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WO2021185006A1 - Composition pharmaceutique de lenvatinib, son procédé de préparation et son application - Google Patents

Composition pharmaceutique de lenvatinib, son procédé de préparation et son application Download PDF

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Publication number
WO2021185006A1
WO2021185006A1 PCT/CN2021/076021 CN2021076021W WO2021185006A1 WO 2021185006 A1 WO2021185006 A1 WO 2021185006A1 CN 2021076021 W CN2021076021 W CN 2021076021W WO 2021185006 A1 WO2021185006 A1 WO 2021185006A1
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WIPO (PCT)
Prior art keywords
lenvatinib
pharmaceutical composition
active drug
weight
preparation
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PCT/CN2021/076021
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English (en)
Chinese (zh)
Inventor
王璇
郭桢
董睿
李洪
王婷婷
应述欢
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上海博志研新药物技术有限公司
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Publication of WO2021185006A1 publication Critical patent/WO2021185006A1/fr

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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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a lenvatinib pharmaceutical composition, a preparation method and an application thereof.
  • LENVIMA (lenvatinib), the chemical name is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide.
  • Lenvatinib is a multi-target drug. It is an oral multi-RTK inhibitor developed by Eisai.
  • VEGF vascular endothelial growth factor
  • FGF fibroblast growth factor
  • CN 200580026468.7 discloses a lenvatinib tablet, which contains stabilizers, such as magnesium oxide, calcium oxide, anhydrous sodium carbonate or sodium bicarbonate, etc.; and gelatinization inhibitors, such as light silicon dioxide, silicic acid, etc. Calcium, magnesium silicate or magnesium aluminosilicate, etc. solve the problem of incomplete dissolution caused by gelation during the dissolution process of the bulk drug, but the stability of the composition has certain problems.
  • stabilizers such as magnesium oxide, calcium oxide, anhydrous sodium carbonate or sodium bicarbonate, etc.
  • gelatinization inhibitors such as light silicon dioxide, silicic acid, etc.
  • Calcium, magnesium silicate or magnesium aluminosilicate, etc. solve the problem of incomplete dissolution caused by gelation during the dissolution process of the bulk drug, but the stability of the composition has certain problems.
  • CN 201080030508.6 discloses a lenvatinib capsule, which contains calcium carbonate and magnesium carbonate, uses wet granulation to prepare granules, and uses hypromellose capsule shells for filling, and the stability of the resulting composition is improved.
  • the dissolution rate of the composition was lower in the first 15 minutes.
  • PCT patent application WO 2006/030826 discloses that when lenvatinib is used as a medicinal ingredient into a pharmaceutical composition, it will decompose under humidified and heated storage conditions. In addition, when the pharmaceutical composition absorbs moisture, the surface of the composition will Gelation occurs, resulting in extremely strong viscosity, which delays the dissolution of lenvatinib and affects the onset and absorption of the drug.
  • LENVIMATM of Eisai Japan which has been on the market, uses a combination of lenvatinib and calcium carbonate. Calcium carbonate is a conventional excipient in effervescent tablets.
  • the technical problem to be solved by the present invention is to overcome the defects of unsatisfactory dissolution effect, poor stability, complicated preparation process, and unsuitability for industrial production in lenvatinib preparations in the prior art, and provides a lenvatinib drug
  • the composition, its preparation method and application The lenvatinib pharmaceutical composition prepared by the invention has a good dissolution rate, can reach a dissolution rate of more than 90% within 15 minutes, has good stability, a simple preparation process, and is suitable for industrial production.
  • the present invention provides a lenvatinib pharmaceutical composition, which comprises the following components: an active drug and calcium bicarbonate, and the active drug contains 4-[3-chloro-4-(ring as shown in formula I) Propylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide and/or a pharmaceutically acceptable salt thereof;
  • the lenvatinib pharmaceutical composition comprises the following components: an active drug and calcium bicarbonate, and the active drug is 4-[3-chloro-4-(cyclopropyl) as shown in formula I (Aminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof;
  • the lenvatinib pharmaceutical composition further comprises one, two or more of diluents, disintegrants, binders and lubricants.
  • the present invention provides a lenvatinib pharmaceutical composition, which preferably contains the following components: 1%-30% active drug, 10%-50% calcium bicarbonate, 10%-50% diluent, 10%-30% Disintegrant, 0 ⁇ 5% binder, 0.5% ⁇ 5% lubricant; the active drug contains 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminobenzene as shown in formula I Oxy]-7-methoxy-6-quinolinecarboxamide and/or its pharmaceutically acceptable salt; the percentage refers to the weight percentage, and the weight percentage refers to the weight of a single component in the combination Percentage of total weight;
  • the lenvatinib pharmaceutical composition preferably comprises the following components: 1%-30% active drug, 10%-50% calcium bicarbonate, 10%-50% diluent, 10%-30% disintegration Solution agent, 0-5% binder, 0.5%-5% lubricant;
  • the active drug is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy as shown in formula I Yl]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof;
  • the percentages refer to weight percentages, and the weight percentages refer to the weight of a single component in the total weight of the composition Percentage of
  • the 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide shown in formula I The pharmaceutically acceptable salt is preferably the methanesulfonate salt of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide.
  • the diluent is selected from lactose, microcrystalline cellulose, starch (such as corn starch), mannitol, glucose, sucrose, modified starch (such as pregelatinized starch) and microcrystalline cellulose (Such as silicified microcrystalline cellulose); preferably one or more of lactose, mannitol, starch, microcrystalline cellulose and pregelatinized starch.
  • starch such as corn starch
  • mannitol glucose, sucrose
  • modified starch such as pregelatinized starch
  • microcrystalline cellulose preferably one or more of lactose, mannitol, starch, microcrystalline cellulose and pregelatinized starch.
  • it is a mixture of mannitol and starch, a mixture of starch and lactose, mannitol and/or microcrystalline cellulose.
  • the disintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, effervescent disintegrant, One or more of carmellose calcium and carmellose. Exemplary is low-substituted hydroxypropyl cellulose.
  • the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and copovidone.
  • hydroxypropyl cellulose is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and copovidone.
  • exemplary is hydroxypropyl cellulose.
  • the lubricant is selected from one or more of talc powder, magnesium stearate, hydrogenated castor oil, glyceryl behenate and micronized silica gel. It is exemplified by talc.
  • the content of the active drug is preferably 1%-10%, such as 2%, 4%, 4.9%, 5%, 10%, 15% %, 20%, 25%, 30% or any point within the range of any two combinations of the above.
  • the content of calcium bicarbonate is preferably 10.0% to 50.0%, more preferably 15.0% to 40.0%, such as 10.0%, 20.0%, 33.0 %, 40.0%, 50.0%, or any point within the range of any two combinations of the above.
  • the content of the diluent is preferably 15.0% to 50.0%, more preferably 20.0% to 40.0%, such as 17.0%, 19.1%, 22.0% , 24.1%, 25.0%, 30.0%, 31.1%, 35.0%, 44.1%, 45.0%, 49.1%, or any point value within the combination of any two of the above values.
  • the content of the disintegrant is preferably 20.0% to 30.0%, such as 15.0%, 20.0%, 25.0%, 30.0% or any two of the foregoing. Any point value within the range of a combination of two values.
  • the content of the binder is preferably 1.0% to 4.0%, such as 0.5%, 1.0%, 2.0%, 2.5%, 3.0%, 3.5%, 4.5%, or any point within the range of any two combinations of the above.
  • the content of the lubricant is preferably 1.0% to 4.0%, such as 0.5%, 1.0%, 2.0%, 2.5%, 3.0%, 3.5%. %, 4.5%, or any point within the range of any two combinations of the above.
  • the lenvatinib pharmaceutical composition preferably includes the following components: 1.0% to 10.0% active drug, 10.0% to 50.0% calcium bicarbonate, 15.0% to 50.0% diluent, 20.0 % ⁇ 30.0% disintegrant, 1.0% ⁇ 4.0% binder, 1.0% ⁇ 4.0% lubricant;
  • the active drug is 4-[3-chloro-4-(cyclopropyl) as shown in formula I Aminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate, the percentage refers to the weight percentage, and the weight percentage refers to the weight of a single component in the combination Percentage of total weight;
  • the lenvatinib pharmaceutical composition further preferably includes the following components: 4.9% active drug, 10.0% to 50.0% calcium bicarbonate, 15.0% to 50.0% diluent, 20.0% to 30.0% disintegrant, 3.0% binder, 3.0% lubricant;
  • the active drug is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy] as shown in formula I
  • the present invention also provides a lenvatinib pharmaceutical composition, which is composed of the following components: 1.0% ⁇ 30.0% active drug, 10.0% ⁇ 50.0% calcium bicarbonate, 10.0% ⁇ 50.0% diluent, 10.0% ⁇ 30.0% disintegrant, 0-5.0% binder, 0.5%-5.0% lubricant;
  • the active drug is 4-[3-chloro-4-(cyclopropylaminocarbonyl) as shown in formula I Aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof, the percentages refer to weight percentages, and the weight percentages refer to the weight of a single component in the combination Percentage of total weight;
  • the diluent is a mixture of microcrystalline cellulose and mannitol
  • the disintegrant is low-substituted hydroxypropyl cellulose
  • the binder is hydroxypropyl cellulose
  • the lubricant is talc pink.
  • the lenvatinib pharmaceutical composition preferably consists of the following components: 1.0% to 10.0% active drug, 10.0% to 50.0% calcium bicarbonate, 15.0% to 50.0% diluent, 20.0% ⁇ 30.0% disintegrant, 1.0% ⁇ 4.0% binder, 1.0% ⁇ 4.0% lubricant;
  • the active drug is 4-[3-chloro-4-(cyclopropyl) as shown in formula I (Aminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate, the percentage refers to the weight percentage, the weight percentage refers to the weight of a single component Percentage of the total weight of the composition;
  • the diluent is a mixture of microcrystalline cellulose and mannitol
  • the disintegrant is low-substituted hydroxypropyl cellulose
  • the binder is hydroxypropyl cellulose
  • the lubricant is talc pink.
  • the lenvatinib pharmaceutical composition is further preferably composed of the following components: 4.9% active drug, 10.0% to 50.0% calcium bicarbonate, 15.0% to 50.0% diluent, 20.0% ⁇ 30.0% disintegrant, 3.0% binder, 3.0% lubricant;
  • the active drug is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy as shown in formula I ]-7-methoxy-6-quinolinecarboxamide methanesulfonate, the percentage refers to the weight percentage, and the weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;
  • the diluent is a mixture of microcrystalline cellulose and mannitol
  • the disintegrant is low-substituted hydroxypropyl cellulose
  • the binder is hydroxypropyl cellulose
  • the lubricant is talc pink.
  • the lenvatinib pharmaceutical composition is further preferably any of the following formulations:
  • Formulation 1 4.9% active drug, 33.0% calcium bicarbonate, 15.1% microcrystalline cellulose, 16.0% mannitol, 25.0% low-substituted hydroxypropyl cellulose, 3.0% hydroxypropyl cellulose, 3.0% talc;
  • the active drug is the methanesulfonate of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide as shown in formula I ,
  • the percentage refers to the weight percentage, and the weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;
  • Formulation 2 4.9% active drug, 10.0% calcium bicarbonate, 25.1% microcrystalline cellulose, 24.0% mannitol, 30.0% low-substituted hydroxypropyl cellulose, 3.0% hydroxypropyl cellulose, 3.0% talc;
  • the active drug is the methanesulfonate of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide as shown in formula I ,
  • the percentage refers to the weight percentage, and the weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;
  • Formulation 3 4.9% active drug, 20.0% calcium bicarbonate, 22.1% microcrystalline cellulose, 22.0% mannitol, 25.0% low-substituted hydroxypropyl cellulose, 3.0% hydroxypropyl cellulose, 3.0% talc;
  • the active drug is the methanesulfonate of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide as shown in formula I ,
  • the percentage refers to the weight percentage, and the weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;
  • Formulation 4 4.9% active drug, 40.0% calcium bicarbonate, 12.1% microcrystalline cellulose, 12.0% mannitol, 25.0% low-substituted hydroxypropyl cellulose, 3.0% hydroxypropyl cellulose, 3.0% talc;
  • the active drug is the methanesulfonate of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide as shown in formula I ,
  • the percentage refers to the weight percentage, and the weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;
  • Formulation 5 4.9% active drug, 50.0% calcium bicarbonate, 10.1% microcrystalline cellulose, 9.0% mannitol, 20.0% low-substituted hydroxypropyl cellulose, 3.0% hydroxypropyl cellulose, 3.0% talc;
  • the active drug is the methanesulfonate of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide as shown in formula I ,
  • the percentage refers to the weight percentage, and the weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;
  • the lenvatinib pharmaceutical composition is preferably a solid preparation, such as a capsule, tablet, granule, powder, sustained-release agent or dropping pill; preferably, the sustained-release agent is Sustained release pellets or tablets.
  • the present invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
  • Step 1 Mix the active drug, calcium bicarbonate, diluent and disintegrant to obtain a premix;
  • Step 2 Granulate and dry the premix and the binder obtained in Step 1 to obtain dry granules;
  • Step 3 The dry granules obtained in step 2 are dried and granulated, and then mixed with a lubricant to obtain the pharmaceutical composition.
  • the active drug, diluent, disintegrant and lubricant all have the selection and dosage as shown above.
  • the calcium bicarbonate has an amount as indicated above.
  • step 1 the wet granulation can be carried out in a wet granulator.
  • the moisture of the dry particles is less than 2%, and the percentage refers to the percentage of the weight of water to the total weight of the dry particles.
  • step 3 the mixing can be carried out in a three-dimensional mixer.
  • the pharmaceutical composition obtained in step 3 can also be capsule-filled to obtain a capsule.
  • the invention also provides a lenvatinib pharmaceutical composition prepared by the preparation method of the lenvatinib pharmaceutical composition.
  • the present invention also provides a lenvatinib pharmaceutical preparation, which contains the above-mentioned lenvatinib pharmaceutical composition.
  • the preparation may be a solid preparation, such as a capsule, tablet, granule, powder, sustained-release agent or dripping pill; preferably, the sustained-release agent is a sustained-release pellet capsule or a sustained-release pellet. Release tablets.
  • the dissolution rate of the lenvatinib pharmaceutical preparation at 15 minutes is not less than 90%, for example, greater than 90%.
  • the dissolution rate is the data obtained by using hydrochloric acid solution as the dissolution medium of the lenvatinib pharmaceutical preparation.
  • the present invention also provides a preparation method of the above-mentioned lenvatinib pharmaceutical preparation, and the preparation method includes the preparation of the pharmaceutical composition.
  • the preparation method of the lenvatinib pharmaceutical preparation includes the preparation of the above-mentioned pharmaceutical composition.
  • the preparation method of the pharmaceutical preparation comprises: capsule filling the pharmaceutical composition obtained in step 3 of the preparation method of the pharmaceutical composition to obtain a capsule.
  • the present invention also provides the application of the pharmaceutical composition and/or preparation in the preparation of drugs for the treatment and/or prevention of tumor-related diseases.
  • the tumor-related disease may be thyroid cancer, non-small cell lung cancer, melanoma, laryngopharyngeal cancer, esophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, bladder cancer, breast cancer , Uterine cancer, ovarian cancer, prostate cancer, testicular cancer, gastrointestinal stromal tumor, sarcoma, osteosarcoma, hemangioma, malignant lymphoma, myelogenous leukemia, neuroma, glioma, etc.
  • the present invention also provides a method for preventing and/or treating the above-mentioned tumor-related diseases, including administering the pharmaceutical composition and/or preparation to a patient in need, such as a human.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the invention can provide a lenvatinib pharmaceutical composition with good stability and a dissolution rate of more than 90% within 15 minutes, and the pharmaceutical composition has a simple preparation process and is suitable for large-scale technological production.
  • Step 1 The mesylate of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (compound of formula I) (below Abbreviated as compound A, prepared by referring to the method reported in CN1478078A, purity: 99.83%), microcrystalline cellulose, calcium bicarbonate, low-substituted hydroxypropyl cellulose, mannitol, according to the ratio in Table 1, using a high-speed wet granulator Mix to obtain a premix;
  • Step 2 Using the aqueous solution of hydroxypropyl cellulose (the concentration of hydroxypropyl cellulose is 12%) as the binder, granulate and dry the premix and the binder obtained in step 1 to obtain dry granules ;
  • Step 3 Dry the dry granules (moisture ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition. Capsule filling the obtained lenvatinib pharmaceutical composition to obtain a capsule.
  • Step 1 Combine 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), Microcrystalline cellulose, dibasic calcium phosphate, low-substituted hydroxypropyl cellulose, and mannitol were mixed according to the ratio in Table 2 using a high-speed wet granulator to obtain a premix;
  • Step 2 Using an aqueous solution of hydroxypropyl cellulose as a binder, granulate and dry the premix and the binder obtained in step 1 to obtain dry particles;
  • Step 3 Dry the dry granules (moisture ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition. Capsule filling the obtained lenvatinib pharmaceutical composition to obtain a capsule.
  • Element Proportion (%, weight percentage) Compound A 4.9 Microcrystalline cellulose 15.1 Mannitol 16.0 Dicalcium Phosphate 33.0 Low-substituted hydroxypropyl cellulose 25.0 Hydroxypropyl cellulose 3.0 talcum powder 3.0 total 100
  • Step 1 Combine 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), Microcrystalline cellulose, calcium phosphate, low-substituted hydroxypropyl cellulose, and mannitol were mixed according to the proportions in Table 3 using a high-speed wet granulator to obtain a premix;
  • Step 2 Using an aqueous solution of hydroxypropyl cellulose as a binder, granulate and dry the premix and the binder obtained in step 1 to obtain dry particles;
  • Step 3 Dry the dry granules (moisture ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition. Capsule filling the obtained lenvatinib pharmaceutical composition to obtain a capsule.
  • Step 1 Combine 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), Microcrystalline cellulose, calcium citrate, low-substituted hydroxypropyl cellulose, and mannitol are mixed according to the proportions in Table 4 using a high-speed wet granulator to obtain a premix;
  • Step 2 Using an aqueous solution of hydroxypropyl cellulose as a binder, granulating and drying the premix and the binder obtained in step 1 to obtain dry particles;
  • Step 3 Dry the dry granules (moisture content ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition. Capsule filling the obtained lenvatinib pharmaceutical composition to obtain a capsule.
  • Element Proportion (%, weight percentage) Compound A 4.9 Microcrystalline cellulose 15.1 Mannitol 16.0 Calcium Citrate 33.0 Low-substituted hydroxypropyl cellulose 25.0 Hydroxypropyl cellulose 3.0 talcum powder 3.0 total 100
  • Step 1 Combine 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), Microcrystalline cellulose, calcium citrate, calcium hydroxide, low-substituted hydroxypropyl cellulose, and mannitol are mixed according to the proportions in Table 5 using a high-speed wet granulator to obtain a premix;
  • Step 2 Using an aqueous solution of hydroxypropyl cellulose as a binder, granulating and drying the premix and the binder obtained in step 1 to obtain dry particles;
  • Step 3 Dry the dry granules (moisture ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition. Capsule filling the obtained lenvatinib pharmaceutical composition to obtain a capsule.
  • Element Proportion (%, weight percentage) Compound A 4.9 Microcrystalline cellulose 15.1 Mannitol 16.0 Calcium Citrate 32.1 Calcium hydroxide 0.9 Low-substituted hydroxypropyl cellulose 25.0 Hydroxypropyl cellulose 3.0 talcum powder 3.0 total 100
  • Step 1 Combine 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), Microcrystalline cellulose, calcium gluconate, low-substituted hydroxypropyl cellulose, and mannitol were mixed according to the proportions in Table 6 using a high-speed wet granulator to obtain a premix;
  • Step 2 Using an aqueous solution of hydroxypropyl cellulose as a binder, granulating and drying the premix and the binder obtained in step 1 to obtain dry particles;
  • Step 3 Dry the dry granules (moisture ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition.
  • the obtained lenvatinib pharmaceutical composition is capsule-filled to obtain a capsule.
  • Element Proportion (%, weight percentage) Compound A 4.9 Microcrystalline cellulose 15.1 Mannitol 16.0 Calcium gluconate 33.0 Low-substituted hydroxypropyl cellulose 25.0 Hydroxypropyl cellulose 3.0 talcum powder 3.0 total 100
  • compound A 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), microcrystalline fiber Vegetarian, dibasic calcium phosphate, anhydrous sodium carbonate, low-substituted hydroxypropyl cellulose, mannitol, according to the proportions in Table 7, are mixed with a high-speed wet granulator to obtain a premix;
  • Step 2 Using an aqueous solution of hydroxypropyl cellulose as a binder, granulating and drying the premix and the binder obtained in step 1 to obtain dry particles;
  • Step 3 Dry the dry granules (moisture ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition. Capsule filling the obtained lenvatinib pharmaceutical composition to obtain a capsule.
  • Step 1 Combine 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), Microcrystalline cellulose, calcium carbonate, low-substituted hydroxypropyl cellulose, and mannitol are mixed according to the proportions in Table 8 using a high-speed wet granulator to obtain a premix;
  • Step 2 Using an aqueous solution of hydroxypropyl cellulose as a binder, granulating and drying the premix and the binder obtained in step 1 to obtain dry particles;
  • Step 3 Dry the dry granules (moisture ⁇ 2%) obtained in step 2 into granules, then add the prescription amount of talc, and mix them with a three-dimensional mixer to obtain the lenvatinib pharmaceutical composition. Capsule filling the obtained lenvatinib pharmaceutical composition to obtain a capsule.
  • Element Proportion (%, weight percentage) Compound A 4.9 Microcrystalline cellulose 15.1 Mannitol 16.0 Calcium carbonate 33.0 Low-substituted hydroxypropyl cellulose 25.0 Hydroxypropyl cellulose 3.0 talcum powder 3.0 total 100
  • the capsules of Examples 1-11 and Comparative Example 1 were tested for dissolution.
  • Example 1-5 calcium hydrogen carbonate
  • Example 6 calcium hydrogen phosphate
  • Example 9 calcium citrate + calcium hydroxide
  • Example 7 Calcium Phosphate
  • Example 8 Calcium Citrate
  • Example 10 Calcium Gluconate
  • Example 11 Calcium Hydrogen Phosphate + Anhydrous Sodium Carbonate
  • Compound A could not be completely dissolved, and during the dissolution process The phenomenon of gelation occurs in the process.
  • Comparative Example 1 the dissolution of compound A in 15 minutes can only reach more than 80%.
  • Example 1-5 The capsules of Examples 1-5, Example 6, Example 9 and Comparative Example 1 were placed in a 40°C/75% RH environment for six months, and the generation of degradation products was determined by HPLC. Stability data are shown in Tables 11, 12 and 13.
  • HPLC determination method is:
  • the present invention uses calcium bicarbonate as the stabilizer of the lenvatinib pharmaceutical composition, which is comparable to the quality of Comparative Example 1 (ie, the original research agent, with calcium carbonate as the stabilizer), but the degradation impurities are significantly reduced.

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Abstract

L'invention concerne une composition pharmaceutique de lenvatinib, un procédé de préparation associé et son application, la composition pharmaceutique de lenvatinib comprenant les composants suivants : un médicament actif et du bicarbonate de calcium, le médicament actif étant du 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophénoxy]-7-méthoxy-6-quinoléine formamide représenté par La formule I ou un sel pharmaceutiquement acceptable de celui-ci. La composition pharmaceutique de lenvatinib a une vitesse de dissolution satisfaisante, peut atteindre un taux de dissolution de plus de 90 % en 15 minutes, a une stabilité satisfaisante et est simple à préparer, et elle est appropriée pour une production industrielle.
PCT/CN2021/076021 2020-03-18 2021-02-08 Composition pharmaceutique de lenvatinib, son procédé de préparation et son application WO2021185006A1 (fr)

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