Solid pharmaceutical composition comprising TLR7 agonist

Abstract

To provide a solid pharmaceutical composition excellent in stability and elution properties comprising a TLR7 agonist (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine).SOLUTION: A solid pharmaceutical composition comprises a TLR7 agonist (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine), a diluent, a binder, a disintegrant, and a lubricant. The diluent is selected from among microcrystalline cellulose and the like. The disintegrant is selected from among sodium carboxymethyl starch and the like. The binder is selected from among hydroxypropyl methylcellulose and the like. The lubricant is selected from among magnesium stearate and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority from Chinese Patent Application No. 201910326899.9, filed with the State Intellectual Property Office of China on April 23, 2019, the entire contents of which are incorporated herein by reference.

[0002] [Technical field] The present application is in the field of medicinal chemistry, and specifically relates to a solid pharmaceutical composition comprising a TLR7 agonist (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine), its preparation method and its medical use. [Background technology]

[0003] Toll-like receptors are expressed in various immune cells. Toll-like receptors recognize highly conserved structural motifs such as pathogen-associated molecular patterns (PAMPs) expressed by microbial pathogens and damage-associated molecular patterns (DAMPs) released by necrotic cells. PAMPs or DAMPs stimulate Toll-like receptors to trigger signal cascades that activate transcription factors such as AP-1, NF-κB, and interferon regulatory factor (impulse response function). This triggers various cellular responses such as the production of interferons, proinflammatory cytokines, and effector cytokines, resulting in an immune response. To date, 13 types of Toll-like receptors have already been discovered in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are mainly expressed on the cell surface, while Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. Different Toll-like receptors recognize different pathogen-derived ligands. Toll-like receptor 7 (TLR7) is mainly expressed by plasmacytoid dendritic cells (pDCs), and induces the secretion of interferon-α (IFN-α) when recognized by its ligand. Toll-like receptor 7 (TLR7) and toll-like receptor 8 (TLR8) are highly homologous, so in many cases TLR7 ligands are also TLR8 ligands. Cytokines such as tumor necrosis factor-α (TNF-α) and chemokines are mainly produced in response to TLR8 stimulation. Interferon-α is one of the main therapeutic drugs for chronic hepatitis B or C, and TNF-α is an inflammatory cytokine whose excessive secretion can cause serious side effects. WO2016 / 023511 discloses several compounds for use as TLR7 agonists. Nevertheless, there remains a need in the art for the development of pharmaceutical compositions comprising suitable TLR7 agonist compounds. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2016 / 023511 Brochure Summary of the Invention

[0005] One aspect of the present application is [ka] The present invention relates to a solid pharmaceutical composition comprising a compound of formula I comprising: a diluent, a binder, a disintegrant and a lubricant.

[0006] In one embodiment, the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or a mixture thereof, preferably microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof, more preferably microcrystalline cellulose, pregelatinized starch, or a mixture thereof.

[0007] In one embodiment, the binder is selected from hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, partially hydrolyzed starch, pregelatinized starch, glucose, polyethylene glycol, polyvinyl alcohol or mixtures thereof, preferably hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), polyvinylpyrrolidone or mixtures thereof, more preferably hydroxypropyl methylcellulose.

[0008] In one embodiment, the disintegrant is selected from sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose or crospovidone, sodium dodecyl sulfate or magnesium dodecyl sulfate or mixtures thereof, preferably sodium carboxymethyl starch, croscarmellose sodium or mixtures thereof, more preferably sodium carboxymethyl starch.

[0009] In one embodiment, the lubricant is selected from magnesium stearate, colloidal silicon dioxide (also referred to as colloidal silica), talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate, sodium dodecyl sulfate, or a mixture thereof, preferably magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof, more preferably magnesium stearate, colloidal silica, or a mixture thereof.

[0010] Another aspect of the present application relates to a method for preparing the solid pharmaceutical composition of the present application, the method comprising direct compression.

[0011] Yet another aspect of the present application relates to the use of the solid pharmaceutical composition of the present application for the manufacture of a medicament for treating or preventing a disease associated with TLR7. In a preferred embodiment, the disease is selected from a viral infection. In a preferred embodiment, the viral infection is selected from hepatitis B or hepatitis C.

[0012] [Definitions and explanations] Unless otherwise specified, the terms and expressions used herein have the following meanings. Unless otherwise defined, a particular term or expression is not indefinite or unclear, but is to be interpreted in its ordinary sense by those skilled in the art. When a product name is mentioned herein, it means the corresponding product or its active ingredient.

[0013] Unless otherwise defined or in general usage, all ratios (including percentages) or parts given herein are by weight, such as wt% or mass%.

[0014] The expression "comprising..." and similar expressions with the same meaning, such as "containing...", "having...", etc., are open ended expressions and do not exclude any unspecified elements, steps or ingredients. The expression "consisting of..." excludes all unspecified elements, steps or ingredients. The expression "consisting essentially of..." means that the scope is limited to the specified elements, steps or ingredients, and that, if desired, elements, steps or ingredients may be added that do not substantially affect the basic and novel characteristics of the subject matter sought to be protected. It should be noted that the expression "comprising..." includes "consisting essentially of..." and "consisting of...".

[0015] The terms "desired" or "desirably" refer to the fact that the subsequently described event or circumstance may or may not occur, and includes the occurrence of the event or circumstance and the absence of the event or circumstance.

[0016] As used herein, "one (1) or more" or "at least one (1)" means one (1), two (2), three (3), four (4), five (5), six (6), seven (7), eight (8), nine (9) or more species (quantity). Similarly, two (2) or more species (quantity) means two (2), three (3), four (4), five (5), six (6), seven (7), eight (8), nine (9) or more species (quantity).

[0017] As used herein, the compounds of formula I include the free base form and pharma- ceutically acceptable salts thereof, including, but not limited to, trifluoroacetate and maleate.

[0018] In the present application, the content of the compound of formula I in the pharmaceutical composition is its free base. Calculate using the same formula as above.

[0019] The amount "wt%" of a particular component (including active substances, excipients) described herein refers to the percentage of the mass of that component in the total mass of the solid pharmaceutical composition (the mass of the compound of formula I is calculated as its free base), not including the mass of any coating agent.

[0020] The method for preparing the solid pharmaceutical composition described in this application may be a method well known in the art. The preparation method specifically includes steps such as grinding, mixing, sieving, granulation, filling, tableting, etc., and steps are set according to the actual situation, and the method or device for performing the step is selected. For example, the grinding step is performed using a mortar, a ball mill, a roller press, an impact mill, a hammer mill, and / or a jet mill, the mixing step is performed as stirring mixing, grinding mixing, and / or sieving mixing, and the sieving step is performed using a sieve shaker. Alternatively, You may also refer to "Pharmaceutics" by Futoku et al. (6th or 7th edition, People's Health Press).

[0021] The "preparation of a mixture" in the manufacturing process of the solid pharmaceutical composition of the present application can be achieved by one or more steps. For example, "preparation of a mixture with the compound of formula I, a diluent, a disintegrant, a binder, and a lubricant" may mean that all components are mixed in one step, or that some components are mixed and then mixed with the remaining components in multiple steps.

[0022] The term "treatment" refers to the administration of a compound or pharmaceutical composition described herein to improve or eliminate a disease or one or more symptoms associated with said disease, including (i) inhibiting the disease or pathological condition, i.e., arresting its progression, and (ii) palliating the disease or pathological condition, i.e., relieving the disease or pathological condition.

[0023] The term "prevention" refers to the administration of a compound or pharmaceutical composition described herein to prevent the occurrence of a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or pathological condition in a mammal, particularly when a mammal susceptible to the pathological condition has not been diagnosed with the pathological condition.

[0024] The term "therapeutically effective amount" refers to a dose of a compound of the present application to (i) treat a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound itself, the pathological condition and its severity, the form of administration, and the age of the mammal being treated, but may be determined by one of skill in the art based on his or her knowledge and the contents of this disclosure.

[0025] The term "pharmacologically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, not toxic or irritating, and not likely to cause an allergic reaction or other problem or complication, and for which the benefit-to-risk ratio is reasonable.

[0026] The term "or a mixture thereof" means "or a mixture of two or more of them." For example, "the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or a mixture thereof" means "the diluent is selected from one or a mixture of two or more of microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin."

[0027] The excipients used in the present application may be those commonly used in the field. For example, microcrystalline cellulose that can be used includes, but is not limited to, PH101, PH102, PH103, and PH105. For example, pregelatinized starch that can be used includes, but is not limited to, Starch 1500, Spress B820, and Unipure WG220. For example, sodium carboxymethyl starch that can be used includes, but is not limited to, types A and B. For example, hydroxypropyl methylcellulose that can be used includes, but is not limited to, E3, E5, and E6. For example, colloidal silicon dioxide (also called colloidal silica) that can be used includes, but is not limited to, Pharma 200, AEROSIL 200, and AEROSIL 300. Those skilled in the art may select specifically according to their needs, or may select by referring to literature such as "Handbook of Pharmaceutical Excipients" 6th Edition by Raymond C. Rowe et al. and "Complete Guide to Pharmaceutical Excipients" 2nd Edition by Luo Mingsheng et al.

[0028] The term "bulk density" refers to the density measured by filling a standard container with powder to the brim, i.e., the mass per unit volume when the powder is filled with a margin, and is calculated as mass / volume and expressed in g / mL. It can be measured by a method or device commonly used in this field, for example, a powder flowability tester BEP2.

[0029] The term "tap density" refers to the mass of a powder per unit volume measured after tapping, calculated as mass / volume, and expressed in g / mL. It can be measured by a method or device commonly used in this field, for example, a tap density tester SOTAX TD1.

[0030] The "Hausner ratio" is calculated by tap density / bulk density.

[0031] The term "particle size distribution" refers to the percentage of particles of different sizes in the total amount of particles in a powder (calculated by mass). Parameters related to particle size distribution can be measured by methods commonly used in the field, such as mechanical sieving methods or devices, such as the sieve shaker AS200.

[0032] [Pharmaceutical composition of the present application] The present application, [ka] The present invention provides a solid pharmaceutical composition comprising a compound of formula I comprising: a diluent; a binder; a disintegrant; and a lubricant.

[0033] The compound of formula I (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine) is a TLR7 agonist and is used to treat or prevent viral infections.

[0034] In some embodiments, the dosage form of the solid pharmaceutical composition is selected from powders, granules, tablets, capsules, pills, pellets, dispersions or inhalable powders, preferably tablets.

[0035] In some embodiments, the solid pharmaceutical composition is prepared by direct compression.

[0036] In some embodiments, the process for producing the solid pharmaceutical composition does not involve a polishing operation on the mixture containing the compound of formula I and a diluent. In some embodiments, the process for producing the solid pharmaceutical composition does not involve a polishing operation on the mixture containing the compound of formula I and a diluent such as microcrystalline cellulose or pregelatinized starch. In some embodiments, the process for producing the solid pharmaceutical composition does not involve a polishing operation on the mixture containing the compound of formula I and a diluent such as pregelatinized starch. By carrying out the polishing operation in this manner, the solid pharmaceutical composition of the present application has excellent uniformity, stability and dissolution properties.

[0037] In some embodiments, the solid pharmaceutical composition is a unit dose pharmaceutical composition. In one embodiment, the mass of the compound of formula I per unit dose composition is 0.01 mg to 10 mg. In some embodiments, the mass of the compound of formula I per unit dose composition is 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.10 mg, 0.20 mg, 0.30 mg, 0.40 mg, 0.50 mg, 0.60 mg, 0.70 mg, 0.80 mg, 0.90 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, or 10.0 mg, or any ranges extending between any of the preceding values. In some embodiments, the mass of the compound of Formula I per unit dose of the composition is 0.02-8.0 mg, 0.03-6.0 mg, 0.04-4.0 mg, or 0.05-2.0 mg.

[0038] In some embodiments, the amount of the compound of Formula I in the solid pharmaceutical composition is selected from 0.01 to 10 wt%. In some embodiments, the amount of the compound of Formula I is selected from 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.10 wt%, 0.15 wt%, 0.20 wt%, 0.235 wt%, 0.25 wt%, 0.30 wt%, 0.35 wt%, 0.40 wt%, 0.45 wt%, 0.50 wt%, 0.55 wt%, 0.59 wt%, 0.60 wt%, 0.65 wt%, 0.70 wt%, 0.75 wt%, 0.80 wt%, 0.90 ... t%, 0.85 wt%, 0.90 wt%, 0.95 wt%, 1.00 wt%, 1.20 wt%, 1.40 wt%, 1.60 wt%, 1.80 wt%, 2.00 wt%, 2.00 wt%, 2.20 wt%, 2.35 wt%, 2.40 wt%, 2.60 wt%, 2.80 wt%, 3.00 wt%, 3.50 wt%, 4.00 wt%, 4.50 wt%, 5.00 wt%, 6.00 wt%, 7.00 wt%, 8.00 wt%, 9.00 wt%, or 10 wt%, or any range having an endpoint thereof. In some embodiments, the amount of the compound of formula I is preferably selected from 0.02-8.0 wt%, 0.03-6.0 wt%, 0.04-4.0 wt%, 0.05-3.0 wt%, 0.05-2.6 wt%, 0.06-3.0 wt%, 0.06-2.6 wt%, or 0.06-2.4 wt%. In some embodiments, the amount of the compound of formula I is selected from 0.06-2.4 wt%.

[0039] In some embodiments, the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or mixtures thereof. In some embodiments, the diluent is selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or mixtures thereof. In some embodiments, the diluent is selected from microcrystalline cellulose, pregelatinized starch, or mixtures thereof.

[0040] In some embodiments, the amount of diluent is selected from 50 wt% or greater. In some embodiments, the amount of diluent is selected from 55 wt% or greater. In some embodiments, the amount of diluent is selected from 60 wt% or greater. In some embodiments, the amount of diluent is selected from 65 wt% or greater. In some embodiments, the amount of diluent is selected from 70 wt% or greater. In some embodiments, the amount of diluent is selected from 75 wt% or greater. In some embodiments, the amount of diluent is selected from 80 wt% or greater. In some embodiments, the amount of diluent is selected from 85 wt% or greater. In some embodiments, the amount of diluent is 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, or 98 wt%, or any range ending therein. In some embodiments, the amount of diluent is selected from the range of 80-98 wt%, 81-98 wt%, 82-98 wt%, 83-97 wt%, 84-97 wt%, 85-97 wt%, 86-96 wt%, 87-96 wt%, or 88-96 wt%. In some embodiments, the amount of diluent is selected from the range of 88-96 wt%.

[0041] In some embodiments, the diluent comprises microcrystalline cellulose and the amount of microcrystalline cellulose is selected from 30-90 wt%. In some embodiments, the amount of microcrystalline cellulose is selected from 30 wt%, 35 wt%, 40 wt%, 42 wt%, 44 wt%, 46 wt%, 48 wt%, 50 wt%, 52 wt%, 54 wt%, 56 wt%, 58 wt%, 60 wt%, 62 wt%, 64 wt%, 66 wt%, 68 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 76 wt%, 78 wt%, 80 wt%, 85 wt%, or 90 wt%, or any range endpoint therein. In some embodiments, the amount of microcrystalline cellulose is selected from 40-90 wt%, 46-90 wt%, 50-85 wt%, 56-85 wt%, 60-80 wt%, 62-78 wt%, 64-76 wt%, or 66-74 wt%. In some embodiments, the amount of microcrystalline cellulose is selected from 66-74 wt%.

[0042] In some embodiments, the diluent comprises pregelatinized starch and the amount of pregelatinized starch is selected from 5-35 wt%, hi some embodiments, the amount of pregelatinized starch is selected from 5 wt%, 8 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 32 wt%, or 35 wt%, or any range endpoint therein. In some embodiments, the amount of pregelatinized starch is selected from 8-32 wt%, 10-30 wt%, 11-29 wt%, 12-28 wt%, 13-27 wt%, 14-26 wt%, 15-25 wt%, 16-24 wt%, 17-23 wt%, or 18-23 wt%. In some embodiments, the amount of pregelatinized starch is selected from 18-23 wt%.

[0043] In some embodiments, the diluents are microcrystalline cellulose and pregelatinized starch. The total amount of the microcrystalline cellulose and pregelatinized starch is the amount of diluent as described above, e.g., 50 wt% or more, or other range or specified value. The respective amounts of the microcrystalline cellulose and pregelatinized starch are as described above, e.g., 30-90 wt% microcrystalline cellulose, 5-35 wt% pregelatinized starch, or other range or specified value.

[0044] In some embodiments, the disintegrant is selected from sodium carboxymethyl starch, dry starch, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, crospovidone, sodium dodecyl sulfate, magnesium dodecyl sulfate, or mixtures thereof. In some embodiments, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, or mixtures thereof. In some embodiments, the disintegrant is sodium carboxymethyl starch.

[0045] In some embodiments, the amount of disintegrant is selected from 1.0 to 7.0 wt%. In some embodiments, the amount of disintegrant is selected from 1.0 wt%, 1.2 wt%, 1.4 wt%, 1.6 wt%, 1.8 wt%, 2.0 wt%, 2.2 wt%, 2.4 wt%, 2.6 wt%, 2.8 wt%, 3.0 wt%, 3.2 wt%, 3.4 wt%, 3.6 wt%, 3.8 wt%, 4.0 wt%, 4.2 wt%, 4.4 wt%, 4.6 wt%, 4.8 wt%, 5.0 wt%, 5.2 wt%, 5.4 wt%, 5.6 wt%, 5.8 wt%, 6.0 wt%, 6.2 wt%, 6.4 wt%, 6.6 wt%, 6.8 wt%, or 7.0 wt%, or any range having an endpoint of said value. In some embodiments, the amount of the disintegrant is selected from 1.2-6.8 wt%, 1.4-6.6 wt%, 1.6-6.4 wt%, 1.8-6.2 wt%, 2.0-6.0 wt%, 2.2-5.8 wt%, 2.4-5.6 wt%, 2.6-5.4 wt%, 2.8-5.2 wt%, 3.0-5.0 wt%, 3.2-4.8 wt%, 3.4-4.6 wt%, 3.6-4.4 wt%, or 3.8-4.2 wt%. In some embodiments, the amount of the disintegrant is 3.8-4.2 wt%.

[0046] In some embodiments, the binder is selected from hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), gelatin, polyvinylpyrrolidone (PVP), partially hydrolyzed starch, pregelatinized starch, glucose, polyethylene glycol (PEG), polyvinyl alcohol, or mixtures thereof. In some embodiments, the binder is selected from hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpyrrolidone, or mixtures thereof. In some embodiments, the binder is hydroxypropyl methylcellulose.

[0047] In some embodiments, the amount of binder is selected from 0.1 to 5 wt%. In some embodiments, the amount of binder is selected from 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 ... %, 2.2wt%, 2.3wt%, 2.4wt%, 2.5wt%, 2.6wt%, 2.7wt%, 2.8wt%, 2.9wt%, 3.0wt%, 3.2wt%, 3.4wt%, 3.6wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.4wt%, 4.6wt%, 4.8wt%, or 5.0wt%, or a range extending to any of the preceding values. In some embodiments, the amount of the binder is selected from 0.1-3.0 wt%, 0.1-2.8 wt%, 0.1-2.6 wt%, 0.1-2.4 wt%, 0.1-2.2 wt%, 0.1-2.0 wt%, 0.2-3.0 wt%, 0.2-2.8 wt%, 0.2-2.6 wt%, 0.2-2.4 wt%, 0.2-2.2 wt%, 0.2-2.0 wt%, 0.2-1.9 wt%, 0.3-1.8 wt%, 0.4-1.7 wt%, 0.5-1.6 wt%, 0.6-1.5 wt%, 0.7-1.4 wt%, or 0.8-1.2 wt%. In some embodiments, the amount of the binder is 0.8-1.2 wt%.

[0048] In some embodiments, the lubricant is selected from magnesium stearate, colloidal silica, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate, sodium dodecyl sulfate, or mixtures thereof. In some embodiments, the lubricant is selected from magnesium stearate, colloidal silica, sodium dodecyl sulfate, or mixtures thereof. In some embodiments, the lubricant is selected from magnesium stearate, colloidal silica, or mixtures thereof.

[0049] In some embodiments, the amount of the lubricant is selected from 0.1 to 5 wt %. In some embodiments, the amount of lubricant is 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 ... t%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.2 wt%, 3.4 wt%, 3.6 wt%, 3.8 wt%, 4.0 wt%, 4.2 wt%, 4.4 wt%, 4.6 wt%, 4.8 wt%, or 5.0 wt%, or a range having any of the preceding endpoints. In some embodiments, the amount of the lubricant is selected from 0.1-3.0 wt%, 0.1-2.8 wt%, 0.1-2.6 wt%, 0.1-2.4 wt%, 0.1-2.2 wt%, 0.1-2.0 wt%, 0.2-3.0 wt%, 0.2-2.8 wt%, 0.2-2.6 wt%, 0.2-2.4 wt%, 0.2-2.2 wt%, 0.2-2.0 wt%, 0.2-1.9 wt%, 0.3-1.8 wt%, 0.4-1.7 wt%, 0.5-1.6 wt%, 0.6-1.5 wt%, 0.7-1.4 wt%, 0.8-1.2 wt%, or 0.9-1.1 wt%. In some embodiments, the amount of the lubricant is 0.8-1.2 wt %.

[0050] In some embodiments, the lubricant comprises colloidal silicon dioxide, and the amount of colloidal silicon dioxide is selected from 0.05 to 3.0 wt%. In some embodiments, the amount of colloidal silicon dioxide is selected from 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.10 wt%, 0.15 wt%, 0.20 wt%, 0.25 wt%, 0.30 wt%, 0.35 wt%, 0.40 wt%, 0.45 wt%, 0.50 wt%, 0.55 wt%, 0.60 wt%, 0.65 wt%, 0.70 wt%, 0.75 wt%, 0.80 wt%, 0.85 wt%, 0.90 wt%, 0.95 wt%, 0.10 wt%, 0.15 wt%, 0.10 wt%, 0.15 wt%, 0.15 wt%, 0.16 wt%, 0.17 wt%, 0.18 wt%, 0.19 wt%, 0.20 wt%, 0.25 wt%, 0.30 wt%, 0.35 wt%, 0.40 wt%, 0.45 wt%, 0.50 wt%, 0.55 wt%, 0.60 wt%, 0.65 wt%, 0.70 wt%, 0.75 ... 5 wt%, 0.80 wt%, 0.85 wt%, 0.90 wt%, 0.95 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.2 wt%, 2.4 wt%, 2.6 wt%, 2.8 wt%, or 3.0 wt%, or any range having an endpoint of said value. In some embodiments, the amount of colloidal silicon dioxide is 0.05-2.6 wt%, 0.05-2.2 wt%, 0.05-1.9 wt%, 0.05-1.8 wt%, 0.06-1.7 wt%, 0.06-1.6 wt%, 0.07-1.5 wt%, 0.07-1.4 wt%, 0.08-1.3 wt%, 0.08 In some embodiments, the amount of colloidal silicon dioxide is selected from the group consisting of 0.45-0.55 wt%.

[0051] In some embodiments, the lubricant comprises magnesium stearate, and the amount of magnesium stearate is selected from 0.05 to 3.0 wt%. In some embodiments, the amount of magnesium stearate is selected from 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.10 wt%, 0.15 wt%, 0.20 wt%, 0.25 wt%, 0.30 wt%, 0.35 wt%, 0.40 wt%, 0.45 wt%, 0.50 wt%, 0.55 wt%, 0.60 wt%, 0.65 wt%, 0.70 wt%, 0.75 wt%, 0.80 wt%, 0.85 wt%, 0.90 wt%, 0.95 wt%, 0.10 wt%, 0.15 wt%, 0.16 wt%, 0.17 wt%, 0.18 wt%, 0.19 wt%, 0.20 wt%, 0.25 wt%, 0.30 wt%, 0.35 wt%, 0.40 wt%, 0.45 wt%, 0.50 wt%, 0.55 wt%, 0.60 wt%, 0.65 wt%, 0.70 wt%, 0.75 wt%, 0.80 wt%, 0.85 wt%, 0.90 wt%, 0.95 ... In some embodiments, the amount of magnesium stearate is 0.05-2.6 wt%, 0.05-2.2 wt%, 0.05-1.9 wt%, 0.05-1.8 wt%, 0.06-1.7 wt%, 0.06-2.5 wt%, 0.05-3.0 wt%, 0.05-4.0 wt%, 0.05-5.0 wt%, 0.05-6.0 wt%, 0.05-7.0 wt%, 0.05-8.0 ...9.0 wt%, 0.05-1.9 wt%, 0.05-1.8 wt%, 0.06-1.7 wt%, 0.06-2.5 wt%, 0.05-3.0 wt%, 0.05-4.0 wt%, 0.05-5.0 wt%, 0.05-6.0 wt%, 0.05-7.0 wt%, 0.05-8.0 wt%, 0.05-1.9 wt%, 0.05-1.8 wt%, 0.06-1.7 wt%, 0.06-2.5 wt%, 0.05-3.0 wt%, 0.05-4.0 wt%, 0.05-5.0 wt%, 0.05-6.0 wt%, 0.05- In some embodiments, the amount of magnesium stearate is selected from the group consisting of 0.1.6 wt%, 0.07-1.5 wt%, 0.07-1.4 wt%, 0.08-1.3 wt%, 0.08-1.2 wt%, 0.09-1.1 wt%, 0.09-1.0 wt%, 0.10-0.90 wt%, 0.15-0.85 wt%, 0.20-0.80 wt%, 0.25-0.75 wt%, 0.30-0.70 wt%, 0.35-0.65 wt%, 0.40-0.60 wt%, and 0.45-0.55 wt%. In some embodiments, the amount of magnesium stearate is 0.45-0.55 wt%.

[0052] In some embodiments, the lubricant is colloidal silicon dioxide and magnesium stearate. The total amount of the colloidal silicon dioxide and magnesium stearate is the amount of lubricant described above, e.g., 0.1-5 wt% or other range or specified value. The respective amounts of the colloidal silicon dioxide and magnesium stearate are as described above, e.g., 0.05-3.0 wt% colloidal silicon dioxide, 0.05-3.0 wt% magnesium stearate, or other range or specified value.

[0053] [Powder Technology Parameters] In some embodiments, the bulk density of the solid pharmaceutical composition of the present application is ≦0.50 g / mL, ≦0.49 g / mL, ≦0.48 g / mL, ≦0.47 g / mL, ≦0.46 g / mL, ≦0.45 g / mL, or ≦0.44 g / mL. In some specific embodiments, the bulk density of the solid pharmaceutical composition of the present application is 0.30 to 0.50 g / mL. In some embodiments, the bulk density of the solid pharmaceutical compositions herein is 0.30 g / mL, 0.31 g / mL, 0.32 g / mL, 0.33 g / mL, 0.34 g / mL, 0.35 g / mL, 0.36 g / mL, 0.37 g / mL, 0.38 g / mL, 0.39 g / mL, 0.40 g / mL, 0.41 g / mL, 0.42 g / mL, 0.43 g / mL, 0.44 g / mL, 0.45 g / mL, 0.46 g / mL, 0.47 g / mL, 0.48 g / mL, 0.49 g / mL or 0.50 g / mL, or a range incorporating any of the foregoing endpoints. In some embodiments, the bulk density of the solid pharmaceutical composition of the present application is 0.40 to 0.50 g / mL, 0.41 to 0.49 g / mL, 0.42 to 0.48 g / mL, 0.43 to 0.47 g / mL, or 0.44 to 0.46 g / mL.

[0054] In some embodiments, the tap density of the solid pharmaceutical composition of the present application is ≦0.65 g / mL, ≦0.64 g / mL, ≦0.63 g / mL, ≦0.62 g / mL, ≦0.61 g / mL, ≦0.60 g / mL, or ≦0.59 g / mL. In some embodiments, the tap density of the solid pharmaceutical composition of the present application is 0.50 to 0.65 g / mL. In some embodiments, the tap density of the solid pharmaceutical composition of the present application is 0.50 g / mL, 0.51 g / mL, 0.52 g / mL, 0.53 g / mL, 0.54 g / mL, 0.55 g / mL, 0.56 g / mL, 0.57 g / mL, 0.58 g / mL, 0.59 g / mL, 0.60 g / mL, 0.61 g / mL, 0.62 g / mL, 0.63 g / mL, 0.64 g / mL, or 0.65 g / mL, or a range including any of the preceding endpoints. In some embodiments, the tap density of the solid pharmaceutical composition of the present application is 0.52-0.64 g / mL, 0.54-0.63 g / mL, 0.56-0.62 g / mL, or 0.58-0.61 g / mL.

[0055] In some embodiments, the Hausner ratio of the solid pharmaceutical composition of the present application is 1.31 to 1.40. In some embodiments, the Hausner ratio of the solid pharmaceutical composition of the present application is 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, or 1.40, or a range having any of the preceding values ​​as endpoints. In some embodiments, the Hausner ratio of the solid pharmaceutical composition of the present application is 1.31 to 1.38, 1.32 to 1.37, 1.32 to 1.36, 1.33 to 1.36, or 1.33 to 1.35.

[0056] [Particle size distribution] The solid pharmaceutical composition of the present application has a particle size distribution characteristic. The majority of particles in the solid pharmaceutical composition of the present application are distributed in the range of <75 μm. In some embodiments, ≧50%, ≧51%, ≧52%, ≧53%, ≧55%, ≧55%, ≧56%, ≧57%, ≧58%, ≧59%, ≧60%, ≧61%, ≧62%, ≧63%, ≧66%, ≧65%, ≧66%, ≧67%, or ≧68% of the particles in the solid pharmaceutical composition of the present application are <75 μm. In some embodiments, 50-80% of the particles in the solid pharmaceutical composition of the present application are <75 μm. In some embodiments, 50%, 51%, 52%, 53%, 55%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 66%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 77%, 75%, 77%, 77%, 78%, 79%, or 80% of the particles in the solid pharmaceutical composition are <75 μm, or any of the ranges between said values. In some embodiments, 56-80%, 58-78%, 60-76%, 62-74%, 64-72%, or 66-70% of the particles in the solid pharmaceutical composition are <75 μm. The percentages are distributions based on mass (i.e., calculated by mass).

[0057] In some embodiments, 24-40% of the particles in the solid pharmaceutical composition of the present application are between 75 μm and 150 μm. In some embodiments, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% of the particles in the solid pharmaceutical composition of the present application are between 75 μm and 150 μm, or any of the ranges between 75 μm and 150 μm. In some embodiments, 24-40%, 25-38%, 26-36%, 27-34%, or 28-32% of the particles in the solid pharmaceutical composition of the present application are between 75 μm and 150 μm. The percentages are distributions based on mass (i.e., calculated by mass).

[0058] Only a minority of the particles in the pharmaceutical compositions of the present application are >150 μm in size. In some embodiments, <10%, <9%, <8%, <7%, <6%, <5%, <4%, <3%, <2%, or <1% of the particles in the solid pharmaceutical compositions of the present application are >150 μm. In some embodiments, 0.1-10% of the particles in the solid pharmaceutical compositions of the present application are >150 μm. In some embodiments, the solid pharmaceutical composition of the present application may comprise 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 5.1%, 5.2%, 5.4%, 5.5%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 5.1%, 5.2 ... %, 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%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, or 10% of the particles are >150 μm, or any of the aforementioned endpoints in the range of particles are >150 μm. In some embodiments, 0.1-5.0%, 0.1-4.8%, 0.2-4.6%, 0.2-4.4%, 0.3-4.2%, 0.3-4.0%, 0.4-3.8%, 0.4-3.6%, 0.5-3.4%, 0.5-3.2%, 0.6-3.0%, 0.7-2.8%, 0.8-2.6%, 0.9-2.4%, 1.0-2.2%, 1.2-2.0%, or 1.4-1.8% of the particles in the solid pharmaceutical composition of the present application are >150 μm, said percentages being a distribution based on mass (i.e., calculated by mass).

[0059] As will be appreciated by those skilled in the art, in addition to the above-mentioned active ingredient, the compound of formula I, diluents, binders, disintegrants, and lubricants, the pharmaceutical composition of the present application may optionally contain other pharma- ceutically acceptable excipients or additives, such as, but not limited to, antioxidants, preservatives, colorants, flavoring agents, etc., the selection and amount of which may be adjusted by those skilled in the art according to actual needs.

[0060] The pharmaceutical composition of the present application has a high purity (i.e., a low content of impurities). In one embodiment, the total content of impurities in the pharmaceutical composition of the present application is 0.5% or less, preferably 0.45% or less, more preferably 0.4% or less, and particularly preferably 0.3% or less.

[0061] The pharmaceutical composition of the present application has excellent stability. In one embodiment, under accelerated 6-month (40±2°C, RH75±5%) conditions, the total content of impurities in the pharmaceutical composition of the present application is 1.2% or less, preferably 1.1% or less, more preferably 1% or less, for example, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less.

[0062] The pharmaceutical composition of the present application has excellent dissolution properties. In one embodiment, the dissolution rate of the pharmaceutical composition of the present application after 20 minutes reaches 90% or more.

[0063] The pharmaceutical composition of the present application has excellent blend uniformity, and the uniformity meets the limit (A+2.2S≦15.0, see Examples) and is far below the upper limit specified.

[0064] [Manufacturing method] Another aspect of the present application provides a method for preparing a solid pharmaceutical composition comprising a compound of formula I of the present application, the method comprising direct compression.

[0065] In one embodiment, a method for preparing a solid pharmaceutical composition comprising a compound of formula I of the present application comprises the steps of: step 1) mixing a compound of formula I with some or all of the diluent and, optionally, at least one of a binder, a disintegrant, and a lubricant; Step 2) mixing the mixture obtained in step 1) with the remaining diluent and at least one of the remaining binder, disintegrant and lubricant; step 3) optionally blending the mixture obtained in step 2) with any remaining excipients; Step 4) compressing the mixture obtained in step 2) or step 3) into tablets.

[0066] The selection and amounts of Formula I compounds and excipients, such as diluents, binders, disintegrants, lubricants, etc. used in the method are as described above.

[0067] However, as one skilled in the art will appreciate, if all of the diluent is used in step 1), the remaining diluent may not be used in step 2).

[0068] In one embodiment, the diluent, binder, disintegrant and lubricant are each added independently in several batches or at once and mixed.When adding excipients such as diluent, binder, disintegrant and lubricant in several batches, those skilled in the art can determine the ratio of each addition according to needs.

[0069] The manufacturing method of the present application may be carried out by direct compression without (dry) granulation.

[0070] The solid pharmaceutical composition obtained by the manufacturing method of the present application has excellent uniformity, stability and dissolution properties.

[0071] In an exemplary embodiment, the manufacturing method of the present application or the direct compression method may include the steps of: 1) preparing a mixture with the compound of formula I, a diluent, a disintegrant, a binder, and a lubricant; 2) tableting. In some embodiments, the direct compression method includes the steps of: 1) preparing a mixture with the compound of formula I, a diluent, a disintegrant, and a binder; 2) preparing a mixture with the mixture obtained in step 1 and a lubricant; 3) tableting. In another embodiment, the direct compression method includes the steps of: 1) preparing a mixture with the compound of formula I and a portion of the diluent; 2) preparing a mixture with the mixture obtained in step 1, the remaining diluent, a disintegrant, and a binder; 3) mixing the mixture obtained in step 2 with a lubricant. 4) Tableting. In an optional embodiment, the direct compression method includes the steps of: 1) preparing a mixture with the compound of formula I and a part of a diluent; 2) preparing a mixture with the mixture obtained in step 1, the remaining diluent, a disintegrant, and a binder; 3) preparing a mixture with the mixture obtained in step 2 and a part of a lubricant; 4) preparing a mixture with the mixture obtained in step 3 and the remaining lubricant; 5) Tableting. In some other embodiments, the direct compression method includes the steps of: 1) preparing a mixture with the compound of formula I and a diluent; 2) preparing a mixture with the mixture obtained in step 1, a disintegrant, and a binder; 3) preparing a mixture with the mixture obtained in step 2 and a lubricant; 4) Tableting. In some embodiments, the direct compression method includes the steps of: 1) preparing a mixture with the compound of formula I and a diluent; 2) preparing a mixture with the mixture obtained in step 1, a disintegrant, and a binder; 3) preparing a mixture with the mixture obtained in step 2 and a lubricant. 4) The mixture obtained in step 3 and the remaining lubricant are mixed to prepare a mixture. 5) Tableting. The active ingredient and excipients are added in the ratio required for the pharmaceutical composition. When the excipients are added in several portions, those skilled in the art can determine the ratio to be added each time according to their needs.

[0072] In some embodiments, the process for preparing a solid pharmaceutical composition comprising a compound of formula I does not involve a polishing operation on the mixture comprising the compound of formula I and a diluent. In some embodiments, the process for preparing a solid pharmaceutical composition comprising a compound of formula I does not involve a polishing operation on the mixture comprising the compound of formula I and a diluent such as microcrystalline cellulose or pregelatinized starch. In some embodiments, the process for preparing a solid pharmaceutical composition comprising a compound of formula I does not involve a polishing operation on the mixture comprising the compound of formula I and a diluent such as pregelatinized starch. By carrying out a polishing operation in this manner, the solid pharmaceutical composition of the present application has excellent uniformity, stability and dissolution properties.

[0073] The parameters for tableting may be selected by those skilled in the art according to practical needs. In an exemplary embodiment, the parameters include using a shallow concave 6mm circular press and a hardness of 6-9Kp.

[0074] [Embodiments of the present application] In some embodiments of the present application, the solid pharmaceutical composition is as follows: A) In some embodiments, the solid pharmaceutical composition comprises: 0.02 to 8.0 wt % of a compound of formula I; 50 wt% or more of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 1.0 to 7.0 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.1 to 5 wt % of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or a mixture thereof; and 0.1 to 5 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0075] B) In some embodiments, the solid pharmaceutical composition comprises: 0.03 to 7.0 wt % of a compound of formula I; 50 wt. % or more of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 1.0 to 7.0 wt % sodium carboxymethyl starch; 0.1 to 5 wt % of hydroxypropyl methylcellulose; and 0.1 to 5 wt % of magnesium stearate, colloidal silica, or a mixture thereof.

[0076] C) In some embodiments, the solid pharmaceutical composition comprises: 0.03 to 6.0 wt % of a compound of formula I; 60 wt% or more of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 1.6 to 6.4 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.1 to 2.2 wt % of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or a mixture thereof; and 0.1 to 2.2 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0077] D) In ​​some embodiments, the solid pharmaceutical composition comprises: 0.04 to 5.0 wt % of a compound of formula I; 60 wt. % or more of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 1.6 to 6.4 wt. % sodium carboxymethyl starch; 0.1 to 2.2 wt% hydroxypropyl methylcellulose; and 0.1 to 2.2 wt % of magnesium stearate, colloidal silica, or a mixture thereof.

[0078] E) In some embodiments, the solid pharmaceutical composition comprises: 0.05 to 3.5 wt % of a compound of formula I; 70 wt% or more of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 2.4 to 5.6 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.2 to 2.4 wt % of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or a mixture thereof; and 0.2 to 2.4 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0079] F) In some embodiments, the solid pharmaceutical composition comprises: 0.05 to 3.5 wt % of a compound of formula I; 70 wt. % or more of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 2.4 to 5.6 wt. % sodium carboxymethyl starch; 0.2 to 2.4 wt % hydroxypropyl methylcellulose; and 0.2 to 2.4 wt % of magnesium stearate, colloidal silica, or a mixture thereof.

[0080] G) In some embodiments, the solid pharmaceutical composition comprises: 0.05 to 2.8 wt % of a compound of formula I; 80 wt% or more of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 3.0 to 5.0 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.2-1.9wt% of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose , hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, or a mixture thereof; and 0.2 to 1.9 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0081] H) In some embodiments, the solid pharmaceutical composition comprises: 0.05 to 2.8 wt % of a compound of formula I; 80 wt% or more of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 3.0 to 5.0 wt % sodium carboxymethyl starch; 0.2 to 1.9 wt% hydroxypropyl methylcellulose; and 0.2 to 1.9 wt % of magnesium stearate, colloidal silica, or a mixture thereof.

[0082] I) In some embodiments, the solid pharmaceutical composition comprises: 0.05 to 2.6 wt % of a compound of formula I; 82 to 98 wt % of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 3.4 to 4.6 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.5 to 1.6 wt % of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or a mixture thereof; and 0.5 to 1.6 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0083] J) In some embodiments, the solid pharmaceutical composition comprises: 0.05 to 2.6 wt % of a compound of formula I; 82 to 98 wt % of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 3.4 to 4.6 wt. % sodium carboxymethyl starch; 0.5 to 1.6 wt% hydroxypropyl methylcellulose; and 0.5 to 1.6 wt % of magnesium stearate, colloidal silica, or a mixture thereof.

[0084] K) In some embodiments, the solid pharmaceutical composition comprises: 0.05 to 2.6 wt % of a compound of formula I; 82-98 wt% microcrystalline cellulose and pregelatinized starch, with 56-85 wt% microcrystalline cellulose and 12-28 wt% pregelatinized starch; 3.4 to 4.6 wt. % sodium carboxymethyl starch; 0.5 to 1.6 wt% hydroxypropyl methylcellulose; 0.5-1.6 wt% magnesium stearate and colloidal silica, including 0.09-1.0 wt% magnesium stearate and 0.09-1.0 wt% colloidal silicon dioxide.

[0085] L) In some embodiments, the solid pharmaceutical composition comprises: 0.06 to 2.6 wt % of a compound of formula I; 85 to 97 wt % of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 3.6 to 4.4 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.7 to 1.4 wt % of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or a mixture thereof; and 0.7 to 1.4 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0086] M) In some embodiments, the solid pharmaceutical composition comprises: 0.06 to 2.6 wt % of a compound of formula I; 85 to 97 wt % of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 3.6 to 4.4 wt. % sodium carboxymethyl starch; 0.7 to 1.4 wt% hydroxypropyl methylcellulose; and 0.7 to 1.4 wt % of magnesium stearate, colloidal silica, or a mixture thereof.

[0087] N) In some embodiments, the solid pharmaceutical composition comprises: 0.06 to 2.6 wt % of a compound of formula I; 85-97 wt% microcrystalline cellulose and pregelatinized starch, with 62-78 wt% microcrystalline cellulose or 15-25 wt% pregelatinized starch; 3.6 to 4.4 wt. % sodium carboxymethyl starch; 0.7 to 1.4 wt% hydroxypropyl methylcellulose; 0.7-1.4 wt% magnesium stearate and colloidal silica, including 0.20-0.80 wt% magnesium stearate and 0.20-0.80 wt% colloidal silicon dioxide.

[0088] O) In some embodiments, the solid pharmaceutical composition comprises: 0.06 to 2.4 wt % of a compound of formula I; 88 to 96 wt % of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 3.8 to 4.2 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.8 to 1.2 wt % of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or a mixture thereof; and 0.8 to 1.2 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0089] P) In some embodiments, the solid pharmaceutical composition comprises: 0.06 to 2.4 wt % of a compound of formula I; 88 to 96 wt % of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 3.8 to 4.2 wt. % sodium carboxymethyl starch; 0.8 to 1.2 wt% hydroxypropyl methylcellulose; and 0.8 to 1.2 wt % of magnesium stearate, colloidal silica, or a mixture thereof.

[0090] Q) In some embodiments, the solid pharmaceutical composition comprises: 0.06 to 2.4 wt % of a compound of formula I; 88-96 wt% microcrystalline cellulose and pregelatinized starch, with 66-74 wt% microcrystalline cellulose or 18-23 wt% pregelatinized starch; 3.8 to 4.2 wt. % sodium carboxymethyl starch; 0.8 to 1.2 wt% hydroxypropyl methylcellulose; 0.8-1.2 wt% magnesium stearate and colloidal silica, including 0.35-0.65 wt% magnesium stearate and 0.35-0.65 wt% colloidal silicon dioxide.

[0091] In some embodiments, the solid pharmaceutical composition further comprises a coating agent. In some embodiments, the coating agent is formed from an aqueous film coating composition, which comprises a film-forming polymer, water and / or alcohol as a carrier, and optionally one or more additives, such as additives well known in the film coating art. In some embodiments, the coating agent is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, sodium ethylcellulose sulfate, carboxymethylcellulose, polyvinylpyrrolidone, zein-acrylic acid polymers (e.g., methacrylic acid / methacrylate copolymers, such as methacrylic acid / methyl methacrylate copolymers), and polyvinyl alcohol.

[0092] The present application further includes the following embodiments. 1. [ka] A solid pharmaceutical composition comprising a compound of formula I, a diluent, a binder, a disintegrant and a lubricant.

[0093] 2. The solid pharmaceutical composition according to 1, which is a unit-dose pharmaceutical composition, and the mass of the compound of formula I per unit-dose composition is 0.01 mg to 10 mg.

[0094] 3. The solid pharmaceutical composition according to 1, wherein the amount of the compound of formula I is selected from the range of 0.01 to 10 wt %.

[0095] 4. The solid pharmaceutical composition according to 1, characterized in that the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or a mixture thereof, preferably microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof, more preferably microcrystalline cellulose, pregelatinized starch, or a mixture thereof.

[0096] 5. The solid pharmaceutical composition according to 1, characterized in that the amount of the diluent is selected from 50 wt% or more.

[0097] 6. The solid pharmaceutical composition according to 4, characterized in that the diluent contains microcrystalline cellulose and the amount of the microcrystalline cellulose is selected from the range of 30 to 90 wt %.

[0098] 7. The diluent contains pregelatinized starch, and the amount of pregelatinized starch is 5 to 35%. 5. The solid pharmaceutical composition according to claim 4, wherein the wt% is selected from the group consisting of:

[0099] 8. The solid pharmaceutical composition according to claim 4, characterized in that the diluent is microcrystalline cellulose and pregelatinized starch, preferably 30-90 wt% microcrystalline cellulose and 5-35 wt% pregelatinized starch, and the amount of the diluent is 50 wt% or more.

[0100] 9. The solid pharmaceutical composition according to 1, characterized in that the disintegrant is selected from sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose or crospovidone, sodium dodecyl sulfate or magnesium dodecyl sulfate or a mixture thereof, preferably sodium carboxymethyl starch, croscarmellose sodium or a mixture thereof, more preferably sodium carboxymethyl starch.

[0101] 10. The solid pharmaceutical composition according to 9, wherein the amount of the disintegrant is selected from the range of 1.0 to 7.0 wt %.

[0102] 11. The solid pharmaceutical composition according to claim 9, wherein the disintegrant is selected from sodium carboxymethyl starch and the amount of the sodium carboxymethyl starch is selected from 1.0 to 7.0 wt%.

[0103] 12. The solid pharmaceutical composition according to claim 1, characterized in that the binder is selected from hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, partially hydrolyzed starch, pregelatinized starch, glucose, polyethylene glycol, polyvinyl alcohol or a mixture thereof, preferably hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpyrrolidone or a mixture thereof, more preferably hydroxypropyl methylcellulose.

[0104] 13. The solid pharmaceutical composition according to claim 12, characterized in that the amount of the binder is selected from the range of 0.1 to 5 wt %.

[0105] 14. The solid pharmaceutical composition according to claim 12, characterized in that the binder is selected from hydroxypropyl methylcellulose and the amount of the hydroxypropyl methylcellulose is selected from 0.1 to 5 wt%.

[0106] 15. The solid pharmaceutical composition according to 1, characterized in that the lubricant is selected from magnesium stearate, colloidal silica, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate, sodium dodecyl sulfate, or a mixture thereof, preferably magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof, more preferably magnesium stearate, colloidal silica, or a mixture thereof.

[0107] 16. A solid pharmaceutical composition according to claim 15, characterized in that the amount of the lubricant is selected from the range of 0.1 to 5 wt %.

[0108] 17. The solid pharmaceutical composition according to claim 15, characterized in that the lubricant contains colloidal silicon dioxide, and the amount of the colloidal silicon dioxide is selected from the range of 0.05 to 3.0 wt%.

[0109] 18. The solid pharmaceutical composition according to claim 15, characterized in that the lubricant comprises magnesium stearate, and the amount of the magnesium stearate is selected from the range of 0.05 to 3.0 wt%.

[0110] 19. The solid pharmaceutical composition according to claim 15, characterized in that the lubricant is selected from colloidal silicon dioxide and magnesium stearate, preferably 0.05-3.0 wt% colloidal silicon dioxide and 0.05-3.0 wt% magnesium stearate, and the amount of the lubricant is selected from 0.1-5 wt%.

[0111] 20. 0.02 to 8.0 wt % of a compound of formula I; 50 wt% or more of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; 1.0 to 7.0 wt % of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof; 0.1 to 5 wt % of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or a mixture thereof; 20. The solid pharmaceutical composition according to any one of 1 to 19, comprising 0.1 to 5 wt % of magnesium stearate, colloidal silica, sodium dodecyl sulfate, or a mixture thereof.

[0112] 21. A solid pharmaceutical composition according to any one of claims 1 to 20, further comprising a coating agent.

[0113] 22. A solid pharmaceutical composition according to any one of claims 1 to 20, characterized in that the dosage form is selected from powders, granules, tablets, capsules, pills, pellets, dispersions or inhalable powders, preferably tablets.

[0114] 23. A solid pharmaceutical composition according to any one of 1 to 22, which is produced by direct compression.

[0115] 24. The solid pharmaceutical composition according to claim 23, characterized in that the direct compression method comprises step 1) of preparing a mixture of a compound of formula I, a diluent, a disintegrant, a binder and a lubricant, and step 2) of compressing the mixture into tablets.

[0116] 25. A process for preparing a solid pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 22, said process being selected from direct compression processes.

[0117] 26. The method according to claim 25, characterized in that the direct compression method comprises step 1) of preparing a mixture of a compound of formula I, a diluent, a disintegrant, a binder, and a lubricant, and step 2) of compressing the mixture into tablets.

[0118] 27. Use of a solid pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 22 for the manufacture of a medicament for treating a disease associated with TLR7.

[0119] 28. The use according to 27, wherein the TLR7-related disease is selected from viral infections, and the viral infection is preferably selected from hepatitis B or hepatitis C. .

[0120] [Methods and uses for treatment or prevention] In yet another embodiment of the present application, there is provided a use of a solid pharmaceutical composition comprising the compound of formula I for the manufacture of a medicament for treating or preventing a disease associated with TLR7. In yet another embodiment of the present application, there is provided a solid pharmaceutical composition comprising the compound of formula I for treating or preventing a disease associated with TLR7. In a further embodiment of the present application, there is provided a method for treating or preventing a disease associated with TLR7, comprising administering to an individual in need thereof a solid pharmaceutical composition comprising the compound of formula I of the present application. The individual is, for example, a mammal, preferably a human.

[0121] In some embodiments, the TLR7-associated disease is selected from a viral infection, preferably, the viral infection is selected from hepatitis B or hepatitis C. Effect of the Invention

[0122] In the process of developing a solid pharmaceutical composition containing the compound of formula I, the adhesive force of powder particles repels each other, resulting in uneven mixing. If the mixing process continues for a long time, this phenomenon will become more obvious due to the accumulation of electric charges due to friction, and will also lead to the formation of lumps. Therefore, there will be a large difference in the content of active ingredients in the unit preparation, which will affect the efficacy of the drug. In addition, in the case of small-dose preparations, the uneven content of active ingredients will increase toxicity and side effects. Therefore, in the process of developing a solid pharmaceutical composition containing the compound of formula I, it is necessary to solve the above problems in order to obtain a pharmaceutical composition for clinical use with excellent uniformity, solubility and stability.

[0123] The inventors of the present application have found that the solid pharmaceutical composition of the present application has specific powder engineering parameters, particle size distribution characteristics, and exhibits excellent uniformity, stability and dissolution properties, and also has excellent pharmacokinetic properties, making it suitable for clinical use. The solid pharmaceutical composition of the present application prepared by direct powder compression has excellent uniformity, stability and dissolution properties, and also has excellent pharmacokinetic properties, making it suitable for clinical use. In addition, when the compound of formula I and the diluent are not ground together during the preparation process, the final solid pharmaceutical composition of the present application has excellent uniformity, stability and dissolution properties, and also has excellent pharmacokinetic properties, making it suitable for clinical use. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0124] [Example] Next, the contents of the present application are illustrated in specific examples, but these examples are not intended to limit the scope of the present application. The excipients and reagents used are all commercially available products. For example, the excipients used may be provided by Colorcon, Dow Chemical, FMC Corporation, etc. The compound of formula I may be a commercially available product, or may be synthesized with reference to the method described in WO2016 / 023511. In the examples of the present specification, unless otherwise stated, the compound of formula I used is in the form of its free base. The device or equipment used may be a typical formulation device in the field, such as a dry and wet granulator U5 or a hopper type mixer HBD-5.

[0125] Example 1: Direct Powder Compression (Powder) The pharmaceutical composition is prepared by direct compression, and the ingredients and proportions are as shown in the table below. [Table 1]

[0126] Manufacturing method: 1. Pretreatment: The compound of formula I and pregelatinized starch in a mass ratio of 20:1 with the compound of formula I (compound of formula I:pregelatinized starch, w:w=1:20) were mixed manually, passed through a 60 mesh sieve to obtain a pretreated material, and then waited.

[0127] 2. Premixing: The pretreated material was mixed with the remaining amount of pregelatinized starch, and the amounts of microcrystalline cellulose, sodium carboxymethyl starch, and hydroxypropyl methylcellulose, and then put into a wet-dry granulator to obtain a premixed material.

[0128] 3. Total mixing: Colloidal silicon dioxide was added to the premixed materials, which were then mixed in a hopper mixer, after which magnesium stearate was added and the whole was mixed.

[0129] 4. Tabletting: The intermediate after the entire mixing was tableted using a shallow concave 6 mm circular press to obtain a hardness of 6-9 Kp.

[0130] Example 2: Direct Powder Compression (Powder) The pharmaceutical composition is prepared by direct compression, and the ingredients and proportions are as shown in the table below. [Table 2]

[0131] Manufacturing method: 1. Pretreatment: The compound of formula I in the amount of formula I compound and pregelatinized starch in a mass ratio of 20:1 (compound of formula I compound: pregelatinized starch, w:w=1:20) were mixed manually, passed through a 60 mesh sieve to obtain a pretreatment material, and then waited.

[0132] 2. Premixing: The pretreated material was mixed with the remaining amount of pregelatinized starch, and the amounts of microcrystalline cellulose, sodium carboxymethyl starch, and hydroxypropyl methylcellulose, and then put into a wet-dry granulator to obtain a premixed material.

[0133] 3. Total mixing: Colloidal silicon dioxide was added to the premixed materials, which were then mixed in a hopper mixer, after which magnesium stearate was added and the whole was mixed.

[0134] 4. Tabletting: The intermediate after the entire mixing was tableted using a shallow concave 6 mm circular press to obtain a hardness of 6-9 Kp.

[0135] Example 3: Direct Powder Compression (Powder) The pharmaceutical composition is prepared by direct compression, and the ingredients and proportions are as shown in the table below. [Table 3]

[0136] Manufacturing method: 1. Pretreatment: The compound of formula I and pregelatinized starch in the prescribed amounts were manually mixed, and passed through a 60 mesh sieve to obtain a pretreatment material, which was then left to stand by.

[0137] 2. Premixing: The pretreated material was mixed with the formulation of microcrystalline cellulose, sodium carboxymethyl starch, and hydroxypropyl methylcellulose, and then put into a wet-dry granulator to obtain a premixed material.

[0138] 3. Total mixing: Colloidal silicon dioxide was added to the premixed materials, which were then mixed in a hopper mixer, after which magnesium stearate was added and the whole was mixed.

[0139] 4. Tabletting: The intermediate after the entire mixing was tableted using a shallow concave 6 mm circular press to obtain a hardness of 6-9 Kp.

[0140] Example 4: Direct Powder Compression The pharmaceutical composition was prepared by direct compression (powder) and the ingredients and ratios were as shown in the table below. Example 4 was carried out according to the method of Example 1. [Table 4]

[0141] Comparative Example 1: Dry Granulation [Table 5]

[0142] Manufacturing method: 1. Pretreatment: The compound of formula I and pregelatinized starch in a mass ratio of 20:1 (compound of formula I:pregelatinized starch, w:w=1:20) were mixed manually, passed through a 60 mesh sieve, and then jet-milled to obtain a blended powder, which was then left to stand.

[0143] 2. Premixing: The blended powder was mixed with the remaining amount of pregelatinized starch, the remaining amount of microcrystalline cellulose, sodium carboxymethyl starch (added internally), and hydroxypropyl methylcellulose, passed through a 60 mesh sieve, and mixed in a wet-dry granulator to obtain a premixed material.

[0144] 3. Dry granulation: Dry granulation was carried out on the premixed materials.

[0145] 4. Total mixing: After dry granulation, sodium carboxymethyl starch (additional addition) and colloidal silicon dioxide were added to the materials, which were then mixed in a hopper mixer. After that, magnesium stearate was added and the whole was mixed.

[0146] 5. Tableting: The intermediate after the entire mixing was pressed into tablets using a shallow concave 6 mm circular press to obtain a hardness of 6-9 Kp.

[0147] Comparative Example 2: Dry Granulation [Table 6]

[0148] Manufacturing method: 1. Premixing: The compound of formula I and pregelatinized starch in the prescribed amounts were mixed manually and passed through a 60 mesh sieve, then mixed with microcrystalline cellulose, sodium carboxymethyl starch (added internally), and hydroxypropyl methylcellulose in the prescribed amounts in a hopper-type mixer to obtain a premixed material.

[0149] 2. Dry granulation: Dry granulation was carried out on the premixed materials.

[0150] 3. Total mixing: After dry granulation, sodium carboxymethyl starch (added additionally) and colloidal silicon dioxide were added to the materials, which were then mixed in a hopper mixer. After that, magnesium stearate was added and the whole was mixed.

[0151] 4. Tabletting: The intermediate after the entire mixing was tableted using a shallow concave 6 mm circular press to obtain a hardness of 6-9 Kp.

[0152] Comparative Example 3: Dry Granulation [Table 7]

[0153] Manufacturing method: 1. Premixing: The compound of formula I and pregelatinized starch in the prescribed amounts were mixed manually and passed through a 60 mesh sieve, then mixed with microcrystalline cellulose, sodium carboxymethyl starch (added internally), and hydroxypropyl methylcellulose in the prescribed amounts in a hopper-type mixer to obtain a premixed material.

[0154] 2. Dry granulation: Dry granulation was carried out on the premixed materials.

[0155] 3. Total mixing: After dry granulation, sodium carboxymethyl starch (added additionally) and colloidal silicon dioxide were added to the materials, which were then mixed in a hopper mixer. After that, magnesium stearate was added and the whole was mixed.

[0156] 4. Tabletting: The intermediate after the entire mixing was tableted using a shallow concave 6 mm circular press to obtain a hardness of 6-9 Kp.

[0157] Test Example 1: Dissolution Rate Test The sample of Example 4 was subjected to a dissolution test using 900 mL of pH 6.8 phosphate buffer as the dissolution medium according to the method for measuring dissolution rate (Chinese Pharmacopoeia 2015, Part 4 General Rules 0931, Method 2). The test was performed using the paddle method, with the rotation speed at 50 rpm. According to the instructions of the method, samples were taken at 5, 10, 15, 20, 30, 45 and 60 minutes to measure the dissolution rate. The results are shown in the table below. [Table 8]

[0158] The above results demonstrate that the pharmaceutical composition of the present invention has excellent dissolution properties, with the dissolution rate reaching 90% or more after 20 minutes.

[0159] Test Example 2: Stability test Impurity measurements were performed on the samples of Comparative Example 1, Comparative Example 2, Comparative Example 3, Example 1, Example 2, and Example 3 on day 0 and after an accelerated test for 6 months (40±2°C, RH75±5%), and the results are as follows: [Table 9]

[0160] From the above results, it can be seen that the pharmaceutical composition of the present application has high purity and excellent stability. In particular, under the accelerated 6-month test conditions, the amount of total impurities is almost unchanged. In the example, under the accelerated 6-month test conditions, the amount of total impurities increased obviously by up to 4 times or more. From the change in impurities, the increase in impurities in the pharmaceutical composition manufactured by the powder direct compression process was obviously lower than that by the dry granulation process. The pharmaceutical composition of the present application has obvious advantages in stability.

[0161] Test example 3: Verification of blend uniformity The samples of Example 2, Example 3, and Example 4 were each subjected to verification of blend uniformity according to the content uniformity measurement method (Chinese Pharmacopoeia 2015 Edition, Four Parts General Principles 0941). 1. The diluent, mobile phase solution and control solution were prepared according to the content uniformity verification method. 2. Randomly select 10 tablets as samples, accurately weigh each one, transfer to a measuring flask, add diluent and treat with ultrasound for 10 minutes to disintegrate the tablets, then cool to room temperature, make up to volume with diluent, add a stirrer and stir for 2 hours. 3. An appropriate amount of the solution was taken into a centrifuge tube and centrifuged at 8000 rpm for 10 minutes, the supernatant was transferred to an HPLC sample vial, and the sample was injected to measure the content of the sample.

[0162] 4. Measurement method: For 10 samples, the relative content x when the indicated amount is 100 i Measure the average value X - , standard deviation S(

number

[0163] The measurement results are as follows. [Table 10]

[0164] The above results show that the pharmaceutical composition of the present application exhibits excellent blending uniformity, not only meeting the limits but also with the actual measured results being far below the prescribed upper limit.

[0165] Test Example 4: Determination of powder technological parameters and particle size distribution For the solid pharmaceutical compositions containing 0.5 mg of the compound of formula I in Comparative Example 2 and Example 2, the mixtures obtained in the overall mixing step were used as samples to detect or calculate the bulk density, tap density, Hausner ratio, and particle size distribution (distribution based on mass), respectively.

[0166] The bulk density was detected or calculated using a powder flowability tester BEP2. The tap density was detected or calculated using a tap density tester SOTAX TD1. The particle size distribution was detected or calculated by a mechanical sieving method using a sieve shaker AS200. The results are shown below. [Table 11]

[0167] From the above results, it can be seen that the pharmaceutical composition of the present application has desirable powder technologic properties and exhibits excellent flowability. [Table 12]

[0168] The above results show that the particle size of the pharmaceutical composition of the present application is mainly distributed in the range of <75 μm, the second most common particle size distribution is 75 μm-150 μm, and only a small amount of the particle size is distributed in the range of >150 μm.

[0169] Although exemplary embodiments are shown and described herein, the present invention is not limited to the details thereof. Various other modifications or substitutions are possible without departing from the spirit of the present invention, and those skilled in the art can easily make such modifications or equivalents with conventional testing equipment, and these modifications and equivalents are also included in the scope of protection defined by the claims.

Claims

[Claim 1] Formula I; 【Chemistry 1】 a diluent, a binder, a disintegrant, and a lubricant, the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or mixtures thereof; The disintegrant is selected from sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose or crospovidone, sodium dodecyl sulfate or magnesium dodecyl sulfate or mixtures thereof; the binder is selected from hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, partially hydrolyzed starch, pregelatinized starch, glucose, polyethylene glycol, polyvinyl alcohol, or mixtures thereof; The solid pharmaceutical composition, wherein the lubricant is selected from magnesium stearate, colloidal silicon dioxide, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate, sodium dodecyl sulfate, or mixtures thereof.

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