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WO2022100641A1 - Composition pharmaceutique contenant un inhibiteur de r-egf, et son procédé de préparation - Google Patents

Composition pharmaceutique contenant un inhibiteur de r-egf, et son procédé de préparation Download PDF

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Publication number
WO2022100641A1
WO2022100641A1 PCT/CN2021/129946 CN2021129946W WO2022100641A1 WO 2022100641 A1 WO2022100641 A1 WO 2022100641A1 CN 2021129946 W CN2021129946 W CN 2021129946W WO 2022100641 A1 WO2022100641 A1 WO 2022100641A1
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Prior art keywords
pharmaceutical composition
unit dosage
dosage form
weight
active ingredient
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2021/129946
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English (en)
Chinese (zh)
Inventor
王吉标
江涛涛
杨菡
但招陵
朱科屹
金勋奇
曾振亚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
Original Assignee
Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Filing date
Publication date
Application filed by Yangtze River Pharmaceutical Group Co Ltd, Shanghai Haiyan Pharmaceutical Technology Co Ltd filed Critical Yangtze River Pharmaceutical Group Co Ltd
Priority to CN202180063364.2A priority Critical patent/CN116157391B/zh
Publication of WO2022100641A1 publication Critical patent/WO2022100641A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention belongs to the field of pharmacy, and particularly relates to a pharmaceutical composition comprising an EGFR inhibitor and a preparation method for preparing the pharmaceutical composition.
  • the present invention provides N-(2-(4-(dimethylamino)piperidin-1-yl)-5-(5) with reducing, eliminating or preventing sticking phenomenon.
  • an optional binder component up to 10% by weight of the pharmaceutical composition
  • a lubricant component from about 0.01% to about 10% by weight of the pharmaceutical composition
  • the pharmaceutically acceptable carrier comprises: a) a filler component, comprising about 75% to about 92% by weight of the pharmaceutical composition; b) a disintegrant component, comprising about 75% by weight of the pharmaceutical composition 1% to about 8%; and c) a lubricant component, from about 1% to about 5% by weight of the pharmaceutical composition.
  • the pharmaceutically acceptable carrier comprises: a) a filler component, comprising about 80% to about 90% by weight of the pharmaceutical composition; b) a disintegrant component, comprising about 80% by weight of the pharmaceutical composition 1% to about 5%; and c) a lubricant component from about 1% to about 3% by weight of the pharmaceutical composition.
  • the lubricant component can be selected from a variety of lubricants available in the pharmaceutical field.
  • suitable lubricants include talc, magnesium stearate, hydrogenated soybean oil, glyceryl behenate, micronized silica gel, polyethylene glycol 6000, sodium stearate fumarate, and mixtures thereof.
  • the lubricant component is selected from the group consisting of talc, magnesium stearate, and combinations thereof.
  • the lubricant component will comprise from about 0.01% to about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant component comprises from about 0.1% to about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant component comprises from about 0.1% to about 8% by weight of the pharmaceutical composition. In some embodiments, the lubricant component comprises from about 1% to about 8% by weight of the pharmaceutical composition. In some embodiments, the lubricant component comprises from about 0.1% to about 5% by weight of the pharmaceutical composition. In some embodiments, the lubricant component comprises from about 0.5% to about 8% by weight of the pharmaceutical composition. In some embodiments, the lubricant component comprises from about 0.5% to about 5% by weight of the pharmaceutical composition.
  • lactose can be selected from commercially available lactose applicable in the pharmaceutical field, including Flowlac 100, FlowLac 90, Tablettose 100, and SpheroLac 100.
  • the microcrystalline cellulose can be selected from commercially available microcrystalline cellulose suitable for use in the pharmaceutical field, including MCC pH101, MCC pH102, MCC pH302, MCC pH112, MCC pH200.
  • Pregelatinized starch also known as modified starch
  • the silicified microcrystalline cellulose can be selected from commercially available silicified microcrystalline cellulose suitable for the pharmaceutical field, including SMCC50 and SMCC90.
  • active ingredient refers to N-(2-(4-(dimethylamino)piperidin-1-yl)-5-(5-fluoro-4-(1-methyl-1H-) Pyrazol-4-yl)pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide maleate salt (ie compound of formula (X)).
  • the X-ray powder diffraction pattern of the crystal form C-1 further has a peak at the following diffraction angle 2 ⁇ (°) value: 37.10 ⁇ 0.10.
  • the active ingredient exists in the form of crystal form C-1, the X-ray powder diffraction pattern of which is substantially as shown in FIG. 1 .
  • Tablets can be prepared by conventional compression, wet granulation or dry granulation methods.
  • the dosage form of the present invention is a direct-mix compressed tablet.
  • Such tablets can generally be between about 50 mg and about 1000 mg, and in some embodiments, the weight of the tablet includes about 150 mg, about 200 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, etc. , depending on the dose required for therapeutic use.
  • the unit dosage form comprises about 74 mg of Form C-1 having XRPD peaks at the following diffraction angle 2 ⁇ (°) values: 8.73 ⁇ 0.10, 13.37 ⁇ 0.10, 18.08 ⁇ 0.10, and 25.55 ⁇ 0.10; About 631 mg of cellulose lactose complex (eg, cellulose lactose complex Cellactose 80); about 22.5 mg of crospovidone (eg, PVPP XL-10); about 7.5 mg of talc and about 15 mg of magnesium stearate.
  • cellulose lactose complex eg, cellulose lactose complex Cellactose 80
  • crospovidone eg, PVPP XL-10
  • the pharmaceutical composition is prepared by a non-aqueous method (ie, a method that does not employ water) such as dry granulation, roller compaction, or direct powder mixing.
  • a non-aqueous method ie, a method that does not employ water
  • dry granulation roller compaction, or direct powder mixing.
  • roller compaction roller compaction
  • direct powder mixing a non-aqueous method
  • the use of non-aqueous methods can provide pharmaceutical compositions and formulations thereof with more improved properties, such as improved stability, compared to aqueous preparation methods such as wet granulation.
  • non-aqueous processes ie, processes that do not employ water
  • non-aqueous methods include dry granulation, roller compaction or direct powder mixing as known in the art.
  • the active ingredient N-(2-(4-(dimethylamino)piperidin-1-yl)-5-(5-fluoro-4-(1-methyl) be mixed with the other ingredients of the formulation -1H-pyrazol-4-yl)pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide maleate was micronized.
  • the order of addition of the active ingredient, filler component, optional binder component, optional disintegrant component, lubricant component is not critical, although it is generally preferred that the active ingredient be added prior to mixing with the lubricant component.
  • the ingredients, filler component, optional binder component, optional disintegrant component are mixed.
  • Tablets may also include one or more surface coatings, such as clear coatings and/or colored coatings.
  • surface coatings such as clear coatings and/or colored coatings.
  • Various coatings and methods of their application are known in the art, including those disclosed in Remington's Pharmaceutical Sciences (17th Edition, Mack Publishing Company, Easton, Pa., 1985).
  • Film coatings useful in the formulations of the present invention are known in the art and typically contain polymers (usually cellulosic polymers), colorants and plasticizers. Additional ingredients such as sugars, flavors, oils and lubricants can be included in the film coating formulation to impart certain properties to the film coating.
  • the compositions and formulations herein can also be combined and processed into solids that are then placed in capsule forms such as gelatin capsules.
  • the word “about” used in the present invention before weight percent means a range value of ⁇ 5%, or ⁇ 2%, or ⁇ 1%.
  • the word “about” used before a weight value indicates a range value of ⁇ 10 mg, or ⁇ 5 mg, or ⁇ 2 mg, or ⁇ 1 mg.
  • Fig. 2 is the dissolution curves of DF12, DF13 and DF14 formulations (the abscissa is time (min), and the ordinate is dissolution rate (%)).
  • Figure 3 is the dissolution curve diagram of the DF15 prescription (the abscissa is time (min), the ordinate is the dissolution rate (%)).
  • the pharmaceutically acceptable carriers used in the following examples of the present invention are all commercially available.
  • crystal form C-1 takes the diffraction peak with the highest peak height (the peak with a 2 ⁇ (°) value of 25.55) as the base peak, and defines its relative intensity as 100% as I 0 .
  • the ratio of the peak height to the base peak peak height is used as its relative intensity I/I 0 , and the definition of the relative intensity of each peak is shown in the following table:
  • the pharmaceutical composition and the preparation thereof of the present invention have good stability and no sticking phenomenon in the preparation production process, and are suitable for industrial production.
  • Preparation of DF1 The crystal form C-1 and SMCC 50 were mixed uniformly by the method of adding equal amounts, and magnesium stearate was added and mixed for 3 minutes, and then directly compressed.
  • Preparation of DF2 The crystal form C-1 and SMCC 90 were mixed uniformly by the method of adding equal amounts, and magnesium stearate was added and mixed for 3 minutes, and then directly compressed.
  • Preparation of DF9 Premix crystal form C-1, Cellacose 80, talc, and PVPP XL-10 with a mixer for 20 minutes, add magnesium stearate, and carry out total mixing for 3 minutes. Using a 7mm diameter punch, rotary tableting.
  • the difference in filling volume should not exceed ⁇ 5%, and the friability should be checked during the tableting process: the weight loss should not exceed 1%, and broken, cracked and crushed tablets should not be detected, and the hardness should not be lower than 90N and not higher than 150N .
  • DF17 The crystal form C-1, Starch 1500, mannitol 200SD, and HPC-LF were sieved and mixed uniformly. Glyceryl behenate was added to the mixed powder and mixed for 3 min. Magnesium stearate was added and mixed for 3 min. Direct compression.
  • Preparation of WF3 Weigh the prescribed amount of PVP k30 in 100 g of water, and the preparation concentration is 10%. Pass all the accessories through a 60-mesh sieve for later use. Weigh the raw and auxiliary materials (except magnesium stearate) in the recipe amount, sieve through a 30-mesh sieve for 5 times, and mix in a mixer for 10 minutes. Slowly add the binder solution to the mixed powder for granulation, and pass the soft material through a 20-mesh sieve. Dry the wet granules to LOD ⁇ 2%. The dried granules were passed through a 24 mesh screen. Add the magnesium stearate of the prescription amount to the dry granules, and mix in the mixer for 3min. Tablet, hardness 60-70N, punch diameter 7mm.
  • the following tablet formulation DF18 containing Form C-1 was prepared using a dry granulation method, and the tablet composition is shown in Table 6. Its preparation method is as follows:
  • the following tablet formulation D1 containing Form C-1 was prepared using the powder direct mixing and tableting method, and the tablet composition is shown in Table 7.
  • the preparation method is as follows: the crystal form C-1 and starch are mixed and sieved, and then mixed with the above-mentioned other components evenly, and directly compressed into tablets.
  • Table 8 shows the one-sided conditions of the tablet formulations from Tables 1 to 6 in Preparation Examples 2-4 and the D1 tablet formulation of Comparative Example 1 after compressing 1000 tablets:
  • the prepared DF7, DF8, and DF9 prescription tablets were placed at 40°C and 60°C, respectively, and samples were taken at certain time points to detect impurities and investigate their stability.
  • the test results are shown in Table 9.
  • the prepared DF12 to DF14 prescription tablets were placed at 40°C/75% RH and 60°C, respectively, and samples were taken at a certain time point to detect impurities and investigate their stability.
  • the test results are shown in Table 10.
  • the prepared WF1, WF2, WF3, and WF4 prescription tablets were respectively set out at 60°C, and samples were taken after 30 days to detect impurities and investigate their stability. The test results are shown in Table 11.
  • the prepared DF12 and D1 prescription tablets were set out at a high temperature of 80°C, and samples were taken after 48 hours to detect impurities and investigate their stability. The test results are shown in Table 12.
  • the prepared DF18 prescription tablets were placed under the conditions of 60°C and 40°C/75% RH, and samples were taken at a certain time point to detect impurities and investigate their stability.
  • the test results are shown in Table 13.
  • the tablet formulation prepared in the above preparation example was subjected to in vitro dissolution test, and its dissolution in the dissolution medium was pH6.8 buffer + 0.1% SDS.
  • the device is a paddle method, the water bath temperature is 37.0 °C, the dissolution volume is 900 ml, the rotation speed is 50 rpm, and the sampling time is 5 min, 10 min, 15 min, 20 min, 30 min, 45 min and 60 min.
  • the sampling volume is 5ml.
  • the filter membrane is a polyethersulfone filter.

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

Abstract

La présente invention concerne une composition pharmaceutique contenant du maléate de N-(2-(4-(diméthylamino)pipéridin-1-yl)-5-(5-fluoro-4-(1-méthyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-4-méthoxyphényl)acrylamide, ainsi qu'un procédé de préparation et une utilisation de celle-ci. Selon la composition pharmaceutique, l'agglutination dans un processus de préparation est évitée, et la stabilité de la composition pharmaceutique est améliorée.
PCT/CN2021/129946 2020-11-11 2021-11-11 Composition pharmaceutique contenant un inhibiteur de r-egf, et son procédé de préparation Ceased WO2022100641A1 (fr)

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CN202180063364.2A CN116157391B (zh) 2020-11-11 2021-11-11 包含egfr抑制剂的药物组合物及其制备方法

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CN202011254166.8 2020-11-11

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2024255858A1 (fr) * 2023-06-15 2024-12-19 西藏海思科制药有限公司 Composition pharmaceutique orale de composé amide peptidique et son procédé de préparation
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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CN110368367A (zh) * 2019-08-27 2019-10-25 佛山市南海东方澳龙制药有限公司 盐酸多西环素片剂及其制备方法和应用、抗菌药物

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WO2017016463A1 (fr) * 2015-07-24 2017-02-02 上海海雁医药科技有限公司 Inhibiteur de l'egfr et sel pharmaceutiquement acceptable et polymorphe de celui-ci, et utilisation associée
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2024255858A1 (fr) * 2023-06-15 2024-12-19 西藏海思科制药有限公司 Composition pharmaceutique orale de composé amide peptidique et son procédé de préparation
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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CN116157391A (zh) 2023-05-23
CN116157391B (zh) 2025-06-24

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