CSF-1R inhibitor pharmaceutical composition, method of preparing the same, and its pharmaceutical applications.

Abstract

CSF-1R inhibitor pharmaceutical compositions, methods for preparing the same, and their pharmaceutical uses. The CSF-1R inhibitor composition contains a free base of a compound of formula (I) having the following structure or an acid salt of a compound of formula (I) as an active ingredient. By using appropriate diluents and other pharmaceutically acceptable carriers to adjust the formulation components of the pharmaceutical product, the fluidity and color uniformity of the active pharmaceutical ingredient powder are improved, thereby obtaining formulations and pharmaceutical products. [Formula 1] TIFF2026518324000040.tif37142

Description

Detailed Description of the Invention

[0001] [Technical Field] The present invention belongs to the field of pharmaceutical development, and particularly relates to a CSF-1R inhibitor pharmaceutical composition, a preparation method thereof, and a pharmaceutical use.

[0002] [Background] The official name of CSF-1R (cFMS) is colony stimulating factor 1 receptor. CSF-1R belongs to the same family as three growth hormone receptors such as cKIT, FLT3, and PDGFR-a and b. This receptor is a membrane protein expressed on the surface of macrophages and monocytes. The extracellular region of CSF-1R can bind to macrophage colony stimulating factor, and the intracellular tyrosine kinase of CSF-1R can activate downstream signaling pathways (including MAPK, PI3K, etc.) in macrophage and monocyte cell proliferation and growth. Therefore, the CSF-1R signaling pathway has an important impact on the generation and differentiation of macrophages and monocytes, as well as the physiological functions of tumor-associated macrophages (TAM).

[0003] With the progress of tumor immunotherapy in recent years, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are considered to be directly involved in the formation of the immunosuppressive microenvironment in tumors and angiogenesis that supports tumor growth. At the same time, clinical studies have shown that the content of TAM is inversely correlated with the prognosis of cancer patients. Pharmacological experiments using mice have shown that inhibiting the CSF-1R signaling pathway can significantly reduce the number of macrophages in tumors that suppress the immune system and increase the content of CD8-positive T cells. These experimental results suggest that CSF-1R small molecule inhibitors can reverse the immunosuppressive environment in tumors, promote the activation of the immune system, and extend the lifespan of cancer patients.

[0004] Abbisko Therapeutics Co., Ltd. has been developing small molecule compounds (WO2018214867A1, international publication date: November 29, 2018) with CSF-1R inhibitory effects through a long-term research process. Representative compounds are as follows:

[0005] [ka] The Chinese name is 3,3-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazole-4-yl)pyridine-4-yl)oxy)pyridine-2-yl)-2-oxopyrrolidine-1-carboxamide (referred to as the compound of formula (I) or the free base of the compound of formula (I)). This compound can significantly enhance the inhibitory effect on the CSF-1R target and selectivity for other kinase receptors, thereby expanding the therapeutic range and reducing clinical toxic side effects. This compound can be used for targeted therapy in tumors such as lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, melanoma, pancreatic cancer, head and neck cancer, glioma, and tenosynovial giant cell tumor.

[0006] However, in the subsequent formulation research process, the free base of the compound of formula (I) is fluid. It became clear that the compound has poor composition and low bulk density, which prevents it from meeting GMP manufacturing requirements. There is a risk of significant discrepancies in the amount of filling during capsule filling, which prevents it from meeting capsule filling requirements. Therefore, it is urgent to overcome the above technical deficiencies and develop pharmaceutical compositions and formulation processes that meet the needs of clinical research and drug sales for the compound of formula (I).

[0007] [Overview of the prefecture] The object of the present invention is to solve the problem of accessibility to pharmaceuticals and to provide a CSF-1R inhibitor pharmaceutical composition that meets the needs in clinical research and pharmaceutical sales of compounds of formula (I).

[0008] To address the problems present in the prior art, the inventors improved the fluidity and color uniformity of the active pharmaceutical ingredient powder by employing appropriate diluents, optimizing the types and proportions of drug carriers such as flow promoters, lubricants, and disintegrants, and adjusting the formulation components in the drug formulation. The inventors further researched and developed a formulation with dissolution effects that meet clinical needs. All physicochemical properties meet clinical requirements. The inventors further obtained a formulation with good discharge and / or uniform capsule filling. This formulation and its manufacturing process are suitable for industrial production and can meet the needs of clinical research and pharmaceutical sales of the compound of formula (I).

[0009] A first aspect of the present invention provides a pharmaceutical composition comprising, as an active ingredient, a free base or salt of a compound of formula (I), a pharmaceutically acceptable diluent, and another pharmaceutically acceptable carrier, wherein the other pharmaceutically acceptable carrier is one or more of a flow promoter, a lubricant, and a disintegrant.

[0010] [ka] .

[0011] In preferred embodiments, the salts of the compound of formula (I) include hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, phosphate, acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, benzoate, decanoate, hexanoate, caprylate, cinnamate, citrate, cyclohexanesulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, and glucuronate. Tamate, isoascorbate, lactate, aspartate, malate, mandelate, pyroglutamate, tartrate, lauryl sulfate, dibenzoyl tartrate, formate, fumarate, galactonate, gentisinate, acetohydroxamate, malonate, succinate, glutarate, adipine, sebacinate, 2-ketoglutarate, glycolate, hippoate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, maleate, nicotinate, oleate, orotinate, oxalate, palmitate, pamoate, propionate, 4-acetamidebenzoate, 4-aminobenzoate Selected from salts, salicylates, 4-aminosalicylates, 2,5-dihydroxybenzoates, 1-hydroxy-2-naphthates, stearates, thiocyanates, undecylenates, or succinates.

[0012] In a more preferred embodiment, the salt of the compound of formula (I) is selected from hydrochloride, sulfate, phosphate, methanesulfonate, citrate, malate, fumarate, or tartrate.

[0013] In a preferred embodiment, the active ingredient is further an anhydride, hydrate, or solvate of a free base or salt of the compound of formula (I). In a more preferred embodiment, the active ingredient is a solvate of a free base or salt of the compound of formula (I), and the solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides or mixtures thereof, or aqueous solutions thereof.

[0014] In a more preferred embodiment, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or mixtures thereof, or aqueous solutions thereof.

[0015] In a more preferred embodiment, the active ingredient is a hydrate of the free base or salt of the active ingredient, where each molecule of the hydrate contains one to three water molecules. In a more preferred embodiment, the active ingredient is the anhydride or hydrate of the free base or salt of the active ingredient.

[0016] In a more preferred embodiment, the active ingredient is a hydrate of the free base or salt of the active ingredient. In a more preferred embodiment, the active ingredient is a hydrate of the free base or salt of the active ingredient, where each molecule in the hydrate contains one water molecule.

[0017] In a preferred embodiment, the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the pharmaceutical composition contains 0.1% to 60.0% w / w of the active ingredient relative to the total weight of the composition.

[0018] In a more preferred embodiment, the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the pharmaceutical composition contains 1.0% to 40.0% w / w of the active ingredient based on the total weight of the composition.

[0019] As a more preferred embodiment, the content of the active ingredient is calculated as the hydrochloride monohydrate of the compound of formula (I), and the pharmaceutical composition contains 3.0% to 32.0% w / w of the active ingredient based on the total weight of the composition.

[0020] As a preferred embodiment, the diluent is one or more of lactose, lactose hydrate, and microcrystalline cellulose. As a more preferred embodiment, the pharmaceutical composition contains 40.0% to 99.9% w / w of the diluent based on the total weight of the composition.

[0021] As a more preferred embodiment, the pharmaceutical composition contains 50.0% to 94.0% w / w of the diluent based on the total weight of the composition. As a more preferred embodiment, the pharmaceutical composition contains 60.0% to 9^2.0% w / w of the diluent based on the total weight of the composition.

[0022] As a more preferred embodiment, the diluent is a mixture of lactose monohydrate and microcrystalline cellulose, and the mass ratio w / w of lactose monohydrate to microcrystalline cellulose is from 1:5 to 5:1.

[0023] As a more preferred embodiment, the mass ratio w / w of lactose monohydrate to microcrystalline cellulose is from 1:3 to 3:1. As a more preferred embodiment, the mass ratio w / w of lactose monohydrate to microcrystalline cellulose is from 1:1 to 3:1.

[0024] As a more preferred embodiment, the lactose monohydrate is lactose monohydrate T^80 or lactose monohydrate 316, and the microcrystalline cellulose is microcrystalline cellulose PH102 or microcrystalline cellulose PH101.

[0025] As a more preferred embodiment, the diluent is a mixture of lactose monohydrate T80 and microcrystalline cellulose PH102, and the mass ratio w / w of lactose monohydrate T80 to microcrystalline cellulose PH102 is from 1:5 to 5:1.

[0026] In a more preferred embodiment, the mass ratio w / w of lactose monohydrate T80 to microcrystalline cellulose PH102 is 1:3 to 3:1. In a more preferred embodiment, the mass ratio w / w of lactose monohydrate T80 to microcrystalline cellulose PH102 is 1:1 to 3:1, and more preferably 2:1 or 3:1.

[0027] In a more preferred embodiment, the diluent is a mixture of lactose monohydrate T80 and microcrystalline cellulose PH101, where the mass ratio w / w of lactose monohydrate T80 to microcrystalline cellulose PH101 is 1:5 to 5:1.

[0028] In a more preferred embodiment, the mass ratio w / w of lactose monohydrate T80 to microcrystalline cellulose PH101 is 1:3 to 3:1. In a more preferred embodiment, the mass ratio w / w of lactose monohydrate T80 to microcrystalline cellulose PH101 is 1:3 to 3:1, and more preferably 2:1 or 3:1.

[0029] In a more preferred embodiment, the diluent is a mixture of lactose monohydrate 316 and microcrystalline cellulose PH102, where the mass ratio w / w of lactose monohydrate 316 to microcrystalline cellulose PH102 is 1:5 to 5:1.

[0030] In a more preferred embodiment, the mass ratio w / w of lactose monohydrate 316 to microcrystalline cellulose PH102 is 1:3 to 3:1. In a more preferred embodiment, the mass ratio w / w of lactose monohydrate 316 to microcrystalline cellulose PH102 is 1:1 to 3:1, and more preferably 2:1 or 3:1.

[0031] In a more preferred embodiment, the diluent is a mixture of lactose monohydrate 316 and microcrystalline cellulose PH101, where the mass ratio w / w of lactose monohydrate 316 to microcrystalline cellulose PH101 is 1:5 to 5:1.

[0032] In a more preferred embodiment, the mass ratio w / w of lactose monohydrate 316 to microcrystalline cellulose PH101 is 1:3 to 3:1. In a more preferred embodiment, the mass ratio w / w of lactose monohydrate 316 to microcrystalline cellulose PH101 is 1:1 to 3:1, and more preferably 2:1 or 3:1.

[0033] In a preferred embodiment, the flow promoter is one or more of colloidal silicon dioxide, precipitated silicon dioxide, and talc. In a more preferred embodiment, the flow promoter is colloidal silicon dioxide.

[0034] In a more preferred embodiment, the flow promoter is colloidal silicon dioxide 200. In a preferred embodiment, the flow promoter is one or more of colloidal silicon dioxide, precipitated silicon dioxide, and talc, and the pharmaceutical composition contains 0.1% to 10.0% w / w of the flow promoter based on the total weight of the composition.

[0035] In a more preferred embodiment, the flow promoter is colloidal silicon dioxide, and the pharmaceutical composition contains 0.5% to 5.0% w / w of the flow promoter based on the total weight of the composition.

[0036] In a more preferred embodiment, the flow promoter is colloidal silicon dioxide, and the pharmaceutical composition contains 1.0% to 3.0% w / w of the flow promoter based on the total weight of the composition.

[0037] In a more preferred embodiment, the flow promoter is colloidal silicon dioxide, and the pharmaceutical composition contains 1.0% to 2.0% w / w of the flow promoter based on the total weight of the composition.

[0038] In a preferred embodiment, the flow promoter is colloidal silicon dioxide 200, and the pharmaceutical composition contains 0.1% to 10.0% w / w of the flow promoter based on the total weight of the composition.

[0039] In a more preferred embodiment, the flow promoter is colloidal silicon dioxide 200, and the pharmaceutical composition contains 0.5% to 5.0% w / w of the flow promoter based on the total weight of the composition.

[0040] In a more preferred embodiment, the flow promoter is colloidal silicon dioxide 200, and the pharmaceutical composition contains 1.0% to 3.0% w / w of the flow promoter based on the total weight of the composition.

[0041] In a more preferred embodiment, the flow promoter is colloidal silicon dioxide 200, and the pharmaceutical composition contains 1.0% to 2.0% w / w of the flow promoter based on the total weight of the composition.

[0042] In a preferred embodiment, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, colloidal silicon dioxide, talc, other hydrogenated vegetable oils, and triglycerides, and the pharmaceutical composition contains 0.1% to 5.0% w / w of the lubricant based on the total weight of the composition.

[0043] In a more preferred embodiment, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, and glyceryl dibehenate, and the lubricant is included in an amount of 0.5% to 2.0% w / w of the total weight of the composition.

[0044] In a preferred embodiment, the lubricant is magnesium stearate or sodium stearyl fumarate, and the pharmaceutical composition is present in an amount of 0.1% to 5.0% of the total weight of the composition. Contains w / w lubricant.

[0045] In a more preferred embodiment, the lubricant is magnesium stearate or sodium stearyl fumarate, and the lubricant is included in an amount of 0.5% to 2.0% w / w of the total weight of the composition.

[0046] In a more preferred embodiment, the lubricant is magnesium stearate or sodium stearyl fumarate, and the lubricant is included in an amount of 0.5% to 1.5% w / w of the total weight of the composition.

[0047] In a preferred embodiment, the disintegrant is one or more of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium glycolate starch, and their analogues.

[0048] In a more preferred embodiment, the disintegrant is croscarmellose sodium. In a preferred embodiment, the disintegrant is one or more of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium glycolate starch, and analogs thereof, and the pharmaceutical composition contains 0.1% to 10.0% w / w of the disintegrant based on the total weight of the composition.

[0049] In a preferred embodiment, the disintegrant is croscarmellose sodium, and the pharmaceutical composition contains 0.1% to 10.0% w / w of the disintegrant based on the total weight of the composition.

[0050] In a more preferred embodiment, the disintegrant is croscarmellose sodium, and the pharmaceutical composition contains 0.5% to 5.0% w / w of the disintegrant based on the total weight of the composition.

[0051] In a more preferred embodiment, the disintegrant is croscarmellose sodium, and the pharmaceutical composition contains 1.0% to 5.0% w / w of the disintegrant based on the total weight of the composition.

[0052] In a preferred embodiment, the pharmaceutical composition comprises an active ingredient and a diluent, with a mass ratio w / w of (1.0 to 50.0):(50.0 to 94.0), the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the diluent is lactose monohydrate and microcrystalline cellulose, with a mass ratio w / w of 1:1 to 3:1.

[0053] In a preferred embodiment, the pharmaceutical composition comprises an active ingredient and a diluent, with a mass ratio w / w of (1.0-50.0):(60.0-92.0), the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the diluent is lactose monohydrate T80 and microcrystalline cellulose PH102, with a mass ratio w / w of 1:1-3:1.

[0054] In a preferred embodiment, the pharmaceutical composition comprises an active ingredient and a diluent, with a mass ratio w / w of (1.0-50.0):(60.0-92.0), the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the diluent is lactose monohydrate T80 and microcrystalline cellulose PH101, with a mass ratio w / w of 1:1-3:1.

[0055] In a preferred embodiment, the pharmaceutical composition comprises an active ingredient and a diluent, with a mass ratio w / w of (1.0~50.0):(60.0~92.0), the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the diluent is lactose monohydrate 316 and microcrystalline cellulose PH102, with a mass ratio w / w of 1:1~3:1.

[0056] In a preferred embodiment, the pharmaceutical composition comprises an active ingredient and a diluent, in a mass ratio w / w The ratio is (1.0~50.0):(60.0~92.0), the active ingredient content is calculated as the hydrochloride monohydrate of the compound of formula (I), the diluents are lactose monohydrate 316 and microcrystalline cellulose PH101, and the mass ratio w / w is 1:1 to 3:1.

[0057] In a more preferred embodiment, the pharmaceutical composition further contains colloidal silicon dioxide as a flow enhancer, wherein the content of colloidal silicon dioxide is 0.5% to 5.0% w / w of the total weight of the composition.

[0058] In a more preferred embodiment, the content of the flow promoter is 1.0% to 3.0% w / w of the total weight of the composition. In a more preferred embodiment, the content of the flow promoter is 1.0% to 2.0% w / w of the total weight of the composition.

[0059] In a more preferred embodiment, the pharmaceutical composition further comprises magnesium stearate or sodium stearyl fumarate as a lubricant, wherein the lubricant content is 0.5% to 2.0% w / w of the total weight of the composition.

[0060] In a more preferred embodiment, the lubricant content is 0.5% to 1.5% w / w of the total weight of the composition. In a more preferred embodiment, the pharmaceutical composition further comprises croscarmellose sodium as a disintegrant, wherein the content of the disintegrant is 0.5% to 5.0% w / w of the total weight of the composition.

[0061] In a more preferred embodiment, the lubricant content is 1.0% to 5.0% w / w relative to the total weight of the composition. In a preferred embodiment, the total content of each component in the pharmaceutical composition is 100 wt%. In a more preferred embodiment, the total content of the active ingredient, diluent, flow promoter, lubricant, and disintegrant is 100 wt%.

[0062] In a more preferred embodiment, the active ingredient, diluent, flow promoter, lubricant, and disintegrant are as described above. In a more preferred embodiment, the pharmaceutical composition contains an active ingredient which is a hydrochloride monohydrate of the compound of formula (I), a diluent which is microcrystalline cellulose PH102 and lactose monohydrate T80, a flow promoter which is colloidal silicon dioxide 200, a lubricant which is magnesium stearate, and a disintegrant which is croscarmellose sodium.

[0063] In a more preferred embodiment, the pharmaceutical composition contains an active ingredient which is a hydrochloride monohydrate of the compound of formula (I), a diluent which is microcrystalline cellulose PH101 and lactose monohydrate 316, a flow enhancer which is colloidal silicon dioxide 200, a lubricant which is magnesium stearate, and a disintegrant which is croscarmellose sodium.

[0064] In a preferred embodiment, the pharmaceutical composition is in the form of a capsule. In a more preferred embodiment, the content of the active ingredient in the unit dosage form of the capsule is from 1 mg to 500 mg, and the content of the active ingredient is calculated as the free base of the compound of formula (I).

[0065] In a more preferred embodiment, the content of the active ingredient in the unit dosage form of the capsule is from 1 mg to 200 mg, and the content of the active ingredient is calculated as the free base of the compound of formula (I).

[0066] In a more preferred embodiment, the content of the active ingredient in the unit dosage form of the capsule is 1 mg, 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg, and the content of the active ingredient is calculated as the free base of the compound of formula (I).

[0067] A second aspect of the present invention provides a method for preparing a pharmaceutical composition, comprising the following steps: Step A: Pre-treat the free base or salt of the compound of formula (I) and the flow enhancer separately or together by sieving;

[0068] [ka]

[0069] Pre-treating the diluent, disintegrant, and lubricant separately or together by sieving; Step B: Place the mixture of the free base or salt of the compound of formula (I) prepared in Step A and the flow enhancer into a hopper mixer with the pre-treated diluent and disintegrant, and mix uniformly; Step C: Place the mixed material prepared in Step B and the pre-treated lubricant into a mixing barrel and mix them uniformly.

[0070] In a preferred embodiment, the preparation method further includes step D: filling capsules with the entire mixed powder prepared in step C. In a preferred embodiment, the preparation method includes: mixing the free base or salt of the compound of formula (I) with a flow promoter, then pre-treating the mixture by passing it through a 50-80 mesh sieve and / or pre-treating the diluent separately by passing it through a 30-80 mesh sieve and / or pre-treating the disintegrant separately by passing it through a 30-50 mesh sieve and / or pre-treating the lubricant separately by passing it through a 20-40 mesh sieve.

[0071] In a preferred embodiment, in step A of the preparation method, the free base or salt of the compound of formula (I) is pulverized. A third aspect of the present invention relates to the use of the above-described pharmaceutical composition in the manufacture of a CSF-1R inhibitor.

[0072] A fourth aspect of the present invention relates to the use of the above-described pharmaceutical composition in the manufacture of a pharmaceutical for treating tumors, autoimmune diseases, metabolic diseases, or metastatic diseases associated with CSF1-R.

[0073] In a preferred embodiment, the tumor is cancerous. In preferred embodiments, tumors, autoimmune diseases, metabolic diseases or metastatic diseases associated with CSF1-R include ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastases, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumors, solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative disorders, metabolic diseases, neurodegenerative diseases, metastases of primary tumor sites, myeloproliferative disorders, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, auto It is a drug for immune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, eosinophilia syndrome, mastocytosis, or mast cell leukemia.

[0074] A fifth aspect of the present invention relates to the above-mentioned pharmaceutical composition for use as an agent for treating tumors, autoimmune diseases, metabolic diseases, or metastatic diseases associated with CSF1-R.

[0075] The present invention further provides a method for inhibiting CSF-1R activity, comprising administering an effective therapeutic dose of the above-described pharmaceutical composition to a patient in need of treatment. The present invention further provides a method for treating ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastasis cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumors, solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative disorders, metabolic disorders, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative disorders, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, eosinophilia, mastocytosis, or mast cell leukemia, comprising administering an effective therapeutic dose of the above-described pharmaceutical composition to a patient in need of treatment. [Modes for carrying out the invention]

[0076] [Detailed description of the invention] 1. Specific Definition Detailed explanation: Unless otherwise specified or designated, the following terms used in this specification and in the claims have the following meanings:

[0077] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds described herein, or their physiologically / pharmaceutically acceptable crystalline form, salt form, or prodrug, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, promote the absorption of the active ingredient, and consequently exert biological activity.

[0078] The term "free base of compound (I)" refers to the compound of formula (I).

[0079] [ka] .

[0080] The term "active ingredient" refers to the free base or salt of the compound of formula (I), and the active ingredient is preferably the anhydride, hydrate, or solvate of the free base or salt of the compound of formula (I). The solvent refers to an organic solvent selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides, or mixtures thereof, or aqueous solutions thereof. Preferably, the solvent is methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether Selected from 2-methoxyethyl ether, a mixture thereof, or an aqueous solution thereof.

[0081] The pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable carriers, including, but are not limited to, diluents, flow enhancers, lubricants, disintegrants, binders, stabilizers, buffers, auxiliary agents, carriers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavoring agents, or colorants. Medically acceptable excipients can be illustrated in the examples provided in R.C. Rowe, Paul J. Sheskey, "The Handbook of Pharmaceutical Excipients."

[0082] As used herein, the term “diluent” refers to any pharmaceutically acceptable substance or composition added to a composition to increase its volume. Suitable diluents include, but are not limited to, lactose (e.g., lactose monohydrate, anhydrous lactose, or amorphous lactose), microcrystalline cellulose (e.g., PH101, PH102, PH301, PH302, PH200, Ceolus KG-802, Ceolus KG-1000, Ceolus UF-711, Ceolus UF-702, Prosolv SMCC50, SMCC90, etc.), silica-co-treated microcrystalline cellulose, mannitol, and dicalcium phosphate.

[0083] As used herein, the term “flow enhancer” refers to any pharmaceutically acceptable substance or composition added to a composition to improve its flowability. Suitable flow enhancers include, but are not limited to, colloidal silicon dioxide, precipitated silicon dioxide, and / or talc.

[0084] As used herein, the term “lubricant” refers to any pharmaceutically acceptable agent added to a composition to reduce surface friction, lubricate particle surfaces, reduce the tendency for electrostatic buildup, and / or reduce particle brittleness. Thus, lubricants can act as anti-agglutinating agents. Conventional lubricants include stearic acid and related compounds such as magnesium stearate and sodium stearyl fumarate. Alternative lubricants include glyceryl dibehenates, colloidal silicon dioxide, talc, other hydrogenated vegetable oils, and triglycerides. Examples of suitable alternative lubricants include, but are not limited to, glyceryl dibehenates.

[0085] As used herein, the term “disintegrant” refers to a substance added to a composition to help the composition break up (disintegrate) and release a drug. Examples of disintegrants include, but are not limited to, non-sugar water-soluble polymers such as cross-linked polyvinylpyrrolidone. Other disintegrants that may be used include, for example, croscarmellose sodium, sodium starch glycolate, and their analogues; see, for example, Khattab (1992) J. Pharm. Pharmacol. 45:687-691.

[0086] The terms "Lactose Monohydrate T80" and "Lactose Monohydrate 316" refer to block-shaped particles obtained by granulating lactose monohydrate powder. This specification indicates roughness and a large specific surface area.

[0087] The term "Lactose Monohydrate FLOWLAC (Registered Trademark) 100" refers to spherical particles having a porous surface structure obtained by spray-drying an aqueous lactose solution.

[0088] The term "silica-co-treated microcrystalline cellulose" refers to a substance prepared by blending microcrystalline cellulose and colloidal silicon dioxide in water, followed by drying. On a dry weight basis, silica-co-treated microcrystalline cellulose typically contains 94.0–100% microcrystalline cellulose.

[0089] 2. Laboratory equipment and materials 2.1 Apparatus and Equipment

[0090] [Table 1]

[0091] 2.2 Material Information

[0092] [Table 2]

[0093] To objectively evaluate the compatibility between active pharmaceutical ingredients (APIs) and the excipients used, this invention uses common excipients for oral solid dosage forms. These excipients are mixed with the API in various ratios and exposed to various storage conditions. Samples are taken at specific points in time and evaluated based on appearance, hygroscopic weight increase, content, and related substances to determine the compatibility between the API and the excipients. In accordance with the excipient manual, all excipients used are commonly used in oral solid dosage forms and are listed in the current edition of the Chinese Pharmacopoeia. The properties of each excipient are stable. This invention conducts compatibility tests between active pharmaceutical ingredients and various excipients. The ratio of active pharmaceutical ingredients to excipients is set in accordance with the "Basic Technical Guidelines for the Study of Chemical Formulations." Excipients with high content (e.g., microcrystalline cellulose) are mixed according to a weight ratio of active pharmaceutical ingredient:diluent = 1:5, and excipients with low content (e.g., magnesium stearate) are mixed according to a weight ratio of active pharmaceutical ingredient:lubricant = 5:1. The sample was subjected to high temperature (60°C, 40°C), high humidity (25°C / 92.5%RH), accelerated conditions (40°C / 75%RH), and light exposure (visible light 4500 lux ± 500 lux, near ultraviolet 85 μw / cm²). 2 The samples are placed under the specified test conditions, and samples are collected and tested on day 0, day 10, day 30, and month 6. The samples are tested for relevant indicators (including appearance, increase in weight due to moisture absorption, content, and related substances), and the results are compared with the control sample API.

[0094] Test results regarding the compatibility of the active pharmaceutical ingredient with excipients showed that the API performed well under conditions of high temperature (60°C), high humidity (25°C / 92.5%RH), accelerated conditions (40°C / 75%RH), and light exposure, with lactose monohydrate T80, lactose monohydrate 316, microcrystalline cellulose PH101, microcrystalline cellulose PH102, croscarmellose sodium, colloidal silicon dioxide 200, magnesium stearate, and empty gelatin capsules. This indicates that it has the necessary compatibility.

[0095] 3. Dissolution Test Method

[0096] [Table 3]

[0097] 4. Method for measuring uniformity of content Multiple capsules prepared in Example 7 of this application are taken, and the relative content of each capsule relative to the stated amount (100%) is measured. The mean, standard deviation (SD%), and the absolute difference (A) between the stated amount and the mean are calculated. The content uniformity CP in the pharmaceutical composition of this application is calculated as CP = A + 2.2S (CP ≤ 15.0 satisfies the requirements of the Chinese Pharmacopoeia).

[0098] Chromatography conditions: Octadecylsilane-bonded silica gel as packing material (Waters XBridge® C18, 4.6 × 150 mm, 3.5 μm column); 0.1 vol% trifluoroacetic acid aqueous solution as mobile phase A, 0.1 vol% trifluoroacetic acid acetonitrile solution as mobile phase B, isoconcentration elution using mobile phase A-mobile phase B (60:40), detection wavelength 245 nm, flow rate 1.0 mL / min, column temperature 40°C, injection volume 10 μL, and runtime 7 minutes.

[0099] 5. Determination of related substances Chromatography conditions: Octadecylsilane-bonded silica gel (Waters CORTECS) (registered trademark) C18+, 2.1 × 100 mm, 2.7 μm column) as packing material; 0.05 vol% trifluoroacetic acid aqueous solution (adjusted to pH 3.0 with triethylamine) as mobile phase A; acetonitrile as mobile phase B; detection wavelength 245 nm, flow rate 0.4 mL / min, column temperature 25 °C, and injection volume 2 μL. Gradient elution was performed according to the table below, with a runtime of 24.1 minutes and a post-runtime of 5 minutes.

[0100] [Table 4]

[0101] The reagents used in the examples of this invention are known and commercially available. The reagents used are commercially available industrial-grade or analytical-grade reagents, or can be synthesized by or in accordance with methods known in the art. In particular, the free base in the compound of formula (I) is prepared according to WO2018214867A1. All test methods not explicitly described in this invention are carried out in accordance with the prior art or methods in the art and are not listed one by one herein.

[0102] The present invention is described in detail and in whole in the following examples, which are used solely to illustrate specific embodiments of the invention and should not be construed as limiting the scope of the invention in any way.

[0103] Example 1 (Evaluation of the fluidity of pharmaceutical compositions) 1. Conventional technical challenges During the course of pharmaceutical research, the inventors of this application revealed that APIs have poor fluidity and low bulk density, which prevents them from meeting GMP manufacturing requirements. There is a risk of significant discrepancies in the amount of filling during capsule filling, which prevents them from meeting capsule filling requirements.

[0104] 2. Liquidity Assessment Program Taking into account the limitations of the prior art, the inventors of this application designed pharmaceutical compositions in three specifications (5 mg, 25 mg, and 100 mg) and evaluated the fluidity of the pharmaceutical compositions by examining parameters such as bulk density, Carr index, and angle of repose.

[0105] According to the ingredients and quantities shown in the table below, the inventors mixed API and colloidal silicon dioxide 200 and sieved them. Sieved lactose monohydrate FLOWLAC® 100 or lactose monohydrate T80, microcrystalline cellulose PH102, and croscarmellose sodium were added and mixed uniformly in a hopper mixer at 20 rpm for 15 to 45 minutes. Then, sieved magnesium stearate was added and mixed uniformly. The mixture was placed in a mixing barrel and mixed at 20 rpm for 3 to 6 minutes.

[0106] After preliminary process screening, the inventors ultimately decided to use a direct powder filling process, examining the powder properties of the formulation and using dissolution as a product indicator.

[0107] 3. Drug components and content

[0108] [Table 5] Note: The formulation specifications in this application are based on the free base of the compound of formula (I). The "API" actually used is the hydrochloride monohydrate of the compound of formula (I), with a molecular weight of 474.95 and a free base molecular weight of 420.47. The conversion factor is 1.1296. Unless otherwise specified in the following examples, the API used is the same as that used in Example 1.

[0109] 4. Powder property data

[0110] [Table 6]

[0111] From the data above, it can be seen that although API has poor fluidity and low bulk density, the bulk density of the powder after preparation into a pharmaceutical composition is significantly improved, and the angle of repose and curl index are significantly reduced. This reduces the risk of large discrepancies in filling volume during capsule filling, making it possible to meet capsule filling requirements and thus facilitating the implementation of a direct powder filling process.

[0112] Example 2 (Evaluation of the diluent's effectiveness) 1. Mixing homogeneity test 1.1 Drug components and content The inventors prepared pharmaceutical compositions 2-1 to 2-4 according to the drug components and their contents listed in the following table, and referring to the method of Example 1.

[0113] [Table 7]

[0114] 1.2 Powder Properties Data

[0115] [Table 8]

[0116] Based on the experimental results in the table above, all pharmaceutical compositions containing lactose monohydrate FLOWLAC (registered trademark) 100, lactose monohydrate T80, and compound diluents consisting of lactose monohydrate T80 and microcrystalline cellulose PH102, or lactose monohydrate 316 and microcrystalline cellulose PH101, exhibit acceptable powder flowability. It can be revealed that it has [certain properties]. However, during the experiment, it was revealed that the powder mixture of the pharmaceutical composition containing lactose monohydrate FLOWLAC (registered trademark) 100 as a diluent had a non-uniform color, exhibited color differences, and carried a risk of non-uniform powder mixing and segregation. The powder mixture of the pharmaceutical composition containing lactose monohydrate T80, lactose monohydrate 316, and / or microcrystalline cellulose PH101, microcrystalline cellulose PH102 as diluents had a uniform color and no risk of segregation.

[0117] 2. Investigation of fluidity and dissolution effects 2.1 Drug components and content The inventors prepared pharmaceutical compositions 2-5 to 2-9 according to the drug components and their contents listed in the following table, and referring to the method of Example 1.

[0118] [Table 9]

[0119] 2.2 Powder Properties Data

[0120] [Table 10]

[0121] From the above experimental results, it can be shown that all various pharmaceutical compositions containing lactose monohydrate T80 or lactose monohydrate 316, and / or microcrystalline cellulose PH102 or microcrystalline cellulose PH101, have acceptable powder flowability.

[0122] 2.3 Drug elution results

[0123] [Table 11]

[0124] From the experimental results above, it can be shown that all various pharmaceutical compositions containing lactose monohydrate T80, lactose monohydrate 316, and / or microcrystalline cellulose PH101 and microcrystalline cellulose PH102 exhibit good dissolution behavior. Pharmaceutical compositions containing a mixture of lactose monohydrate T80 and microcrystalline cellulose PH102, or a mixture of lactose monohydrate 316 and microcrystalline cellulose PH101, as a diluent exhibit even better dissolution behavior. In particular, when a mixture of lactose monohydrate 316 and microcrystalline cellulose PH101 is used as a diluent, the pharmaceutical composition achieves a dissolution rate of over 90% within 5 minutes, demonstrating rapid efficacy.

[0125] In particular, when the ratio of lactose monohydrate T80 to microcrystalline cellulose PH102 is 2:1, or when the ratio of lactose monohydrate 316 to microcrystalline cellulose PH101 is 2:1 or 3:1, the pharmaceutical composition not only exhibits improved dissolution behavior but also higher bulk density and tap density, making it easier to fill the pharmaceutical composition.

[0126] Example 3 (Evaluation of the effect of flow promoters) 1. Drug components and content The inventors prepared pharmaceutical compositions 3-1 to 3-6 according to the drug components and contents listed in the following table, and referring to the method of Example 1, and investigated the dosage of the fluidity enhancer.

[0127] [Table 12]

[0128] 2. Powder property data

[0129] [Table 13]

[0130] 3. Drug elution results

[0131] [Table 14]

[0132] The experimental results above indicate that a good flow-enhancing effect can be obtained when the amount of flow accelerator added is 0.5%. As the amount increases, the angle of repose also increases accordingly, which is particularly pronounced at 3%. This indicates that excessive use of the flow accelerator affects the flowability of the powder. Therefore, the effect is better when the amount of colloidal silicon dioxide is between 1% and 2%. The drug elution results show that the three pharmaceutical compositions with colloidal silicon dioxide in the range of 0.5% to 2.0% have a faster elution rate and good elution consistency in a pH 1.2 elution solvent (0.1 mol / L hydrochloric acid solution).

[0133] Example 4 (Evaluation of the effectiveness of lubricants) 1. Drug components and content The inventors prepared pharmaceutical compositions 4-1 to 4-6 according to the drug components and contents listed in the following table and referring to the method of Example 1, and investigated the amount of lubricant used.

[0134] [Table 15]

[0135] 2. Powder property data

[0136] [Table 16]

[0137] 3. Drug elution results

[0138] [Table 17]

[0139] The powder properties data show that all three pharmaceutical compositions with different lubricant dosages exhibited good powder flowability, and that powder flowability tended to improve with increasing lubricant dosage. The drug dissolution results show that all three pharmaceutical compositions with magnesium stearate concentrations ranging from 0.5% to 1.5% exhibited faster dissolution rates and good dissolution consistency in a pH 1.2 dissolution solvent (0.1 mol / L hydrochloric acid solution).

[0140] Example 5 (Evaluation of the effect of disintegrants) 1. Drug components and content Pharmaceutical compositions 5-1 to 5-6 were prepared according to the drug components and their contents listed in the table below, referring to the method of Example 1, and the dosage of the disintegrant was investigated.

[0141] [Table 18]

[0142] 2. Powder property data

[0143] [Table 19]

[0144] 3. Drug elution results

[0145] [Table 20]

[0146] The experimental results above indicate that the powder exhibits good fluidity when the croscarmellose sodium content as a disintegrant is within the range of 1% to 5%. Various pharmaceutical compositions exhibit a faster dissolution rate and good dissolution consistency in a pH 1.2 elution solvent (0.1 mol / L hydrochloric acid solution).

[0147] Example 6 (Development of small-scale formulations) 1. Drug components and content Based on the component ratios and test results of the 100 mg dosage form of pharmaceutical composition 5-2 in Example 5, the inventors prepared pharmaceutical compositions 6-1 and 6-2 in 5 mg and 25 mg dosage forms. The target filling weight was achieved by adjusting the amount of diluent while maintaining the same ratio of flow promoter and lubricant. The manufacturing process followed the same procedure as in Example 5.

[0148] [Table 21]

[0149] 2. Drug dissolution effect

[0150] [Table 22]

[0151] The above test results demonstrate that the 5 mg and 25 mg small dosage forms of the pharmaceutical composition prepared using this formulation also exhibit good dissolution behavior, further indicating that this formulation design is reasonable and meets the requirements for clinical research and drug sales.

[0152] Example 7 (Formulation development and results) 1. Formulation composition This invention provides pharmaceutical compositions of CSF-1R inhibitors prepared in three specifications: 5 mg, 25 mg, and 100 mg capsules. The excipients used and their proportions differ among the three formulations. The excipients used include lactose monohydrate T80 / lactose monohydrate 316, microcrystalline cellulose PH101 / microcrystalline cellulose PH102, croscarmellose sodium, colloidal silicon dioxide 200, magnesium stearate, and empty gelatin capsules. The dosage of each component is detailed in the table below.

[0153] [Table 23]

[0154] 2. Preparation process 1) Weighing: API (for 5 mg specification, should be ground for 60 seconds beforehand), lactose monohydrate 316 (or lactose monohydrate T80), microcrystalline cellulose PH101 (or microcrystalline cellulose PH102), croscarmellose sodium, colloidal silicon dioxide 200, and magnesium stearate were weighed according to the specified amounts. 2) Screening of APIs and excipients: APIs and colloidal silicon dioxide 200 were sieved through a 60-mesh sieve for later use, microcrystalline cellulose PH101 (or microcrystalline cellulose PH102) were sieved through a 60-mesh sieve for later use, lactose monohydrate 316 (or lactose monohydrate T80) and croscarmellose sodium were sieved separately through a 40-mesh sieve for later use, and magnesium stearate was sieved through a 30-mesh sieve for later use. 3) Main mixing: Except for magnesium stearate, the excipients and API were placed in a hopper mixer and blended at a mixing speed of 20 rpm for 20 minutes to obtain the main mixed powder. 4) Overall mixing: Magnesium stearate was added to the main mixed powder and mixed at a mixing speed of 20 rpm for 5 minutes to obtain the overall mixed powder. 5) Discharge: The entire mixed powder was removed and placed in an LDPE bag. 6) Capsule filling: The mixed powder was placed into a capsule filling machine and filled into opaque, dark yellow #3 or #0 capsules.

[0155] 3. Formulation Analysis

[0156] [Table 24]

[0157] 4. Test for uniformity of content The applicant of the present invention focused on testing the uniformity of the content of pharmaceutical compositions 7-2 and 7-4 during the overall mixing, dispensing, and capsule filling processes. The specific sampling timing and method for measuring content uniformity were as follows: 1) 11 samples were taken for testing after overall mixing; 2) samples were taken and tested at three stages of the dispensing process: the initial, middle, and late stages; 3) 2 to 3 capsules were sampled and tested at least every 5 minutes during the capsule filling process. The specific measurement results are as follows.

[0158] 4.1 Measurement of Content Uniformity After Overall Mixing

[0159] [Table 25]

[0160] 4.2 Measurement of Uniformity of Content in Discharges

[0161] [Table 26]

[0162] 4.3 Measurement of Content Uniformity During Capsule Filling Process

[0163] [Table 27]

[0164] The experimental results described above clearly show that pharmaceutical compositions 7-2 and 7-4 exhibit good uniformity after overall mixing. During dispensing, pharmaceutical composition 7-4 shows better content uniformity, while pharmaceutical composition 7-2 shows a tendency towards segregation. During capsule filling, pharmaceutical composition 7-4 maintains better content uniformity, while pharmaceutical composition 7-2 shows significant content fluctuations and pronounced segregation.

[0165] 5. Stability Test To investigate the rationality and stability of the capsule formulations, preliminary influencing factor and stability tests were conducted on pharmaceutical compositions 7-1 to 7-4.

[0166] 5.1 Stability Samples

[0167] [Table 28]

[0168] 5.2 Sample Placement Conditions

[0169] [Table 29]

[0170] 5.3 Stability Data

[0171] [Table 30-1]

[0172] [Table 30-2]

[0173] The data above demonstrates that accelerated conditions (40°C / 75%RH or 30°C / 65%RH) do not affect capsule dissolution under various specifications. 5.4 Related substances (%)

[0174] [Table 31]

[0175] As shown by the data above, when capsules of various specifications are exposed to a variety of different conditions, the relevant substances do not increase and remain in an essentially stable state. 5.5 Test Results This invention develops immediate-release capsules for CSF-1R inhibitors, which can be manufactured using a direct powder filling process, and all excipients used are pharmaceutically acceptable, common excipients. The key quality characteristics of the 5 mg, 25 mg, and 100 mg dosage forms manufactured according to this invention all meet release criteria. Stability tests have shown that the physical (dissolution) and chemical properties of this product remain stable even after storage for 30 days and even 6 months under accelerated conditions (40°C / 75%RH and 60°C), meeting clinical drug standards. The good stability supports such storage at room temperature.

[0176] This invention involves a comprehensive and systematic study of the product, examining not only the types and content of functional excipients but also the feasibility of the key processes and the tolerance of parameters. The direct powder filling process used in this invention offers advantages such as simplified manufacturing steps, reduced time and labor costs, and ease of scale-up, enabling the production of uniform and stable formulations with excellent release performance.

[0177] All references made in this invention are cited individually, This application is incorporated by reference. Furthermore, it should be understood that various modifications or changes may be made by those skilled in the art who have carefully read the above disclosure of the present invention, and that these equivalent forms also fall within the scope defined by the claims appended herein.

Claims

1. A pharmaceutical composition comprising a free base or salt of a compound of formula (I), a pharmaceutically acceptable diluent, and another pharmaceutically acceptable carrier as an active ingredient, 【Chemistry 1】 Herein, the other pharmaceutically acceptable carrier is one or more of a flow promoter, a lubricant, and a disintegrant, in the pharmaceutical composition.

2. The salts of the compound of formula (I) above include hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, phosphate, acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, benzoate, decanoate, hexanoate, caprylate, cinnamate, citrate, cyclohexanesulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, aspartate, malate, mandelate, and pyroglutamate. Selected from tartrate, lauryl sulfate, dibenzoyl tartrate, formate, fumarate, galactonate, gentidine, acetohydroxamate, malonate, succinate, glutarate, adipate, sebacinate, 2-ketoglutarate, glycolate, hippoate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, maleate, nicotinate, oleate, orotinate, oxalate, palmitate, pamoate, propionate, 4-acetamidobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthate, stearate, thiocyanate, undecylenate, or succinate; Preferably, the salt of the compound of formula (I) is selected from hydrochloride, sulfate, phosphate, methanesulfonate, citrate, malate, fumarate, or tartrate, according to claim 1.

3. The active ingredient is the anhydride, hydrate, or solvate of the free base or salt of the compound of formula (I). Preferably, the active ingredient is a solvate of the free base or salt of the compound of formula (I), and the solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides or mixtures thereof, or aqueous solutions thereof. More preferably, the active ingredient is a solvate of the free base or salt of the compound of formula (I), and the solvent is methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or a mixture thereof, or an aqueous solution thereof. Preferably, the active ingredient is the anhydrous or hydrated form of the free base or salt of the active ingredient. It is an object, More preferably, the active ingredient is the anhydride of the free base or salt of the active ingredient. More preferably, the active ingredient is a hydrate of the free base or salt of the active ingredient, where each molecule in the hydrate contains one to three water molecules. More preferably, the active ingredient is a hydrate of the free base or salt of the active ingredient, where each molecule in the hydrate contains one water molecule. The pharmaceutical composition according to claim 1 or claim 2.

4. The content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the pharmaceutical composition contains the active ingredient in an amount of 0.1% to 60.0% w / w of the total weight of the composition. Preferably, the pharmaceutical composition contains the active ingredient in an amount of 0.1% to 40.0% w / w relative to the total weight of the composition. More preferably, the pharmaceutical composition comprises 3.0% to 32.0% w / w of the active ingredient based on the total weight of the composition, according to claim 1.

5. The diluent is one or more of lactose, lactose hydrate, and microcrystalline cellulose. In particular, the pharmaceutical composition contains the diluent in an amount of 40.0% to 99.9% w / w relative to the total weight of the composition. Preferably, the pharmaceutical composition comprises 50.0% to 94.0% w / w of the diluent based on the total weight of the composition. More preferably, the pharmaceutical composition comprises 60.0% to 92.0% w / w of a diluent based on the total weight of the composition, according to claim 1.

6. The pharmaceutical composition according to claim 5, wherein the diluent is a mixture of lactose monohydrate and microcrystalline cellulose, the mass ratio w / w of the lactose monohydrate to the microcrystalline cellulose is 1:5 to 5:1, preferably 1:3 to 3:1, and more preferably 1:1 to 3:

1.

7. The pharmaceutical composition according to claim 6, wherein the lactose monohydrate is lactose monohydrate T80 or lactose monohydrate 316, and the microcrystalline cellulose is microcrystalline cellulose PH102 or microcrystalline cellulose PH101.

8. The pharmaceutical composition according to claim 7, wherein the diluent is a mixture of lactose monohydrate T80 and microcrystalline cellulose PH102, the mass ratio w / w of lactose monohydrate T80 to microcrystalline cellulose PH102 is 1:5 to 5:1, preferably 1:3 to 3:1, and more preferably 1:1 to 3:

1.

9. The pharmaceutical composition according to claim 7, wherein the diluent is a mixture of lactose monohydrate 316 and microcrystalline cellulose PH101, the mass ratio (w / w) of the lactose monohydrate 316 to the microcrystalline cellulose PH101 is 1:5 to 5:1, preferably the mass ratio (w / w) of the lactose monohydrate 316 to the microcrystalline cellulose PH101 is 1:3 to 3:1, and more preferably the mass ratio w / w of the lactose monohydrate 316 to the microcrystalline cellulose PH101 is 1:1 to 3:

1.

10. The aforementioned flow promoter is one or more colloidal silicon dioxide, precipitated silicon dioxide, and talc. Preferably, the flow promoter is colloidal silicon dioxide. More preferably, the flow promoter is colloidal silicon dioxide 200, In particular, the pharmaceutical composition contains the flow promoter in an amount of 0.1% to 10.0% w / w relative to the total weight of the composition. Preferably, the pharmaceutical composition comprises 0.5% to 5.0% w / w of the flow promoter based on the total weight of the composition. More preferably, the pharmaceutical composition comprises the flow promoter in an amount of 1.0% to 3.0% w / w based on the total weight of the composition, according to claim 1.

11. The lubricant is one or more of magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, colloidal silicon dioxide, talc, other hydrogenated vegetable oils, and triglycerides. Preferably, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, and glyceryl dibehenate. More preferably, the lubricant is magnesium stearate or sodium stearyl fumarate. In particular, the pharmaceutical composition contains the lubricant in an amount of 0.1% to 5.0% w / w relative to the total weight of the composition. Preferably, the pharmaceutical composition contains the lubricant in an amount of 0.5% to 2.0% w / w relative to the total weight of the composition. More preferably, the pharmaceutical composition comprises the lubricant in an amount of 0.5% to 1.5% w / w based on the total weight of the composition, according to claim 1.

12. The disintegrant is one or more of the following: croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium glycolate starch, and their analogues. Preferably, the disintegrant is croscarmellose sodium. In particular, the pharmaceutical composition contains the disintegrant in an amount of 0.1% to 10.0% w / w relative to the total weight of the composition. Preferably, the pharmaceutical composition contains the disintegrant in an amount of 0.5% to 5.0% w / w relative to the total weight of the composition. More preferably, the pharmaceutical composition comprises 1.0% to 5.0% w / w of the disintegrant based on the total weight of the composition, according to claim 1.

13. The pharmaceutical composition according to claim 1, comprising the active ingredient and the diluent, wherein the mass ratio w / w is (1.0 to 50.0):(50.0 to 94.0), the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the diluent is lactose monohydrate and microcrystalline cellulose, wherein the mass ratio w / w is 1:1 to 3:

1.

14. The pharmaceutical composition according to claim 1, comprising the active ingredient and the diluent, wherein the mass ratio w / w is (1.0 to 50.0):(60.0 to 92.0), the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the diluent is lactose monohydrate T80 and microcrystalline cellulose PH102, with a mass ratio w / w of 1:1 to 3:

1.

15. The pharmaceutical composition comprises the active ingredient and the diluent, with a mass ratio w / w of (1.0 to 50.0):(60.0 to 92.0), the content of the active ingredient is calculated as a hydrochloride monohydrate of the compound of formula (I), and the diluent is lactose monohydrate 316 The pharmaceutical composition according to claim 1, wherein the composition is microcrystalline cellulose PH101, and the mass ratio is 1:1 to 3:

1.

16. The pharmaceutical composition further comprises colloidal silicon dioxide as a flow promoter, wherein the content of colloidal silicon dioxide is 0.5% to 5.0% w / w, preferably 1.0% to 3.0% w / w, based on the total weight of the composition, and / or The pharmaceutical composition further comprises magnesium stearate or sodium stearyl fumarate as a lubricant, wherein the content of magnesium stearate or sodium stearyl fumarate is 0.5% to 2.0% w / w, preferably 0.5% to 1.5% w / w, based on the total weight of the composition, and / or The pharmaceutical composition according to any one of claims 13 to 15, further comprising croscarmellose sodium as a disintegrant, wherein the content of croscarmellose sodium is 0.5% to 5.0% w / w; preferably 1.0% to 5.0% w / w based on the total weight of the composition.

17. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a capsule.

18. The content of the active ingredient in the unit dosage form of the capsule is from 1 mg to 500 mg, and the content of the active ingredient is calculated as the free base of the compound of formula (I). Preferably, the content of the active ingredient in the unit dosage form is 1 mg to 200 mg, and the content of the active ingredient is calculated as the free base of the compound of formula (I). The pharmaceutical composition according to claim 17, more preferably, the content of the active ingredient in the unit dosage form is 1 mg, 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg, and the content of the active ingredient is calculated as the free base of the compound of formula (I).

19. A method for preparing the pharmaceutical composition described in claim 1, comprising the following steps: Step A: Pre-treat the free base or salt of the compound of formula (I) and the flow enhancer separately or together by sieving; The diluent, the disintegrant, and the lubricant are pre-treated by sieving, either separately or together; 【Chemistry 2】 Step B: The mixture of the free base or salt of the compound of formula (I) prepared in Step A and the flow enhancer is placed in a hopper mixer together with the pre-treated diluent and disintegrant and mixed uniformly; Step C: Place the mixed material prepared in Step B and the pre-treated lubricant into a mixing barrel and mix them uniformly; Optionally, step D: Fill the capsule with the entire mixed powder prepared in step C.

20. The free base or salt of the compound of formula (I) is mixed with the flow promoter, and then the mixture is pretreated by passing it through a sieve of 50 to 80 mesh, and / or The diluent is pre-treated independently by passing it through a sieve of 30 to 80 mesh, and / or teeth The disintegrant is pre-treated independently by passing it through a 30-50 mesh sieve, and / or The lubricant is pre-treated independently by passing it through a sieve with a mesh size of 20 to 40. The preparation method according to claim 19.

21. The preparation method according to claim 19, further comprising grinding the free base or salt of the compound of formula (I) in step A.

22. Use of the pharmaceutical composition according to any one of claims 1 to 18 in the manufacture of a CSF-1R inhibitor.

23. Use of a pharmaceutical composition according to any one of claims 1 to 18 in the manufacture of a pharmaceutical for treating a tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF1-R, wherein the tumor is cancer.

24. The use according to claim 23, wherein the tumor, autoimmune disease, metabolic disease, or metastatic disease associated with CSF1-R is an agent for ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastasis, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative disorders, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative disorders, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, eosinophilia syndrome, mastocytosis, or mast cell leukemia.

25. A pharmaceutical composition according to any one of claims 1 to 18, for use as an agent for treating tumors, autoimmune diseases, metabolic diseases, or metastatic diseases associated with CSF1-R.

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