WO2020088364A1

WO2020088364A1 - Anti-viral infection pharmaceutical composition and preparation method therefor

Info

Publication number: WO2020088364A1
Application number: PCT/CN2019/113280
Authority: WO
Inventors: 丁纪钱; 陈玮琦; 王小雷; 刘明健; 纪古月
Original assignee: 江苏豪森药业集团有限公司
Priority date: 2018-10-29
Filing date: 2019-10-25
Publication date: 2020-05-07
Also published as: TW202034904A; CN111386104B; CN111386104A; CN111096954A; TWI827715B; CN111096954B

Abstract

A pharmaceutical composition for anti-viral infection treatment containing 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphino]methoxy]propyl]adenine, a preparation method therefor, and a use thereof. The pharmaceutical composition has good stability and fluidity, as well as high dissolution, and sticking and picking does not happen during formulation production.

Description

Medicinal composition for antiviral infection and preparation method

Technical field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an antiviral infection pharmaceutical composition and a preparation method thereof.

Background technique

Hepatitis B virus (hepatitis B virus) refers to the DNA virus that causes human acute hepatitis and chronic hepatitis, referred to as HBV. Because HBV infection directly causes severe liver diseases in humans, including cirrhosis and hepatocellular carcinoma, hepatitis B is a major threat to human health. Hepatitis B virus DNA (deoxyribonucleic acid) is the core substance of hepatitis B virus and the basis of viral replication. Nucleoside compounds can inhibit viral polymerase by directly competitively combining with natural deoxyribose substrates and by inserting The DNA chain is terminated in DNA, so nucleoside compounds are the main drugs for the treatment of hepatitis B, including cidofovir, adefovir, lamivudine, and tenofovir. Tenofovir is a novel nucleotide reverse transcriptase inhibitor that can effectively fight against a variety of viruses and is used to treat viral infectious diseases. Tenofovir is a double anion phosphonate group at physiological pH, so tenofovir is not easily absorbed through the cell membrane, the bioavailability is very low, and there is also dose-dependent nephrotoxicity, which limits its therapeutic effect Therefore, it must be made into phosphonate prodrug by means of esterification and salt formation before it can be used in clinic.

Many pharmaceutical companies are conducting research and development of a new generation of tenofovir prodrugs, and have achieved some results. For example, WO0208241 discloses a class of tenofovir phosphoramidate prodrugs synthesized with natural amino acids (monosubstituted) For example, GS-7340); WO2009105513 discloses a new class of tenofovir phosphate bisamide prodrugs, which increase the stability in plasma and increase the active metabolites in peripheral blood mononuclear cells (PBMCs) The cumulative concentration of tenofovir improves the therapeutic effect; WO2014032481 discloses a series of prodrugs of tenofovir phosphoramidate synthesized using disubstituted amino acids (for example, 9-[(R) -2-[[ (S)-[[[1- (isopropoxycarbonyl) -1-methyl] ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine), the half-life of the prodrugs Tinofovir (TDF) is significantly prolonged. It takes less than 1/10 of tenofovir (TDF) to achieve the same antiviral effect, and greatly reduces the drug's renal toxicity, which can significantly improve the patient's bones 1. Renal laboratory parameters, a higher proportion of patients return to normal ALT levels, is a type of high efficacy, toxic and side effects The novel prodrug of tenofovir.

9-[(R) -2-[[(S)-[[[1- (isopropoxycarbonyl) -1-methyl] ethyl] amino] phenoxyphosphinyl] methoxy] propane Base] Adenine, with good water solubility, can be quickly absorbed by the gastrointestinal tract after oral preparation into a solid preparation, but the compound is unstable to moisture, heat, acid, and alkali, under high temperature, humidity, acid, and alkali conditions Degradation impurities A and B are easy to produce. The higher the degree of impurity degradation, the greater the impact on clinical safety. Therefore, high temperature, water, and acidic or alkaline accessories should be avoided as much as possible during the preparation process.

And 9-[(R) -2-[[(S)-[[[1- (isopropoxycarbonyl) -1-methyl] ethyl] amino] phenoxyphosphinyl] methoxy) Propyl] adenine and its salts also have the characteristics of poor fluidity, strong viscosity, and poor compatibility of raw and auxiliary materials. In the actual operation of the preparation, there is a serious sticky roller phenomenon, and the production compliance is extremely poor, which makes 9-[(R ) -2-[[(S)-[[[1- (isopropoxycarbonyl) -1-methyl] ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine solid The preparation of oral preparations is very difficult.

Therefore, we are looking for a 9-[(R) -2-[[(S)-[[[1- (isopropyloxycarbonyl) -1-methylmethanone with stable quality, good fluidity, good dissolution and suitable for clinical application Radical] ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine solid oral preparation is a technical problem that needs to be solved urgently.

Summary of the invention

The object of the present invention is to provide a 9-[(R) -2-[[(S)-[[[1- (isopropoxycarbonyl) -1-methyl] ethyl] amino] phenoxyl Phosphonyl] methoxy] propyl] adenine pharmaceutical composition, which has the characteristics of good stability, good fluidity and high dissolution.

9-[(R) -2-[[(S)-[[[1- (isopropoxycarbonyl) -1-methyl] ethyl] amino] phenoxyphosphinyloxy]] Methoxy] propyl] adenine, hereinafter referred to as the compound of formula I, its structure is as follows:

The purpose of the present invention is achieved by the following technical solutions:

The present invention provides a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof and a diluent. Wherein the dosage of the diluent is 50-90%, preferably 70-85%, more preferably 75-85%. The diluent is selected from water-soluble diluents, one or more selected from lactose, sucrose, starch, sorbitol, mannitol, pregelatinized starch, preferably lactose and / or mannitol, more preferably monohydrate Lactose or anhydrous lactose, in which the amount of lactose is 60-85%, and the amount of mannitol is 0-25%.

The pharmaceutical composition of the present invention further includes a disintegrant, wherein the amount of the disintegrant is 3-15%, preferably 5-15%, and further preferably 8-15%. The disintegrant is selected from one or more of calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose sodium, and crospovidone ; Calcium carboxymethyl cellulose or low-substituted hydroxypropyl cellulose is preferred.

The present invention provides a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant and a lubricant.

The pharmaceutically acceptable salts of the compounds of formula I of the present invention include, but are not limited to, fumarate, maleate, citrate or methanesulfonate, preferably fumarate.

The pharmaceutical composition according to the present invention suitably contains, for example, 5 to 20% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof based on the total weight of the composition, preferably 5 to 15% by weight of the compound of formula I or its pharmaceutical The pharmaceutically acceptable salt is more preferably 6-10% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention may contain 1 mg to 100 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition according to the present invention suitably contains, for example, 50 to 90% by weight of diluent based on the total weight of the composition, preferably 70 to 85% by weight of diluent, more preferably 75 to 85% by weight of diluent.

In the pharmaceutical composition of the present invention, the diluent is a water-soluble diluent, one or more selected from lactose, sucrose, starch, sorbitol, mannitol, pregelatinized starch, preferably lactose, more preferably one Water lactose.

The pharmaceutical composition described in the present invention suitably contains, for example, 1 to 20% by weight of a disintegrant based on the total weight of the composition, preferably 3 to 15% by weight of a disintegrant, and more preferably 8 to 12% by weight The disintegrant is more preferably 10 to 12% by weight of the disintegrant.

In the pharmaceutical composition of the present invention, the disintegrant is selected from calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose sodium, crospovidone One or more of these; preferably carboxymethyl cellulose calcium or low-substituted hydroxypropyl cellulose.

The pharmaceutical composition described in the present invention suitably contains, for example, 0.5 to 5% by weight of lubricant based on the total weight of the composition, preferably 0.8 to 3.0% by weight of lubricant, or 2.0 to 4.0% by weight of lubricant Agent.

In the pharmaceutical composition of the present invention, the lubricant is selected from glyceryl behenate, glyceryl palmitate stearate, magnesium stearate, calcium stearate, sodium stearate fumarate or stearic acid, preferably Glyceryl behenate. The lubricant of the present invention can greatly improve the fluidity of the powder and prevent the occurrence of astringency and sticking during subsequent tabletting.

The pharmaceutical composition described in the present invention may further include a glidant, for example, 0 to 1% by weight based on the total weight of the composition, preferably 0.2 to 1.0% by weight, and more preferably 0.2 to 0.5 % By weight glidant.

In the pharmaceutical composition of the present invention, the glidant is selected from silica, micronized silica gel or talc, preferably talc.

In the pharmaceutical composition of the present invention, the weight ratio of lubricant to glidant is 1-10: 1, preferably 5-8: 1.

In a specific embodiment of the invention, the pharmaceutical composition comprises:

Based on the total weight of the composition,

5-20% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof;

55 to 90% by weight of thinner;

1-20% by weight of disintegrant;

0.5 to 5% by weight of lubricant;

0 to 1% by weight of glidant.

In another specific embodiment of the invention, the pharmaceutical composition comprises:

Based on the total weight of the composition,

70 to 85% by weight of thinner;

1-20% by weight of disintegrant;

0.5 to 5% by weight of lubricant;

0 to 1% by weight of glidant.

Based on the total weight of the composition,

75 to 85% by weight of thinner;

3 to 15% by weight of disintegrant;

0.5 to 5% by weight of lubricant;

0 to 1% by weight of glidant.

Based on the total weight of the composition,

75 to 85% by weight of thinner;

3 to 15% by weight of disintegrant;

0.5 to 5% by weight of lubricant;

0.2 to 1% by weight of glidant.

Based on the total weight of the composition,

5 to 15% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof;

75 to 85% by weight of thinner;

3 to 15% by weight of disintegrant;

0.5 to 5% by weight of lubricant;

0.2 to 1% by weight of glidant.

Based on the total weight of the composition,

5-10% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof;

75 to 85% by weight of thinner;

8 to 12% by weight of disintegrant;

0.8 to 3% by weight of lubricant;

0.2 to 1% by weight of glidant.

Based on the total weight of the composition,

75 to 85% by weight of thinner;

8 to 12% by weight of disintegrant;

0.8 to 3% by weight of lubricant;

0.2 to 0.5% by weight of glidant.

Based on the total weight of the composition,

75 to 85% by weight of thinner;

3 to 15% by weight of disintegrant;

2 to 4% by weight of lubricant;

0.2 to 1% by weight of glidant.

Based on the total weight of the composition,

75 to 85% by weight of thinner;

3 to 15% by weight of disintegrant;

2 to 4% by weight of lubricant;

0.2 to 1% by weight of glidant.

Based on the total weight of the composition,

5-20% by weight of fumarate compound of formula I

55 to 90% by weight of thinner;

1-20% by weight of disintegrant;

0.5 to 5% by weight of glyceryl behenate;

0 to 1% by weight of glidant.

Based on the total weight of the composition,

5-20% by weight of fumarate compound of formula I;

70 to 85% by weight of thinner;

1-20% by weight of disintegrant;

0.8-3% by weight of glyceryl behenate;

0 to 1% by weight of glidant.

Based on the total weight of the composition,

5-20% by weight of fumarate compound of formula I;

70 to 85% by weight of lactose;

1-20% by weight of disintegrant;

0.8 to 3% by weight of lubricant;

0 to 1% by weight of glidant.

Based on the total weight of the composition,

5-20% by weight of fumarate compound of formula I;

55-90% by weight of lactose;

1-20% by weight of disintegrant;

0.5 to 5% by weight of glyceryl behenate;

0 to 1% by weight of glidant.

Based on the total weight of the composition,

5-20% by weight of fumarate compound of formula I;

75-85% by weight of lactose;

3 to 15% by weight of disintegrant;

0.8-3% by weight of glyceryl behenate;

0.2 to 1% by weight of glidant.

Based on the total weight of the composition,

5-20% by weight of fumarate compound of formula I;

55-90% by weight of lactose monohydrate;

1-20% by weight of disintegrant;

0.5 to 5% by weight of glyceryl behenate;

0 to 1% by weight of glidant.

Based on the total weight of the composition,

5-20% by weight of fumarate compound of formula I;

75 to 85% by weight of lactose monohydrate;

3 to 15% by weight of disintegrant;

0.8-3% by weight of glyceryl behenate;

0.2 to 1% by weight of glidant.

Based on the total weight of the composition,

7.75% by weight of fumarate compound of formula I;

78.75% by weight of thinner;

10% by weight of disintegrant;

3% by weight of lubricant;

0.5% by weight of glidant.

Based on the total weight of the composition,

7.75% by weight of fumarate compound of formula I;

78.75% by weight of lactose;

10% by weight of low-substituted hydroxypropyl cellulose or carboxymethyl cellulose calcium;

3% by weight of glyceryl behenate or magnesium stearate;

0.5% by weight of talc.

The pharmaceutical composition of the present invention includes suitable administration routes for oral administration and injection, preferably oral administration routes. Dosage forms include tablets, capsules, dispersants and suspensions, preferably tablets.

Another object of the present invention is to provide a method for preparing the pharmaceutical composition, which specifically includes: mixing the compound of formula I or a pharmaceutically acceptable salt thereof with a diluent, a disintegrant, a lubricant, and a glidant After homogenization, it is prepared by powder direct pressure method.

Another object of the present invention is to provide the use of the pharmaceutical composition in the preparation of a medicament for the treatment of viral infectious diseases, preferably in the preparation of a medicament for the treatment of diseases caused by AIDS infection, hepatitis B or hepatitis B virus.

The pharmaceutical composition of the present invention has the following beneficial effects:

1. It has good stability. Under the accelerated test condition of 40 ℃ ± 2 ℃ / RH75% ± 5%, compared with the result of day 0, there is no obvious change in the quality indicators of the sample, especially impurity A and impurity B Almost no significant increase in the content.

2. It has good fluidity, strong compressibility, no sticking and punching phenomenon, and the surface of the obtained tablet is round and smooth.

3. It has a good dissolution rate, and the cumulative dissolution rate of the pharmaceutical composition in 15 minutes is all> 80%.

4. The invention adopts the powder direct compression method, which greatly shortens the process flow and reduces the production cost.

detailed description

Experimental Example 1 Examination of the compatibility of different diluents with fumarate of formula Ⅰ

According to the compatibility method of raw materials and excipients in the "Basic Technical Guiding Principles for the Research of Chemical Drug Preparations", the phases of the drug substance (compound fumarate of formula I) and diluent were investigated at 40 RH 75% (open and closed) and 60 ℃ Capacitive, the specific results are shown in Table 1.

Table 1

Experimental Example 2. Examination of the compatibility of different lubricants with fumarate of formula Ⅰ

According to the compatibility method of raw materials and excipients in the "Basic Technical Guiding Principles for the Research of Chemical Drug Preparations", the drug substance (compound of formula I fumarate) was investigated under 4 conditions of 40 ° RH75% (open), 60 ° C, and light 4500lx For compatibility with lubricants, the mixing ratio of APIs and lubricants is 20: 1. See Table 2 for specific results.

Table 2

It can be seen from Table 2 that the compound of formula I fumarate has good compatibility with glyceryl behenate, but has poor compatibility with silica and stearic acid.

Experimental Example 3 Diluent Investigation

table 3

Weigh the corresponding raw materials and mix them thoroughly.

Determination of angle of repose: using the fixed funnel method, place the watch glass directly under the funnel, adjust the watch glass so that its origin is perpendicular to the funnel, slowly add the material from the funnel, and add it to the edge of the watch glass to hold the material. As long as it is a regular cone, measure the position of the height of the funnel, measure the diameter of the bottom of the cone, and calculate the angle of repose. The angle of repose ≤40 meets the requirements for the fluidity of materials in the production process.

Table 4

Determination of dissolution: take this product, according to the second method of the "0931 Dissolution and Release Measurement Method" of the Chinese Pharmacopoeia 2015 Edition, with pH4.5 acetate buffer 900mL as the dissolution medium, speed 50rpm, operate according to the law, sampling The dissolution rate was measured, and the specific results are shown in Table 5.

The total mixed material is compressed according to the theoretical tablet weight.

Preparation of acetic acid buffer solution of pH4.5: Weigh 108.4g anhydrous sodium acetate, measure 98ml of acetic acid and add water to 10L to obtain.

table 5

It can be seen from the data that the lactose screened by the present invention and its usage, dissolution and angle of repose all meet the preparation requirements.

Experimental Example 4 Investigation of disintegrant

Table 6

The preparation and dissolution methods are consistent with Experimental Example 3, and the specific results are shown in Table 7.

Table 7

The following examples further describe the practical effects of the present invention. The examples are for illustrative purposes only and do not limit the scope of the present invention, and obvious changes and modifications made by those of ordinary skill in the art based on the scope of the present invention are also included in this Within the scope of the invention.

Example 1

Table 8

Preparation:

The fumarate compound of formula I is processed through a 60-mesh sieve, and it is added to the hopper mixer with half of the prescribed amount of lactose for premixing. Then add the other half of the prescribed amount of lactose and the prescribed amount of low-substituted hydroxypropylcellulose, glyceryl behenate and talc to the hopper mixer, mix evenly and then press.

Example 2 to Example 10

Referring to the preparation process of Example 1, each of the examples prepared 1000 tablets, and the weight parts of each component in the tablet are as follows:

Table 9

Example 11

Mixing uniformity: after mixing, take samples from different parts of the mixing container (upper 5 parts, middle 5 parts, lower 1 part) to detect the mixing uniformity, RSD should be <3%.

Fritability check method: According to the "General Pharmacopoeia" 2015 edition of the four general rules "0923 tablet fragility check method", take the tablets to make the total weight of about 6.5g, use a hair dryer to blow off the powder falling off the tablet, and weigh precisely , Place in the cylinder and turn 100 times. Take it out, remove the powder in the same way, weigh it accurately, and lose no more than 1% of the weight, and no broken, cracked or crushed pieces can be detected. This test is generally done only once. If the weight loss exceeds 1%, it should be retested twice, the average weight loss of the three times should not exceed 1%, and no broken, cracked or crushed pieces can be detected.

Dissolution determination method: take this product, according to the second method of "0931 Dissolution and Release Determination Method" of the Chinese Pharmacopoeia 2015 Edition Four Parts, use 0.1M hydrochloric acid buffer 900mL as the dissolution medium, the speed is 50rpm, operate according to the law, in Sampling 15min to determine the dissolution.

Specific test results are shown in Table 10.

Table 10

It can be seen from Table 10 that during the tabletting process of Examples 1-10 of the present invention, the surface of the punch is smooth and smooth, and there is no sticking and punching, and the tablet is produced smoothly. Claim.

Example 12 accelerated experiment

The samples of Example 2, Example 6, Example 7, Example 8 and Example 10 were placed under the condition of 40 ° C ± 2 ° C / RH75% ± 5%, and samples were taken at 0, 1, 2, and 3 months respectively Investigate related substances and dissolution rate. The specific test results are shown in Table 11.

It can be seen from Table 11 that, under accelerated test conditions, the pharmaceutical composition of the present invention, compared with the 0-day result, impurity A hardly degrades, impurity B degrades slightly, but all are within the standard range, and the remaining quality indicators are not Significant changes have occurred and meet the requirements of quality standards. The pharmaceutical composition prepared by the present invention can significantly improve the stability of the compound of formula I.

Claims

A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a diluent, optionally, a disintegrant,
A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant and a lubricant,
The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutically acceptable salts of the compound of formula I include fumarate, maleate, citrate or mesylate, preferably Fumarate.
The pharmaceutical composition according to claim 1 or 2, characterized in that, based on the total weight of the pharmaceutical composition, it contains 5 to 20% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof, preferably 6 to 10% By weight of the compound of formula I or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 2, characterized in that, based on the total weight of the pharmaceutical composition, it contains 0.5 to 5% by weight of lubricant, preferably 0.8 to 3.0% by weight of lubricant.
The pharmaceutical composition according to claim 2, characterized in that, based on the total weight of the pharmaceutical composition, it contains 1.5 to 5% by weight of lubricant, preferably 2.0 to 4.0% by weight of lubricant.
The pharmaceutical composition according to claim 2, wherein the lubricant is selected from glyceryl behenate, glyceryl palmitate stearate, magnesium stearate, calcium stearate, and stearic fumaric acid Sodium or stearic acid, preferably glyceryl behenate.
The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition may further include a glidant.
The pharmaceutical composition according to claim 8, characterized in that, based on the total weight of the pharmaceutical composition, it contains 0 to 1% by weight of glidant, preferably 0.2 to 1% by weight of glidant, more preferably 0.2 to 0.5% by weight of glidant.
The pharmaceutical composition according to claim 8, characterized in that the glidant is selected from silica, micronized silica gel or talc, preferably talc.
The pharmaceutical composition according to claim 1 or 2, wherein the diluent is a water-soluble diluent, one or more selected from lactose, sorbitol, mannitol, and pregelatinized starch, preferably Lactose, more preferably lactose monohydrate.
The pharmaceutical composition according to claim 1 or 2, characterized in that, based on the total weight of the pharmaceutical composition, it contains 50 to 90% by weight of diluent, preferably 70 to 85% by weight of diluent, more preferably 75 to 85% by weight of diluent.
The pharmaceutical composition according to claim 1 or 2, wherein the disintegrant is selected from calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose One or more of sodium starch starch and crospovidone; preferably carboxymethyl cellulose calcium or low-substituted hydroxypropyl cellulose.
The pharmaceutical composition according to claim 1 or 2, characterized in that, based on the total weight of the pharmaceutical composition, it contains 1 to 20% by weight of a disintegrant, preferably 3 to 15% by weight of a disintegrant, It is more preferably 8 to 12% by weight of a disintegrant, and still more preferably 10 to 12% by weight of a disintegrant.
The pharmaceutical composition according to claim 1 or 2, wherein the weight percentage of each component is calculated based on the total weight of the pharmaceutical composition as follows:

5-20% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof,

55 to 90% by weight of thinner,

1-20% by weight of disintegrant,

0.5 to 5% by weight of lubricant,

0 to 1% by weight of glidant;

Preferably, the weight percentage of each component is as follows:

5-20% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof,

70 to 85% by weight of thinner,

1-20% by weight of disintegrant,

0.5 to 5% by weight of lubricant,

0 to 1% by weight of glidant;

More preferably, the weight percentage of each component is as follows:

5-10% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof,

75 to 85% by weight of thinner,

3 to 15% by weight of disintegrant,

0.5 to 5% by weight of lubricant,

0.2 to 1% by weight of glidant;

Further preferably, the weight percentage of each component is as follows:

5-10% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof,

75 to 85% by weight of thinner,

3 to 15% by weight of disintegrant,

2 to 4% by weight of lubricant,

0.2 to 1% by weight of glidant;

Further preferably, the weight percentage of each component is as follows:

7.75% by weight of fumarate compound of formula I,

78.75% by weight of thinner,

10% by weight of disintegrant,

3% by weight of lubricant,

0.5% by weight of glidant.
A method for preparing the pharmaceutical composition according to claim 1 or 2, characterized in that the compound of formula I or a pharmaceutically acceptable salt thereof is combined with a diluent, disintegrant and lubricant, optionally containing a glidant After mixing, the tablets are directly compressed.
The use of the pharmaceutical composition according to any one of claims 1-15 in the preparation of a medicament for the treatment of viral infectious diseases, preferably in the preparation of a medicament for the treatment of diseases caused by AIDS infection, hepatitis B or hepatitis B virus.