WO2021185006A1 - Lenvatinib pharmaceutical composition, preparation method therefor and application thereof - Google Patents

Abstract

A lenvatinib pharmaceutical composition, a preparation method therefor and an application thereof, the lenvatinib pharmaceutical composition comprising the following components: an active drug and calcium bicarbonate, the active drug being 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline formamide represented by formula I or a pharmaceutically acceptable salt thereof. The lenvatinib pharmaceutical composition has good dissolution rate, may reach a dissolution rate of more than 90% within 15 minutes, has good stability and a simple preparation process, and is suitable for industrial production.

Description

A lenvatinib pharmaceutical composition, its preparation method and application

This application requires the applicant to submit a patent application number of 202010190116.1 to the State Intellectual Property Office of China on March 18, 2020. The title of the invention is "a lenvatinib pharmaceutical composition, its preparation method and application". priority. The full text of the prior application is incorporated into this application by reference.

Technical field

The invention belongs to the field of pharmaceutical preparations, and specifically relates to a lenvatinib pharmaceutical composition, a preparation method and an application thereof.

Background technique

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. It inhibits other pro-angiogenic and carcinogenic signal pathways related RTKs involved in tumor proliferation (including platelet-derived growth factor [PDGF] In addition to receptors PDGFR, KIT and RET), it can also selectively inhibit vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3, FGFR3) The kinase activity. Lunvatinib was approved for listing in the United States in February 2015, Japan PMDA approved for listing in May 2015, and EMEA approved for listing in May 2015.

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.

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. However, according to CN106551935A, 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. In order to overcome such problems, 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. A large number of bubbles will be generated under the pressure, which separates the molecules of lenvatinib from each other and prevents its gelation. However, oral calcium carbonate may cause constipation and flatulence, and it is not suitable for the elderly and patients with gastric ulcers and other gastric diseases to take directly (see "Pharmaceutical Excipients Manual" (translated by Zheng Junmin and others), fourth edition, page 86" Calcium carbonate” part), and such patients may account for a considerable proportion of cancer patients.

At present, there is an urgent need to find a lenvatinib preparation with complete dissolution, good stability, suitable for pharmaceutical preparation, simple process and suitable for industrial production.

Summary of the invention

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;

Preferably, 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;

Preferably, 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;

Preferably, 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

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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. For example, it is a mixture of mannitol and starch, a mixture of starch and lactose, mannitol and/or microcrystalline cellulose.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and copovidone. Exemplary is hydroxypropyl cellulose.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, in the lenvatinib pharmaceutical composition, 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.

According to an embodiment of the present invention, in the lenvatinib pharmaceutical composition, 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.

According to an embodiment of the present invention, in the lenvatinib pharmaceutical composition, 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.

According to an embodiment of the present invention, in the lenvatinib pharmaceutical composition, 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.

According to an embodiment of the present invention, in the lenvatinib pharmaceutical composition, 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.

According to an embodiment of the present invention, in the lenvatinib pharmaceutical composition, 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.

According to an embodiment of the present invention, 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;

According to an embodiment of the present invention, 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 methanesulfonate of -7-methoxy-6-quinoline carboxamide, where 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 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;

Preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc pink.

According to an embodiment of the present invention, 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;

Preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc pink.

According to an embodiment of the present invention, 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;

Preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc pink.

According to an embodiment of the present invention, 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;

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, the active drug, diluent, disintegrant and lubricant all have the selection and dosage as shown above.

According to an embodiment of the present invention, the calcium bicarbonate has an amount as indicated above.

According to an embodiment of the present invention, in step 1, the wet granulation can be carried out in a wet granulator.

According to an embodiment of the present invention, in step 2, 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.

According to an embodiment of the present invention, in step 3, the mixing can be carried out in a three-dimensional mixer.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, the dissolution rate of the lenvatinib pharmaceutical preparation at 15 minutes is not less than 90%, for example, greater than 90%. Preferably, 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.

Preferably, the preparation method of the lenvatinib pharmaceutical preparation includes the preparation of the above-mentioned pharmaceutical composition.

Preferably, 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. Preferably, 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.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The beneficial effects of the present invention

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.

Detailed ways

The technical solution of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only illustrative and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the foregoing contents of the present invention are covered by the scope of the present invention.

Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Example 1-5

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.

Table 1 The proportions of the components in Examples 1-5

Example 6

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.

Table 2 Comparative Example 1 Each component ratio table

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

Example 7

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.

Table 3 Example 7 of each component ratio table

Element	Proportion (%, weight percentage)
Compound A	4.9
Microcrystalline cellulose	15.1

Mannitol	16.0
Calcium phosphate	33.0
Low-substituted hydroxypropyl cellulose	25.0
Hydroxypropyl cellulose	3.0
talcum powder	3.0
total	100

Example 8

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.

Table 4 Example 8 of each component ratio table

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

Example 9

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.

Table 5 Example 9 Each component ratio table

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

Example 10

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.

Table 6: The proportion of each component of Example 10

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

Example 11

Combine 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.

Table 7: The proportion of each component in Example 11

Element	Proportion (%, weight percentage)
Compound A	4.9
Microcrystalline cellulose	12
Mannitol	12.1
Dicalcium Phosphate	20.0
Anhydrous Sodium Carbonate	20.0

Low-substituted hydroxypropyl cellulose	25.0
Hydroxypropyl cellulose	3.0
talcum powder	3.0
total	100

Comparative example 1

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.

Table 8 Comparative Example 1 Each component ratio table

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

Experimental example 1: Dissolution test

According to the second method (paddle method) of the Chinese Pharmacopoeia for the 2020 version of the dissolution test, the capsules of Examples 1-11 and Comparative Example 1 were tested for dissolution. Use 900ml of 0.1N (equivalent concentration) hydrochloric acid solution as the dissolution medium, and conduct the dissolution test at 37±0.5°C at a rotation speed of 50rpm. See Table 9 and Table 10 for dissolution data.

Table 9 Example 1-6 dissolution data table

Table 10 Dissolution data table of Examples 7-11 and Comparative Example 1

The dissolution results show that compound A in Examples 1-5 (calcium hydrogen carbonate), Example 6 (calcium hydrogen phosphate) and Example 9 (calcium citrate + calcium hydroxide) can dissolve quickly, among which Example 1- 5 The dissolution can reach more than 90% in 15min. Example 7 (Calcium Phosphate), Example 8 (Calcium Citrate), Example 10 (Calcium Gluconate) and 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. In Comparative Example 1, the dissolution of compound A in 15 minutes can only reach more than 80%.

Experimental example 2: Stability study

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.

The HPLC determination method is:

The specific process of gradient method:

Table 11 Degradation impurities (RRT=0.69) of Examples 1-6, Example 9 and Comparative Example 1

Table 12 Degradation impurities (RRT=0.96) of Examples 1-6, Example 9 and Comparative Example 1

Table 13 Total miscellaneous table of Examples 1-6, Example 9 and Comparative Example 1

The stability results showed that in Examples 1-5 (calcium bicarbonate), degradation products (RRT=0.69), degradation products (RRT=0.96) and total impurities did not increase significantly. Example 6 (calcium hydrogen phosphate) and examples 9 (Calcium Citrate + Calcium Hydroxide), the degradation products increased significantly. In Comparative Example 1, degradation products (RRT=0.69), degradation products (RRT=0.96) and total impurities increased significantly.

In summary, 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.

In the foregoing, the embodiments of the present invention have been described. However, the present invention is not limited to the above-mentioned embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. A lenvatinib pharmaceutical composition, which is characterized in that it comprises the following components: an active drug and calcium bicarbonate, and the active drug contains 4-[3-chloro-4-(cyclopropyl) as shown in formula I (Aminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof;

   

   Preferably, the active drug is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide as shown in formula I or Its pharmaceutically acceptable salt.
2. The lenvatinib pharmaceutical composition of claim 1, wherein the composition further comprises one, two or more of diluents, disintegrants, binders and lubricants;

   Preferably, the composition contains the following components: 1%-30% active drug, 10%-50% calcium bicarbonate, 10%-50% diluent, 10%-30% disintegrant, 0-5% Binder, 0.5% to 5% lubricant; the active drug contains 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy as shown in formula I Yl-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof, where the percentages refer to weight percentages, and the weight percentages refer to the percentage of the weight of a single component to the total weight of the composition;

   

   Preferably, the active drug is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide as shown in formula I or Its pharmaceutically acceptable salt;

   Preferably, the 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide represented by formula I is pharmaceutically acceptable The salt of is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate.

   Preferably, the diluent is selected from one of lactose, microcrystalline cellulose, starch (such as corn starch), mannitol, glucose, sucrose, modified starch (such as pregelatinized starch) and silicified microcrystalline cellulose. Kind or more

   and / or,

   The disintegrant is selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, effervescent disintegrant, carboxymethyl cellulose calcium and carboxymethyl cellulose. One or more of methylcellulose;

   and / or,

   The binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and copovidone;

   and / or,

   The lubricant is selected from one or more of talc powder, magnesium stearate, hydrogenated castor oil, glyceryl behenate and micronized silica gel.

   Preferably, in the lenvatinib pharmaceutical composition, the content of the active drug is 1.0% to 10.0%;

   and / or,

   In the lenvatinib pharmaceutical composition, the content of calcium bicarbonate is 10.0% to 50.0%;

   and / or,

   In the lenvatinib pharmaceutical composition, the content of the diluent is 15.0% to 50.0%;

   and / or,

   In the lenvatinib pharmaceutical composition, the content of the disintegrant is 20.0% to 30.0%;

   and / or,

   In the lenvatinib pharmaceutical composition, the content of the binder is 1.0% to 4.0%;

   and / or,

   In the lenvatinib pharmaceutical composition, the content of the lubricant is 1.0%-4.0%.
3. The lenvatinib pharmaceutical composition of claim 1 or 2, wherein the lenvatinib pharmaceutical composition comprises the following components: 1.0% to 10.0% active drug, 10.0% to 50.0% Calcium bicarbonate, 15.0%～50.0% diluent, 20.0%～30.0% disintegrant, 1.0%～4.0% binder, 1.0%～4.0% lubricant; the active drug is as shown in formula I 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate, the percentage refers to weight percentage, so The stated weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;

   

   Preferably, the lenvatinib pharmaceutical composition 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]-7-methoxy as shown in formula I -The methanesulfonate of 6-quinoline carboxamide, where the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component to the total weight of the composition;

   

   Preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc pink.
4. The lenvatinib pharmaceutical composition according to any one of claims 1 to 3, wherein the lenvatinib pharmaceutical composition is selected from any of the following formulas:

   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;

   
5. The lenvatinib pharmaceutical composition according to any one of claims 1 to 4, wherein the lenvatinib pharmaceutical composition is a solid preparation.

   Preferably, the solid preparations are capsules, tablets, granules, powders, sustained-release preparations or dropping pills.
6. The preparation method of lenvatinib pharmaceutical composition according to any one of claims 1 to 4, characterized in that it 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.
7. A lenvatinib pharmaceutical preparation, characterized in that the preparation contains the lenvatinib pharmaceutical composition according to any one of claims 1-4.

   Preferably, the preparation is a solid preparation, such as a capsule, a tablet, a granule, a powder, a sustained-release preparation, or a dripping pill.

   Preferably, the dissolution rate of the lenvatinib pharmaceutical preparation at 15 minutes is not less than 90%.
8. The preparation method of lenvatinib pharmaceutical preparation according to claim 7, characterized in that the preparation method comprises formulation of the pharmaceutical composition.

   Preferably, the preparation method of the lenvatinib pharmaceutical preparation comprises the preparation method of the pharmaceutical composition according to claim 6.

   Preferably, 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 according to claim 6 to obtain a capsule.
9. The use of the lenvatinib pharmaceutical composition according to any one of claims 1 to 4 or the preparation according to claim 6 in the preparation of drugs for the treatment and/or prevention of tumor-related diseases.
10. The application according to claim 9, wherein the tumor-related disease is 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 or neuroglia Mass tumor.