Antitumor drug apatinib mesylate tablet and preparation method thereof

Abstract

The invention belongs to the technical field of antitumor drug preparations, and relates to an antitumor drug apatinib mesylate tablet and a preparation method thereof. The apatinib mesylate tablet is composed of apatinib mesylate lipidosome and pharmaceutically acceptable auxiliary materials, apatinib mesylate is entrapped in a lipid material by using a lipidosome technology, and the apatinib mesylate tablet is prepared by optimizing a carrier material and a preparation process. The apatinib mesylate liposome and pharmaceutically acceptable auxiliary materials are prepared into tablets, and an acceleration test proves that compared with apatinib mesylate tablets sold in the market, the apatinib mesylate tablets have more excellent stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of anti-tumor drug preparations, and in particular relates to an anti-tumor drug apatinib mesylate tablet and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Tumor is one of the major diseases that seriously threaten human health. Its pathogenesis is complex and difficult to treat. At present, the main clinical treatment methods for tumors include surgery, radiotherapy, chemotherapy, targeted therapy, etc. With the continuous development of medical technology, targeted therapy has gradually become one of the important means of tumor treatment due to its advantages such as high specificity and small side effects. Apatinib mesylate tablets are a new type of small molecule anti-angiogenesis inhibitor, which specifically inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor 2, thereby blocking the formation of tumor angiogenesis and achieving the purpose of inhibiting tumor growth. At present, apatinib mesylate tablets have been widely used in the treatment of various malignant tumors such as advanced non-small cell lung cancer, advanced gastric cancer, and advanced liver cancer, and have achieved significant clinical efficacy. However, apatinib mesylate still faces some challenges in clinical application. Apatinib mesylate has poor water solubility, which not only limits the preparation of its preparations, but also affects the absorption and distribution of the drug in the body, resulting in relatively low bioavailability. It is difficult for the drug to fully reach the tumor tissue to exert its effect, which affects the further improvement of its therapeutic effect.

[0004] As a new type of drug carrier, liposomes have unique advantages. It can wrap hydrophobic drugs in the lipid bilayer inside it, significantly improve the water solubility of the drug, and promote the absorption and distribution of the drug. At the same time, the particle size and surface properties of liposomes can be regulated, and by modifying specific targeting ligands on the surface, such as antibodies, peptides, etc., active targeted delivery to tumor tissues can be achieved, so that drugs can act more accurately on tumor cells and reduce damage to normal tissues. The Chinese patent with publication number CN 115990136 A discloses an anti-tumor composition, nanoformulation, preparation method and use, which is to compound two lipophilic drugs, apatinib and bufotoxin, and encapsulate them in liposome-Prussian blue nanoformulation in an active drug-carrying manner. The Chinese patent with publication number CN 118680881 A discloses a drug-loaded membrane fusion liposome for overcoming tumor multidrug resistance, and its preparation method and application. The drug-loaded liposome is mainly composed of four lipids, dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine, cholesterol and sphingomyelin, and two drugs, apatinib and doxorubicin. However, most of the liposome preparations loaded with apatinib in the prior art have poor stability. Therefore, it is necessary to develop a new apatinib mesylate preparation to meet the needs of clinical treatment. Summary of the invention

[0005] The shortcomings of the prior art are overcome. The present invention uses liposome drug delivery technology to provide a stable apatinib mesylate tablet. Specifically, the apatinib mesylate tablet is composed of apatinib mesylate liposomes and pharmaceutically acceptable excipients; the apatinib mesylate liposomes include apatinib mesylate, lecithin, cholesterol, lactitol, and sodium tripolyphosphate.

[0006] Wherein, the preparation method of the apatinib mesylate liposome is:

[0007] (1) dissolving apatinib mesylate, lecithin, cholesterol and lactitol in an organic solvent, performing vacuum rotary evaporation at 35°C to 45°C until a thin film appears, adding a buffer solution of pH=4.0-5.0 containing sodium tripolyphosphate to hydrate for 5-15 minutes, then adding a buffer solution of pH=5.5-6.5 to hydrate for 10-20 minutes, and homogenizing under high pressure to obtain a crude product;

[0008] (2) The crude product is freeze-dried to obtain apatinib mesylate liposomes.

[0009] Furthermore, the weight ratio of apatinib mesylate, lecithin, cholesterol, lactitol, and sodium tripolyphosphate is 2-5:4-8:1-3:0.05-0.2:0.5-1. The buffer solution is at least one of a citrate buffer solution, a phosphate buffer solution, an acetate buffer solution, and a lactate buffer solution. The pressure of the high-pressure homogenization is 1000-2000 bar, the temperature is 35-45°C, and the number of cycles is 10-30 times. The freeze-drying procedure is: control the temperature to -30°C to -40°C at normal pressure for 6-10 hours, increase the temperature to -10°C to 0°C under vacuum pressure for 4-6 hours, reduce the temperature to -25°C to -15°C under vacuum pressure for 1-3 hours, and increase the temperature to 5°C to 15°C under vacuum pressure for 10-14 hours.

[0010] In order to ensure the dissolution of apatinib mesylate, lecithin, cholesterol and lactitol, the organic solvent is selected as an ethanol-methanol mixed solvent or an ethanol-chloroform mixed solvent.

[0011] Furthermore, the pharmaceutically acceptable excipient is selected from at least one of a filler, a disintegrant, a lubricant, a binder, a wetting agent, and a flavoring agent.

[0012] Compared with the prior art, the technical effects of the present invention are:

[0013] The present invention utilizes liposome technology to encapsulate apatinib mesylate in a lipid material, and improves the drug loading capacity and encapsulation rate of apatinib mesylate liposomes and the stability of apatinib mesylate liposomes by optimizing the carrier material and the preparation process. Furthermore, apatinib mesylate liposomes and pharmaceutically acceptable excipients are used to prepare tablets. It can be verified by accelerated tests that, compared with commercially available apatinib mesylate tablets, the apatinib mesylate tablets of the present invention have more excellent stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The uniformity of particle size distribution of apatinib mesylate liposomes on day 1 and day 120 of the experiment.

[0015] Figure 2 The drug loading amount of apatinib mesylate liposomes of Examples 1 to 4 and apatinib mesylate liposomes of Comparative Examples 1 to 5 is compared.

[0016] Figure 3 The encapsulation rates of apatinib mesylate liposomes of Examples 1 to 4 and apatinib mesylate liposomes of Comparative Examples 1 to 5 are shown.

[0017] Figure 4 It is a graph showing the changes in content in the accelerated test of apatinib mesylate tablets of Examples 5 to 7, apatinib mesylate tablets of Comparative Examples 6 to 7, and commercially available apatinib mesylate tablets. DETAILED DESCRIPTION

[0018] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0019] Example 1 Apatinib mesylate liposomes

[0020] formula:

[0021] Weight(g) Apatinib mesylate 3 Lecithin 6 cholesterol 2 Lactitol 0.1 Sodium tripolyphosphate 0.8

[0022] Preparation method:

[0023] (1) Apatinib mesylate, lecithin, cholesterol, and lactitol were dissolved in 100 ml of a mixed solvent of ethanol and methanol in a volume ratio of 2:1, and vacuum evaporated at 35° C. to 45° C. until a thin film appeared, and 50 ml of a pH 4.5 citrate buffer solution containing sodium tripolyphosphate was added to hydrate for 10 min, and then 20 ml of a pH 6.0 citrate buffer solution was added to hydrate for 15 min, and the mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 40° C. The number of cycles was 20, and a crude product was obtained;

[0024] (2) The crude product was freeze-dried, and the temperature was controlled to -35°C at normal pressure for 8 h, and then the temperature was raised to -5°C under vacuum for 5 h, and then the temperature was lowered to -20°C under vacuum for 2 h, and then the temperature was raised to 10°C under vacuum for 12 h, and then sealed to obtain apatinib mesylate liposomes.

[0025] Example 2 Apatinib mesylate liposomes

[0026] formula:

[0027] Weight(g) Apatinib mesylate 2 Lecithin 4 cholesterol 1 Lactitol 0.05 Sodium tripolyphosphate 0.5

[0028] Preparation method:

[0029] (1) Apatinib mesylate, lecithin, cholesterol, and lactitol were dissolved in 80 ml of a mixed solvent of ethanol and chloroform with a volume ratio of 2:1, and the mixture was evaporated under reduced pressure at 35° C. to 45° C. until a thin film appeared, 40 ml of a phosphate buffer solution with a pH of 4.5 containing sodium tripolyphosphate was added to hydrate for 5 min, and then 30 ml of a phosphate buffer solution with a pH of 6.0 was added to hydrate for 20 min, and the mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 35° C. The number of cycles was 30 to obtain a crude product;

[0030] (2) The crude product was freeze-dried, and the temperature was controlled to -40°C at normal pressure for 6 h. The temperature was raised to -10°C under vacuum pressure for 4 h. The temperature was lowered to -25°C under vacuum pressure for 1 h. The temperature was raised to 5°C under vacuum pressure for 10 h. The product was sealed to obtain apatinib mesylate liposomes.

[0031] Example 3 Apatinib mesylate liposomes

[0032] formula:

[0033]

[0034]

[0035] Preparation method:

[0036] (1) Apatinib mesylate, lecithin, cholesterol, and lactitol were dissolved in 120 ml of a 3:1 ethanol-chloroform mixed solvent, and the mixture was evaporated under reduced pressure at 35° C. to 45° C. until a thin film appeared. 60 ml of a pH 4.5 acetate buffer solution containing sodium tripolyphosphate was added to hydrate for 15 min, and then 20 ml of a pH 6.0 acetate buffer solution was added to hydrate for 10 min. The mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 45° C. The number of cycles was 10, and a crude product was obtained.

[0037] (2) The crude product was freeze-dried, and the temperature was controlled to -30°C at normal pressure for 10 h. The temperature was raised to 0°C under vacuum for 6 h. The temperature was lowered to -15°C under vacuum for 3 h. The temperature was raised to 15°C under vacuum for 14 h. The product was sealed to obtain apatinib mesylate liposomes.

[0038] Example 4 Apatinib mesylate liposomes

[0039] formula:

[0040] Weight(g) Apatinib mesylate 3 Lecithin 5 cholesterol 2 Lactitol 0.15 Sodium tripolyphosphate 0.7

[0041] Preparation method:

[0042] (1) Apatinib mesylate, lecithin, cholesterol, and lactitol were dissolved in 100 ml of a 4:1 ethanol-methanol mixed solvent, and the mixture was evaporated under reduced pressure at 35° C. to 45° C. until a thin film appeared. 50 ml of a pH 4.5 lactate buffer solution containing sodium tripolyphosphate was added to hydrate for 10 min, and then 20 ml of a pH 6.0 lactate buffer solution was added to hydrate for 15 min. The mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 40° C. The number of cycles was 25 to obtain a crude product.

[0043] (2) The crude product was freeze-dried, and the temperature was controlled to -38°C at normal pressure for 7 h, and then the temperature was raised to -8°C under vacuum for 5 h, and then the temperature was lowered to -18°C under vacuum for 2 h, and then the temperature was raised to 8°C under vacuum for 13 h, and then sealed to obtain apatinib mesylate liposomes.

[0044] Comparative Example 1 Apatinib mesylate liposome

[0045] formula:

[0046] Weight(g) Apatinib mesylate 3 Lecithin 6 cholesterol 2 Sodium tripolyphosphate 0.8

[0047] Preparation method:

[0048] (1) Apatinib mesylate, lecithin, and cholesterol were dissolved in 100 ml of a 2:1 ethanol-methanol mixed solvent, and the mixture was evaporated under reduced pressure at 35° C. to 45° C. until a thin film appeared. 50 ml of a pH 4.5 citrate buffer solution containing sodium tripolyphosphate was added to hydrate for 10 min, and then 20 ml of a pH 6.0 citrate buffer solution was added to hydrate for 15 min. The mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 40° C. The number of cycles was 20 to obtain a crude product.

[0049] (2) The crude product was freeze-dried, and the temperature was controlled to -35°C at normal pressure for 8 h, and then the temperature was raised to -5°C under vacuum for 5 h, and then the temperature was lowered to -20°C under vacuum for 2 h, and then the temperature was raised to 10°C under vacuum for 12 h, and then sealed to obtain apatinib mesylate liposomes.

[0050] Comparative Example 2 Apatinib mesylate liposomes

[0051] formula:

[0052] Weight(g) Apatinib mesylate 3 Lecithin 6 cholesterol 2 Lactitol 0.1

[0053] Preparation method:

[0054] (1) Apatinib mesylate, lecithin, cholesterol, and lactitol were dissolved in 100 ml of a 2:1 ethanol-methanol mixed solvent, and the mixture was evaporated under reduced pressure at 35° C. to 45° C. until a thin film appeared. 50 ml of a pH 4.5 citrate buffer solution was added to hydrate for 10 min, and then 20 ml of a pH 6.0 citrate buffer solution was added to hydrate for 15 min. The mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 40° C. The number of cycles was 20 to obtain a crude product.

[0055] (2) The crude product was freeze-dried, and the temperature was controlled to -35°C at normal pressure for 8 h, and then the temperature was raised to -5°C under vacuum for 5 h, and then the temperature was lowered to -20°C under vacuum for 2 h, and then the temperature was raised to 10°C under vacuum for 12 h, and then sealed to obtain apatinib mesylate liposomes.

[0056] Comparative Example 3 Apatinib mesylate liposomes

[0057] formula:

[0058] Weight(g) Apatinib mesylate 3 Lecithin 6 cholesterol 2

[0059] Preparation method:

[0060] (1) Apatinib mesylate, lecithin and cholesterol were dissolved in 100 ml of a mixed solvent of ethanol and methanol with a volume ratio of 2:1, and vacuum evaporated at 35° C. to 45° C. until a thin film appeared, and 50 ml of a pH = 4.5 citrate buffer solution was added to hydrate for 10 min, and then 20 ml of a pH = 6.0 citrate buffer solution was added to hydrate for 15 min, and the mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 40° C. The number of cycles was 20 to obtain a crude product;

[0061] (2) The crude product was freeze-dried, and the temperature was controlled to -35°C at normal pressure for 8 h, and then the temperature was raised to -5°C under vacuum for 5 h, and then the temperature was lowered to -20°C under vacuum for 2 h, and then the temperature was raised to 10°C under vacuum for 12 h, and then sealed to obtain apatinib mesylate liposomes.

[0062] Comparative Example 4 Apatinib mesylate liposomes

[0063] formula:

[0064] Weight(g) Apatinib mesylate 3 Lecithin 6 cholesterol 2 Lactitol 0.1 Sodium tripolyphosphate 0.8

[0065] Preparation method:

[0066] (1) Apatinib mesylate, lecithin, cholesterol, and lactitol were dissolved in 100 ml of a 2:1 ethanol-methanol mixed solvent, and the mixture was evaporated under reduced pressure at 35° C. to 45° C. until a thin film appeared. 50 ml of a pH 6.0 citrate buffer solution containing sodium tripolyphosphate was added and hydrated for 20 min. The mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 40° C. The number of cycles was 20 to obtain a crude product.

[0067] (2) The crude product was freeze-dried, and the temperature was controlled to -35°C at normal pressure for 8 h, and then the temperature was raised to -5°C under vacuum for 5 h, and then the temperature was lowered to -20°C under vacuum for 2 h, and then the temperature was raised to 10°C under vacuum for 12 h, and then sealed to obtain apatinib mesylate liposomes.

[0068] Comparative Example 5 Apatinib mesylate liposomes

[0069] formula:

[0070] Weight(g) Apatinib mesylate 3 Lecithin 6 cholesterol 2 Lactitol 0.1 Sodium tripolyphosphate 0.8

[0071] Preparation method:

[0072] (1) Apatinib mesylate, lecithin, cholesterol, and lactitol were dissolved in 100 ml of a 2:1 ethanol-methanol mixed solvent, and the mixture was evaporated under reduced pressure at 35° C. to 45° C. until a thin film appeared. 50 ml of a pH 6.0 citrate buffer solution containing sodium tripolyphosphate was added to hydrate for 10 min, and then 20 ml of a pH 4.5 citrate buffer solution was added to hydrate for 15 min. The mixture was homogenized under high pressure at a pressure of 1000-2000 bar and a temperature of 40° C. The number of cycles was 20 to obtain a crude product.

[0073] (2) The crude product was freeze-dried, and the temperature was controlled to -35°C at normal pressure for 8 h, and then the temperature was raised to -5°C under vacuum for 5 h, and then the temperature was lowered to -20°C under vacuum for 2 h, and then the temperature was raised to 10°C under vacuum for 12 h, and then sealed to obtain apatinib mesylate liposomes.

[0074] Quality evaluation of apatinib mesylate liposomes

[0075] The quality of apatinib mesylate liposomes was evaluated based on the particle size and distribution, encapsulation efficiency, drug loading and other indicators. Specifically, the apatinib mesylate liposomes of Examples 1 to 4 and the apatinib mesylate liposomes of Comparative Examples 1 to 5 were placed at a temperature of 40±2° C. and a relative humidity of 75%±5%, and samples were taken during the test to measure the above indicators.

[0076] Figure 1 The results show the uniformity of particle size distribution of apatinib mesylate liposomes on the 1st day and the 120th day of the experiment. The results show that the particle size distribution of apatinib mesylate liposomes in Examples 1 to 4 of the present invention is concentrated and stable, with good fluid dynamics and stability, which is beneficial to the circulation and targeting effect in the body.

[0077] Figure 2 Comparison of drug loading of apatinib mesylate liposomes in Examples 1 to 4 and Comparative Examples 1 to 5. Figure 3 The encapsulation rates of apatinib mesylate liposomes of Examples 1 to 4 and apatinib mesylate liposomes of Comparative Examples 1 to 5 are shown. Figure 2 and Figure 3The data show that the apatinib mesylate liposomes of Examples 1 to 4 of the present invention have strong drug encapsulation capacity, indicating that the formula and preparation process of the apatinib mesylate liposomes of the present invention are well optimized, so that a large amount of apatinib mesylate can be effectively encapsulated inside the liposomes. During the accelerated test, the drug loading and encapsulation efficiency of the apatinib mesylate liposomes changed little, indicating that the optimization of the formula, reasonable selection and preparation method led to good membrane structural integrity of the liposomes, strong interaction between the lipid bilayers, forming a tight and stable structure, resisting the damage that may be caused under accelerated test conditions (such as high temperature, high humidity, etc.), and effectively preventing the drug from leaking out from the inside, and the apatinib mesylate liposomes have excellent physical stability.

[0078] Example 5 Apatinib Mesylate Tablets

[0079] formula:

[0080] Example 1 Apatinib mesylate liposomes (containing 250 g of apatinib mesylate), 20 g of starch, 5 g of microcrystalline cellulose, 3 g of sodium starch glycolate, and 0.5 g of magnesium stearate.

[0081] Preparation method:

[0082] The above raw and auxiliary materials are sieved, mixed, and directly pressed into tablets to obtain the product.

[0083] Example 6 Apatinib Mesylate Tablets

[0084] formula:

[0085] Example 2 Apatinib mesylate liposomes (containing 250 g of apatinib mesylate), 20 g of starch, 5 g of lactose, 10 g of mannitol, 3 g of low-substituted hydroxypropyl methylcellulose, and 1 g of talc.

[0086] Preparation method:

[0087] The above raw and auxiliary materials are sieved, mixed, and directly pressed into tablets to obtain the product.

[0088] Example 7 Apatinib Mesylate Tablets

[0089] formula:

[0090] Example 4 Apatinib mesylate liposomes (containing 250 g of apatinib mesylate), 20 g of starch, 5 g of sucrose, 2 g of dextrin, 2 g of cross-linked polyvinylpyrrolidone, and 0.5 g of micropowder silica gel.

[0091] Preparation method:

[0092] The above raw and auxiliary materials are sieved, mixed, and directly pressed into tablets to obtain the product.

[0093] Comparative Example 6 Apatinib Mesylate Tablets

[0094] formula:

[0095] Comparative Example 3: apatinib mesylate liposomes (containing 250 g apatinib mesylate), 20 g starch, 5 g microcrystalline cellulose, 3 g sodium starch glycolate, and 0.5 g magnesium stearate.

[0096] Preparation method:

[0097] The above raw and auxiliary materials are sieved, mixed, and directly pressed into tablets to obtain the product.

[0098] Comparative Example 7 Apatinib Mesylate Tablets

[0099] formula:

[0100] Comparative Example 5: apatinib mesylate liposomes (containing 250 g apatinib mesylate), 20 g starch, 5 g microcrystalline cellulose, 3 g sodium starch glycolate, and 0.5 g magnesium stearate.

[0101] Preparation method:

[0102] The above raw and auxiliary materials are sieved, mixed, and directly pressed into tablets to obtain the product.

[0103] Commercially available apatinib mesylate tablets: National Medicine Approval No. H20140103.

[0104] The apatinib mesylate tablets of Examples 5 to 7, and the apatinib mesylate tablets of Comparative Examples 6 and 7 were placed in commercial packaging with commercially available apatinib mesylate tablets at a temperature of 40±2°C and a relative humidity of 75%±5%, and samples were taken during the test to determine the apatinib mesylate content by high performance liquid chromatography.

[0105] Figure 4 The accelerated test content change diagram of apatinib mesylate tablets of Examples 5 to 7, apatinib mesylate tablets of Comparative Examples 6 to 7, and commercially available apatinib mesylate tablets. The results show that the content of active ingredients in apatinib mesylate tablets of Examples 5 to 7 of the present invention is stable, indicating that apatinib mesylate tablets have reached a higher standard in quality control, reducing the risk of failure of apatinib mesylate tablets due to changes in storage conditions.

Claims

1. Apatinib mesylate tablet, characterized in that: The apatinib mesylate tablets are composed of apatinib mesylate liposomes and pharmaceutically acceptable excipients; the apatinib mesylate liposomes include apatinib mesylate, lecithin, cholesterol, lactitol, and sodium tripolyphosphate.

2. The apatinib mesylate tablets according to claim 1, characterized in that: The preparation method of the apatinib mesylate liposome is as follows: (1) dissolving apatinib mesylate, lecithin, cholesterol and lactitol in an organic solvent, performing vacuum rotary evaporation at 35°C to 45°C until a thin film appears, adding a buffer solution of pH=4.0-5.0 containing sodium tripolyphosphate to hydrate for 5-15 minutes, then adding a buffer solution of pH=5.5-6.5 to hydrate for 10-20 minutes, and homogenizing under high pressure to obtain a crude product; (2) The crude product is freeze-dried to obtain apatinib mesylate liposomes.

3. The apatinib mesylate tablets according to claim 1 or 2, characterized in that: The weight ratio of apatinib mesylate, lecithin, cholesterol, lactitol and sodium tripolyphosphate is 2-5:4-8:1-3:0.05-0.2:0.5-1.

4. The apatinib mesylate tablets according to claim 3, characterized in that: The weight ratio of apatinib mesylate, lecithin, cholesterol, lactitol and sodium tripolyphosphate is 3:6:2:0.1:0.

8.

5. The apatinib mesylate tablets according to claim 2, characterized in that: The organic solvent is a mixed solvent of ethanol-methanol or a mixed solvent of ethanol-chloroform.

6. The apatinib mesylate tablets according to claim 2, characterized in that: The buffer solution is at least one of a citrate buffer solution, a phosphate buffer solution, an acetate buffer solution, and a lactate buffer solution.

7. The apatinib mesylate tablets according to claim 2, characterized in that: The pressure of the high-pressure emulsification is 1000-2000 bar, the temperature is 35-45° C., and the number of cycles is 10-30 times.

8. The apatinib mesylate tablets according to claim 2, characterized in that: The freeze-drying procedure is: control the temperature to -30°C to -40°C at normal pressure for 6 to 10 hours, increase the temperature to -10°C to 0°C under vacuum pressure for 4 to 6 hours, reduce the temperature to -25°C to -15°C under vacuum pressure for 1 to 3 hours, and increase the temperature to 5°C to 15°C under vacuum pressure for 10 to 14 hours.

9. The apatinib mesylate tablets according to claim 2 or 8, characterized in that: The freeze-drying procedure is: control the temperature to -35°C under normal pressure for 8 hours, increase the temperature to -5°C under vacuum pressure for 5 hours, reduce the temperature to -20°C under vacuum pressure for 2 hours, and increase the temperature to 10°C under vacuum pressure for 12 hours.

10. The apatinib mesylate tablets according to claim 1, characterized in that: The pharmaceutically acceptable excipient is selected from at least one of a filler, a disintegrant, a lubricant, a binder, a wetting agent, and a flavoring agent.

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