WO2013078973A1 - Dasatinib à grand diamètre des particules et sa préparation et son utilisation - Google Patents

Dasatinib à grand diamètre des particules et sa préparation et son utilisation Download PDF

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Publication number
WO2013078973A1
WO2013078973A1 PCT/CN2012/085282 CN2012085282W WO2013078973A1 WO 2013078973 A1 WO2013078973 A1 WO 2013078973A1 CN 2012085282 W CN2012085282 W CN 2012085282W WO 2013078973 A1 WO2013078973 A1 WO 2013078973A1
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WO
WIPO (PCT)
Prior art keywords
dasatinib
organic solvent
particle size
temperature
large particle
Prior art date
Application number
PCT/CN2012/085282
Other languages
English (en)
Chinese (zh)
Inventor
安晓霞
吕峰
申淑匣
张静
李小强
Original Assignee
上海创诺制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201110386631.8A external-priority patent/CN102429880B/zh
Priority claimed from CN 201110388046 external-priority patent/CN102408423B/zh
Application filed by 上海创诺制药有限公司 filed Critical 上海创诺制药有限公司
Publication of WO2013078973A1 publication Critical patent/WO2013078973A1/fr

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Classifications

    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to a large particle size dasatinib and its preparation and application, and belongs to the technical field of pharmaceutical preparations.
  • Dasatinib is a potent carcinogenic kinase inhibitor developed by Bristol-Myers Squibb and has been used clinically to treat imatinib mesylate/Gleevec resistance. Treatment of adult patients with all stages of chronic myeloid leukemia (chronic phase, accelerated phase, lymphoid cell blast phase, and myelocyte blast crisis), Philadelphia chromosome-positive acute lymphoblastic leukemia, and solid tumor patients. Among the approved drugs, Sprycel is the first oral chemotherapeutic drug that inhibits multiple configurations of the tyrosine kinase Abl.
  • the drug inhibits multiple kinases such as Bcr-Abl, the SRC kinase family (SRC, LCK, YES, FYN), c-KIT, EPHA2 and PDGFR-B.
  • SRC SRC kinase family
  • c-KIT c-KIT
  • EPHA2 EPHA2
  • PDGFR-B PDGFR-B
  • Monohydrate 48 g of dasatinib, 1056 ml (22 ml/g) of ethanol and 144 ml of water were added, heated to 75 ° C to dissolve, and purified by filtration and transferred to a receiver.
  • the dissolution reactor and transfer line were rinsed with a mixture of 43 ml of ethanol and 5 ml of water.
  • the solution was heated to 75-80 ° C to completely dissolve, 384 ml of water was added and the solution temperature was maintained between 75 and 80 ° C.
  • Pure form of TIHI-7 (pure form and pharmaceutically acceptable carrier):
  • the dasatinib monohydrate is prepared by heating at a temperature above the dehydration temperature.
  • the saturated solubility of anhydrate in water is greater than that of monohydrate (anhydrous
  • the existing dasatinib tablets are made of dasatinib monohydrate as a raw material, how to use dasatinib anhydrate as a raw material to prepare quality dasatinib tablets, which has not been seen yet.
  • the solid physical properties of the drug also have an important influence on the dissolution rate of the preparation and the difficulty of tableting.
  • the particle size of a drug can affect the fluidity and compressibility of the drug.
  • the filtration and washing treatment of small particles takes a long time and the loss is large, which tends to lead to an increase in the production cost, which is disadvantageous for industrial production requirements. Summary of the invention
  • Another object of the present invention is to provide a quality-compliant dasatinib tablet prepared by using dasatinib anhydrate as a raw material to meet the requirements of industrial mass production of dasatinib raw materials and preparations: low cost
  • the process is simple and the quality meets the requirements.
  • the dasatinib is obtained by the following method, comprising the steps of: a) adding dasatinib to an organic solvent to obtain a slurry;
  • 1 gram of dasatinib is added with 10 to 50 ml of an organic solvent.
  • the dasatinib is any known crystal form.
  • the organic solvent is a low boiling organic solvent; preferably, the organic solvent is any one of acetone, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile.
  • the dasatinib is an anhydrate; preferably, the dasatinib is obtained by the following method, comprising the steps of:
  • a second aspect of the present invention provides a method for preparing a large particle size dasatinib, comprising the steps of: a) adding dasatinib to an organic solvent to obtain a slurry;
  • the dasatinib is any known crystal form, for example: dasatinib monohydrate, butanol solvate, ethanol solvate, pure form N-6, pure form hydrazine-7.
  • the organic solvent is preferably a low boiling point solvent, and is preferably any one of acetone, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile.
  • the dasatinib tablet comprises dasatinib and a filler, a binder, a disintegrant, and a lubricant.
  • the dasatinib tablet has the following composition prescription:
  • Lubricant 0.5 to 1.5 parts by mass.
  • the filler is any one or a mixture of two or more of microcrystalline cellulose, lactose, and pregelatinized starch.
  • the binder is hydroxypropylmethylcellulose or starch.
  • the disintegrant is crospovidone, croscarmellose sodium or sodium carboxymethyl starch.
  • the lubricant is magnesium stearate.
  • the dasatinib anhydrate of the particle size range described in the present invention can be obtained by the following chemical treatment:
  • the organic solvent is preferably a low boiling point solvent, and is preferably any one of acetone, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile.
  • the dasatinib anhydrate of the particle size range described in the present invention can also be obtained by a physical sieving method or other methods.
  • the dasatinib tablet of the present invention can be obtained by first wet granulation and then tableting, or can be obtained by direct powder tableting.
  • the present invention uses dasatinib anhydrate as a raw material to obtain a dasatinib tablet of satisfactory quality, and solves the problem that the dasatinib anhydrate has a large saturation solubility in water, and is easy to be
  • the tablets which result in the preparation of anhydrate have a dissolution rate too fast, an adverse reaction caused by drug burst release, a shortened time for maintaining the efficacy, and a problem that the dissolution is unacceptable, and can satisfy the raw materials and preparations of dasatinib.
  • Industrial mass production requirements low cost, simple process, quality meets requirements. The invention will be further elucidated below in conjunction with specific implementations.
  • the particle sizes described in the examples were obtained by Malvern laser diffraction using a Mastersizer 2000 laser granulometer.
  • the dasatinib described in the examples is any crystal form prepared by the preparation method disclosed in Chinese Patent No. CN200580011916.6.
  • the dasatinib anhydrate used in the examples was prepared by the preparation method of the pure form of N-6 disclosed in Chinese Patent No. CN200580011916.6.
  • Example 1
  • the tablet prescription is as follows:
  • the angle of repose of the mixed powder was measured in accordance with the measurement method of the United States Pharmacopoeia USP32 angle of repose.
  • the hardness and disintegration time of the prepared tablets were measured by a four-way meter.
  • the angle of repose of the mixed powder of this example was measured to be 36°, indicating that it had good fluidity.
  • the hardness and disintegration time of the prepared tablets were measured by a four-way meter, and the results were as follows:
  • Disintegration time 1.5min, in line with the quality requirements of the tablet.
  • the tablets prepared in this example and the existing tablets were measured at pH 4.0 + 1.0%.
  • the dissolution results in the Triton medium are shown in Table 2.
  • the angle of repose of the mixed powder of this example was measured to be 33°, indicating that it had good fluidity.
  • the hardness and disintegration time of the prepared tablets were measured by a four-way meter, and the results were as follows:
  • Disintegration time 2.5min, in line with tablet quality requirements.
  • the prescribed amount of dasatinib anhydrate and microcrystalline cellulose and 70% of the prescribed amount of starch are evenly mixed, and the remaining 30% of the prescribed amount of starch is made into 8% starch slurry, which is wet granulated with starch slurry. Dry, then add a prescribed amount of croscarmellose sodium and magnesium stearate, mix and compress.
  • the angle of repose of the mixed powder of the present example was measured with reference to the method for determining the angle of repose of the USP 32 USP. It is 30°, indicating good fluidity.
  • the hardness and disintegration time of the prepared tablets were measured by a four-way meter, and the results were as follows:
  • Disintegration time 3.5min, in line with tablet quality requirements.
  • the tablets prepared in this example and the existing tablets were measured at pH 4.0 + 1.0%.
  • the dissolution results in the Triton medium are shown in Table 4.
  • the mixed powder of the present example was measured to have an angle of repose of 48°, which was inferior in fluidity.
  • the hardness and disintegration time of the prepared tablets were measured by a four-way meter, and the results were as follows:
  • the tablets prepared in this example were compared with the existing tablets according to the dissolution test method published by the FDA.
  • the dissolution results of the tablets of the same specification prepared with dasatinib monohydrate as raw materials in the pH 4.0 + 1.0% Triton medium are shown in Table 5.
  • the tablet prepared by directly using the dasatinib anhydrate prepared by the prior art has a dissolution rate too fast, and is easy to produce an adverse reaction caused by drug burst release, and the maintenance time of the drug is short, and the dissolution rate is not
  • the present invention effectively solves the above problems, and obtains a tablet having a certain particle size range to obtain a tablet having a certain particle size range, thereby obtaining a Dashatin which is comparable or superior to the existing tablet.
  • Niobium meets the requirements for industrial mass production of dasatinib raw materials and preparations: low cost, simple process and quality.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur du désatinibe à grand diamètre des particules et sur sa préparation et son utilisation, la plage du diamètre des particules du Dasatinibe à grand diamètre des particules étant : D(0,1)=3,0-10µm, D(0,5)=15-60µm, D(0,9)=100-150µm. Avec une fluidité et une compressibilité élevée et une solubilité modérée, le Dasatinibe ayant un grand diamètre des particules facilite la préparation de formulation qualifiée et réduit les coûts de matière première et de préparation de formulation, ce qui satisfait ainsi aux exigences pour une production industrialisée. Le dasatinib à grand diamètre des particules de la présente invention peut être utilisé pour préparer des comprimés de dasatinib et les comprimés préparés permettent de résoudre les problèmes d'une vitesse de dissolution trop élevée, d'une réaction non voulue provoquée par une libération trop rapide de médicament, d'une durée efficace du médicament raccourcie et de la survenue facile de dissolution non qualifiée.
PCT/CN2012/085282 2011-11-29 2012-11-26 Dasatinib à grand diamètre des particules et sa préparation et son utilisation WO2013078973A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201110386631.8A CN102429880B (zh) 2011-11-29 2011-11-29 一种达沙替尼片
CN201110386631.8 2011-11-29
CN201110388046.1 2011-11-29
CN 201110388046 CN102408423B (zh) 2011-11-29 2011-11-29 一种制备大粒径达沙替尼的方法

Publications (1)

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WO2013078973A1 true WO2013078973A1 (fr) 2013-06-06

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053854A2 (fr) * 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2010139979A2 (fr) * 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2010139981A2 (fr) * 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2011095588A1 (fr) * 2010-02-04 2011-08-11 Ratiopharm Gmbh Composition pharmaceutique comprenant du n-(2-chloro-6-méthylphényl)-2-[[6-[4-(2-hydroxyéthyl)-1-pipérazinyl]-2-méthyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide
CN102408423A (zh) * 2011-11-29 2012-04-11 上海希迪制药有限公司 一种制备大粒径达沙替尼的方法
CN102429880A (zh) * 2011-11-29 2012-05-02 上海希迪制药有限公司 一种达沙替尼片

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053854A2 (fr) * 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2010139979A2 (fr) * 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2010139981A2 (fr) * 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2011095588A1 (fr) * 2010-02-04 2011-08-11 Ratiopharm Gmbh Composition pharmaceutique comprenant du n-(2-chloro-6-méthylphényl)-2-[[6-[4-(2-hydroxyéthyl)-1-pipérazinyl]-2-méthyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide
CN102408423A (zh) * 2011-11-29 2012-04-11 上海希迪制药有限公司 一种制备大粒径达沙替尼的方法
CN102429880A (zh) * 2011-11-29 2012-05-02 上海希迪制药有限公司 一种达沙替尼片

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