WO2024016993A1 - Apixaban tablet and method for preparing same - Google Patents

Abstract

A method for preparing an apixaban tablet, comprising: weighing raw materials, taking apixaban, a part of lactose, first cross-linked sodium carboxymethyl cellulose and lauryl sodium sulfate as pretreatment materials which account for 10wt%-50wt% of the total weight of the raw materials, and performing first premixing to obtain a first premix; mixing the first premix, microcrystalline cellulose and the remaining part of lactose, and adding first magnesium stearate to prepare a second premix; granulating the second premix to obtain granules; and mixing the granules, second cross-linked sodium carboxymethyl cellulose and second magnesium stearate, and performing tableting. This preparation method does not produce dust pollution, the obtained tablet has uniform quality, and the in-vitro dissolution rate meets the requirement.

Description

Apixaban tablets and preparation method thereof

This application claims priority to the Chinese patent application with the application number 202210860634.9 and the invention name is "Apixaban tablets and preparation method thereof" submitted to the China Patent Office on July 21, 2022, the entire content of which is incorporated herein by reference. Applying.

Technical field

The present application relates to the technical field of pharmaceutical preparations, in particular to apixaban tablets and their preparation methods.

Background technique

The chemical name of apixaban is 1-(4-methoxyphenyl)-7-oxo-6[4-(2-oxopiperidin-1-yl)phenyl]-4,5 ,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxamide, a new oral selective inhibitor of activated factor Xa, used for the treatment of deep venous thrombosis (deep venous thrombosis, Venous thrombotic diseases including DVT) and pulmonary embolism (PE). Its molecular structure is:

Apixaban was jointly developed by Pfizer and Bristol-Myers Squibb (BMS). It was approved for marketing by the European Medicines Agency (EMA) on May 18, 2011, under the trade name The dosage form is tablet, with specifications of 2.5mg and 5.0mg. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on December 28, 2012. The dosage form is tablets with specifications of 2.5 mg and 5.0 mg. Apixaban is a white to light yellow crystalline powder, a non-ionic compound, and its solubility in water is approximately 0.04 mg/mL under physiological pH conditions of 1.2 to 6.8.

Currently, in order to ensure the in vitro dissolution of apixaban tablets and control product quality, researchers are trying to start with the preparation method of apixaban tablets. However, it was discovered during the preparation process that if ideal in vitro dissolution and stable product quality are achieved, a large amount of dust pollution will be generated on the production line, causing difficulties in industrial production.

Contents of the invention

The purpose of this application is to provide an apixaban tablet and its preparation method, which can ensure that the in vitro dissolution rate of the apixaban tablet meets the requirements and solve the conflicting problem of dust pollution during the preparation process.

A first aspect of the application provides a method for preparing apixaban tablets. The technical solution is as follows:

A preparation method of apixaban tablets, including the following steps:

Weigh the following raw materials according to the amounts required for preparation: apixaban, lactose, microcrystalline cellulose, croscarmellose sodium, Sodium alkyl sulfate and magnesium stearate; wherein, croscarmellose sodium includes the first croscarmellose sodium and the second croscarmellose sodium, and magnesium stearate includes the first stearic acid Magnesium and secondary magnesium stearate;

Take the apixaban, a part of lactose, the first croscarmellose sodium and sodium lauryl sulfate as pre-treatment materials, the pre-treatment materials account for 10wt% to 50wt% of the total weight of the raw materials, Perform a first premixing of the pre-treatment materials to prepare a first mixture;

Mix the first mixture, microcrystalline cellulose and the remaining lactose, and then add the first magnesium stearate to prepare a second mixture;

Granulating the second mixture to obtain granules;

The granules, the second croscarmellose sodium and the second magnesium stearate are mixed and tableted to obtain plain tablets.

By optimizing the mixing process and selecting the appropriate proportion of pre-treatment materials, the amount of material pre-treatment can be greatly reduced, further improving production efficiency, while reducing dust pollution and reducing the impact of this product on the production environment. Compared with adding materials in equal amounts for mixing, selecting the appropriate proportion of pre-treatment materials can avoid cumbersome operations. Preferably, the weight of the pretreatment material accounts for 10wt% to 45wt% of the total weight of the raw material. Further preferably, the weight of the pre-treatment material accounts for 10wt% to 40wt% of the total weight of the raw material. Further preferably, the weight of the pre-treatment material accounts for 10wt% to 35wt% of the total weight of the raw material. Further preferably, the weight of the pre-treatment material accounts for 10wt% to 20wt% of the total weight of the raw material. Further preferably, the weight of the pre-treatment material accounts for 10wt% to 15wt% of the total weight of the raw material.

In some embodiments, the step of particle size screening is further included after the first premixing.

In some embodiments, the method for first pre-mixing the pre-treatment materials includes: a) mixing the pre-treatment materials and then performing a sieving step; or b) passing the pre-treatment materials through The processing steps are carried out by the rapid granulator with built-in screen.

In some embodiments, the pore size of the sieved screen is 0.2 to 1.5 mm. It is preferably 0.4mm to 1.0mm, for example, it can be 0.4mm, 0.425mm, 0.6mm, 0.7mm, 0.71mm or 1.0mm.

In some embodiments, the aperture of the built-in screen is 0.2-1.5 mm, preferably 0.4-1.0 mm, and may be, for example, 0.4 mm, 0.425 mm, 0.6 mm, 0.7 mm, 0.71 mm or 1.0 mm.

In some embodiments, the method of first premixing the pre-processed material includes: c) using a wet granulator for processing.

In some embodiments, the working parameters of the wet granulator include: the stirring speed is 15 Hz to 25 Hz, for example, it may be 20 Hz. The stirring time is 15 min to 25 min, for example, it can be 20 min.

In some embodiments, the particle size D90 of apixaban does not exceed 10 μm.

In some embodiments, the lactose is anhydrous lactose.

In some of the embodiments, the apixaban is weighed at 2wt%~3wt%, the lactose is weighed at 50wt%~55wt%, and the lactose is weighed at 35wt%~42wt% as a percentage of the total weight of the raw materials. Take the microcrystalline cellulose, weigh the first croscarmellose sodium at 1.8wt% to 2.2wt%, weigh the second croscarmellose sodium at 1.8wt% to 2.2wt%, and weigh 0.8 Weigh sodium lauryl sulfate at wt% to 1.2wt%, weigh the first magnesium stearate at 0.4wt% to 0.6wt%, and weigh the second magnesium stearate at 0.6wt% to 0.9wt%.

Preferably, in terms of percentage of the total weight of raw materials, the apixaban is weighed at 2.2wt% to 2.8wt%, the lactose is weighed at 50wt% to 53wt%, and the lactose is weighed at 38wt% to 42wt%. For the microcrystalline cellulose, weigh the first croscarmellose sodium at 1.9wt% to 2.1wt%, weigh the second croscarmellose sodium at 1.9wt% to 2.1wt%, and weigh 0.9wt% Weigh sodium lauryl sulfate at ~1.1 wt%, weigh the first magnesium stearate at 0.45 to 0.55 wt%, and weigh the second magnesium stearate at 0.65 to 0.85 wt%.

Further preferably, in terms of percentages of the total weight of raw materials, the apixaban is weighed at 2.5wt%, the lactose is weighed at 51.5wt%, the microcrystalline cellulose is weighed at 39.75wt%, Weigh the first croscarmellose sodium at 2wt%, the second croscarmellose sodium at 2wt%, sodium lauryl sulfate at 1wt%, and the first hard croscarmellose sodium at 0.5wt%. Magnesium fatty acid and the second magnesium stearate were weighed at 0.75wt%.

In some embodiments, after tableting, the step of coating the obtained plain tablets is further included.

Optionally, the amount of film coating premix accounts for 2.7wt% to 3.3wt% of the mass of the plain tablet after tableting, preferably 2.9wt% to 3.1wt%, and more preferably 3wt%.

The second aspect of this application provides an apixaban tablet, which is prepared by the above preparation method.

Beneficial effects of this application:

During the research process, the researchers of this application discovered that during the preparation process of apixaban tablets, the mixing process of each raw material has an important impact on the in vitro dissolution and quality stability of the final preparation. In the preparation process of this application, 10wt% to 50wt% of raw materials are first taken as pre-treatment materials. These pre-treatment materials are preliminarily dispersed through premixing, and then mixed with a part of the raw materials step by step, then granulated, and then mixed after granulation. part of the raw material. Through the above method, the granulated raw materials can be fully mixed and dispersed, and finally apixaban tablets with uniform mixing, uniform finished product quality and in vitro dissolution meeting the requirements are obtained. At the same time, by screening a specific proportion of pre-treatment materials, dust pollution will not be generated during the entire preparation process, reducing the impact of the product on the production environment, and the production efficiency is high.

Detailed ways

In order to make the purpose, technical solutions, and advantages of the present application clearer, the present application will be described in further detail below. Obviously, the described embodiments are only some of the embodiments of the present application, but not all of the embodiments. All other embodiments obtained by those skilled in the art based on this application fall within the scope of protection of this application.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing specific embodiments only and is not intended to limit the application.

the term

Unless otherwise stated or contradictory, the terms or phrases used in this article have the following meanings:

In this application, the selection range involving "and/or", "or/and", "and/or" includes any one of two or more related listed items, and also includes any of the related listed items. and all combinations, including any two of the related listed items, any more of the related listed items, or a combination of all of the related listed items. It should be noted that when at least three items are connected with at least two conjunctions selected from "and/or", "or/and", "and/or", it should be understood that the technical solution undoubtedly includes The technical solutions that are all connected by "logical AND" also undoubtedly include the technical solutions that are all connected by "logical OR". For example, "A and/or B" includes three parallel solutions: A, B and A+B. For another example, the technical solution of "A, and/or, B, and/or, C, and/or, D" includes any one of A, B, C, and D (that is, they are all connected with "logical OR" technical solution), also includes any and all combinations of A, B, C, and D, that is, including combinations of any two or any three of A, B, C, and D, and also includes A, B, C , four combinations of D (that is, technical solutions that are all connected by "logical AND").

In this application, references to "multiple", "multiple", "multiple", "multiple", etc., unless otherwise specified, mean that the number is greater than or equal to 2. For example, "one or more" means one or more than two.

In this application, "combinations thereof", "any combinations thereof", "any combinations thereof", etc. include all suitable combinations of any two or more than two of the listed items.

In this application, "suitable" mentioned in "appropriate combination", "appropriate way", "any suitable way", etc. is involved, so as to be able to implement the technical solution of the present application, solve the technical problems of the present application, and realize the present application. The expected technical effects of the application shall prevail.

In this application, references to "preferred", "better", "better", and "appropriate" are only used to describe implementations or examples with better effects. It should be understood that they do not limit the scope of protection of this application.

In this application, references to "further", "further", "especially", etc. are used for descriptive purposes and indicate differences in content, but should not be understood as limiting the scope of protection of this application.

In this application, references to "optional", "optional" and "optional" mean that it is optional, that is, it means to be selected from "yes" or "no" Either of two parallel options. If there are multiple "optionals" in a technical solution, each "optional" will be independent unless otherwise specified and there is no contradiction or mutual restriction.

In this application, when referring to the "first aspect", "second aspect", "third aspect", "fourth aspect", etc., the terms "first", "second", "third" and "fourth" ", etc. are only for descriptive purposes and cannot be understood as indicating or implying the relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Furthermore, “first”, “second”, “third”, “fourth”, etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation of quantity.

In this application, the technical features described in open format include closed technical solutions composed of the listed features, and also include open technical solutions including the listed features.

In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, the optional numerical distribution is considered to be continuous within the above numerical interval and includes the two numerical endpoints of the numerical range (i.e., the minimum value and the maximum value). value), and every value between the two numeric endpoints. Unless otherwise specified, when a numerical interval only points to integers within the numerical interval, including the two endpoint integers of the numerical range, and every integer between the two endpoints, in this article, it is equivalent to directly enumerating each Integer, for example, t is an integer selected from 1 to 10, indicating that t is any integer selected from the integer group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Additionally, when multiple scopes are provided to describe a feature or characteristic, these scopes can be combined. In other words, unless otherwise indicated, the ranges disclosed herein should be understood to include any and all subranges subsumed therein.

The temperature parameters in this application, unless otherwise specified, are allowed to be treated at a constant temperature, and are also allowed to vary within a certain temperature range. It should be understood that the thermostatic treatment described allows the temperature to fluctuate within the accuracy of the instrument control. It is allowed to fluctuate within the range of ±5℃, ±4℃, ±3℃, ±2℃ and ±1℃.

In this application, when it comes to percentage content, unless otherwise specified, for solid-liquid mixing and solid-solid phase mixing, it refers to mass percentage, and for liquid-liquid phase mixing, it refers to volume percentage.

In this application, percentage concentration refers to the final concentration unless otherwise specified. The final concentration refers to the proportion of the added component in the system after adding the component.

In this application, % (w/w) and wt% both represent weight percentage, % (v/v) refers to volume percentage, and % (w/v) refers to mass volume percentage.

In this application, "reference preparation" refers to the control drug used to evaluate the quality and efficacy consistency of generic drugs. It is usually the object of imitation, such as the original drug or the internationally recognized drug of the same kind. The reference preparation should be a drug with reasonable prescription technology, stable quality and definite efficacy. The reference preparation in this application is the reference preparation of apixaban, with the trade name Eliquis.

The following will be further described in conjunction with specific examples. The raw materials involved in the following specific examples, unless otherwise specified, All can be commercially available. The instruments used, unless otherwise specified, can all be commercially available. The involved processes, unless otherwise specified, are routine choices by those skilled in the art.

Example 1

This embodiment provides an apixaban tablet and a preparation method thereof. The steps are as follows:

Step 1. Weigh each raw material according to Table 1:

Table 1

Among them, the particle size D90 of apixaban does not exceed 10 μm, and is obtained by crushing the raw material of apixaban using a jet mill.

Step 2. Prepare the first mixture

Take sodium lauryl sulfate, first croscarmellose sodium, part of anhydrous lactose and apixaban as pre-treatment materials, and make the pre-treatment materials account for 10wt% of the total weight of the raw materials of the plain tablets, and use rapid processing The granulator squeezes the pre-processed material through the built-in screen of the rapid granulator (aperture is 0.7mm) at a rotation speed of 500 rpm, thereby realizing pre-mixing of the pre-processed material and obtaining the first mixture.

Step 3. Prepare the second mixture

Add microcrystalline cellulose, the first mixture prepared in step 2 and the remaining anhydrous lactose to the lifting hopper mixer in sequence. Turn on the power of the lifting hopper mixer and mix for 20 minutes at a speed of 20 rpm. After completion, add the second mixture. Magnesium stearate, mix for 5 minutes at a speed of 15 rpm to obtain the second mixture.

Step 4. Granulation

Add the second mixture prepared in step 3 to the dry granulator, start granulation, and obtain granules.

Step 5. Final mix

Add the granules prepared in step 4 and the second croscarmellose sodium into the lifting hopper mixer, start mixing for 10 minutes at a speed of 20 rpm; then add the second magnesium stearate, and start mixing for 5 minutes , the rotation speed is 15 rpm, and the final mixed particles are obtained.

Step 6. Tablet pressing

Use a 6.0mm shallow concave circular punch, control the speed to (100,000 to 150,000 tablets/hour, and the main pressure to (6.0 to 8.0) KN) to tablet the final mixed granules prepared in step 5 to obtain plain tablets.

Step 7. Coating

Use film coating premix to coat the plain tablets prepared in step 6, and the coating weight gain is 3.0 wt% of the weight of the plain tablets.

Example 2-7

Examples 2 to 7 were prepared with reference to the prescription and preparation method of apixaban tablets in Example 1. Among them, relative to

The difference between Embodiment 1, Embodiment 4 and Embodiment 5 is that: the method of first premixing the pre-treatment materials is different; relative to Embodiment 1, the difference between Embodiment 2 and Embodiment 3 is that: the pre-treatment materials are taken The weight is different; compared with Example 2, the difference between Example 6 and Example 7 is that the aperture of the built-in screen of the rapid granulator is different, as shown in Table 2.

Table 2

Comparative Example 1-6

Comparative Examples 1-6 were prepared with reference to the prescription and preparation method of apixaban tablets in Example 1. Among them, compared with Example 1, the difference between Comparative Example 1 and Comparative Example 1 is that: the first mixture does not contain anhydrous lactose, and when preparing the second mixture, all anhydrous milk is added Sugar; The difference between Comparative Example 2 and Comparative Example 2 is that the first mixture does not contain anhydrous lactose and the first croscarmellose sodium (2wt%). When preparing the second mixture, all anhydrous lactose and the first croscarmellose sodium are added. Sodium methylcellulose (2wt%); the difference between Comparative Example 3 and Comparative Example 3 is that: the first mixture does not contain anhydrous lactose and sodium lauryl sulfate (1wt%). When preparing the second mixture, add all anhydrous lactose and sodium lauryl sulfate. Sodium dialkyl sulfate (1wt%); The difference between Comparative Example 4 and Comparative Example 4 is that the first mixture does not contain anhydrous lactose and the first croscarmellose sodium (2wt%), but contains microcrystalline cellulose (39.75wt %), when preparing the second mixture, add all anhydrous lactose and the first croscarmellose sodium (2wt%), but do not add microcrystalline cellulose (39.75wt%); the difference between Comparative Example 5 and Comparative Example 5 is that: One mixture does not contain anhydrous lactose and sodium lauryl sulfate (1wt%), but contains microcrystalline cellulose (39.75wt%). When preparing the second mixture, add all anhydrous lactose and sodium lauryl sulfate. (1 wt%), but no more microcrystalline cellulose (39.75 wt%) was added. The difference between Comparative Example 6 and Comparative Example 6 is that the first mixture contains all the excipients of the plain tablets, and is then dry-granulated to obtain the final mixed granules, but there is no step 3 of preparing the second mixture, step 4 of granulation, and step 5 of final mixing. The specific prescriptions of Comparative Examples 1-6 are shown in Table 3:

table 3

Effect example 1. Process effect

The mixing uniformity of the final mixed particles of Examples 1-7 and Comparative Examples 1-6 was tested. The detection method was as follows: sampling 10 locations of the final mixed particles obtained in step 5, and measuring the activity in the final mixed particles. The content of the component apixaban is calculated, and then the relative standard deviation of the 10 values is calculated. Based on the relative standard deviation, the mixing uniformity of the final mixed particles can be judged. when When RSD <5%, the mixing uniformity of the final mixed particles meets the quality control of pharmaceuticals, and the smaller the RSD, the higher the mixing uniformity of the final mixed particles.

(1) Examination of the weight proportion of pre-processed materials

The difference between Example 1, Example 2 and Example 3 lies in the weight of the pre-treatment materials. The results of testing the mixing uniformity of the final mixed particles of Example 1, Example 2 and Example 3 are shown in Table 4.

Table 4

It can be seen from Table 4 that good mixing uniformity can be obtained when the proportion of pre-treatment materials is between 10wt% and 50wt%. Considering that the less pre-treatment materials, the operation will be easier, the production efficiency will be improved, and dust pollution will be reduced. , to reduce the impact of the product on the production environment. Preferably, the proportion of pre-treatment materials is 10wt% to 15wt%.

(2) Investigation of the handling methods of pre-processed materials

The difference between Example 1, Example 4 and Example 5 lies in the method of first premixing the pre-treatment materials. The mixing uniformity of the final mixed particles of Example 1, Example 4 and Example 5 was tested, and the results are shown in Table 5.

table 5

It can be seen from Table 5 that the first premixing of pre-processed materials using a rapid granulator, manual mixing and screening (40 mesh screen) and wet granulator can meet the pharmaceutical requirements for uniformity of final mixed particles. However, compared with manual sieving, the rapid granulator greatly reduces the uncontrollable factors introduced by manual operation. Compared with the wet granulator, the pre-processed materials are processed by the rapid finishing machine, the mixing uniformity of the final mixed particles is higher, and the operation is simpler and easier.

(3) Rapid granulator built-in screen aperture screening

The difference between Example 2, Example 6 and Example 7 is that the aperture of the built-in screen of the rapid granulator is different. The final mixed particles of Example 2, Example 6 and Example 7 were tested for material mixing uniformity, and the results are shown in Table 6.

Table 6

It can be seen from Table 6 that using a fast granulator (0.4mm, 0.7mm, 1.0mm) to perform the first premixing of the pre-treatment materials can achieve better mixing uniformity of the final mixed particles. And the smaller the pore size (that is, the smaller the particle size of the first mixture), the more evenly the final mixed particles will be mixed. However, it was found during operation that the smaller the pore size, the lower the mixing rate of the pre-treatment materials. When the pore size is 0.7mm, it can have higher production at the same time. efficiency and relatively good mixing uniformity.

(4) Screening of material composition of the first mixture

The difference between Example 1 and Comparative Examples 1-6 lies in the material composition of the first mixture. The final mixed particles of Example 1 and Comparative Examples 1-6 were tested for material mixing uniformity, and the results are shown in Table 7.

Table 7

As can be seen from the table above, the results of Comparative Example 6 show that the RSD of the granules obtained by dry granulation after direct mixing of the raw materials of the plain tablets is >10%, and the mixing uniformity cannot meet the uniformity requirements for pharmaceutical production.

The results of Comparative Examples 1-5 show that the material composition of the first mixture has an important influence on the uniformity of the final mixed particles, especially apixaban (2.5wt%) and sodium lauryl sulfate (1wt%) and the third When one or two of the croscarmellose sodium (2wt%) are directly mixed, the RSD of the final mixed particles exceeds 10%, and the mixing uniformity of the final mixed particles is greatly reduced, which may affect the medicine. of release.

Effect example 2. Final mixed particle yield

According to the prescription and preparation method of apixaban tablets in Example 2, three batches of samples were prepared, and the yield of the final mixed particles obtained in step 5 was measured. The results are shown in Table 8, where The calculation method for yield is: final mixed particle yield = (weight of final mixed particles obtained in step 5/total weight of plain tablet ingredients in the prescription) × 100%.

Table 8

As can be seen from Table 8, the preparation method of apixaban of the present application has a higher final mixed particle yield, less material loss during the preparation process, and is more suitable for industrial production.

Effect example 3. In vitro dissolution

According to the prescription and preparation method of apixaban tablets in Example 2, 3 batches of samples were prepared and compared with the purchased reference preparation (Aleux, manufacturer: Sino-US Shanghai Bristol-Myers Squibb Pharmaceutical Co., Ltd.) Comparison of in vitro dissolution measurements.

In accordance with the provisions of the Pharmacopoeia (2020) No. 0931 for the determination of dissolution and release of preparations, the slurry method was used to determine the apixaban tablets and reference preparations in Example 2 in pH 1.0 medium and pH 4.5 medium. , pH6.8 medium and in vitro dissolution in water. The measurement results are shown in Tables 9 to 12.

Table 9 Dissolution results in medium pH 1.0

Table 10 Dissolution results in medium pH 4.5

Table 11 Dissolution results in medium pH 6.8

Table 12 Dissolution results in medium water

It can be seen from Tables 9 to 12 that the apixaban tablets prepared by the preparation method of the apixaban tablets provided in this application have similar dissolution to the reference preparation, and meet the requirements for consistency evaluation of generic drugs.

In summary, this application improves the material mixing process in the preparation process, and finally obtains apixaban tablets with a simple process, easy to scale up, uniform quality, bioequivalence, and quality that meets the requirements. After the production of multiple batches of preparation samples, it is proved that The prescription applied for is stable and feasible. The test results show that the finished product has good stability and all test indicators meet the standard requirements.

The technical features of the above-described embodiments can be combined in any way. To simplify the description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, All should be considered to be within the scope of this manual.

The above-described embodiments only express several implementation modes of the present application, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the patent application. It should be noted that, for those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present application, and these all fall within the protection scope of the present application. Therefore, the scope of protection of this patent application should be determined by the appended claims.

Claims (10)

1. A preparation method of apixaban tablets, characterized by comprising the following steps:

   Weigh the following raw materials according to the amounts required for preparation: apixaban, lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate; among them, croscarmellose Sodium includes a first croscarmellose sodium and a second croscarmellose sodium, and magnesium stearate includes a first magnesium stearate and a second magnesium stearate;

   Take the apixaban, a part of lactose, the first croscarmellose sodium and sodium lauryl sulfate as pre-treatment materials, the pre-treatment materials account for 10wt% to 50wt% of the total weight of the raw materials, Perform a first premixing of the pre-treatment materials to prepare a first mixture;

   Mix the first mixture, microcrystalline cellulose and the remaining lactose, and then add the first magnesium stearate to prepare a second mixture;

   Granulating the second mixture to obtain granules;

   The granules, the second croscarmellose sodium and the second magnesium stearate are mixed and tableted to obtain plain tablets.
2. The method for preparing apixaban tablets according to claim 1, wherein the weight of the pretreatment material accounts for 10wt% to 20wt% of the total weight of the raw materials.
3. The preparation method according to claim 1, characterized in that the step of particle size screening is further included after the first premixing.
4. The preparation method according to claim 3, characterized in that the method of first premixing the pre-treatment materials includes: a) mixing the pre-treatment materials and then performing a sieving process; or b) The step of processing the pre-processed materials through a rapid granulator with a built-in screen.
5. According to the preparation method of claim 4, the pore diameter of the sieved screen is 0.2 to 1.5 mm; or the pore diameter of the built-in screen is 0.2 to 1.5 mm.
6. The method for preparing apixaban tablets according to claim 1, wherein the method of first premixing the pre-processed materials includes: c) using a wet granulator for processing.
7. The method for preparing apixaban tablets according to claim 6, wherein the working parameters of the wet granulator include: a stirring speed of 15 Hz to 25 Hz, and a stirring time of 15 min to 25 min.
8. The method for preparing apixaban tablets according to any one of claims 1 to 7, wherein the particle size D90 of the apixaban does not exceed 10 μm; and/or

   The lactose is anhydrous lactose; and/or

   Calculated as a percentage of the total weight of raw materials, the apixaban is weighed at 2.2wt% to 2.8wt%, and the apixaban is weighed at 50wt% to 53wt%. Take the lactose, weigh the microcrystalline cellulose at 38wt% to 42wt%, weigh the first croscarmellose sodium at 1.9wt% to 2.1wt%, and weigh 1.9wt% to 2.1wt%. The second croscarmellose sodium, sodium lauryl sulfate at 0.9wt% to 1.1wt%, the first magnesium stearate at 0.45wt% to 0.55wt% and the first magnesium stearate at 0.65wt% to 0.85 Weigh the second magnesium stearate wt%.
9. The method for preparing apixaban tablets according to any one of claims 1 to 8, characterized in that after the tableting, it further includes the step of coating the obtained plain tablets.
10. An apixaban tablet, characterized in that it is prepared by the preparation method described in any one of claims 1 to 9.