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WO2017028660A1 - Composition pharmaceutique contenant un dérivé de la quinoléine ou un sel correspondant - Google Patents

Composition pharmaceutique contenant un dérivé de la quinoléine ou un sel correspondant Download PDF

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Publication number
WO2017028660A1
WO2017028660A1 PCT/CN2016/091717 CN2016091717W WO2017028660A1 WO 2017028660 A1 WO2017028660 A1 WO 2017028660A1 CN 2016091717 W CN2016091717 W CN 2016091717W WO 2017028660 A1 WO2017028660 A1 WO 2017028660A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
arginine
total weight
group
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/CN2016/091717
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English (en)
Chinese (zh)
Inventor
陈爱玲
王聪
刘凯
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.)
Jiangsu Hengrui Medicine Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
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
Application filed by Jiangsu Hengrui Medicine Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CN201680003848.7A priority Critical patent/CN106999483B/zh
Publication of WO2017028660A1 publication Critical patent/WO2017028660A1/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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a quinoline derivative containing 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide.
  • a pharmaceutical composition of the salt which has the characteristics of rapid dissolution and good stability.
  • WO2002032872 discloses a quinoline derivative 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, which is known to have inhibitory participation.
  • RTK which is involved in other proangiogenic and oncogenic signaling pathways of tumor proliferation, can also selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptor, and is clinically useful for the treatment of various tumors such as thyroid cancer, lung cancer, and melanoma.
  • VEGF vascular endothelial growth factor
  • 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof is prepared into a pharmaceutical combination
  • the drug is decomposed under the conditions of wetness and heat, and the drug composition absorbs moisture, resulting in a decrease in drug dissolution.
  • Patent CN101001629A discloses a composition comprising 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof
  • alkaline inorganic compounds such as magnesium oxide
  • silicic acid compounds to solve the problem of drug dissolution.
  • the amount of the silicic acid compound is large, the density of the silicic acid compound is extremely small, and it is easy to fly in production, causing damage to the operator's respiratory system.
  • the risk of uneven material mixing may be caused, which makes the industrialization of the preparation difficult.
  • the pharmaceutical composition provided by the present invention includes an active pharmaceutical ingredient and a basic substance.
  • the active pharmaceutical ingredient is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable salt thereof, and
  • the pharmaceutical compositions described are free of microcrystalline cellulose.
  • Alkaline substances include one or more of the following:
  • the basic amino acid is preferably selected from one or more of lysine, arginine and histidine.
  • the basic substance is a mixture of at least one compound of arginine or meglumine and at least one compound of potassium carbonate or potassium hydrogencarbonate.
  • the basic substance is a mixture of at least one compound of arginine or meglumine and potassium hydrogencarbonate.
  • the basic substance is a mixture of arginine and meglumine.
  • the ratio of the two kinds of the mixture is not particularly limited, and in a preferred embodiment, their weight ratio may be between 1:0.1 and 1:10, preferably. Between 1:0.5 and 1:2, most preferably 1:1.
  • the content of the basic substance is not limited, and as long as a small amount of the above-mentioned basic substance is contained, the effect of improving elution and increasing stability can be achieved.
  • the content of the basic substance may range from 0.5% to 90%, preferably from 1% to 50%; more preferably from 1 to 35%, based on the total weight of the composition; Most preferably 5-20%.
  • the pharmacologically acceptable salt of the active ingredient may be selected from the group consisting of a hydrochloride, a hydrobromide, a p-toluenesulfonate, a methanesulfonate, a sulfate or an ethanesulfonate.
  • the active ingredient may be included in an amount ranging from 0.5% to 30%, preferably from 1% to 25%, most preferably from 1% to 15%, based on the total weight of the composition.
  • the pharmaceutical composition provided by the present invention may contain a filler such as one or more of calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose.
  • a filler such as one or more of calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose.
  • the filler content is from about 5% to 80%, based on the total weight of the composition.
  • the pharmaceutical composition provided by the present invention may contain a disintegrating agent, wherein the disintegrant is one of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. Or a variety.
  • the disintegrant content is from about 1% to about 30%, based on the total weight of the composition.
  • the pharmaceutical composition may contain a binder, which may be selected from the group consisting of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, and the like.
  • the binder may be present in an amount of from about 0.5% to about 15%, based on the total weight of the composition.
  • the pharmaceutical compositions provided herein may also comprise one or more lubricants to aid in filling the capsule or tableting.
  • the lubricant may be selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal silica, and the like.
  • the lubricant is present in an amount of from about 0.5% to about 5%, based on the total weight of the composition.
  • composition consists of the following ingredients:
  • composition consists of the following ingredients:
  • the pharmaceutical composition of the present invention can be prepared by a method common in the art, for example, high shear wet granulation, dry granulation, one-step granulation, etc., to prepare granules of a pharmaceutical composition, and then filled into capsules to prepare a hard capsule.
  • microcrystalline cellulose-free pharmaceutical composition provided by the invention has higher stability, reduces the generation of new impurities, and has good dissolution properties.
  • Figure 1 shows the dissolution profiles of the capsules of Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 2 shows the dissolution profiles of the capsules of Examples 4 to 6 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 3 shows the dissolution profiles of the capsules of Comparative Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.
  • Example 4 shows the dissolution profile of the capsule of Example 3 and the 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.
  • Figure 5 shows the dissolution profile of the capsule of Example 6 in a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.
  • Fig. 6 shows a dissolution profile of the capsule of Comparative Example 1 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.
  • Fig. 7 shows a dissolution profile of the capsule of Comparative Example 2 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.
  • Fig. 8 shows a dissolution profile of the capsule of Comparative Example 3 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.
  • compound A 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), refined ammonia Acid, potassium bicarbonate, D-mannitol, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, wet granulation by high-speed shear granulator according to the ratio in Table 1, to purify Water is a wetting agent, wet and granules are dried and dried, then dry granules (less than 2% moisture) are dry granulated, and a prescribed amount of talc powder is added and mixed by a rotary total mixer. The obtained total mixed particles are filled into capsules to prepare capsules.
  • compound A 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate
  • Example 1 Example 2
  • Example 3 Compound A 2.5 4.9 12.3 Arginine 10.0 10.0 10.0 Potassium bicarbonate 20.0 20.0 20.0 D-mannitol 56.5 54.1 46.7 Hydroxypropyl cellulose 3.0 3.0 3.0 Low substituted hydroxypropyl cellulose 5.0 5.0 5.0 talcum powder 3.0 3.0 3.0 total 100 100 100
  • compound A 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), refined ammonia Acid, potassium carbonate, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, wet granulation using a high-speed shear granulator according to the ratio in Table 2, using purified water as a wetting agent Wet granules and drying the wet materials, then dry granules (less than 2% moisture), add the prescribed amount of talc, and mix with a rotary total mixer. The obtained total mixed particles are filled into capsules to prepare capsules.
  • Example 4 Compound A 2.5 4.9 12.3 Arginine 10.0 10.0 10.0 Potassium carbonate 20.0 20.0 20.0 D-mannitol 56.5 54.1 46.7 Hydroxypropyl cellulose 3.0 3.0 3.0 Low substituted hydroxypropyl cellulose 5.0 5.0 5.0 talcum powder 3.0 3.0 3.0 total 100 100 100
  • compound A 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter abbreviated as compound A) arginine , potassium bicarbonate or potassium carbonate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, wet granulation using a high-speed shear granulator according to the ratio in Table 3.
  • Comparative example 1 Comparative example 2 Comparative example 3 Compound A 12.3 12.3 12.3 Arginine 0 10 10 Potassium carbonate 0 20 0 Potassium bicarbonate 0 0 20 D-mannitol 43.7 13.7 13.7 Microcrystalline cellulose 33 33 33 Hydroxypropyl cellulose 3 3 3 Low substituted hydroxypropyl cellulose 5 5 5 talcum powder 3 3 3 total 100 100 100
  • the dissolution rates of the capsules of Examples 1 to 6 were measured according to the second method (paddle method) of the dissolution test of the Appendix 2 of the Chinese Pharmacopoeia. 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. As a result, in the capsules of Examples 1 to 6 containing arginine and potassium carbonate or potassium hydrogencarbonate in the formulation, the dissolution of Compound A was quickly completed.
  • the dissolution profile is shown in Figure 1 and Figure 2.
  • the dissolution rate of the capsules of Comparative Examples 1 to 3 was measured according to the second method (paddle method) for the dissolution measurement of the second edition of the Chinese Pharmacopoeia 2010 edition.
  • 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 in the comparative example 1 which did not contain the alkaline adjuvant in the prescription, the dissolution of the compound A was slow; in the capsule of Comparative Example 2 and Comparative Example 3 containing arginine, potassium carbonate or potassium hydrogencarbonate, the dissolution of the compound A was rapid. Completely, indicating that the addition of microcrystalline cellulose does not affect the drug Dissolution of matter.
  • the dissolution profile is shown in Figure 3.
  • the capsules of Examples 3 and 6 and the capsules of Comparative Examples 1 to 3 were packaged in high-density polyethylene, and placed in an environment of a temperature of 40 ° C and a relative humidity of 75% for one month, two months, and three. After month and 6 months, the formation of the degradant was determined by HPLC.
  • the second method (paddle method) of the dissolution test of the second edition of the Chinese Pharmacopoeia 2010 was used to determine the dissolution of the sample after the placement.
  • Example 3 containing arginine and potassium hydrogencarbonate
  • Example 6 containing arginine and potassium carbonate
  • Comparative Example 1 did not contain alkaline adjuvants.
  • the degradant increased significantly with the extension of the standing time.
  • Comparative Example 2 and Comparative Example 3 contained alkaline excipients and microcrystalline cellulose, and the new impurities were produced after being left for 1 month in a temperature of 40 ° C and a relative humidity of 75%.
  • the impurity increases significantly with the extension of the standing time, and the other degradants do not increase.
  • Example 3 containing arginine and potassium hydrogencarbonate
  • Example 6 containing arginine and potassium carbonate
  • the dissolution rate of Compound A was 40 ° C and the relative humidity was 75%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique, comprenant du 4-[3-chloro-4-(cyclopropylaminocarbonyl)-aminophénoxy]-7-méthoxy-6-quinoléinecarboxamide ou un sel pharmaceutiquement acceptable correspondant ; et au moins un composé d'un acide aminé basique ou de la méglumine et/ou au moins un composé choisi parmi le carbonate de potassium ou le bicarbonate de potassium. La composition ne contient pas de cellulose microcristalline.
PCT/CN2016/091717 2015-08-17 2016-07-26 Composition pharmaceutique contenant un dérivé de la quinoléine ou un sel correspondant Ceased WO2017028660A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680003848.7A CN106999483B (zh) 2015-08-17 2016-07-26 一种含有喹啉衍生物或其盐的药物组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510506161 2015-08-17
CN201510506161.2 2015-08-17

Publications (1)

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WO2017028660A1 true WO2017028660A1 (fr) 2017-02-23

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CN (1) CN106999483B (fr)
TW (1) TWI739756B (fr)
WO (1) WO2017028660A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3384901A1 (fr) * 2017-04-04 2018-10-10 Synthon B.V. Composition pharmaceutique contenant du lenvatinib mesylate
US10583133B2 (en) 2018-03-12 2020-03-10 Shilpa Medicare Limited Pharmaceutical compositions of lenvatinib
WO2021226738A1 (fr) * 2020-05-09 2021-11-18 北京睿创康泰医药研究院有限公司 Composition pharmaceutique de niveau moléculaire comprenant du lenvatinib, et sa méthode de préparation et son utilisation
EP4147689A1 (fr) * 2021-09-13 2023-03-15 Lotus Pharmaceutical Co., Ltd. Formulation de lenvatinib
EP4424303A1 (fr) * 2023-02-28 2024-09-04 Stada Arzneimittel Ag Composition de lenvatinib présentant une biodisponibilité améliorée

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115068620A (zh) * 2022-07-20 2022-09-20 天津睿创康泰生物技术有限公司 能够减少芳胺类杂质生成的药物组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101001629A (zh) * 2004-09-17 2007-07-18 卫材R&D管理有限公司 药物组合物
CN101316590A (zh) * 2005-11-07 2008-12-03 卫材R&D管理有限公司 血管生成抑制剂和c-kit激酶抑制剂的组合使用
CN102470133A (zh) * 2009-08-19 2012-05-23 卫材R&D管理有限公司 含有喹啉衍生物的药物组合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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WO2004101526A1 (fr) * 2003-04-22 2004-11-25 Eisai Co., Ltd. Cristal polymorphe de 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide et procede de preparation
TWI501950B (zh) * 2011-02-09 2015-10-01 Eisai R&D Man Co Ltd 含喹啉衍生物的藥學組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101001629A (zh) * 2004-09-17 2007-07-18 卫材R&D管理有限公司 药物组合物
US20130237565A1 (en) * 2004-09-17 2013-09-12 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
CN101316590A (zh) * 2005-11-07 2008-12-03 卫材R&D管理有限公司 血管生成抑制剂和c-kit激酶抑制剂的组合使用
CN102470133A (zh) * 2009-08-19 2012-05-23 卫材R&D管理有限公司 含有喹啉衍生物的药物组合物

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3384901A1 (fr) * 2017-04-04 2018-10-10 Synthon B.V. Composition pharmaceutique contenant du lenvatinib mesylate
WO2018185175A1 (fr) * 2017-04-04 2018-10-11 Synthon B.V. Composition pharmaceutique comprenant du mésylate de lenvatinib
US20200188380A1 (en) * 2017-04-04 2020-06-18 Synthon B.V. Pharmaceutical composition comprising lenvatinib mesylate
EP3606511B1 (fr) 2017-04-04 2022-04-20 Synthon B.V. Composition pharmaceutique contenant du lenvatinib mesylate
US11911509B2 (en) * 2017-04-04 2024-02-27 Synthon B.V. Pharmaceutical composition comprising Lenvatinib mesylate
US10583133B2 (en) 2018-03-12 2020-03-10 Shilpa Medicare Limited Pharmaceutical compositions of lenvatinib
WO2021226738A1 (fr) * 2020-05-09 2021-11-18 北京睿创康泰医药研究院有限公司 Composition pharmaceutique de niveau moléculaire comprenant du lenvatinib, et sa méthode de préparation et son utilisation
CN115397416A (zh) * 2020-05-09 2022-11-25 北京睿创康泰医药研究院有限公司 包含仑伐替尼的分子水平的药物组合物及其制备方法和应用
CN115397416B (zh) * 2020-05-09 2023-12-05 北京睿创康泰医药研究院有限公司 包含仑伐替尼的分子水平的药物组合物及其制备方法和应用
EP4147689A1 (fr) * 2021-09-13 2023-03-15 Lotus Pharmaceutical Co., Ltd. Formulation de lenvatinib
EP4424303A1 (fr) * 2023-02-28 2024-09-04 Stada Arzneimittel Ag Composition de lenvatinib présentant une biodisponibilité améliorée
WO2024180153A3 (fr) * 2023-02-28 2024-11-14 Stada Arzneimittel Ag Composition de lenvatinib à biodisponibilité améliorée

Also Published As

Publication number Publication date
CN106999483A (zh) 2017-08-01
TWI739756B (zh) 2021-09-21
CN106999483B (zh) 2019-05-03
TW201707702A (zh) 2017-03-01

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