WO2022166778A1 - A pharmaceutical composition of a capsid protein inhibitor and preparation method thereof - Google Patents

Abstract

A pharmaceutical composition of a capsid protein inhibitor and a preparation method thereof. Specifically, provided is a composition, comprising (S)-N⁵-(3,4-difluorophenyl)-6-methyl-N³-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a pharmaceutically acceptable salt thereof and a hydroxypropylmethyl fiber. The composition has a good dissolution rate and superior stability.

Description

A kind of pharmaceutical composition of capsid protein inhibitor and preparation method thereof technical field

The present disclosure belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of capsid protein inhibitor and a preparation method thereof. Specifically, it relates to a composition comprising (S)-N ⁵ -(3,4-difluorophenyl)-6-methyl-N ³ -((R)-1,1,1-trifluoropropane -2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a pharmaceutically acceptable of salt and hypromellose.

Background technique

The low cure rate of chronic hepatitis B virus (HBV) infection is closely related to its viral characteristics. HBV is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnaviridae family. The outermost layer of mature HBV virus particles is an envelope protein that wraps the HBV nucleocapsid (Nucleocapsid). Nucleocapsids, also known as core particles, are composed of capsid protein, HBV relaxed circular DNA (rcDNA) and HBV reverse transcriptase bound to the 5' end of the negative strand of rcDNA. Upon infection, rcDNA is converted into covalently closed circular DNA (cccDNA) in the host nucleus, which serves as a template for HBV replication. In the process of HBV replication, an important step is capsid assembly (Encapsidation). Pregenomic RNA (pgRNA) transcribed from cccDNA needs to be encapsulated in capsid protein together with HBV reverse transcriptase to complete the assembly step to trigger subsequent reverse transcription. Before reverse transcription, HBV reverse transcriptase, pgRNA needs to be properly encapsulated by capsid protein. Therefore, blocking capsid protein assembly, or accelerating capsid protein degradation, will block the capsid assembly process, thereby affecting viral replication. In addition, the N-terminal 149 amino acid residues (Cp149) that constitute the core protein dimerization motif (Dimerization motif) and assembly domain (Assemblydomain) do not have human protein homologous sequences. Therefore, capsid protein assembly inhibitors are regarded as new targets for anti-HBV drug development. Due to the different mechanism of action of traditional antiviral drugs, the combination therapy of capsid protein inhibitors and DNA polymerase inhibitors can synergistically suppress HBV replication and prevent the emergence of drug resistance, providing a safer and more effective treatment for chronic hepatitis B infection.

WO2019020070 discloses a novel structural capsid protein inhibitor, such as the compound shown in formula I, whose compound name is (S)-N ⁵ -(3,4-difluorophenyl)-6-methyl-N ³ -((R)-1,1,1-Trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3 ,5(4H)-dicarboxamide, the inhibitor exhibits strong capsid protein inhibitory activity and the effect of treating chronic hepatitis B virus (HBV),

In order to meet the medication needs of patients, the above compound (S)-N ⁵ -(3,4-difluorophenyl)-6-methyl-N ³ -((R)-1,1,1-trifluoropropane -2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a pharmaceutically acceptable salt thereof To prepare a suitable formulation, in the case of a solid formulation, the formulation needs to have good dissolution properties and formulation stability.

SUMMARY OF THE INVENTION

The purpose of the present disclosure is to provide an active ingredient (S)-N ⁵ -(3,4-difluorophenyl)-6-methyl-N ³ -((R)-1,1,1-trifluoropropane -2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a pharmaceutically acceptable salt thereof The pharmaceutical composition has good dissolution and formulation stability.

The present disclosure provides a pharmaceutical composition comprising an active ingredient (S)-N ⁵ -(3,4-difluorophenyl)-6-methyl-N ³ -((R)-1, 1,1-Trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dimethyl amide or a pharmaceutically acceptable salt thereof and hydroxypropyl methylcellulose.

In certain embodiments, the hydroxypropyl methylcellulose is present in an amount of 0.01-25%, preferably 0.05-20%, more preferably 0.1-15%, non-limiting examples including 0.1%, based on the total weight of the composition , 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6 %, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2% , 9.4%, 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6 %, 12.8%, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0%, 14.2%, 14.4%, 14.6%, 14.8%, 15.0%, or any value in between.

In certain embodiments, the pharmaceutical composition further comprises a disintegrant selected from one of starch, croscarmellose sodium, sodium carboxymethyl starch, crospovidone or variety. In certain embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch and crospovidone, preferably croscarmellose One or more of sodium and sodium carboxymethyl starch, more preferably croscarmellose sodium.

In certain embodiments, the content of the disintegrant is 0.01-25% based on the total weight of the composition, preferably 0.05-20%, more preferably 0.1-15%, non-limiting examples include: 0.1%, 0.2% , 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8 %, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2%, 9.4% , 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6%, 12.8 %, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0%, 14.2%, 14.4%, 14.6%, 14.8%, 15.0% or any value in between.

The pharmaceutical composition of the present disclosure further comprises one or more of fillers, lubricants, and glidants.

In certain embodiments, the filler is selected from one or more of microcrystalline cellulose, dextrin, lactose, sucrose, mannitol, calcium hydrogen phosphate, preferably one or more of microcrystalline cellulose and lactose or more, more preferably microcrystalline cellulose and lactose.

In certain embodiments, the filler content is 20-95% based on the total weight of the composition, preferably 50-95%, non-limiting examples include: 51%, 52%, 53%, 54%, 55% , 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or anything in between.

In certain embodiments, the glidant is selected from the group consisting of stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate , silicon dioxide, hydrogenated vegetable oil, sodium lauryl sulfate, one or more of talc, preferably silicon dioxide.

In certain embodiments, the content of the glidant is 0.01-10%, preferably 0.05-5%, based on the total weight of the composition, non-limiting examples include: 0.05%, 0.06%, 0.07%, 0.08%, 0.09 %, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0% or any value in between .

In certain embodiments, the lubricant is selected from the group consisting of stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate, One or more of silicon dioxide, hydrogenated vegetable oil, sodium lauryl sulfate, talc, preferably magnesium stearate.

In certain embodiments, the content of the lubricant is 0.01-10%, preferably 0.05-5%, based on the total weight of the composition, non-limiting examples include: 0.05%, 0.06%, 0.07%, 0.08%, 0.09% , 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4 %, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0% or any value in between.

In certain embodiments, the active ingredient (S) ^-N5- (3,4-difluorophenyl)-6-methyl ^- N3-((R)-1,1,1-trifluoropropane- 2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a pharmaceutically acceptable salt thereof The content is 0.1-40% based on the total weight of the composition, preferably 1-35%, non-limiting examples include: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% %, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, or any number in between.

The present disclosure provides a pharmaceutical composition comprising, based on the total weight of the composition,

1-35% of active ingredient which is (S) ^-N5- (3,4-difluorophenyl)-6-methyl ^- N3-((R)-1,1,1-tris Fluoroprop-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a medicament thereof With salt, hydroxypropyl methylcellulose 0.1-15%,

50-95% of filler, which is selected from one or more of microcrystalline cellulose and lactose,

The disintegrant is 0.1-15%, and the disintegrant is croscarmellose sodium.

Disintegrants refer to substances that can rapidly disintegrate solid preparations into fine particles in gastric juice, so that functional components can be rapidly dissolved and absorbed, and most of them have good water absorption and swelling properties, thereby realizing the disintegration of oral preparations. There are many types of different disintegrants, and different disintegrants have different effects on the disintegration of solid preparations. For the desired dissolution characteristics, it is necessary to select an appropriate disintegrant.

The present disclosure provides a pharmaceutical composition comprising an active ingredient (S)-N5-(3,4-difluorophenyl)-6-methyl-N3-((R)-1,1,1-tris Fluoroprop-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a medicament thereof With salt and disintegrant.

In certain embodiments, the disintegrant is selected from one or more of starch, croscarmellose sodium, sodium carboxymethyl starch, and crospovidone. In certain embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch and crospovidone, preferably croscarmellose One or more of sodium and sodium carboxymethyl starch, more preferably croscarmellose sodium.

In certain embodiments, the content of the disintegrant is 0.01-25% based on the total weight of the composition, preferably 0.05-20%, more preferably 0.1-15%, non-limiting examples include: 0.1%, 0.2% , 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8 %, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2%, 9.4% , 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6%, 12.8 %, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0%, 14.2%, 14.4%, 14.6%, 14.8%, 15.0% or any value in between.

In certain embodiments, the composition further comprises hydroxypropyl methylcellulose.

In certain embodiments, the content of the hydroxypropyl methylcellulose is 0.01-25%, preferably 0.05-20%, more preferably 0.1-15%, based on the total weight of the composition, non-limiting examples include 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6% , 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0 %, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2%, 9.4%, 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6% , 12.8%, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0%, 14.2%, 14.4%, 14.6%, 14.8%, 15.0%, or any value in between.

Further, the present disclosure provides a pharmaceutical composition, which is in solid form and can exist in the form of tablets, granules or pills, preferably tablets.

In the field of pharmaceutical preparations, the curative effect of the active pharmaceutical ingredient itself is important, but the release characteristics of the preparation also play a crucial role in the curative effect of the drug. For example, immediate-release preparations are made to speed up the dissolution rate of the drug, improve the dissolution rate, and thus improve the bioavailability.

The pharmaceutical composition provided by the present disclosure is very rapidly and completely dissolved. The pharmaceutical composition is in accordance with the second method of Chinese Pharmacopoeia 2015 Edition Four General Principles 0931, using phosphate buffer with pH of 6.8 plus 2% Tween 80 as the dissolution medium. At 37±0.5°C, the dissolution rate is measured at a pulp speed of 75rpm, and the cumulative dissolution rate within 15 minutes is not less than 60%, preferably not less than 65%, more preferably not less than 70%, non-limiting examples include not less than: 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% .

In certain embodiments, the cumulative dissolution rate of the composition within 30 minutes is not less than 75%, preferably not less than 80%, more preferably not less than 85%, non-limiting examples include not less than: 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%.

The pharmaceutical composition provided by the present disclosure has good stability. The composition is stored in a closed chamber at 60°C for 28 days, and the content of 3,4-difluoroaniline in the composition is not more than 0.15%, preferably not more than 0.12% , non-limiting examples include not greater than: 0.12%, 0.11%, 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%.

In certain embodiments, the composition is stored in a closed chamber at 60°C for 28 days, and the impurity (RRT of 0.25) content in the composition is not more than 0.8%, preferably not more than 0.7%, non-limiting examples include not Greater than: 0.7%, 0.69%, 0.68%, 0.67%, 0.66%, 0.65%, 0.64%, 0.63%, 0.62%, 0.61%, 0.60%.

"Pharmaceutically acceptable salt" in this disclosure refers to (S) ^-N5- (3,4-difluorophenyl)-6-methyl ^- N3-((R)-1,1,1-trifluoro Prop-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide salts, such The salt is safe and effective when used in mammals, and has due biological activity.

In certain embodiments, the pharmaceutically acceptable salt is selected from the hydrochloride salt.

Use of the pharmaceutical composition provided by the present disclosure in the preparation of capsid protein inhibitors.

Use of the pharmaceutical composition provided by the present disclosure in the preparation of a medicament for preventing and/or treating viral infectious diseases. The viruses are hepatitis B virus, influenza virus, herpes virus and HIV, and the diseases are hepatitis B, influenza, herpes and AIDS.

The pharmaceutical compositions provided by the present disclosure are useful as medicines. The medicament can be used for the prevention and/or treatment of viral infectious diseases. The viruses are hepatitis B virus, influenza virus, herpes virus and HIV, and the diseases are hepatitis B, influenza, herpes and AIDS.

The present disclosure provides a method of preventing and/or treating a viral infectious disease comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition. The viruses are hepatitis B virus, influenza virus, herpes virus and HIV, and the diseases are hepatitis B, influenza, herpes and AIDS.

Another aspect of the present disclosure provides a method for preparing the composition, comprising: 1) the step of mixing an active ingredient and hydroxypropyl methylcellulose. In certain embodiments, further comprising the step of dry granulation, wet granulation or direct powder mixing of the mixture, preferably wet granulation. In certain embodiments, a further step of compression into a tablet is included.

The present disclosure also provides a method for preparing the composition, comprising: 1) the step of mixing an active ingredient and a disintegrant. In certain embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch and crospovidone, preferably croscarmellose sodium. In certain embodiments, further comprising the step of dry granulation, wet granulation or direct powder mixing of the mixture, preferably wet granulation. In certain embodiments, a further step of compression into a tablet is included.

Detailed ways

The present disclosure is further illustrated in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

Example 1: Compositions with different disintegrants

1. Tablet preparation

Table 1: Composition formulations with different disintegrants

prescription Prescription 1(g) Prescription 2(g) Prescription 3(g) Active ingredient 18.52 18.52 18.52 lactose 49.48 49.48 49.48 microcrystalline cellulose 25 25 25 Croscarmellose sodium 3 --- --- Sodium Carboxymethyl Starch --- 3 --- Crospovidone --- --- 3 Hypromellose 3 3 3 silica 0.5 0.5 0.5 Magnesium stearate 0.5 0.5 0.5 total 100 100 100

Weigh the recipe amount of active ingredient (S)-N ⁵ -(3,4-difluorophenyl)-6-methyl-N ³ -((R)-1,1,1-trifluoropropan-2-yl )-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide with the exception of magnesium stearate and silica other components are mixed. Wet granulation was performed by adding 8.5% (w/w) hypromellose in water. The wet granules are dried on a fluid bed. The dry granules were mixed with magnesium stearate and silicon dioxide and then compressed using a single punch tablet machine. The tablets of prescription 1, prescription 2 and prescription 3 are obtained by preparing according to the above-mentioned scheme.

2. Dissolution testing

According to the dissolution and release determination method (the second method of four general rules of Chinese Pharmacopoeia 2015), 900 ml of phosphate buffer (pH 6.8) (2% Tween 80) was used as the dissolution medium, and the rotation speed was 75 revolutions per minute, respectively. At 10, 15, 30, 45, 60, 90 minutes and 120 minutes, take 2ml of the solution, filter it with a 0.45μm filter membrane, and use it as the test solution.

Reference substance solution: take another appropriate amount of active substance reference substance, add dissolution medium to dissolve and quantitatively dilute to make reference substance solution. Inject the test solution and the reference solution into the liquid chromatograph, record the chromatogram, measure the peak area, and calculate the dissolution amount of each tablet at different times.

Table 2: Dissolution of Tablets with Different Disintegrants

The experimental results show that: croscarmellose sodium is a disintegrant, and the tablet disintegration time and dissolution rate are obviously better than those of sodium carboxymethyl starch or crospovidone, and the use of croscarmellose. The tablet with sodium cellulose as disintegrant can achieve rapid release, more than 87% release within 15min, and basically complete release.

Example 2: Preparation of tablets of different formulations

Table 3: Formulations with different components

prescription Prescription 4(g) Prescription 5(g) Prescription 6(g) Active ingredient 5 5 5 lactose 58 58 58 microcrystalline cellulose 30 30 30 Croscarmellose sodium 3 3 --- Crospovidone --- --- 3 Hypromellose 3 --- --- Hydroxypropyl cellulose --- 3 --- Povidone --- --- 3 silica 0.5 0.5 0.5 Magnesium stearate 0.5 0.5 0.5 total 100 100 100

1. Tablet preparation

Tablets of formulations 4-6 were prepared according to the tablet preparation method of Example 1.

2. Research on high temperature stability

Tablets of prescriptions 4-6 were placed in a stable box at a temperature of 60°C for 14 days and 28 days, respectively, and then regularly sampled, and the content of impurities and active ingredients was determined by HPLC. The experimental results are shown in Table 4.

Table 4: Stability of different formulations

Note: ND means not detected, RRT means relative retention time.

Experimental results: 3,4-difluoroaniline is a genotoxic impurity. According to ICH M7, it is controlled as Class II. The maximum daily dose of this product is 100 mg, and the medication cycle is less than 30 days (acceptable daily intake of 120 μg). This impurity limit is 0.12%. The content of 3,4-difluoroaniline in prescription 6 was 0.15% and 0.18% respectively when placed under high temperature conditions of 60°C for 14 days and 28 days, which has obviously exceeded the limit, and there are potential safety hazards. The 3,4-difluoroaniline of prescription 4 The detected value is small, and the quality is expected to be controllable under long-term storage conditions. Impurities (RRT=0.25) both increased when recipe 4 and recipe 5 were placed at a high temperature of 60°C for 14 days and 28 days, but recipe 5 had a larger increase. Compared with recipe 4, it was better. It is presumed that recipe 4 is under long-term storage conditions. Quality is controllable. According to the above results, it is suitable to use hypromellose as the prescription binder.

Example 3: Long-term accelerated experiment

Table 5: Formulation formulation

The above-mentioned prescription tablets were prepared according to the tablet preparation method of Example 1, placed in high-density polyethylene bottles, and placed for 6 months under the conditions of 25 °C ± 2 ° C, RH 60% ± 5%, and 5 ° C ± 3 6 months under the condition of ℃, sampling regularly. The dissolution rate was detected according to the dissolution detection method in implementation 1, and the contents of prescription impurities and active ingredients were determined according to the HPLC method in implementation 2. The detection results are shown in Table 6.

Table 6: Tablet Stability

Note: ND means not detected, RRT means relative retention time.

The results show that the above-mentioned tablets have good stability under long-term accelerated conditions. In addition, after testing, the above-mentioned tablet has a good dissolution rate after being placed.

Claims (16)

A pharmaceutical composition comprising an active ingredient (S) ^-N5- (3,4-difluorophenyl)-6-methyl ^- N3-((R)-1,1,1-trifluoropropane- 2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a pharmaceutically acceptable salt thereof and Hydroxypropylmethylcellulose. The pharmaceutical composition according to claim 1, wherein the content of the hydroxypropyl methylcellulose is 0.01-25%, preferably 0.05-20%, more preferably 0.1-15% based on the total weight of the composition. The pharmaceutical composition according to claim 1 or 2, further comprising a disintegrating agent, wherein the disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch and crospovidone One or more, preferably one or more of croscarmellose sodium and sodium carboxymethyl starch, more preferably croscarmellose sodium. The composition of claim 3, wherein the disintegrant is present in an amount of 0.01-25%, preferably 0.05-20%, more preferably 0.1-15%, based on the total weight of the composition. The pharmaceutical composition according to any one of claims 1-4, further comprising one or more of fillers, lubricants, and glidants. The pharmaceutical composition according to claim 5, wherein the filler is selected from one or more of microcrystalline cellulose, dextrin, lactose, sucrose, mannitol, calcium hydrogen phosphate, preferably microcrystalline cellulose and One or more of lactose; the filler content is 20-95%, preferably 50-95% based on the total weight of the composition. The pharmaceutical composition according to claim 5, wherein the glidant is selected from the group consisting of stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, One or more of glyceryl behenate, silicon dioxide, hydrogenated vegetable oil, sodium lauryl sulfate, talc, preferably silicon dioxide; the content of the glidant is 0.01-10% based on the total weight of the composition , preferably 0.05-5%. The pharmaceutical composition according to claim 5, wherein the lubricant is selected from the group consisting of stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, One or more of glyceryl citric acid, silicon dioxide, hydrogenated vegetable oil, sodium lauryl sulfate, talc, preferably magnesium stearate; the content of the lubricant is 0.01-10% based on the total weight of the composition, Preferably 0.05-5%. The pharmaceutical composition according to any one of claims 1-8, wherein the content of the active ingredient is 0.1-40%, preferably 1-35%, based on the total weight of the composition. A pharmaceutical composition comprising, based on the total weight of the composition, 1-35% of active ingredient which is (S) ^-N5- (3,4-difluorophenyl)-6-methyl ^- N3-((R)-1,1,1-tris Fluoroprop-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or a medicament thereof With salt, hydroxypropyl methylcellulose 0.1-15%, 50-95% of filler, which is selected from one or more of microcrystalline cellulose and lactose, The disintegrating agent is 0.1-15%, and the disintegrating agent is croscarmellose sodium. The pharmaceutical composition according to any one of claims 1-10, in the form of a tablet, granule or pill, preferably a tablet. The pharmaceutical composition according to any one of claims 1-11, wherein the composition is in accordance with the second method of Chinese Pharmacopoeia 2015 Edition Four General Principles 0931, using pH 6.8 phosphate buffer plus 2% Tween 80 as the dissolution method medium, the dissolution rate is measured at 37±0.5°C with a pulp speed of 75 rpm, and the cumulative dissolution rate within 15 minutes is not less than 60%, preferably not less than 65%, more preferably not less than 70%. The composition according to any one of claims 3-12, wherein the composition is stored in a closed box at 60° C. for 28 days, and the content of 3,4-difluoroaniline in the composition is not more than 0.15%, preferably not more than 0.15%. greater than 0.12%. Use of the pharmaceutical composition according to any one of claims 1-13 in the preparation of capsid protein inhibitors. Use of the pharmaceutical composition according to any one of claims 1 to 14 in the preparation of a medicine for treating a viral infection, wherein the virus is hepatitis B virus, influenza virus, herpes virus and HIV, and the disease For Hepatitis B, Influenza, Herpes and AIDS. 13. A method of preparing the composition of any one of claims 1-13, comprising the step of mixing the active ingredient and hydroxypropyl methylcellulose.