方法，包括但不限于常压50℃-120℃，干燥0.5h-4h；或真空40℃-100℃，干燥0.5h-4h；或70℃，流化干燥。优选常压105℃，干燥2小时，使得水分不超过1.5％(基于各辅料的重量)。上述步骤c)中的式I化合物或其可药用盐和/或其水合物的水分含量应小于2％，优选≤1.5％(基于式I化合物或其可药用盐和/或其水合物的重量)。
在某些特定的实施方案中，可进一步包括：检测步骤e)得到的混合物的水分，其水分含量应不大于3.0％，优选不大于2.0％，进一步优选不大于1.5％。
在某些特定的实施方案中，可进一步将步骤e)得到的混合物压制成片剂或填充入胶囊壳。
本发明的某些特定的实施方案提供了一种包含式I化合物二盐酸盐的胶囊的制备方法，其中水分含量≤3％，该方法包括以下步骤：
a)将微晶纤维素、甘露醇分别过筛；
b)将低取代羟丙基纤维素和步骤a)中得到的微晶纤维素、甘露醇分别于105℃干燥至水分含量占各辅料重量的≤1.5％；
c)将式I化合物二盐酸盐粉碎、过筛；
d)将步骤b)中得到的甘露醇、低取代羟丙基纤维素和步骤c)中得到的式I化合物二盐酸盐混合、过筛；然后，与步骤b)中得到的微晶纤维素混合、过筛；
e)将步骤d)中得到的混合物与硬脂酸镁混合；
f)将步骤e)中得到的混合物填充入胶囊。
在某些特定的实施方案中，可以进一步将胶囊进行冷铝包装。
上述制备方法中，步骤a)例如可以过0.8mm的筛；步骤c)例如可以过80目筛；步骤d)例如可以过0.8mm的筛；为了混合均匀，可以采用例如剪切混合的方法。上述步骤c)中的式I化合物二盐酸盐的水分含量应小于2％，优选≤1.5％(基于式I化合物二盐酸盐的重量)。
本发明中，所述的可药用盐包括但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、水杨酸等形成的酸加成盐。在一些实施方案中，所述的可药用盐为盐酸盐；在一些实施方案中，为盐酸盐的晶体形式；在某些特定的实施方案中，式I化合物或其可药用盐为式I化合物的二盐酸盐形式；在某些特定的实施方案中，为二盐酸盐的晶体形式。
本文中，所述的式I化合物盐酸盐的晶体形式包括但不限于中国专利申请CN102344438A公开的A、B和C型结晶，其中A和B型结晶为基本上不含结晶水和其他溶剂的结晶，C型结晶为含两个结晶水的结晶。在一些实施方案中，所述的化合物I的二盐酸盐的晶体形式为A型结晶。
本发明所述的药物组合物包括在制备药物组合物的过程中所制备得到的中间体，例如制备得到的步骤d)或步骤e)的混合物。在一些实施方案中，所述的药物组合物为口服固体药物组合物，所述的口服固体药物组合物包括但不限于散剂、颗粒剂、片剂、胶囊或丸剂。在一些实施方案中，所述的口服固体药物组合物为胶囊剂。在一些实施方案中，所述的口服固体药物组合物为硬胶囊剂。
本发明所述的药物组合物中，优选地，所述的辅料(包括但不限于填充剂、崩解剂和润滑剂)的水分含量≤1.5％，基于辅料的重量为基础计算。
本发明中，所述的药学上可接受的辅料包括但不限于填充剂、吸收剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、预胶化淀粉、甘露醇、微晶纤维素、葡萄糖等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等；粘合剂包括纤维素衍生物(例如羟丙甲纤维素、甲基纤维素、羧甲基纤维素钠、乙基纤维素)、海藻酸钠、聚乙二醇、硅酸镁铝、聚维酮、微晶纤维素、淀粉浆、糊精、糖粉、糖浆等；崩解剂包括交联羧甲纤维素钠、交联聚维酮、干淀粉、羧甲淀粉钠、羟丙基淀粉、聚山梨酯80、海藻酸钠、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、硬脂酸钙、硬脂酸、聚乙二醇、十二烷基硫酸钠、十二烷基硫酸镁、氢化蓖麻油、山嵛酸甘油酯、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
本发明中，除非特别说明，所述的百分数均以药物组合物的重量为基础计算。
式I化合物或其可药用盐在储存的过程中，会产生某些杂质，例如杂质A；同时原有 的某些杂质含量会增高，例如杂质B、C。这些杂质均会影响药品的纯度，使药品的质量下降并进一步影响药品的临床使用。上述杂质A、B、C的具体结构如下所示：
Figure PCTCN2015080868-appb-000002
1-(((4-((3-苄基-4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-甲氧基喹啉-7-基)氧基)甲基)环丙胺；
Figure PCTCN2015080868-appb-000003
1-(((4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-羟基喹啉-7-基)氧基)甲基)环丙胺；
Figure PCTCN2015080868-appb-000004
4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-甲氧基-7-羟基喹啉。
经过大量的研究，发明人发现本发明通过控制药物组合物中水分的含量，在储存过程中，组合物具有良好的稳定性，能够有效控制杂质A、B、C以及其他杂质的产生或增长，提高药物组合物中的活性成份的纯度，提高产品质量，提高药品疗效，并降低药品的毒副作用，有利于药品的临床应用。本发明提供的制备药物组合物的方法简便易行，且获得的药品具有良好的稳定性。
具体实施方式
下面结合具体实施例对本发明进行进一步的描述，然而，本发明中这些实施例仅用于阐明而不是限制本发明的范围。
实施例1式I化合物二盐酸盐同辅料湿法制粒后稳定性试验
先将式I化合物二盐酸盐溶于4倍重量的水中，再分别将式I化合物二盐酸盐水溶液滴加入各种辅料粉末中混合均匀制备软材；将软材过20目筛制粒，颗粒在40℃条件下减压干燥；再将所得干颗粒在密封、遮光、60℃环境下放置10天，以性状和杂质总量为指标考察式I化合物二盐酸盐的稳定性。其中杂质总量测定采用HPLC法，试验结果如表1所示。
表1式I化合物二盐酸盐的稳定性试验结果(放置10天后)
Figure PCTCN2015080868-appb-000005
其中，式I化合物二盐酸盐在试验前为类白色粉末，杂质总量为0.78％；在溶于4倍量水时溶解迅速，溶液为淡黄色液体，且粘度较大。所得的药物组合物稳定性差，主要表现在：颜色加深，且有关物质增加明显。
实施例2式I化合物二盐酸盐同辅料干法混合后稳定性试验
将辅料与式I化合物二盐酸盐分别过80目筛后，按照辅料：式I化合物二盐酸盐＝20：1(重量：重量)比例混合均匀。将所得混合粉末在密封、遮光、60℃环境下放置10天，以性状和杂质总量考察式I化合物二盐酸盐的稳定性。其中杂质总量测定采用HPLC法，试验结果如表2所示。
表2式I化合物二盐酸盐的稳定性试验结果(放置10天后)
Figure PCTCN2015080868-appb-000006
其中，式I化合物二盐酸盐在试验前为类白色粉末，杂质总量为0.78％。
实施例3式I化合物二盐酸盐的制剂及其稳定性试验
参照表3和表4的处方和制剂工艺制备得处方1-4，并分别进行高温(40℃10天、40℃10天)、高湿(25℃，相对湿度75％±5％)试验，并采用HPLC测定杂质总量，试验结果如表5所示。
表3
Figure PCTCN2015080868-appb-000007
表4
Figure PCTCN2015080868-appb-000008
表5处方1-4中式I化合物二盐酸盐的稳定性结果
Figure PCTCN2015080868-appb-000009
实施例4式I化合物二盐酸盐的胶囊
表6式I化合物二盐酸盐的胶囊的处方(1000粒用量)
Figure PCTCN2015080868-appb-000010
制备方法：
1)将微晶纤维素、甘露醇过0.8mm筛；
2)将微晶纤维素、甘露醇、低取代羟丙基纤维素，分别于常压105℃干燥2小时备用， 水分均控制在1.5％(基于各辅料的重量)以下；
3)将式I化合物二盐酸盐粉碎，过80目筛；
4)式I化合物二盐酸盐和甘露醇及低取代羟丙基纤维素于塑料袋内初步混合，过0.8mm筛网，剪切混合6遍；
5)向上述粉末中加入微晶纤维素于塑料袋内初步混合，继续过0.8mm筛网，剪切混合6遍；
6)加入硬脂酸镁总混；
7)检测中间体水分及含量，水分应小于2％；
8)填充入明胶胶囊。
实施例5稳定性试验
将实施例4中规格为12mg/粒的胶囊按双铝包装，在加速试验条件(温度40℃±2℃，相对湿度75％±5％)下放置，分别于1个月、2个月、3个月时取样，并采用HPLC方法分析样品的杂质含量。
将实施例4中规格为12mg/粒的胶囊按双铝包装，在长期试验条件(温度25℃±2℃，相对湿度60％±10％)下放置，于3个月时取样，并采用HPLC方法分析样品的杂质含量。
上述试验结果如表7所示。
表7式I化合物二盐酸盐的胶囊的稳定性数据
Figure PCTCN2015080868-appb-000011

Claims (13)

  1. 一种药物组合物，其特征在于，所述药物组合物包含式I化合物或其可药用盐和/或其水合物作为活性成分以及至少一种药学上可接受的辅料，其中所述药物组合物基于该药物组合物的重量含有0-3％重量的水；
    Figure PCTCN2015080868-appb-100001
  2. 权利要求1所述的药物组合物，其特征在于，所述药物组合物包含式I化合物或其可药用盐和/或其水合物作为活性成分、至少一种填充剂、至少一种崩解剂和至少一种润滑剂，其中所述药物组合物基于该药物组合物的重量含有0-3％重量的水；
    Figure PCTCN2015080868-appb-100002
  3. 权利要求2所述的药物组合物，其中：
    所述的填充剂选自乳糖、淀粉、预胶化淀粉、甘露醇、微晶纤维素或葡萄糖中的一种或几种的混合物；
    所述的崩解剂选自低取代羟丙基纤维素、交联羧甲纤维素钠、交联聚维酮、干淀粉、羧甲淀粉钠、羟丙基淀粉、聚山梨酯80、海藻酸钠中的一种或几种的混合物；
    所述的润滑剂选自聚乙二醇、硬脂酸镁、硬脂酸、硬脂酸钙、滑石粉、微粉硅胶、氢化蓖麻油、山嵛酸甘油酯、十二烷基硫酸钠、十二烷基硫酸镁中的一种或几种的混合物。
  4. 权利要求2或3所述的药物组合物，其中：
    式I化合物或其可药用盐和/或其水合物的含量为0.5％-20％、优选1％-10％、更优选2％-8％、进一步优选3.5％-6％；
    所述填充剂的含量为30％-99％、优选50％-96％、更优选85％-96％；
    所述崩解剂的含量为0.5％-10％、优选1％-6％、更优选2％-4％；
    所述润滑剂的含量为0-5％、优选0.1％-2％、更优选0.1％-1％。
  5. 权利要求1所述的药物组合物，其含有：式I化合物盐酸盐和/或其水合物、甘露醇、微晶纤维素、低取代羟丙基纤维素和硬脂酸镁，其特征在于，所述药物组合物基于该药物组合物的重量含有0-3％重量的水；
    Figure PCTCN2015080868-appb-100003
  6. 权利要求5所述的药物组合物，其中式I化合物盐酸盐和/或其水合物为式I化合物二盐酸盐。
  7. 权利要求6所述的药物组合物，其特征在于，所述药物组合物基于该药物组合物的重量含有2％-8％式I化合物二盐酸盐、25％-45％的甘露醇、25％-70％的微晶纤维素、1％-5％的低取代羟丙基纤维素和0.1％-1％的硬脂酸镁。
  8. 权利要求6所述的药物组合物，其特征在于，所述药物组合物基于该药物组合物的重量含有3％-6％式I化合物二盐酸盐、30％-40％的甘露醇、50％-65％的微晶纤维素、1.5％-4％的低取代羟丙基纤维素和0.1％-1％的硬脂酸镁。
  9. 权利要求1-8任一项所述的药物组合物，其特征在于，所述药物组合物基于该药物组合物的重量含有0-2.5％重量的水，优选含有0-2％重量的水，进一步优选含有0-1.5％重量的水。
  10. 权利要求1-9任一项所述的药物组合物，其特征在于，所述药物组合物为治疗患者肿瘤的药物组合物，所述的患者包括哺乳动物，优选人；所述的肿瘤选自结直肠癌、非小细胞肺癌、肾癌、肝癌、乳腺癌或胃肠道间质瘤。
  11. 权利要求1-10任一项所述的药物组合物在制备用于抑制受体酪氨酸激酶的活性的药物中的用途；优选在制备用于治疗肿瘤的药物中的用途；进一步优选在制备用于治疗结直肠癌、非小细胞肺癌、肾癌、肝癌、乳腺癌或胃肠道间质瘤的药物中的用途。
  12. 权利要求2-10任一项所述的药物组合物的制备方法，其特征在于，所述方法包括以下步骤：
    a)将所述填充剂过筛；
    b)将所述崩解剂、步骤a)中得到的填充剂的水分含量分别处理至占各辅料重量的≤1.5％；
    c)将式I化合物或其可药用盐和/或其水合物粉碎、过筛；
    d)将步骤b)和步骤c)中所得的组分混合、过筛；
    e)将步骤d)中得到的混合物与所述润滑剂混合。
  13. 权利要求12所述的制备方法，其中所述药物组合物为胶囊剂，所述制备方法包括以下步骤：
    Figure PCTCN2015080868-appb-100004
    a)将微晶纤维素、甘露醇分别过筛；
    b)将低取代羟丙基纤维素和步骤a)中得到的微晶纤维素、甘露醇分别于105℃干燥至水分含量占各辅料重量的≤1.5％；
    c)将式I化合物二盐酸盐粉碎、过筛；
    d)将步骤b)中得到的甘露醇、低取代羟丙基纤维素和步骤c)中得到的式I化合物二盐酸盐混合、过筛；然后，与步骤b)中得到的微晶纤维素混合、过筛；
    e)将步骤d)中得到的混合物与硬脂酸镁混合；
    f)将步骤e)中得到的混合物填充入胶囊。
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