A lenvatinib mesylate pharmaceutical composition

Abstract

The present invention discloses a lenvatinib mesylate composition, which contains lenvatinib mesylate, sodium bentonite, a filler, a binder, and a lubricant. The preparation method of the composition is also disclosed; compared with the prior art, the preparation product obtained in the present invention still has good dissolution behavior and stability after accelerated examination, which is significantly better than the existing preparations.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a lenvatinib mesylate pharmaceutical composition. Background Art

[0002] Lenvatinib, also known as Lenvima, has the chemical name 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide.

[0003]

[0004] Lenvatinib mesylate is an oral tyrosine kinase inhibitor that targets VEGFR1-3, fibroblast growth factor receptor (FGFR) 1-4, rearranged during transfection receptor (RET), KIT, and platelet-derived growth factor receptor (PDGFR). Its capsule formulation was approved by the US FDA in February 2015 for the treatment of patients with locally recurrent or metastatic, progressive, radioactive, iodine-refractory differentiated thyroid cancer. It was approved in China on September 4, 2018, with the indication of unresectable hepatocellular carcinoma that has not received prior systemic treatment.

[0005] The original company's patent CN101001629A provides a pharmaceutical composition containing a compound with a pH value of more than 8 in a 5% (w / w) aqueous solution or suspension as a stabilizer and silicic acid or its salt or their solvate as an anti-gelling agent. The decomposition of this composition under humid and heated storage conditions or the gelation on the surface of the pharmaceutical composition is reduced to a sufficiently low level, and it has high stability. The original company's patent CN102470133A discloses a lenvatinib capsule, a composition containing a quinoline derivative and a basic substance as essential components. The basic substance refers to basic inorganic salts, such as magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, potassium carbonate, calcium hydrogen phosphate, iron oxide, etc., and the process requires that the particle moisture content is below 2%. In addition, the original company's patent CN101001629A discloses that lenvatinib decomposes under humid and heated storage conditions. The decomposition mechanism is as follows:

[0006]

[0007] The decomposition product A generated under this degradation pathway is a genotoxic impurity (see the Lenvima FDA review report, hereinafter referred to as genotoxic impurity A), and its content in the pharmaceutical composition should be strictly controlled.

[0008] CN110404079A discloses that lenvatinib will degrade into genotoxic impurity B under humid and hot conditions, whether under acidic conditions or under alkaline conditions. The degradation mechanism is as follows:

[0009]

[0010] According to the original Eisai Lenvima FDA review report, there is also a genotoxic impurity, 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (hereinafter referred to as genotoxic impurity B), in the Lenvima raw material and preparation. Genotoxic impurity B is both a key intermediate in the preparation process of lenvatinib and a degradation product during the storage of the active pharmaceutical ingredient or preparation. In the Eisai Lenvima FDA review report, the control limit of genotoxic impurity B in the active pharmaceutical ingredient is 0.006%, and the control limit in the preparation is 0.04%, both of which are significantly higher than the conventional quality control limits of genotoxic impurities.

[0011] Regarding the dissolution and stability problems existing in the original patented technology, quite a number of patents have been published in recent years:

[0012] CN 202011477137.8 relates to a lenvatinib mesylate pharmaceutical composition and its preparation method. The pharmaceutical composition includes: lenvatinib mesylate, potassium bicarbonate or potassium carbonate, microcrystalline cellulose, and other excipients; the selected preparation method is dry granulation. The said composition and preparation method can ensure that the preparation product has good stability and dissolution, and can also ensure that the crystal form of the active pharmaceutical ingredient does not change during the preparation process.

[0013] CN 202011228155.2 relates to a stable lenvatinib capsule and its preparation method. The present invention uses lactitol - aluminum silicate as a stabilizer, which improves the drug stability of lenvatinib, reduces the hygroscopicity of the granules, and greatly improves the problem of significant decrease in dissolution caused by the gradual gelation of the surface of the pharmaceutical composition due to moisture absorption during storage. At the same time, it overcomes the problem in the prior art that the moisture must be dried to less than 2% during the drying process of wet granulation to ensure the moisture content of the finished product.

[0014] CN 202011520160.0 provides a lenvatinib pharmaceutical composition with rapid and complete dissolution and its preparation method. By weight percentage, the lenvatinib pharmaceutical composition includes 2% - 10% of lenvatinib or its pharmaceutically acceptable salt or its solvate, 10% - 45% of calcium phosphate, and other pharmaceutically acceptable carriers. The said lenvatinib pharmaceutical composition can enable the poorly soluble drug lenvatinib to dissolve rapidly and completely, thereby effectively ensuring that the drug is rapidly absorbed into the body to exert its efficacy.

[0015] CN 202111403157.5 provides a lenvatinib composition, which solves the problem of lenvatinib gelling in water by adding acidic and basic regulators. The addition of the acidic regulator reduces the pH of the dissolution system, further avoids the problem of decreased solubility of lenvatinib mesylate that is dependent on pH, and increases the bioavailability of lenvatinib.

[0016] CN 202211427103.7 discloses a lenvatinib mesylate preparation and its preparation method, including the following components: lenvatinib mesylate, calcium carbonate, mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and talc powder. The C crystal form in the lenvatinib mesylate accounts for 15wt% - 30wt%, and the rest is amorphous. However, when the particle size of lenvatinib mesylate is D90 ≤ 40μm, a lenvatinib mesylate preparation with uniform particle size distribution, small filling difference, and good dissolution effect can be obtained.

[0017] CN 202310564990.0 provides a lenvatinib mesylate capsule and its preparation method. Lenvatinib mesylate, internal diluent, disintegrant, binder, and solvent are mixed and then wet granulated to obtain wet granules; the wet granules are dried to obtain dry granules; the dry granules, external diluent, and lubricant are mixed to obtain intermediate granules of the lenvatinib mesylate capsule; the mass percentage of the external diluent in the lenvatinib mesylate capsule is 2% - 8%; the intermediate granules are filled into capsules to obtain the lenvatinib mesylate capsule.

[0018] Through the analysis of the prior art, regarding the stability and dissolution problems of lenvatinib preparations, on the one hand, alkaline protectants such as alkali metals like magnesium oxide, calcium oxide, sodium carbonate, or sodium bicarbonate, and some organic amine solvents such as alkanolamines are added to solve the stability problem. However, carbonate compounds generate gas rapidly when contacting gastric acid, which will cause more discomfort or serious adverse reactions for patients with concurrent diseases such as acute and chronic gastritis, reflux esophagitis, gastric or duodenal ulcers, and bile acid-related diseases, thereby reducing the compliance of patients taking medications. On the other hand, anti-gelation agents such as light silica, calcium silicate, magnesium silicate, or magnesium aluminum silicate are added to solve the problem of low dissolution caused by the gelation of raw material dissolution. However, the above-mentioned alkaline substances, for example, magnesium oxide, calcium oxide, sodium hydroxide, amino acids, etc., are not easy to rapidly release the drug, resulting in slow dissolution, which requires complex processes to solve; in addition, techniques such as micronization of the drug and preparation of solid dispersions to solve the dissolution problem will also cause drug instability.

[0019] Therefore, in the prior art, lenvatinib preparations have defects such as unsatisfactory dissolution effect, poor stability, complex preparation process, and being unsuitable for industrial production. Those skilled in the art need to study the above problems and find better lenvatinib mesylate preparations to meet the clinical needs.

[0020] During the research process, the inventors of the present invention developed a lenvatinib mesylate pharmaceutical composition and a preparation method to solve the above problems and make the product suitable for industrial production. Summary of the Invention

[0021] The object of the present invention is to provide a lenvatinib mesylate pharmaceutical composition and a preparation method thereof in view of the above defects of the prior art. The lenvatinib mesylate pharmaceutical preparation prepared by the present invention has high dissolution rate, good stability, simple preparation process, and is suitable for industrial production.

[0022] Specifically, the present invention is realized through the following technical solutions:

[0023] A lenvatinib mesylate pharmaceutical composition, which contains lenvatinib mesylate, sodium-based bentonite, filler, binder, and lubricant.

[0024] In the lenvatinib mesylate pharmaceutical composition, the mass ratio of lenvatinib mesylate, sodium-based bentonite, filler, binder, and lubricant in each unit preparation of the pharmaceutical composition is (4 - 20):(10 - 35):(20 - 70):(1 - 20):(0.5 - 5).

[0025] The filler is selected from one or a mixture of two or more of lactose, starch, microcrystalline cellulose, sorbitol, and mannitol. Microcrystalline cellulose and mannitol are preferred.

[0026] The binder is selected from one or a mixture of two or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and pregelatinized starch. Hydroxypropyl cellulose is preferred.

[0027] The lubricant is one or more of magnesium stearate, calcium stearate, talc powder, and sodium stearyl fumarate. Talc powder is preferred.

[0028] In the lenvatinib mesylate pharmaceutical composition, each unit preparation of the pharmaceutical composition contains the following components: 4 mg - 20 mg of lenvatinib mesylate, 10 mg - 35 mg of sodium-based bentonite, 10 - 40 mg of microcrystalline cellulose, 10 - 30 mg of mannitol, 1 mg - 20 mg of hydroxypropyl cellulose, and 0.5 mg - 5 mg of talc powder.

[0029] The lenvatinib mesylate pharmaceutical composition contains the following components in each unit dosage form: 12.25 mg of lenvatinib mesylate, 10 mg to 35 mg of sodium bentonite, 10 to 40 mg of microcrystalline cellulose, 10 to 30 mg of mannitol, 1 mg to 20 mg of hydroxypropyl cellulose, and 0.5 mg to 5 mg of talc.

[0030] The lenvatinib mesylate pharmaceutical composition contains the following components in each unit dosage form: 4.9 mg of lenvatinib mesylate, 10 mg to 35 mg of sodium bentonite, 10 to 40 mg of microcrystalline cellulose, 10 to 30 mg of mannitol, 1 mg to 20 mg of hydroxypropyl cellulose, and 0.5 mg to 5 mg of talc.

[0031] The lenvatinib mesylate pharmaceutical composition contains the following components in each unit dosage form:

[0032] 4.9 mg of lenvatinib mesylate, 10 mg of sodium bentonite, 18 mg of microcrystalline cellulose, 21.1 mg of mannitol, 3 mg of hydroxypropyl cellulose, and 3 mg of talc; or,

[0033] 12.25 mg of lenvatinib mesylate, 30 mg of sodium bentonite, 22.75 mg of microcrystalline cellulose, 30 mg of mannitol, 5 mg of hydroxypropyl cellulose, and 5 mg of talc.

[0034] The lenvatinib mesylate pharmaceutical composition is preferably a solid preparation, such as a capsule, tablet, granule, powder, sustained-release preparation, or dripping pill; further preferably, the solid preparation of the lenvatinib mesylate pharmaceutical composition of the present invention is a capsule.

[0035] The present invention also provides a method for preparing the pharmaceutical composition, which includes the following steps:

[0036] Weigh the prescription amount of lenvatinib mesylate, sodium bentonite, and a part of the prescription amount of the filler, mix them evenly, and then use a high-speed stirring granulation device or a fluidized bed granulation device to add an adhesive alcohol solution for wet granulation or fluidized bed granulation. The obtained wet granules are dried, sieved, and sized. Lubricant and the remaining prescription amount of the filler are added to the sized granules, and they are mixed evenly. The prepared powder or granules can be further prepared into a powder, granule, tablet, or directly filled into a capsule to prepare a capsule.

[0037] In a preferred embodiment, the method for preparing the pharmaceutical composition includes the following steps:

[0038] Weigh the prescribed amounts of lenvatinib mesylate, sodium-based bentonite, mannitol, and microcrystalline cellulose (2 / 3 of the prescribed amount). After mixing them thoroughly, use a high-speed stirring granulation device or a fluidized bed granulation device, and add an ethanol solution of hydroxypropyl cellulose for wet granulation or fluidized bed granulation. The obtained wet granules are dried, sieved, and sized. Lubricant talc is added to the sized granules, and the remaining prescribed amount of microcrystalline cellulose is added externally. Mix them thoroughly. The prepared powder or granules can be further prepared into powders, granules, tablets, or directly filled into capsules to prepare capsules.

[0039] Compared with the prior art, the present invention provides a lenvatinib mesylate pharmaceutical composition. The drug has a fast dissolution rate, a simple process, avoids the application of carbonate compounds, and avoids the discomfort or serious adverse reactions that may be caused to patients with concurrent diseases such as acute and chronic gastritis, reflux esophagitis, gastric or duodenal ulcers, and bile acid-related diseases. There is no need for complex technologies such as drug micronization treatment and solid dispersion preparation, and the product preparation process is simple. Accelerated tests have proved that sodium-based bentonite can enable the products obtained by the present invention to still have good dissolution behavior and stability, which is significantly better than existing preparations. Detailed implementation mode

[0040] Now, the beneficial effects of the present invention will be further described through the following examples. These examples are only for illustrative purposes and should not be construed as limiting the present invention. Obvious improvements and modifications made by those skilled in the art to the present invention are also within the protection scope of the present invention.

[0041] The following examples are for preparing lenvatinib mesylate capsules. The operations described are conventional pharmaceutical operations.

[0042] Example 1

[0043]

[0044] Preparation process:

[0045] Weigh the prescribed amounts of lenvatinib mesylate, sodium-based bentonite, mannitol, and microcrystalline cellulose (2 / 3 of the prescribed amount). After mixing them thoroughly, use a high-speed stirring granulation device or a fluidized bed granulation device, and add an ethanol solution of hydroxypropyl cellulose for wet granulation or fluidized bed granulation. The obtained wet granules are dried, sieved, and sized. Lubricant talc is added to the sized granules, and the remaining prescribed amount of microcrystalline cellulose is added externally. Mix them thoroughly. The prepared powder is filled into capsules.

[0046] Example 2

[0047]

[0048] Preparation process: The same as Example 1.

[0049] Example 3

[0050]

[0051] Preparation process: the same as that of Example 1.

[0052] Example 4

[0053]

[0054] Preparation process: the same as that of Example 1.

[0055] Example 5

[0056]

[0057] Preparation process: the same as that of Example 1.

[0058] Example 6

[0059]

[0060] Preparation process: the same as that of Example 1.

[0061] Example 7

[0062]

[0063] Preparation process:

[0064] Weigh the prescribed amounts of lenvatinib mesylate, sodium bentonite, mannitol, and microcrystalline cellulose. After mixing them thoroughly, use a high-speed stirring granulation device or a fluidized bed granulation device, and add an ethanol solution of hydroxypropyl cellulose for wet granulation or fluidized bed granulation. The obtained wet granules are dried, sieved, and sized. Add lubricant talc powder to the sized granules and mix them thoroughly. The prepared powder is filled into capsules.

[0065] Comparative Example 1

[0066]

[0067] Preparation process:

[0068] Prepare lenvatinib mesylate, hydrotalcite, microcrystalline cellulose (2 / 3 amount), mannitol, and low-substituted hydroxypropyl cellulose in the prescription ratio shown in the above table. After mixing them thoroughly, use a high-speed stirring granulation device and add an aqueous solution of hydroxypropyl cellulose for wet granulation. Dry the obtained wet granules at 60 °C, sieve, and size them. Add talc powder and microcrystalline cellulose (1 / 3 amount) to the sized granules in the prescription ratio shown in the above table and mix them thoroughly. The prepared powder is filled into capsules.

[0069] Verification Example

[0070] Dissolution Determination and Stability Study of Lenvatinib Mesylate Capsules

[0071] 1. Stability Study: Take this product and place it under high temperature (60°C), high humidity (92.5%), and light (4500 LuX ± 500 LuX) conditions for 10 days, and determine the related substances and content.

[0072] 2. Dissolution Determination: According to the second method (paddle method) for dissolution determination in the Chinese Pharmacopoeia 2020 Edition, the dissolution of the capsules of Examples 1-7 and Comparative Example 1 was determined. 900 ml of 0.1 N (normal concentration) hydrochloric acid solution and pH 6.8 phosphate buffer + 0.3% sodium dodecyl sulfate (SDS) were used as dissolution media respectively, and the dissolution test was carried out at 37 ± 0.5°C with a rotation speed of 50 rpm. Samples were taken at 15 min to measure their dissolution.

[0073] Table 1 Examination and Determination Results of Samples in Examples and Comparative Examples

[0074]

[0075]

[0076]

[0077] 3. Accelerated Conditions for Stability Study: 40 ± 2°C, 75% ± 5% RH. Accelerated Time: 6 months.

[0078] Table 2 Examination and Determination Results of Samples in Examples and Comparative Examples

[0079]

[0080]

[0081] It can be seen from the table that the samples of Examples 1-7 obtained in the present invention can maintain good stability and dissolution rate for a long time. From the stability data of Comparative Example 1 under high temperature (60°C), high humidity (92.5%), and light (4500 LuX ± 500 LuX) and the examination data of Comparative Example 1 after 6 months, the stability of Comparative Example 1 is poor, especially the genotoxic impurities exceed the standard.

Claims

1. A pharmaceutical composition of lenvatinib mesylate, characterized in that: The composition contains lenvatinib mesylate, sodium bentonite, a filler, a binder, and a lubricant; The mass ratio of lenvatinib mesylate, sodium bentonite, filler, binder and lubricant in the pharmaceutical composition of each unit preparation is (4-20): (10-35): (20-70): (1-20): (0.5-5); The filler is selected from microcrystalline cellulose and mannitol; The binder is hydroxypropyl cellulose; The lubricant is talcum powder.

2. The lenvatinib mesylate pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition of each unit preparation contains the following components: 4 mg to 20 mg of lenvatinib mesylate, 10 mg to 35 mg of sodium bentonite, 10 mg to 40 mg of microcrystalline cellulose, 10 mg to 30 mg of mannitol, 1 mg to 20 mg of hydroxypropyl cellulose and 0.5 mg to 5 mg of talc.

3. The lenvatinib mesylate pharmaceutical composition according to claim 1, characterized in that: Each unit of the pharmaceutical composition contains the following components: Lenvatinib mesylate 4.9 mg, sodium bentonite 10 mg, microcrystalline cellulose 18 mg, mannitol 21.1 mg, hydroxypropyl cellulose 3 mg, and talc 3 mg; or, Lenvatinib mesylate 12.25 mg, sodium bentonite 30 mg, microcrystalline cellulose 22.75 mg, mannitol 30 mg, hydroxypropyl cellulose 5 mg and talc 5 mg.

4. The pharmaceutical composition of lenvatinib mesylate according to claim 1, characterized in that: The method for preparing the pharmaceutical composition comprises the following steps: Weigh the prescribed amount of lenvatinib mesylate, sodium bentonite, and part of the prescribed amount of filler, mix them thoroughly and evenly, add an aqueous binder solution or an alcohol binder solution or an alcohol binder aqueous binder solution for wet granulation or fluidized bed granulation using a high-speed stirring granulator or a fluidized bed granulator, dry the obtained wet granules, sieve and granulate them, add a lubricant or a glidant and the remaining prescribed amount of filler to the granulated granules, and mix them thoroughly and evenly.

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