CN111053772A - Levatinib pharmaceutical composition and application thereof - Google Patents

Abstract

The invention provides a pharmaceutical composition which comprises lenvatinib or pharmaceutically acceptable salt thereof, sodium carbonate and sodium bicarbonate, solves the problem that lenvatinib is difficult to dissolve out, has excellent dissolution behavior, and improves the bioavailability of the medicament; meanwhile, the stability is excellent, and the safety of clinical medication can be ensured.

Description

Levatinib pharmaceutical composition and application thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing lenvatinib, a pharmaceutical preparation and application thereof. More particularly, it relates to a pharmaceutical composition having improved dissolution and stability of lenvatinib or a pharmaceutically acceptable salt thereof.

Background

Lenvatinib, a multi-Receptor Tyrosine Kinase (RTK) inhibitor developed by kawasaki corporation, was approved for the thyroid tumor indication in 2015 in the united states, japan, and europe; registration and declaration of liver cancer indications in japan, the usa and europe was carried out in the last half of 2017. The chemical name of the compound is 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide, and the structural formula is shown as follows:

the lenvatinib compound has poor solubility, is slightly soluble in water and ethanol, and is classified as BCS II in biopharmaceutics

Class (low solubility high permeability drug). The compound is gelled to produce a large viscosity in a hygroscopic or aqueous solution. The poor dissolution of the pharmaceutical preparation containing the lenvatinib is caused by poor solubility and large viscosity, and the bioavailability of the lenvatinib in vivo is influenced. In addition, the lenvatinib compound has poor stability, and easily generates more impurities in the preparation or storage process of the preparation, which is not beneficial to the curative effect and clinical medication safety of the product.

The prior art also discloses a lenvatinib composition containing calcium hydrogen phosphate or anhydrous calcium phosphate. However, studies have shown that calcium hydrogen phosphate is not sufficient to improve product stability, and by comparing formulations containing only anhydrous calcium hydrogen phosphate (without the addition of an alkaline formulation) with formulations with the addition of an alkaline formulation, the former has significantly greater amounts of degradation impurities than the latter, and the degradation impurities grow significantly during standing.

The prior art also discloses a lenvatinib cyclodextrin inclusion compound, which utilizes the hydrophilicity of cyclodextrin to improve the dissolution rate of a product to a certain extent, but the principle is only to increase the dissolution performance of raw materials, and the problem that the raw materials are easy to gel when meeting water and the dissolution rate is hindered to be low is still not solved.

Therefore, it is highly desirable to provide a pharmaceutical composition containing lenvatinib and a pharmaceutically acceptable salt thereof, which can achieve both drug stability and enhanced dissolution of the pharmaceutical composition, thereby improving the bioavailability thereof in vivo.

Disclosure of Invention

In order to solve the above problems, it is an object of the present application to provide a pharmaceutical composition or formulation having improved dissolution, bioavailability, stability of lenvatinib or a pharmaceutically acceptable salt thereof.

In a first aspect, the present application provides a pharmaceutical composition comprising lenvatinib or a pharmaceutically acceptable salt thereof, sodium carbonate and sodium bicarbonate.

Further, in the pharmaceutical composition provided by the present application, the mass of the lenvatinib or the pharmaceutically acceptable salt thereof accounts for 4.5% to 5.5% of the total mass of the composition, and is preferably 4.9%.

The present application also provides a pharmaceutical composition comprising lenvatinib or a pharmaceutically acceptable salt thereof, sodium carbonate and sodium bicarbonate; the quality of the lenvatinib or the pharmaceutically acceptable salt thereof accounts for 12.0-13.0% of the total weight of the composition; preferably 12.3%.

Further, in the pharmaceutical composition provided by the application, the mass percentage of the sodium carbonate in the total mass of the composition is 2% -15%.

Further, in the pharmaceutical composition provided by the application, the mass percentage of the sodium bicarbonate in the total mass of the composition is 10% -45%.

Preferably, in the pharmaceutical composition provided by the application, the mass ratio of the sodium bicarbonate to the sodium carbonate is 1: 1-5: 1.

In the pharmaceutical composition provided by the present application, the pharmaceutically acceptable salt of lenvatinib is selected from hydrochloride, p-toluenesulfonate and methanesulfonate, preferably methanesulfonate.

In the pharmaceutical composition provided by the application, the particle size distribution of the lenvatinib or the pharmaceutically acceptable salt thereof is 10 μm or more and D90 or more and 80 μm or less; preferably 20 μm. ltoreq. D90. ltoreq.60 μm; more preferably, D90 is 40 μm.

In certain embodiments, the sodium carbonate has a particle size D90 ≦ 300 μm; preferably 10 μm. ltoreq. D90. ltoreq.200. mu.m; more preferably, D90 is 200. mu.m.

In certain embodiments, the sodium bicarbonate has a particle size D90 ≦ 300 μm; preferably 10 μm. ltoreq. D90. ltoreq.200. mu.m; more preferably, D90 is 200. mu.m.

The pharmaceutical composition provided by the application can further comprise at least one of a filler, a binder, a disintegrant and a lubricant;

the filler is selected from one or more of mannitol, starch, microcrystalline cellulose and lactose, and the mass percentage of the filler in the total mass of the composition is 15-60%;

the adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and sodium carboxymethyl cellulose, and accounts for 1-5% of the total mass of the composition by mass;

the disintegrating agent is selected from one or more of croscarmellose sodium, crospovidone and carboxymethyl starch sodium, and accounts for 3-15% of the total mass of the composition in percentage by mass;

the lubricant is selected from one or more of magnesium stearate, talcum powder and stearic acid, and the mass percentage of the lubricant in the total mass of the composition is 0.5-5%.

In a second aspect, the pharmaceutical composition provided herein may be formulated into pharmaceutically acceptable dosage forms, including but not limited to granules, capsules or tablets.

In a third aspect, the present application provides a use of a pharmaceutical composition or formulation comprising the lenvatinib or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

Wherein the cancer includes but is not limited to thyroid cancer, lung cancer, liver cancer, kidney cancer or melanoma.

The lenvatinib pharmaceutical composition provided by the application has the following advantages:

(1) the dissolution is rapid, the problem that the lenvatinib is easy to gel and difficult to dissolve is effectively solved, and the dissolution rate in dissolution media under different pH values is obviously superior to that in the prior art; especially in hydrochloric acid solution with pH value of 1.0, the medicine is basically dissolved completely within 30min, and the bioavailability of the medicine is effectively ensured.

(2) The product has a slower dissolution rate in the media of pH4.5 and pH6.8 than that in the hydrochloric acid solution of pH1.0, but the dissolution effect is better than that of the comparative sample. For the elderly patients and patients with gastric acid secretion deficiency, the pH value in the stomach is usually higher, so the product has better bioavailability for the special population.

(3) The quality is stable, after the pharmaceutical composition or preparation of the lenvatinib or the pharmaceutically acceptable salt thereof is placed for 6 months under the accelerated test condition, all indexes are not obviously changed, the stability is excellent, and the clinical medication safety is ensured.

Drawings

Figure 1 dissolution investigation graphs of lenvatinib in different pH solutions;

FIG. 2 the effect of different basic excipients on dissolution at pH 1.0;

FIG. 3 the effect of different basic excipients on dissolution at pH 3.0;

FIG. 4 the effect of different basic excipients on dissolution at pH 4.5;

FIG. 5 the effect of different basic excipients on dissolution at pH 6.8;

FIG. 6 shows the effect of different amounts and ratios of sodium bicarbonate/sodium carbonate on dissolution at pH 1.0;

FIG. 7 shows the effect of different amounts and ratios of sodium bicarbonate/sodium carbonate on dissolution at pH 3.0;

FIG. 8 shows the effect of different amounts and ratios of sodium bicarbonate/sodium carbonate on dissolution at pH 4.5;

FIG. 9 the effect of lenvatinib feedstock particle size on dissolution at pH 1.0;

FIG. 10 the effect of lenvatinib feedstock particle size on dissolution at pH 3.0;

FIG. 11 shows the effect of lenvatinib feedstock particle size on dissolution at pH 4.5.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below by way of embodiments with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The dissolution curve measuring method comprises the following steps:

taking Levatinib capsules, taking 900ml of hydrochloric acid solution with the pH value of 1.0, pH3.0 buffer solution, pH4.5 buffer solution and pH6.8 buffer solution as dissolution media according to a dissolution determination method (0931 second method in 2015 general rules of China pharmacopoeia), respectively, taking a proper amount of solution at the rotating speed of 50rpm for 5min, 10min, 15min, 20min, 30min and 60min to determine the content of Levatinib, and calculating the dissolution rate of each capsule.

The comparative examination of the examples and comparative examples was conducted using the dissolution curve measurement method described above.

D90: refers to the corresponding particle size when the cumulative particle size distribution in the particle distribution curve reaches 90%. For example, D90. ltoreq.300. mu.m means that the total number of fine particles having a particle diameter of 300 μm or less reaches 90%.

1. Solubility study of lenvatinib at different pH conditions

Solubility determination method: taking a proper amount of lenvatinib compound, adding a certain amount of solvent, strongly shaking for 30 seconds at 25 +/-2 ℃ every 5 minutes, and observing the dissolution condition after 30 minutes, wherein if solute particles or liquid drops are not found, the lenvatinib compound is considered to be completely dissolved. The solubility of the lenvatinib raw material drug is judged according to the regulations of the fang solubility test method of 'Chinese pharmacopoeia' 2015 edition.

Table 1 lenvatinib solubility test results

As is clear from table 1 and fig. 1, the lenvatinib compound is an poorly soluble drug, has pH dependency, has a large turning point at pH3.0, and has poor solubility as pH increases. Therefore, how to improve the solubility and the dissolution rate of the lenvatinib is of great importance for improving the bioavailability of the medicament.

2. Screening investigation of different basic auxiliary materials

For oral solid preparations of low solubility and high permeability, the dissolution rate is the rate-limiting factor for absorption in vivo. Levatinib is a poorly soluble drug, has a gelation effect, is prone to sticking to the walls of the vessel, and slows the dissolution rate.

The inventor of the application unexpectedly finds that the alkaline substance can improve the dissolution of the lenvatinib to a certain extent, so that different types of alkaline auxiliary materials are screened and investigated.

TABLE 2.1 screening of different basic adjuvants investigation formulation (1000 granules)

Comparative example 1, comparative example 2 and example 1 lenvatinib capsules were prepared according to the formulation recipes shown in table 2.1 by the following method:

uniformly mixing the above prescription amounts of mevalontinib mesylate (D90: 40 μm), alkaline adjuvant (D90: 300 μm), mannitol, hydroxypropyl cellulose, low-substituted-hydroxypropyl cellulose and microcrystalline cellulose PH101 in a mixer, adding appropriate amount of ethanol for granulation, oven drying the formed granules at below 60 deg.C, controlling water content to be less than 3%, adding microcrystalline cellulose PH102 and pulvis Talci, mixing uniformly, and making into capsule (No. 4 capsule).

The dissolution curves of comparative example 1, comparative example 2 and example 1 were examined, and the experiments of each group were performed under the same conditions. The measured data of the dissolution curve is shown in the following table 2.2, and the graphs are shown in the attached figures 2 to 5.

TABLE 2.2 dissolution results of different basic adjuvant formulations at various pH conditions

According to experimental data and a dissolution curve map, the combined use of the sodium bicarbonate and the sodium carbonate can effectively resist the gelation of the lenvatinib, improve the dissolution rate and is beneficial to improving the bioavailability of the lenvatinib. Comparative example 1 using calcium carbonate, the effect against the gelation of lenvatinib was weak and the dissolution rate in 4 media of different pH values was significantly slower than the sample of example 1 of the present application. Comparative example 2 using anhydrous calcium phosphate, the anti-lenvatinib gelation was not achieved and the dissolution was very slow.

3. Investigation on the amount and the ratio of sodium bicarbonate and sodium carbonate

The invention combines the sodium bicarbonate and the sodium carbonate to resist the gelation of the lenvatinib, and the dosage proportion of the sodium bicarbonate and the sodium carbonate influences the anticoagulation effect. On the other hand, the influence of the basic auxiliary materials on the stability of the lenvatinib is bidirectional, and improper use of the lenvatinib can increase the instability of the lenvatinib, so that the toxic impurities of the lenvatinib are increased. In the application, samples of examples and comparative examples with different dosages and proportions are prepared according to the formula shown in the following table 3.1, dissolution curve experiments are carried out, and all groups of experiments are carried out under the same conditions. The experimental data are shown in the following table 3.2, and the dissolution curve maps are shown in the accompanying fig. 6 to fig. 8.

TABLE 3.1 amount of sodium bicarbonate and sodium carbonate and prescription (1000 granules)

Formulation formula	Comparative example 3	Comparative example 4	Example 2	Example 3	Example 4
						Levatinib mesylate	4.9g	4.9g	4.9g	4.9g	4.9g
Sodium bicarbonate	2g	50g	10g	45g	15g
						Sodium carbonate	10g	10g	2g	15g	15g
Mannitol	37g	7g	37g	8g	19g
						Hydroxypropyl cellulose	3g	3g	3g	3g	3g
Low-substituted hydroxypropyl cellulose	25g	7g	25g	10g	25g
						Microcrystalline cellulose PH101	10g	10g	10g	6g	10g
Microcrystalline cellulose PH102	5.1g	5.1g	5.1g	5.1g	5.1g
						Talcum powder	3g	3g	3g	3g	3g
Total weight of	100g	100g	100g	100g	100g

The capsules of examples 2-4 and comparative examples 3-4 were prepared according to the recipe shown in table 3.1 by the following method:

taking prescription dose of mellitinib mesylate (D90: 40 μm), sodium bicarbonate (D90: 200 μm), sodium carbonate (D90: 200 μm), mannitol, hydroxypropyl cellulose, low-substituted-hydroxypropyl cellulose and microcrystalline cellulose PH101, uniformly mixing in a mixer, adding a proper amount of ethanol for granulation, drying the formed granules in an oven below 60 ℃, controlling the water content to be less than 3%, adding microcrystalline cellulose PH102 and talcum powder, uniformly mixing and filling in capsules (No. 4 capsules).

TABLE 3.2 dissolution of formulations of different sodium bicarbonate to sodium carbonate dosage ratios at various pH conditions

From the experimental results, the dosage of the sodium bicarbonate in the comparative example 3 is lower than that of the sodium carbonate, the anti-gelation effect is weak, and the dissolution is slow; when the mass ratio of the sodium bicarbonate in the composition is 2-15%, the mass ratio of the sodium carbonate is 10-45%, and the dosage ratio of the sodium bicarbonate to the sodium carbonate is in the range of 1:1 to 5:1, the dissolution behavior is excellent. In comparative example 4, the sodium bicarbonate and sodium carbonate are used in a large amount, and the research shows that the sodium bicarbonate and sodium carbonate have high impurity content and poor stability (see table 7.1), do not meet the medicinal requirements and do not need the study on the dissolution curve.

All samples in the examples can be completely dissolved in the dissolution media with pH1.0 and pH3.0, and the cumulative dissolution rate reaches more than 90%. In the dissolution medium with the pH value of 4.5, the dissolution rate is slowed down, and the cumulative dissolution rate can reach more than 70 percent at 60 min. Although the dissolution rate in the dissolution medium is reduced at a lower pH value, the dissolution is still far better than that in the comparative example, and the samples of examples 2-4 can still be well dissolved and produce positive treatment effects for the elderly patients and patients with gastric acid secretion disorder (the pH value of gastric acid is usually higher).

4. Influence of particle size of lenvatinib raw material on dissolution rate

The application comprehensively inspects the particle size of the lenvatinib. Formulations of examples 5-10 lenvatinib (1000 granules) were prepared using the same formulation and preparation method as example 1, and using lenvatinib starting materials of different particle sizes, respectively, wherein the particle sizes of lenvatinib mesylate in each example are shown in table 4.1 below. The dissolution curves were used as an index for investigation, and different particle sizes of lenvatinib were investigated, and the experiments were performed under the same conditions, and the results are shown in table 4.2 below, and fig. 9 to 11.

TABLE 4.1 Levatinib different particle size investigation (D90, unit μm)

TABLE 4.2 dissolution results of lenvatinib formulations of different particle sizes at various pH conditions

As can be seen from the data in Table 4.2 above and FIGS. 9-11, dissolution rates decreased when the size of the lenvatinib particles was too large or too small, for example, in examples 10 and 5, and decreased in the dissolution media at pH1.0 and at pH3.0 and pH4.5 when the size of the lenvatinib particles was 100 μm or 5 μm, respectively. When the particle size of lenvatinib is controlled to 10 μm to 80 μm, the dissolution behavior is excellent, and the cumulative dissolution rate can still reach more than 70% even in a dissolution medium with pH 4.5. Accordingly, the particle size of lenvatinib is selected in the range from 10 μm to 80 μm, preferably from 20 μm to 60 μm, particularly preferably 40 μm.

5. Particle size examination of sodium bicarbonate and sodium carbonate

The application also considers the particle sizes of the sodium bicarbonate and the sodium carbonate in the pharmaceutical composition. Samples (1000 granules) of examples 11 to 14 were prepared according to the same formulation and preparation method as in example 1, using sodium bicarbonate and sodium carbonate having different particle sizes, as shown in table 5.1 below, and the experiments were performed under the same conditions using the dissolution curve as an index, and the experimental data are shown in table 5.2 below.

TABLE 5.1 examination of the particle size of sodium bicarbonate and sodium carbonate (D90, unit. mu.m)

TABLE 5.2 dissolution results of sodium bicarbonate/sodium carbonate formulations of different particle size at various pH conditions

From the experimental results, it can be seen that when the particle sizes of sodium bicarbonate and sodium carbonate are within 300 μm, the dissolution rates are both faster, and when the particle size reaches 400 μm, the dissolution rate of lenvatinib in a dissolution medium with pH4.5 is slowed down, and the cumulative dissolution rate is reduced. Therefore, the particle sizes of the sodium bicarbonate and the sodium carbonate in the pharmaceutical composition are selected to be between 10 and 300 mu m.

6. Investigation of other auxiliary Material types

The pharmaceutical composition of the present invention may further comprise auxiliary materials such as a filler, a binder, a disintegrant, and a lubricant, and the inventors have studied the dissolution conditions of the lenvatinib capsules of different types and dosages, and all the experiments have been performed under the same conditions, and the research results show that the lenvatinib composition with excellent dissolution can be obtained by using the conventional auxiliary materials such as the filler, the binder, the disintegrant, and the lubricant and the conventional dosage ranges thereof when the sodium bicarbonate and the sodium carbonate are used in combination and the dosage ratio of the sodium bicarbonate and the sodium carbonate is controlled within a certain range in the examples of the present application, and the specific data are shown in tables 6.1 and 6.2.

Example 15

Formulation (1000 capsules):

the preparation method comprises the following steps:

taking prescription dose of mellitinib mesylate (D90: 40 μm), sodium bicarbonate (D90: 200 μm), sodium carbonate (D90: 200 μm), lactose, hydroxypropyl cellulose, microcrystalline cellulose KG802 and crosslinked polyvinylpyrrolidone, mixing uniformly in a mixer, adding a proper amount of ethanol for granulation, drying the granules in an oven at the temperature of below 60 ℃, controlling the water content to be less than 3%, adding microcrystalline cellulose PH302 and talcum powder, mixing uniformly, and filling into capsules (No. 4 capsules).

Example 16

Formulation (1000 capsules):

the preparation method comprises the following steps:

taking formula amounts of mellitinib mesylate (D90: 40 mu m), sodium bicarbonate (D90: 200 mu m), sodium carbonate (D90: 200 mu m), starch, povidone k30 and sodium carboxymethyl starch, mixing uniformly, adding a proper amount of ethanol for granulation, drying granules below 60A in an oven, controlling the water content to be less than 3%, adding microcrystalline cellulose PH302 and magnesium stearate, mixing uniformly, and filling into capsules (No. 4 capsules).

Example 17

Formulation (1000 capsules):

the preparation method comprises the following steps:

taking formula amounts of mellitinib mesylate (D90: 40 mu m), sodium bicarbonate (D90: 200 mu m), sodium carbonate (D90: 200 mu m), starch, povidone k30 and sodium carboxymethyl starch, mixing uniformly, adding a proper amount of ethanol for granulation, drying the granules in an oven at the temperature of below 60 ℃, controlling the water content to be less than 3%, adding microcrystalline cellulose PH302 and magnesium stearate, mixing uniformly, and filling into capsules (No. 4 capsules).

Example 18

Formulation (1000 capsules):

the preparation method comprises the following steps:

taking prescription dose of mellitinib mesylate (D90: 40 μm), sodium bicarbonate (D90: 200 μm), sodium carbonate (D90: 200 μm), mannitol, hydroxypropyl cellulose, low-substituted-hydroxypropyl cellulose and microcrystalline cellulose PH101, mixing uniformly, adding a proper amount of ethanol for granulation, drying the granules in an oven at the temperature of below 60 ℃, controlling the water content to be less than 3%, adding microcrystalline cellulose PH102 and talcum powder, mixing uniformly, and filling into capsules (No. 4 capsules).

TABLE 6.1 types of adjuvants in the examples

TABLE 6.2 Effect of other adjuvant species on dissolution

7. Stability survey

Yet another significant advantage of the present application is that the pharmaceutical compositions provided herein are extremely stable. The lenvatinib sample prepared in each example of the application and the lenvatinib sample prepared in the comparative example are respectively placed at 40 ℃ and 75% Relative Humidity (RH), and are sampled and inspected for the change of mass of each sample at 6 months, and the inspection indexes comprise: the total amount of other impurities and the content of genotoxic impurities in related substances. The experimental data are shown in table 7.1 below.

TABLE 7.1 comparison of the quality of the inventive and comparative examples

According to the stability test investigation result, after the samples in the embodiments of the application are placed for 6 months at 0 day and 40 ℃ and RH 75%, the total amount of other impurities and the contents of genotoxic impurity 1 and genotoxic impurity 2 are not obviously changed, which shows that the product is very stable, and the effectiveness and safety of the lenvatinib preparation are effectively guaranteed.

On the other hand, after standing at 40 ℃ under RH 75% for 6 months, the genotoxic impurity 2 in comparative example 1 increased significantly, and the total amount of other impurities slightly increased. In comparative example 2, the total amount of other impurities and genotoxic impurities increased significantly. Comparative example 4 more genotoxic impurities were generated at day 0, and the amount of impurities continuously increased during the standing process, which was not in line with the safety of the drug quality.

In conclusion, the lenvatinib pharmaceutical composition provided by the application has significant advantages in dissolution rate and stability, can effectively improve bioavailability, guarantees curative effect and safety, and can provide a good-quality therapeutic drug for patients with liver cancer, thyroid cancer, kidney cancer and the like.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (11)

1. A pharmaceutical composition comprising lenvatinib or a pharmaceutically acceptable salt thereof, sodium carbonate and sodium bicarbonate, wherein:

the mass of the lenvatinib or the pharmaceutically acceptable salt thereof accounts for 4.5-5.5% of the total mass of the composition, and the preferable mass is 4.9%; alternatively, the first and second electrodes may be,

the quality of the lenvatinib or the pharmaceutically acceptable salt thereof accounts for 12.0-13.0% of the total weight of the composition; preferably 12.3%.

2. The pharmaceutical composition according to claim 1, wherein the mass percentage of the sodium carbonate in the total mass of the composition is 2-15%.

3. The pharmaceutical composition according to claim 1, wherein the mass percentage of the sodium bicarbonate in the total mass of the composition is 10-45%.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the mass ratio of the sodium bicarbonate to the sodium carbonate is 1:1 to 5: 1.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the particle size of the lenvatinib or the pharmaceutically acceptable salt thereof is 10 μm or less and D90 or less and 80 μm or less; preferably 20 μm. ltoreq. D90. ltoreq.60 μm; more preferably, D90 is 40 μm.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the particle size of the sodium carbonate is D90 ≤ 300 μm; preferably 10 μm. ltoreq. D90. ltoreq.200. mu.m; more preferably, D90 is 200. mu.m.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the sodium bicarbonate has a particle size D90 ≤ 300 μm; preferably 10 μm. ltoreq. D90. ltoreq.200. mu.m; more preferably, D90 is 200. mu.m.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of lenvatinib is selected from the group consisting of hydrochloride, p-toluenesulfonate and methanesulfonate; preferably a mesylate salt.

9. The pharmaceutical composition according to any one of claims 1 to 8, further comprising one or more of a filler, a binder, a disintegrant, and a lubricant:

the filler is selected from one or more of mannitol, starch, microcrystalline cellulose and lactose, and the mass percentage of the filler in the total mass of the composition is 15-60%;

the adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and sodium carboxymethyl cellulose, and accounts for 1-5% of the total mass of the composition by mass;

the disintegrating agent is selected from one or more of croscarmellose sodium, crospovidone and carboxymethyl starch sodium, and the mass percentage of the disintegrating agent in the total mass of the composition is 3-15%;

the lubricant is selected from one or more of magnesium stearate, talcum powder and stearic acid, and the mass percentage of the lubricant in the total mass of the composition is 0.5-5%.

10. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1 to 9, said formulation selected from the group consisting of granules, capsules and tablets; preferably capsules.

11. Use of a pharmaceutical composition according to any one of claims 1 to 9 or a pharmaceutical formulation according to claim 10 in the manufacture of a medicament for the treatment of cancer; preferably, the cancer is thyroid cancer, lung cancer, liver cancer, kidney cancer or melanoma.

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