CN114191404B

CN114191404B - Duolavir tablet and preparation method thereof

Info

Publication number: CN114191404B
Application number: CN202210021021.6A
Authority: CN
Inventors: 陈小峰; 王哲; 王志邦; 朱礼根; 邹凌青; 陈建峰; 刘安友; 黄楠; 刘洋; 汪亮太
Original assignee: Anhui Biochem Bio Pharmaceutical Co ltd
Current assignee: Anhui Biochem Bio Pharmaceutical Co ltd
Priority date: 2022-01-10
Filing date: 2022-01-10
Publication date: 2023-06-27
Anticipated expiration: 2042-01-10
Also published as: CN114191404A

Abstract

The invention provides a dorame tablet and a preparation method thereof. The dortezovir tablet comprises 50 parts of dortezovir or pharmaceutically acceptable salts thereof (calculated by the dortezovir), 4-6 parts of dispersing agent, 10-15 parts of filling agent, 8-12 parts of adhesive and other pharmaceutically acceptable auxiliary materials. The preparation method of the entecavir tablet comprises the following steps: weighing the formula amount of the entecavir or the pharmaceutically acceptable salt, the dispersing agent, the filling agent and the adhesive, placing the components into a high-shear wet granulator, uniformly mixing, granulating, drying, granulating and tabletting; and (3) placing the tablets in a coating pot, preparing coating liquid for coating, and preparing the entecavir tablets. The prepared doramevir tablet has good fluidity and dispersibility, the content of medicines prepared in different batches is uniform, the dissolution rate can be improved, the bioavailability is improved, and the stability is still good after long-term placement.

Description

Duolavir tablet and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a entecavir tablet and a preparation method thereof.

Background

Acquired immunodeficiency syndrome (AIDS), AIDS, is a fatal infectious disease caused by infection with the Human Immunodeficiency Virus (HIV). HIV virus continues to spread worldwide and is becoming prevalent worldwide, causing serious harm to human life health and social development, and has remained a major public health threat to date. The disease has serious damage to human immune system, and can cause various symptoms such as hemorrhage, hyperpyrexia, lymphadenectasis, weakness, etc. The onset of the disease is generally related to factors such as blood infection, sexual contact, drug absorption and the like, and part of infant patients generally spread the disease through mother and infant. The HIV virus can be divided into two genotypes of HIV-1 and HIV-2, mainly HIV-1 is the main type in China, and HIV-2 is mainly distributed in western Africa and western Europe, and has lower infectivity and pathogenicity than HIV-1.

The use of anti-HIV drugs can effectively prolong patient life and improve quality of life by inhibiting viral replication or invasion for effective long-term antiretroviral therapy (ART) of HIV-infected or AIDS patients. Antiretroviral (ARV) drugs act by interfering with HIV's attack on T lymphocytes at various stages, preventing viral replication. Current ART is effective in reducing AIDS-related morbidity, extending patient survival and preventing transmission of HIV. Currently, there are more than 30 kinds of ARV single drugs and more than 10 kinds of compound preparations which are internationally applied to clinic, and an integrase chain transfer inhibitor (Integrase Strand Transfer Inhibitor, INSTI) is one of the ARV single drugs. INSTI single drugs which are currently approved for marketing and application are: latefravir, eptitefravir and Dortefravir (DTG). The entecavir is an HIV integrase inhibitor, has higher selectivity and lower toxicity, has high safety in drug treatment, is a hot spot in the field of HIV drug research in recent years, and limits the replication of HIV by blocking the integration of HIV virus DNA into genetic materials of human immune cells (T cells). The dissolution rate of the doramevir tablet is low, and the bioavailability is affected. And the stability of the medicine is reduced after long-term placement, which is unfavorable for being used as a medicine preparation.

Disclosure of Invention

In view of the above, the invention aims to provide a entecavir tablet and a preparation method thereof, which can improve the dissolution rate of the entecavir tablet, enable the medicine to be quickly dissolved out, improve the bioavailability, and ensure that the prepared entecavir tablet has uniform content and good stability, and all indexes meet the requirements.

In order to achieve the above purpose, the technical scheme of the invention is realized as follows:

in one aspect, the invention provides a dortezovir tablet, which comprises 50 parts of dortezovir or pharmaceutically acceptable salts thereof (calculated by dortezovir), 4-6 parts of dispersing agent, 10-15 parts of filling agent, 8-12 parts of adhesive and other pharmaceutically acceptable auxiliary materials. The dortezovir or the pharmaceutically acceptable salt thereof is dortezovir sodium.

Further, the pharmaceutically acceptable salt of the dortezovir is sodium dortezovir.

Further, the dortezovir tablet comprises 50 parts of dortezovir or pharmaceutically acceptable salts thereof (calculated by the dortezovir), 5 parts of dispersing agent, 13 parts of filling agent, 10 parts of adhesive and other pharmaceutically acceptable auxiliary materials.

Further, the doramevir tablet also comprises 6-10 parts of protective agent. Dispersing agent, filler, adhesive and protective agent are pharmaceutically acceptable auxiliary materials.

Further, the protective agent is at least one selected from magnesium stearate and sodium stearate.

Further, the dispersing agent is micro silica gel.

Further, the filler is at least one selected from microcrystalline cellulose, lactose and sodium chloride.

Further, the filler is sodium chloride. The sodium chloride of the invention is prepared by mixing sodium chloride and water according to the following ratio of 1:5, mixing and stirring the materials according to the weight ratio until the materials are dissolved, then placing the materials into an atomizer, and obtaining sodium chloride powder through a spray drying mode.

Further, the binder is at least one selected from hydroxypropyl cellulose, ethyl cellulose and starch slurry.

Further, the binder is a starch slurry.

Further, the binder is 10wt% to 20wt% of the starch slurry. Starch slurry is a slurry of starch formed by adding starch to water. 15wt% starch slurry means that the mass concentration of starch in water is 15%.

Further, the content of the dortezovir or the pharmaceutically acceptable salt thereof (calculated by the dortezovir) in each 1000 dortezovir tablets is 10-50g.

On the other hand, the invention also provides a preparation method of the doramevir tablet, which comprises the following steps: weighing the formula amount of the entecavir or the pharmaceutically acceptable salt, the dispersing agent, the protective agent, the filler and the adhesive, placing the components into a high-shear wet granulator, uniformly mixing, granulating, drying, granulating and tabletting; and (3) placing the tablets in a coating pot, preparing coating liquid for coating, and preparing the entecavir tablets. Granulation, tabletting and coating are prior art and will not be described in detail here.

Further, the preparation method of the entecavir tablet comprises the following steps: weighing the formula amount of the entecavir or the pharmaceutically acceptable salt thereof, the dispersing agent and the protective agent, mixing, grinding for 30-50min, adding the formula amount of the filler and the adhesive, uniformly mixing in a high-shear wet granulator, granulating, drying, granulating and tabletting; and (3) placing the tablets in a coating pot, preparing coating liquid for coating, and preparing the entecavir tablets.

Compared with the prior art, the adefovir dipivoxil tablet and the preparation method thereof have the following advantages:

(1) The mobility and the dispersibility of the entecavir or the pharmaceutically acceptable salt thereof are excellent, the content of the main drug in the entecavir tablets prepared in different batches is uniform, and the quality of batch production is ensured;

(2) The doramevir tablet prepared by the invention improves the dissolution rate and improves the bioavailability;

(3) The doramevir tablet prepared by the invention can effectively protect the doramevir or the pharmaceutically acceptable salts thereof, avoid loss or damage of main medicine components and improve the stability of the doramevir tablet.

Detailed Description

The invention is further described below in conjunction with the detailed description. It should be noted that the data in the following examples are obtained by the inventors through a lot of experiments, and are only shown in some of the descriptions, and those skilled in the art can understand and practice the present invention under the data. These examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. Further, it should be understood that after reading the present disclosure, those skilled in the art may make various changes or modifications to the present disclosure, which also fall within the scope of the present disclosure.

The water solubility of the dortefravir is very small, and the dortefravir is slow to release or dissolve out and low in bioavailability after oral administration. The research on the dissolution rate of the medicine is beneficial to the selection of the biological activity of the medicine, improves the bioavailability and enhances the clinical curative effect. Under the condition that other auxiliary materials are the same and the dosage of each component in the prescription is the same, the influence of the selection of different disintegrating agents on the dissolution of the doramevir tablet is compared. The specific results are shown in Table 1. For reasons of space limitation, only microcrystalline cellulose is used as filler, binder and disintegrant in table 1. The specific preparation method of the entecavir tablet comprises the steps of placing the entecavir sodium, the filler, the adhesive and the disintegrating agent into a high-shear wet granulator, uniformly mixing and granulating. And then drying until the water content is less than 3% -4%, sieving with a 50-mesh sieve, granulating, tabletting and coating with the coating liquid. The disintegrating agent can be at least one selected from croscarmellose sodium, sodium carboxymethyl starch and crospovidone, and the binder is at least one selected from hydroxypropyl cellulose, ethyl cellulose and starch slurry. The dissolution rate measurement method comprises the following steps: the dissolution (%) of entecavir was measured by the dissolution method (second method of appendix XC of Japanese pharmacopoeia 2020 edition) using a buffer solution containing 0.25% SDS at pH6.8 as a dissolution medium for 15 min.

TABLE 1

Group of	Disintegrating agent	Adhesive agent	Dissolution for 15min (%)
				1	Croscarmellose sodium	Hydroxypropyl cellulose	90.0
2	Sodium carboxymethyl starch	Ethylcellulose	89.5
				3	Crosslinked povidone	Hydroxypropyl cellulose	90.2
4	Croscarmellose sodium	15wt% starch slurry	92.2
				5	Sodium carboxymethyl starch	15wt% starch slurry	93.1
6	Crosslinked povidone	15wt% starch slurry	91.8
				7	/	15wt% starch slurry	92.0

As is clear from Table 1, when the binder is selected from either hydroxypropyl cellulose or ethyl cellulose, the dissolution rate of the prepared entecavir tablet at 15min is 89.5 to 90.2%, regardless of the disintegrant. When the binder is 15wt% of starch slurry, the dissolution rate of the entecavir tablet can be improved, and the dissolution rate reaches 91.8-93.1% in 15min, no matter whether a disintegrating agent is added, so that the biological activity of the entecavir tablet is improved. In order to reduce the use amount of auxiliary materials in the preparation process of the entecavir tablet, the application uses starch slurry as an adhesive without adding a disintegrating agent, and reduces the addition of the auxiliary materials while ensuring the dissolution effect. Specifically, the starch slurry is 10-20wt% starch slurry. The starch slurry serves as a binder to aid in the binding of the drug during the preparation of the tablet. After the patient takes the tablet, the starch in the starch slurry can quickly break the entecavir tablet in the gastrointestinal fluid, so that the disintegration of the tablet is realized. And the starch slurry as the binder does not have an inhibiting effect on the dissolution of the drug. The present application thus uses 10-20wt% starch slurry as a binder and does not require the addition of a disintegrant.

Experimental example 1: grinding sodium chloride to below 70 μm, weighing 52.62g of sodium doramensis, 4g of micro powder silica gel and 6g of magnesium stearate, mixing, grinding for 30-50min, adding 10g of ground sodium chloride and 15wt% of starch slurry, uniformly mixing in a high-shear wet granulator, and granulating. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

Experimental example 2: sodium chloride and water were mixed according to 1:5, mixing and stirring the materials according to the weight ratio until the materials are dissolved, then placing the materials into an atomizer, and obtaining sodium chloride powder through a spray drying mode. Spray drying is prior art and is not described in detail herein. 52.62g of sodium doramectinate, 4g of micro silica gel and 6g of magnesium stearate are weighed, mixed and ground for 30-50min, then 10g of ground sodium chloride and 15wt% of starch slurry are added, and the mixture is placed in a high-shear wet granulator to be uniformly mixed and granulated. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

The entecavir tablet obtained in experimental example 1 had slight powder dropping, whereas the entecavir tablet obtained in experimental example 2 had no such phenomenon, and the surface of the prepared entecavir tablet was smooth. The sodium chloride described in this application is thus all sodium chloride powder obtained according to the spray drying process of experimental example 2. The treatment of sodium chloride will not be described one by one in the examples below.

Example 1

The prescription composition of the 1000-granule doramer tablet is as follows:

weighing and mixing the prescription amount of the sodium entecavir, the micro-powder silica gel and the magnesium stearate, grinding for 30-50min, adding the prescription amount of the sodium chloride and 15wt% of starch slurry, and granulating after uniformly mixing in a high-shear wet granulator. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

Example 2

The prescription composition of the 1000-granule doramer tablet is as follows:

weighing and mixing the prescription amount of the sodium entecavir, the micro-powder silica gel and the sodium stearate, grinding for 30-50min, adding the prescription amount of the sodium chloride and 20wt% of starch slurry, and granulating after uniformly mixing in a high-shear wet granulator. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to increase the weight by 5% to prepare the entecavir tablets.

Example 3

The prescription composition of the 1000-granule doramer tablet is as follows:

weighing and mixing the prescription amount of the sodium entecavir, the micro-powder silica gel and the magnesium stearate, grinding for 30-50min, adding the prescription amount of the sodium chloride and 20wt% of starch slurry, and granulating after uniformly mixing in a high-shear wet granulator. Drying until the water content is less than 4%, and sieving with 50 mesh sieve to obtain granule. Tabletting is performed on a high-speed tablet press. Placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating the tablets with weight gain of 6% to obtain the dorame tablets.

Example 4

The prescription composition of the 1000-granule doramer tablet is as follows:

weighing and mixing the prescription amount of the sodium entecavir, the micro-powder silica gel and the sodium stearate, grinding for 30-50min, adding the prescription amount of the sodium chloride and 15wt% of starch slurry, and granulating after uniformly mixing in a high-shear wet granulator. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

Example 5

The prescription components and the dosage of the example 5 are the same as those of the example 4, except that the preparation method is that the prescription dosage of the sodium entecavir, the micro silica gel, the magnesium stearate, the sodium chloride and the 15wt% starch slurry are weighed, and are put into a high-shear wet granulator to be evenly mixed and granulated. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

Comparative example 1

The prescription components and amounts of comparative example 1 were the same as in example 4, except that magnesium stearate was not added. Weighing the prescription amount of the sodium entecavir and the superfine silica powder, mixing, grinding for 30-50min, adding the prescription amount of the sodium chloride and 15wt% of starch slurry, and granulating after uniformly mixing in a high-shear wet granulator. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

Comparative example 2

The prescription components and amounts of comparative example 2 were the same as in example 4, except that no silica fume was added. Weighing and mixing the prescription amount of the sodium entecavir and the magnesium stearate, grinding for 30-50min, adding the prescription amount of the sodium chloride and 15wt% of starch slurry, and granulating after uniformly mixing in a high-shear wet granulator. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

Comparative example 3

The prescription components, amounts and preparation method of comparative example 3 are the same as in example 4 except that lactose is used instead of sodium chloride. Weighing and mixing the prescription amount of the sodium entecavir, the micro-powder silica gel and the sodium stearate, grinding for 30-50min, adding the prescription amount of lactose and 15wt% of starch slurry, and granulating after uniformly mixing in a high-shear wet granulator. Drying until the water content is less than 3%, and sieving with a 50-mesh sieve to obtain granules. Tabletting is performed on a high-speed tablet press. And (3) placing the tablets in a coating pot, preparing hydroxypropyl methylcellulose coating liquid for coating, and coating to gain weight by 3% to prepare the entecavir tablets.

Content uniformity investigation result of Duotila Weak tablet

Five batches of samples were prepared from the entecavir tablets prepared in examples 1-5 and comparative examples 1-3, and the content of sodium entecavir was measured, respectively, and the specific results are shown in table 2. The assay methods are conventional in the art and will not be described in detail herein.

TABLE 2

As can be seen from Table 2, the samples of each batch of the entecavir tablets prepared in examples 1-4 of the present application were uniform in content and satisfactory. This is very important for mass production of pharmaceuticals, and can ensure uniformity of tablet contents of different batches and stability of tablet quality. In comparative example 2, the preparation process of the doramevir tablets is free of micro silica gel, and the medicine content of the tablets in different batches is high or low and has larger difference. In example 5, although the micro silica gel powder was added, the uniformity of the tablets was poor due to no external force of grinding, and the content of the various batches of the entecavir tablets was varied from 93.2 to 98.9%. According to the method, the superfine silica powder is added, the superfine silica powder and the sodium entecavir are mixed and are continuously contacted and collided with each other under the action of external force of grinding, so that the superfine silica powder is attached to the surface of the sodium entecavir, the fluidity of the sodium entecavir is improved, the mixing of the sodium entecavir and other pharmaceutical excipients is more uniform, agglomeration is reduced, the content of the prepared sodium entecavir tablet is uniform, and the content stability during mass production is ensured.

Dissolution investigation

The dissolution (%) of the sodium entecavir for 15min was measured according to the method of experimental example 1 for the entecavir tablets prepared in examples 1-5 and comparative examples 1-3, and the specific results are shown in table 3.

TABLE 3 Table 3

Group of	Dissolution for 15min (%)
		Example 1	94.6
Example 2	95.0
		Example 3	95.8
Example 4	95.3
		Example 5	92.4
Comparative example 1	94.8
		Comparative example 2	92.6
Comparative example 3	93.0

As is clear from Table 3, the dissolution rate of the entecavir tablet prepared in comparative example 2 was 92.6% at 15 min. And the dissolution rate of the Duolawei tablets of examples 1-4 is improved to 94.6-95.8% after adding the micro silica gel. The addition of the micro powder silica gel is not only beneficial to the uniformity of the content of the entecavir tablet, but also can improve the dissolution rate and the bioavailability of the entecavir tablet. The specific surface area of the sodium entecavir is increased after the silica gel micropowder is adsorbed on the surface of the sodium entecavir, a channel for contacting with water is increased, and the water absorption is enhanced. When the doramectin tablet encounters water in the gastrointestinal tract, the doramectin tablet can be rapidly disintegrated, and is beneficial to rapid dissolution. And sodium chloride added into the Duolawei tablet is easy to dissolve in water, and can also be helpful for the rapid dissolution of insoluble drugs after being added as a pharmaceutical auxiliary material. The adefovir dipivoxil tablet prepared in comparative example 3 has reduced dissolution compared with examples 1-4 because sodium chloride is not used in the adjuvant.

Stability of Duolavir tablets

The entecavir tablets prepared in examples 1-5 and comparative examples 1-3 were subjected to an accelerated stability test by standing at 40 deg.c under 75% humidity acceleration for 3 months, and the content of sodium entecavir and the content of the related substances were examined, and the specific results are shown in table 4.

TABLE 4 Table 4

As can be seen from the data in Table 4, after 3 months of acceleration experiments, the content of the sodium entecavir in the entecavir tablets prepared in examples 1-4 of the present application is not obviously reduced, the content of related substances is not obviously increased, and the stability is good. In contrast, the entecavir tablet of comparative example 1 has no magnesium stearate during grinding, and after 3 months of accelerated placement, the content of the sodium entecavir is reduced from 98.3% to 93.0%, the content of related substances is increased from 0.13% to 0.25%, the stability is reduced, the content of active ingredients of the drug is reduced, and the content of impurities is increased. In example 5, although magnesium stearate is added, the grinding effect of external force is reduced, the content of the sodium entecavir is reduced from 97.6% to 95.2% after the composition is left for 3 months, the content of related substances is increased from 0.15% to 0.23%, and the stabilizer is reduced, so that the quality of the medicine is affected, and the medicine is not beneficial to long-term storage. The method is characterized in that under the action of grinding the dortefovir, the surface of the dortefovir sodium and the surface of the micro-powder silica gel are coated after the magnesium stearate or the sodium stearate serving as a protective agent is added, so that the method has a protective effect, the loss of active ingredients of the dortefovir sodium under collision or friction in the grinding process can be reduced, the prepared tablet can effectively maintain the property of the dortefovir sodium and reduce the degradation of the dortefovir sodium after being stored for a long time, and has a good protective effect, thereby being beneficial to the stability of the tablet.

Examination of tabletting Property

Tabletting properties of the entecavir tablets prepared in examples 1-5 and comparative examples 1-3 were examined, and specific results are shown in table 5.

TABLE 5

Group of	Tabletting effect	Yield of pressed tablets (%)
			Example 1	Has no splinter, moderate hardness and no powder falling	98.5
Example 2	Has no splinter, moderate hardness and no powder falling	98.5
			Example 3	Has no splinter, moderate hardness and no powder falling	98.3
Example 4	Has no splinter, moderate hardness and no powder falling	98.7
			Example 5	Has no splinter, moderate hardness and no powder falling	98.0
Comparative example 1	Has no splinter, moderate hardness and no powder falling	98.1
			Comparative example 2	Has no splinter, moderate hardness and no powder falling	98.6
Comparative example 3	Has splinter, moderate hardness and powder falling	87.5

In order to improve the dissolution rate of the medicine in the preparation process of the doramer tablet, the starch slurry is used as a binder and a disintegrating agent, and the pressed tablet is too loose and has a powder falling phenomenon due to poor compressibility of starch. In order to improve the compressibility and tabletting yield of tablets, sodium chloride is used as a filler in the present application. Sodium chloride does not react with the sodium entecavir and is suitable to be added into the sodium entecavir as a pharmaceutical excipient, and meanwhile, as the sodium chloride is in a cubic crystal conformation, the sodium chloride can be used as an excellent filling agent to improve the compressibility of the tablet. As shown in Table 5, the entecavir tablets of examples 1-5 had no splits, were moderately hard, did not fall off powder, and had a tableting yield of 98.0-98.7%. In contrast, in comparative example 3, the conventional lactose was used as the filler, and the tablet had the phenomena of cracking and powder dropping, and the rate of finished tablets was also lower than 87.5%. Experiments were carried out on other common fillers such as microcrystalline cellulose, calcium hydrogen phosphate and the like, and the effect is not as good as that of examples 1-5.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. The dortezovir tablet is characterized by comprising 50 parts of dortezovir or pharmaceutically acceptable salts thereof, 4-6 parts of dispersing agents, 10-15 parts of filling agents, 8-12 parts of binders, 6-10 parts of protective agents and coating components, wherein the binders are 10-20wt% starch slurry, and the protective agents are at least one of magnesium stearate and sodium stearate; the filler is sodium chloride, which is prepared by mixing sodium chloride and water according to the following ratio of 1:5, mixing and stirring the materials according to the weight ratio until the materials are dissolved, then placing the materials into an atomizer, and obtaining sodium chloride powder by spray drying, wherein the dispersing agent is micro silica gel;

the preparation method of the entecavir tablet comprises the following steps: weighing the formula amount of the entecavir or the pharmaceutically acceptable salt thereof, the dispersing agent and the protective agent, mixing, grinding for 30-50min, adding the formula amount of the filler and the adhesive, uniformly mixing in a high-shear wet granulator, granulating, drying, granulating and tabletting; and (3) placing the tablets in a coating pot, preparing coating liquid for coating, and preparing the entecavir tablets.

2. A form of a form of dorame tablet according to claim 1, wherein, the entecavir tablet comprises 50 parts of the entecavir or the pharmaceutically acceptable salt thereof, 5 parts of dispersing agent, 13 parts of filler and 10 parts of adhesive.