CN117177756A

CN117177756A - Pharmaceutical composition of multi-target protein kinase inhibitor, application and preparation method thereof

Info

Publication number: CN117177756A
Application number: CN202380011150.XA
Authority: CN
Inventors: 唐琳; 赫玉霞; 周付刚; 史凯; 齐鹏成; 冯雪; 班萌; 李少茹; 王洁敏; 陈雪桃
Original assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Current assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date: 2022-03-30
Filing date: 2023-03-30
Publication date: 2023-12-05
Also published as: WO2023186031A1

Abstract

The invention relates to a pharmaceutical composition of a multi-target protein kinase inhibitor, application and a preparation method thereof. The pharmaceutical composition comprises a compound represented by formula 2 as an active ingredient and an excipient. The pharmaceutical composition can be used for preparing medicines, particularly medicines for treating protein kinase mediated diseases, and various indexes of oral preparations prepared from the pharmaceutical composition meet the preparation standards, have good stability and are suitable for large-scale production.

Description

Pharmaceutical composition of multi-target protein kinase inhibitor, application and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of a multi-target protein kinase inhibitor, and application and a preparation method thereof.

Background

Protein tyrosine kinases (Protein tyrosine kinases, PTKs) are a very important member of the protein kinase family, and the PTKs transfer the gamma-phosphate group on adenosine triphosphate to the protein tyrosine residue of a substrate, complete information transmission among cells by phosphorylating phenolic hydroxyl groups, and play a vital role in the processes of cell development, regulation, differentiation, migration, apoptosis and the like of tumor cells. If PTKs are out of control during the regulation process, the correct activation of downstream signal channels is affected, and then the regulation function of cell proliferation is disturbed, so that a plurality of diseases are caused, for example, the tyrosine kinase is excessively high to phosphorylate receptors and activate downstream signals, so that cells are over-transformed, proliferate, resist apoptosis, promote cell survival and further form malignant tumors.

Epidermal growth factor receptor (Epidermal Growth Factor Receptor, EGFR), fibroblast growth factor receptor (Fibroblast Growth Factor Receptors, FGFRs), platelet-derived growth factor receptor (Platelet-derived Growth Factor Receptor, PDGFR), and RET protein encoded by RET (Rearranged during Transfection) protooncogene are important members of PTKs, and are important targets for tumor treatment.

EGFR includes EGFR (ErbB-1), type 2 human EGFR HER-2 (ErbB-2), type 3 human EGFR HER3 (ErbB-3) and type 4 human EGFR HER4 (ErbB-4), wherein EGFR and HER-2 are the most closely related targets of EGFR family members. EGFR has been shown to exhibit over-expression, gene mutation or gene fusion in a variety of tumors such as lung cancer, stomach cancer, epidermoid carcinoma, kidney cancer, ovarian cancer, and the like.

FGFR mainly comprises four subtypes FGFR1/2/3/4, and the four subtypes are over-expressed or over-activated in the modes of gene amplification, mutation, fusion or ligand induction and the like, and have important roles in tumor cell proliferation, invasion and migration and tumor angiogenesis. The FGFRs have been found to exhibit mutation, overexpression or overactivation in various tumors such as lung cancer, stomach cancer, biliary tract cancer (e.g., intrahepatic cholangiocarcinoma), colorectal cancer, liver cancer, etc.

The normal physiological functions of RET include kidney development, development of the nervous system, maintenance and renewal of sperm stem cells, differentiation of myelomonocyte, formation of lymphoid tissue, and the like, and are expressed in cells such as human intestinal ganglion cells, neuroblastoma, pheochromocytoma, medullary thyroid carcinoma, thyroid C cells, and melanoma. In recent years, intensive studies on RET have revealed that excessive activation of RET in tumors significantly promotes proliferation, survival, invasion, metastasis, tumor inflammation, and the like of various tumors, and that RET exhibits excessive expression in thyroid cancer (e.g., medullary thyroid cancer, papillary thyroid cancer), lung cancer (e.g., non-small cell lung cancer), colorectal cancer, pancreatic cancer, melanoma, and the like.

Tumors are often related to imbalance of regulation of multiple signal transduction pathways and multiple targets, and single-target drugs cannot necessarily achieve expected therapeutic effects, and are also limited in application by drug toxic and side effects and drug resistance, so that multi-target drugs become a new drug research direction. Compared with single-target drugs, multi-target drugs can act on multiple targets related to tumors, even though the activity of the multi-target drugs against the single targets is possibly reduced compared with that of the single-target drugs, the multi-target drugs can benefit from the synergistic effect generated by multi-target regulation, so that the total effect can be larger than the sum of the single effects, thereby obtaining better curative effect and generating smaller adverse reaction.

CN106660970B discloses a compound (example 22) as shown in formula 1, which is a multi-target inhibitor with the activity of inhibiting RET, KDR, EGFR, FGFR, FLT-1 and other protein tyrosine kinases.

Disclosure of Invention

There are no studies reported to date on pharmaceutical compositions of compound 1 and its pharmaceutically acceptable salts.

The inventor further discovers that the dihydrochloride of the compound 1 with better pharmaceutical property than the compound 1 (shown as a formula 2) is obviously better than the compound 1 on the basis of the compound 1, and the dihydrochloride is more suitable for preparing medicines than other salt forms of the compound 1 through comprehensive index investigation, and can be prepared into various medicine formulations according to clinical medication requirements. The corresponding research and screening procedures have been described in PCT/CN2021/120328 patent application, the entire contents of which are incorporated herein by reference in their entirety.

The technical problem to be solved by the application is to provide a pharmaceutical composition which meets the preparation requirements and satisfies the requirements of oral administration and comprises a compound shown as a formula 2 as an active ingredient.

[ technical solution ]

In the course of continuous research to find desirable pharmaceutical compositions and/or oral formulations comprising the compound of formula 2, the inventors of the present application conducted careful screening experiments on the components of the pharmaceutical compositions, and have found that the prescription composition of a specific pharmaceutical composition can solve the above technical problems, thereby completing the present application.

In a first aspect, the present application provides a pharmaceutical composition suitable for oral administration comprising: a compound represented by formula 2 as an active ingredient and an excipient,

the excipient disclosed by the application can also be called as pharmaceutically acceptable auxiliary materials, auxiliary materials or additives, refers to the general term of all additional materials used in the preparation of prescriptions and the production of medicines except for active ingredients, and is generally pharmaceutically acceptable inert ingredients, and the safety of the excipient is reasonably evaluated. Examples of excipients include, without limitation, fillers (or diluents), disintegrants, lubricating adjuvants (lubricants, glidants, anti-adherents), binders, stabilizers, flavoring agents, thickening agents, dispersing agents, colorants, bacteriostats, antioxidants, pH adjusters, surfactants, fragrances, and coating materials (including plasticizers, opacifiers, pigments, and the like). For example, excipients can enhance the handling characteristics of a pharmaceutical formulation, for example, by increasing flowability and/or adhesiveness to make the formulation acceptable for processing. Further, the "excipient" should have good compatibility with the active ingredient, i.e., the excipient itself or the impurities contained therein do not chemically react with the structural groups in the active ingredient or cause degradation of the active ingredient, resulting in a decrease in the content of the active ingredient. The excipient may be classified into an ionic excipient and a non-ionic excipient, and the "non-ionic excipient" refers to an excipient containing no metal ions, for example, the non-ionic excipient includes a non-ionic filler, a non-ionic lubricant, a non-ionic disintegrant, a non-ionic glidant, and the like; wherein, for example, the nonionic filler comprises microcrystalline cellulose, pregelatinized starch, lactose, mannitol, starch and the like, the nonionic lubricant comprises stearic acid, hydrogenated vegetable oil and the like, the nonionic disintegrant comprises crospovidone, low-substituted hydroxypropyl cellulose and the like, and the nonionic glidant comprises colloidal silicon dioxide; the "ionic excipient" refers to an excipient containing metal ions, and the ionic excipient comprises an ionic filler, an ionic lubricant, an ionic disintegrating agent and the like, wherein the ionic filler comprises calcium hydrophosphate, calcium carbonate and the like, and the ionic lubricant comprises magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate and the like.

"filler" or "diluent" as used herein refers to excipients used to increase the weight and volume of a pharmaceutical composition to facilitate shaping and dosing. The filler according to the present application may be a single filler or a mixture of two or more fillers.

The "disintegrant" as used herein refers to an excipient for promoting the disintegration of a pharmaceutical composition in the gastrointestinal tract and increasing the dissolution rate of an active ingredient.

The application relates to a lubricating auxiliary material, which is a broad lubricant and is an excipient used for reducing friction force between particles and die holes of a pharmaceutical composition and improving force transmission and distribution. The lubricating auxiliary materials are divided into a lubricant, a glidant and an anti-adhesion agent according to the three functions of reducing friction, improving particle mobility and resisting adhesion between a die hole and drug particles.

In some embodiments, the pharmaceutical composition is formulated as an oral formulation. Preferably, the oral formulation is an oral solid formulation.

In some embodiments, the pharmaceutical composition or oral formulation is dissolved for no more than 60 minutes in a dissolution test at 85% using water as the test medium and a paddle speed of 50rpm according to the paddle method described in the fourth edition of chinese pharmacopoeia 2020.

In some embodiments, the pharmaceutical composition or oral formulation is dissolved 85% of the time in the dissolution test for no more than 55 minutes; preferably 50 minutes; more preferably 45 minutes.

In some embodiments, the pharmaceutical composition or oral formulation has a content of 100% ± 10% active ingredient as measured by content; preferably 100% ± 5%; more preferably 100% ± 3%.

In some embodiments, the excipient comprises a disintegrant that is a nonionic disintegrant. Preferably, the excipient further comprises a non-ionic excipient, optionally further comprising an ionic excipient.

In some embodiments, the excipient comprises a disintegrant and a filler, the disintegrant being a nonionic disintegrant, optionally the excipient further comprising a glidant and/or a lubricant.

In some embodiments, the nonionic disintegrant comprises one or more of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose, or crospovidone; preferably, the non-ionic disintegrant comprises crospovidone, optionally further comprising another non-ionic disintegrant selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low substituted hydroxypropyl cellulose.

Preferably, the weight percentage of the disintegrant in the pharmaceutical composition is 5% to 40%; preferably 7% -40%; preferably 8% -35%; further preferably 8% -40%; further preferably 10% -40%; further preferably 8% -30%; more preferably 8% -25%; further preferably 8% -20%; further preferably 8% -15%; more preferably 10 to 15%.

In some embodiments, the excipient comprises a non-ionic disintegrant and a non-ionic filler, optionally further comprising a non-ionic glidant, an ionic filler, and/or an ionic lubricant.

In some embodiments, the excipient comprises a non-ionic disintegrant and a non-ionic filler, optionally further comprising a non-ionic lubricant, a non-ionic glidant, an ionic filler, and/or an ionic lubricant.

In some embodiments, the excipient comprises a non-ionic disintegrant, a non-ionic filler, and a non-ionic glidant, optionally, further comprising a non-ionic lubricant, an ionic filler, and/or an ionic lubricant.

In some embodiments, the compound of formula 2 is in crystalline form.

In some embodiments, the crystalline form of the compound of formula 2 (form I), using Cu-ka radiation, has a powder X-ray diffraction pattern in terms of 2θ degrees (°) with characteristic diffraction peaks (±0.2°): 12.4, 18.8, 20.3, 24.6.

Alternatively, using Cu-ka radiation, a powder X-ray diffraction pattern expressed in terms of 2θ angles (°) has characteristic diffraction peaks (±0.2°): 9.8, 12.4, 18.8, 20.3, 24.6.

Alternatively, using Cu-ka radiation, a powder X-ray diffraction pattern expressed in terms of 2θ angles (°) has characteristic diffraction peaks (±0.2°): 8.1, 9.8, 12.4, 18.8, 20.3, 24.6, 29.9.

Alternatively, using Cu-ka radiation, a powder X-ray diffraction pattern expressed in terms of 2θ angles (°) has characteristic diffraction peaks (±0.2°): 8.1, 9.8, 12.4, 18.8, 19.3, 20.3, 24.6, 28.6, 29.9.

Alternatively, using Cu-ka radiation, a powder X-ray diffraction pattern expressed in terms of 2θ angles (°) has characteristic diffraction peaks (±0.2°): 8.1, 9.8, 12.4, 16.1, 18.8, 19.3, 20.3, 24.6, 28.6, 29.9, 30.9.

Alternatively, using Cu-ka radiation, an X-ray powder diffraction pattern substantially as shown in figure 1 or figure 2 is provided.

In some embodiments, the crystalline form of the compound of formula 2 (form I) has a DSC profile with endothermic peaks at 231.0±5 ℃ and 284.2±5 ℃, respectively.

In some embodiments, the crystalline form of the compound of formula 2 (form I) begins to decompose with a TGA profile at 205.6±5 ℃.

In some embodiments, in the pharmaceutical composition, the active ingredient (compound of formula 2) is present in an amount of 0.5% to 80% by weight; or 1% -75%; or 5% -70%; or 10% -70%; or 15% -70%; or 16% -68%; or 16% -67%; or 20% -70%; or 20% -67%; or 5% -65%; or 5% -60%; or 5% -55%; or 5% -50%; or 10% -55%; or 10% -50%; or 15% -55%; or 15% -50%; or 15% -45%; or 20% -50%; or 20% -45%; or 20% -40%.

In some embodiments, in the pharmaceutical composition, the weight percentage of the nonionic disintegrant in the pharmaceutical composition is 8% to 40%; preferably 8% -30%; preferably 10% -40%; preferably 10% -35%; preferably 10% -30%; preferably 15% -40%; preferably 15% -30%; preferably 20% -30%; preferably 20% -40%; preferably 25% -40%; preferably 30 to 40%.

In some embodiments, in the pharmaceutical composition, the filler is present in the pharmaceutical composition in a weight percentage of: 10% -85%; or 10% -80%; or 15% -75%; or 17% -68%; or 15% -70%; or 15% -65%; or 20% -65%; or 30% -65%; or 30% -60%; or 30% -55%; or 30% -50%; or 35% -50%; or 40% -55%.

In some embodiments, in the pharmaceutical composition, the weight percent of lubricant in the pharmaceutical composition is: 0% -6%; or 0% -5%; or 0% -4%; or 0% -3.5%; or 0% -3%; or 0% -2.5%; or 0% -2%; or 0% -1.5%; or 0% -1%; or,

the weight percentage of the lubricant in the pharmaceutical composition is as follows: 1 to 6 percent; or 1% -5%; or 1.5% -5%; or 1% -4%; or 1.5% -4%; or 1% -3.5%; or 1.5% -3.5%; or 1% -3%; or 1% -2%; or 1.5% -3%; or 2% -3.5%.

In some embodiments, in the pharmaceutical composition,

in some embodiments, the pharmaceutical composition comprises a lubricant, and wherein the lubricant is a non-ionic lubricant, wherein the weight percentage of the non-ionic lubricant in the pharmaceutical composition is 1% to 6%, preferably 1% to 5%, preferably 1% to 4%, further preferably 1% to 3.5%, further preferably 1% to 3%, further preferably 1% to 2%.

In some embodiments, the pharmaceutical composition comprises a lubricant, and wherein the lubricant comprises both a non-ionic lubricant and an ionic lubricant, wherein the non-ionic lubricant is present in the pharmaceutical composition in an amount of 1% to 4%, preferably 1% to 3.5%, further preferably 1% to 3%, further preferably 1% to 2% by weight; and is also provided with

(i) The weight percentage of the active ingredient in the pharmaceutical composition is more than or equal to 40 percent (for example, 40 to 70 percent, 40 to 68 percent), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1 percent, preferably less than or equal to 0.8 percent, preferably less than or equal to 0.7 percent, preferably less than or equal to 0.6 percent, preferably less than or equal to 0.5 percent; or alternatively

(ii) The weight percentage of the active ingredient in the pharmaceutical composition is less than 40% (e.g., 15% or less of the weight percentage of the active ingredient is < 40%,16% to 35%,16% to 34%), the weight percentage of the ionic lubricant in the pharmaceutical composition is 2% or less, preferably 1.5% or less, preferably 1% or less, preferably 0.8% or less, more preferably 0.7% or less, more preferably 0.6% or less, and even more preferably 0.5% or less.

In some embodiments, the pharmaceutical composition comprises a lubricant, and wherein the lubricant is an ionic lubricant, the weight percentage of the active ingredient in the pharmaceutical composition being < 40% (preferably +.35%;, preferably +.34%, e.g. 15% -35%, 15% -34%, 20% -35%, 20% -33.5%), the weight percentage of the ionic lubricant in the pharmaceutical composition being 1% -3%; preferably 1% to 2.5%, preferably 1% to 2%, preferably 1% to 1.5%.

In some embodiments, the glidants are present in the pharmaceutical composition in weight percent: 0% -8%; or 0% -7%; or 0% -6%; or 0% -5.5%; or 0% -5%; or 0% -4%; or 0% -3%; or 0% -2%; or 0% -1.5%; or 0% -1%; or 0% -0.5%; or,

the glidant accounts for 3 to 8 percent of the weight of the pharmaceutical composition; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%; or 3.5% -7%; or 4% -7%; or 4.5% -7%; or 5% -7%; or 4% -7%; or 4% -6%.

In some embodiments, the nonionic disintegrant is selected from one or more of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose, or crospovidone;

Preferably, the nonionic disintegrant is selected from one of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose, or crospovidone, or a combination of crospovidone and one or more of dry starch, microcrystalline cellulose, polyvinylpyrrolidone, corn starch, pregelatinized starch, or low substituted hydroxypropyl cellulose;

more preferably, the nonionic disintegrant is selected from the group consisting of crospovidone, and low substituted hydroxypropylcellulose.

In some embodiments, the filler comprises a non-ionic filler, optionally, further comprising an ionic filler;

preferably, the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose;

further preferably, the nonionic filler is selected from microcrystalline cellulose, or one of pregelatinized starch, mannitol, or lactose; or a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose, or a combination of microcrystalline cellulose and dextrin, or a combination of microcrystalline cellulose and powdered sugar, or a combination of microcrystalline cellulose and sucrose.

In some embodiments, the pharmaceutical composition comprises a lubricant, when the lubricant comprises a non-ionic lubricant, the non-ionic lubricant is selected from one or more of stearic acid, palmitic acid, glyceryl palmitostearate, glyceryl behenate, hydrogenated vegetable oil, talc, or polyethylene glycols; preferably stearic acid; and/or

When the lubricant comprises an ionic lubricant, the ionic lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate; more preferably magnesium stearate.

In some embodiments, the pharmaceutical composition comprises a glidant, and wherein the glidant is a non-ionic glidant; preferably, the nonionic glidant is selected from colloidal silicon dioxide.

In some embodiments, the excipient comprises a filler, a disintegrant, a lubricant, and a glidant, wherein the disintegrant is a non-ionic disintegrant, and the lubricant comprises a non-ionic lubricant, optionally, further comprises an ionic lubricant.

In some embodiments, the excipient comprises a filler, a disintegrant, a lubricant, and a glidant, wherein the disintegrant is a non-ionic disintegrant, the lubricant is an ionic lubricant, the filler comprises a non-ionic filler, and the glidant is a non-ionic glidant.

In a second aspect, the present application provides a pharmaceutical composition suitable for oral administration comprising as an active ingredient a compound of formula 2, a filler, a disintegrant, a lubricant and a glidant, wherein the disintegrant is a non-ionic disintegrant,

in some embodiments, the compound of formula 2 is as defined above for the first aspect.

In some embodiments, when the lubricant is a non-ionic lubricant, wherein the weight percentage of the non-ionic lubricant in the pharmaceutical composition is 1% to 6%, preferably 1% to 5%, preferably 1% to 4%, further preferably 1% to 3.5%, further preferably 1% to 3%, further preferably 1% to 2%.

In some embodiments, when the lubricant comprises both a non-ionic lubricant and an ionic lubricant, wherein the weight percentage of the non-ionic lubricant in the pharmaceutical composition is 1% to 4%, preferably 1% to 3.5%, further preferably 1% to 3%, further preferably 1% to 2%; when the weight percentage of active ingredient in the pharmaceutical composition is equal to or greater than 40% (e.g., 40% -70%, 40% -68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably equal to or less than 0.8%, preferably equal to or less than 0.7%, preferably equal to or less than 0.6%, preferably equal to or less than 0.5%.

In some embodiments, the lubricant comprises a non-ionic lubricant, optionally, further comprising an ionic lubricant; preferably, when an ionic lubricant is included and the weight percentage of active ingredient in the pharmaceutical composition is greater than or equal to 40% (e.g., 40% to 70%,40% to 68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, more preferably less than or equal to 0.7%, more preferably less than or equal to 0.6%, still more preferably less than or equal to 0.5%.

In some embodiments, the lubricant comprises a non-ionic lubricant, optionally, further comprising an ionic lubricant; preferably, when an ionic lubricant is included and the weight percent of active ingredient in the pharmaceutical composition is < 40% (e.g., 15% to 40% active ingredient weight percent < 40%,16% to 35%,16% to 34%), the weight percent of the ionic lubricant in the pharmaceutical composition is less than or equal to 2%, preferably less than or equal to 1.5%, preferably less than or equal to 1%, preferably less than or equal to 0.8%, more preferably less than or equal to 0.7%, more preferably less than or equal to 0.6%, even more preferably less than or equal to 0.5%.

In some embodiments, the lubricant comprises a non-ionic lubricant, optionally, further comprising an ionic lubricant; preferably, when an ionic lubricant is included, the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, more preferably less than or equal to 0.8%, more preferably less than or equal to 0.7%, more preferably less than or equal to 0.6%, more preferably less than or equal to 0.5%, more preferably from 0% to 0.5%.

In some embodiments, the filler comprises a non-ionic filler, optionally, further comprising an ionic filler; preferably, the filler is a nonionic filler.

In some embodiments, the non-ionic filler comprises one or more of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose.

In some embodiments, the non-ionic filler comprises microcrystalline cellulose, optionally further comprising one or more of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose;

alternatively, the non-ionic filler comprises pregelatinized starch, optionally further comprising one or more of microcrystalline cellulose, starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose;

Alternatively, the non-ionic filler comprises lactose, optionally further comprising one or more of microcrystalline cellulose, pregelatinized starch, mannitol, xylitol, dextrin, powdered sugar, or sucrose;

alternatively, the non-ionic filler comprises mannitol, optionally further comprising one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch, xylitol, dextrin, powdered sugar, or sucrose.

In some embodiments, the non-ionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose; preferably, the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose, or the nonionic filler is a combination of two nonionic fillers, including a combination of microcrystalline cellulose and starch, or microcrystalline cellulose and pregelatinized starch, or microcrystalline cellulose and lactose, or microcrystalline cellulose and mannitol, or pregelatinized starch and lactose, or microcrystalline cellulose and dextrin, or microcrystalline cellulose and powdered sugar, or microcrystalline cellulose and sucrose; further preferably, the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose, or a combination of microcrystalline cellulose and starch, or a combination of microcrystalline cellulose and pregelatinized starch, or a combination of microcrystalline cellulose and lactose, or a combination of microcrystalline cellulose and mannitol, or a combination of pregelatinized starch and lactose.

In some embodiments, when the nonionic filler used is a combination of two nonionic fillers, the weight ratio of the two fillers in the combination of two nonionic fillers is 1:10 to 10:1; or 1:9 to 9:1; or 1:8-8:1; or 1:7 to 7:1; or 1:6 to 6:1, or 1:5 to 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2-2:1; or 1:1.

In some embodiments, the ionic filler is selected from one or more of calcium sulfate, calcium hydrogen phosphate, or calcium phosphate.

In some embodiments, the weight percentage of the ionic filler in the pharmaceutical composition is: 0% -20%; or 0% -15%; or 0% -10%; or 0% -9%; or 0% -8%; or 0% -7%; or 0% -6%; or 0% -5%; or 0% -4%; or 0% -3%.

In some embodiments, when the filler used comprises an ionic filler, the weight ratio of the nonionic filler to the ionic filler is from 1000 to 1:1, a step of; or 900-1: 1, a step of; 800-1: 1, a step of; or 700 to 1:1, a step of; or 600-1:1; or 500-1:1; or 300-1:1, or 200-1:1; or 100-1:1; or 50-1:1; or 20-1:1; or 10-1:1.

In some embodiments, the filler is present in the pharmaceutical composition in a weight percentage of: 10% -85%; or 10% -80%; or 15% -75%; or 17% -68%; or 15% -70%; or 15% -65%; or 20% -65%; or 30% -65%; or 30% -60%; or 30% -55%; or 30% -50%; or 35% -50%; or 40% -55%.

In some embodiments, the nonionic disintegrant comprises crospovidone, optionally further comprising another nonionic disintegrant selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, or low substituted hydroxypropyl cellulose. Preferably, the weight percentage of the crospovidone in the pharmaceutical composition is 5-20%, further preferably 5-18%; more preferably 7 to 18%, still more preferably 8 to 15%, still more preferably 5 to 15%, still more preferably 10 to 15%. The weight percentage of the other nonionic disintegrant in the pharmaceutical composition is 0-20%, preferably 5-10%, preferably 0-10%, preferably 10-20%.

In some embodiments, the nonionic disintegrant is selected from one or more of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose, or crospovidone; preferably, the nonionic disintegrant is selected from one of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose, or crospovidone, or a combination of crospovidone and one or more of dry starch, microcrystalline cellulose, polyvinylpyrrolidone, corn starch, pregelatinized starch, or low substituted hydroxypropyl cellulose; preferred are combinations of crospovidone, crospovidone and low substituted hydroxypropyl cellulose.

Preferably, the weight percentage of the crospovidone in the pharmaceutical composition is 5% -20%; more preferably 7% -18%; further preferably 8% -15%; more preferably 5% -15%; more preferably 10 to 15%.

In some embodiments, the weight percent of the disintegrant in the pharmaceutical composition is: 5% -35%; or 5% -30%; or 5% -25%; or 6% -25%; or 7% -20%; or 5% -20%; or 8% -20%; or 8% -18%; or 8% -15%; or 10% -15%.

In some embodiments, the lubricant comprises a non-ionic lubricant, optionally, further comprising an ionic lubricant.

In some embodiments, the non-ionic lubricant is selected from one or more of stearic acid, palmitic acid, glyceryl palmitostearate, glyceryl behenate, hydrogenated vegetable oil, talc, or polyethylene glycols; stearic acid is preferred.

In some embodiments, the non-ionic lubricant comprises stearic acid, optionally further comprising one or more of palmitic acid, glyceryl palmitostearate, hydrogenated vegetable oil, talc, glyceryl behenate, or polyethylene glycols.

In some embodiments, the ionic lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate; more preferably magnesium stearate.

In some embodiments, the lubricant comprises stearic acid, optionally, further comprising another lubricant (i.e., a combination of stearic acid and another lubricant) selected from the group consisting of magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols. Preferably, the further lubricant is magnesium stearate, sodium stearyl fumarate or hydrogenated vegetable oil; more preferably magnesium stearate.

In some preferred embodiments, the lubricant is selected from stearic acid, a combination of stearic acid and magnesium stearate, a combination of stearic acid and sodium stearyl fumarate, or a combination of stearic acid and hydrogenated vegetable oil; more preferably stearic acid, or a combination of stearic acid and magnesium stearate.

In some preferred embodiments, the weight percentage of stearic acid in the pharmaceutical composition is 1% to 4%; further preferably 1% to 3.5%; further preferably 1% -3%; more preferably 1 to 2%. Preferably, when the further lubricant is an ionic lubricant (e.g. magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulphate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulphate, sodium lauryl sulphate or magnesium lauryl sulphate; preferably magnesium stearate or sodium stearyl fumarate) and the weight percentage of active ingredient in the pharmaceutical composition is greater than or equal to 40% (e.g. 40% to 70%,40% to 68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably less than or equal to 0.5%.

In some preferred embodiments, the weight percentage of stearic acid in the pharmaceutical composition is 1% to 4%; further preferably 1% to 3.5%; further preferably 1% -3%; more preferably 1 to 2%. Preferably, when the other lubricant is an ionic lubricant (e.g., magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate) and the weight percent of active ingredient in the pharmaceutical composition is < 40% (e.g., 15% to 40% active ingredient weight percent < 40%,16% to 35%,16% to 34%), the weight percent of the ionic lubricant in the pharmaceutical composition is 2% or less, preferably 1.5% or less, preferably 1% or less, preferably 0.8% or less, more preferably 0.7% or less, more preferably 0.6% or less, and even more preferably 0.5% or less.

In some preferred embodiments, the weight percentage of stearic acid in the pharmaceutical composition is 1% to 4%; further preferably 1% to 3.5%; further preferably 1% -3%; more preferably 1 to 2%. Preferably, when the further lubricant is a non-ionic lubricant (e.g. palmitic acid, glyceryl palmitostearate, glyceryl behenate, hydrogenated vegetable oil, talc or polyethylene glycols, preferably hydrogenated vegetable oil), the non-ionic lubricant is present in the pharmaceutical composition in an amount of 4% by weight or less; preferably less than or equal to 3.5%; preferably less than or equal to 3%; preferably less than or equal to 2.5%; preferably less than or equal to 2 percent; preferably less than or equal to 1.5%; preferably less than or equal to 1%; preferably not more than 0.5%.

In some preferred embodiments, the weight percentage of stearic acid in the pharmaceutical composition is 1% to 4%; further preferably 1% to 3.5%; further preferably 1% -3%; more preferably 1 to 2%. Preferably, the weight percentage of the further lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably between 0% and 0.5%, preferably less than or equal to 0.5%.

In some embodiments, the combination of stearic acid and another lubricant has a weight ratio of stearic acid to another lubricant of 1 to 3:3 to 1; preferably 1 to 2:2 to 1; preferably 2 to 10:1, a step of; preferably 2 to 5:1, a step of; preferably 2 to 3:1, a step of; preferably 2:1. 1: 2. 1:1, a step of; preferably 2:1.

in some embodiments, the weight percent of the lubricant in the pharmaceutical composition is: 1 to 6 percent; or 1% -5%; or 1.5% -5%; or 1% -4%; or 1.5% -4%; or 1% -3.5%; or 1.5% -3.5%; or 1% -3%; or 1% -2%; or 1.5% -3%; or 2% -3.5%.

In some embodiments, the glidant is a non-ionic glidant; preferably, the glidant is 3-8% by weight of the pharmaceutical composition; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%; or 3.5% -7%; or 4% -7%; or 4.5% -7%; or 5% -7%; or 4% -7%; or 4% -6%.

In some embodiments, the glidant is a non-ionic glidant; preferably, the nonionic glidant is selected from colloidal silicon dioxide. Preferably, the colloidal silica is present in the pharmaceutical composition in a weight percentage of: 3% -8%; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%; or 3.5% -7%; or 4% -7%; or 4.5% -7%; or 5% -7%; or 4% -7%; or 4% -6%.

In some embodiments, in the pharmaceutical composition, the filler comprises a non-ionic filler; the disintegrating agent is a nonionic disintegrating agent; the glidant is a nonionic glidant; the lubricant comprises a non-ionic lubricant, optionally further comprising an ionic lubricant;

the nonionic filler, nonionic disintegrant, nonionic lubricant, ionic lubricant, and nonionic glidant are as defined above.

Preferably, the weight percentage of the nonionic lubricant in the pharmaceutical composition is 1% -4%, preferably 1% -3.5%, further preferably 1% -3%, further preferably 1% -2%; the weight percentage of the ionic lubricant in the pharmaceutical composition is not higher than 1%, preferably not higher than 0.8%, preferably not higher than 0.7%, preferably not higher than 0.6%, preferably 0% to 0.5%, preferably not higher than 0.5%.

In some embodiments, in the pharmaceutical composition,

the filler comprises a non-ionic filler, optionally further comprising an ionic filler;

the lubricant comprises stearic acid, optionally further comprising another lubricant selected from the group consisting of magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols; wherein the weight percentage of the stearic acid in the pharmaceutical composition is 1% -4%, preferably 1% -3.5%, more preferably 1% -3%, still more preferably 1% -2%; the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably between 0% and 0.5%, preferably less than or equal to 0.5%; preferably, when the further lubricant is an ionic lubricant and the weight percentage of active ingredient in the pharmaceutical composition is ≡40% (e.g. 40% -70%, 40% -68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ≡0.8%, preferably ≡0.7%, preferably ≡0.6%, preferably ≡0.5%;

The disintegrating agent is a nonionic disintegrating agent, and the nonionic disintegrating agent is selected from one of dry starch, microcrystalline cellulose, powdery cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose or crosslinked povidone, or the combination of the crosslinked povidone and one or more of the dry starch, microcrystalline cellulose, corn starch, powdery cellulose, pregelatinized starch or low-substituted hydroxypropyl cellulose; wherein the weight percentage of the disintegrating agent in the pharmaceutical composition is 5% -35%, preferably 7% -30%, preferably 8% -20%, preferably 8% -18%, preferably 8% -15%, preferably 10% -30%, preferably 10% -20%, preferably 10% -15%;

the glidant is colloidal silicon dioxide;

the nonionic filler or the ionic filler is as defined above.

Preferably, the glidant is 3-8% by weight of the pharmaceutical composition; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%; or 3.5% -7%; or 4% -7%; or 4.5% -7%; or 5% -7%; or 4% -7%; or 4% -6%.

Preferably, the non-ionic filler comprises microcrystalline cellulose, optionally further comprising one or more of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose;

Preferably, the non-ionic filler comprises one or more of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose; further preferably, the non-ionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose, or from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose.

Preferably, when the nonionic filler is a combination of two nonionic fillers, the weight ratio of the two nonionic fillers is 1:10 to 10:1; or 1:9 to 9:1; or 1:8-8:1; or 1:7 to 7:1; or 1:6 to 6:1, or 1:5 to 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2-2:1; or 1:1.

Preferably, when the filler used comprises an ionic filler, the weight ratio of the nonionic filler to the ionic filler is from 1000 to 1:1; or 900-1:1; 800-1:1; or 700-1:1; or 600-1:1; or 500-1:1; or 300-1:1, or 200-1:1; or 100-1:1; or 50-1:1; or 20-1:1; or 10-1:1.

In some embodiments, in the pharmaceutical composition,

the lubricant is selected from stearic acid, a combination of stearic acid and magnesium stearate, a combination of stearic acid and calcium stearate, or a combination of stearic acid and zinc stearate, or a combination of stearic acid and sodium stearyl fumarate, or a combination of stearic acid and hydrogenated vegetable oil; wherein the weight percentage of the stearic acid in the pharmaceutical composition is 1% -4%, preferably 1% -3.5%, more preferably 1% -3%, still more preferably 1% -2%; the weight percentage of the magnesium stearate, the calcium stearate, the sodium stearyl fumarate or the zinc stearate in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably 0-0.5%, preferably less than or equal to 0.5%; preferably, when the weight percentage of active ingredient in the pharmaceutical composition is ≡40% (e.g. 40% -70%, 40% -68%), the weight percentage of magnesium stearate, calcium stearate, sodium stearyl fumarate or zinc stearate in the pharmaceutical composition is less than 1%, preferably ≡0.8%, preferably ≡0.7%, preferably ≡0.6%, preferably ≡0.5%;

The disintegrating agent is selected from one of dry starch, microcrystalline cellulose, powdery cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose or crospovidone, or a combination of the crospovidone and one or more of dry starch, microcrystalline cellulose, powdery cellulose, corn starch, pregelatinized starch or low-substituted hydroxypropyl cellulose; wherein the weight percentage of the disintegrating agent in the pharmaceutical composition is 5% -35%, preferably 7% -30%, preferably 8% -20%, preferably 8% -18%, preferably 8% -15%, preferably 10% -30%, preferably 10% -20%, preferably 10% -15%;

the glidant is colloidal silicon dioxide.

Preferably, in the combination of stearic acid and hydrogenated vegetable oil, the weight percentage of the hydrogenated vegetable oil in the pharmaceutical composition is 0.5% to 4%, preferably 0.5% to 3.5%, more preferably 1% to 3%, still more preferably 1% to 2%.

In some embodiments, when the filler used comprises an ionic filler, the weight ratio of the nonionic filler to the ionic filler is from 1000 to 1:1; or 900-1: 1, a step of; 800-1:1; or 700-1:1; or 600-1:1; or 500-1:1; or 300-1:1, or 200-1:1; or 100-1:1; or 50-1:1; or 20-1:1; or 10-1:1.

In some embodiments, in the pharmaceutical composition,

the lubricant comprises stearic acid, optionally further comprising another lubricant selected from the group consisting of magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols; wherein the weight percentage of the stearic acid in the pharmaceutical composition is 1% -4%, preferably 1% -3.5%, more preferably 1% -3%, still more preferably 1% -2%; the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably 0% -0.5%, preferably less than or equal to 0.5%; preferably, when the further lubricant is an ionic lubricant (e.g. magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulphate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulphate, sodium lauryl sulphate or magnesium lauryl sulphate) and the weight percentage of active ingredient in the pharmaceutical composition is ≡40% (e.g. 40% -70%, 40% -68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ≡0.8%, preferably ≡0.7%, preferably ≡0.6%, preferably ≡0.5%;

The disintegrant is a nonionic disintegrant comprising crospovidone, optionally further comprising another disintegrant selected from the group consisting of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low substituted hydroxypropyl cellulose; wherein, the weight percentage of the crospovidone in the pharmaceutical composition is 5-20%, and more preferably 5-15%; more preferably 7% -15%; further preferably 8% -15%; further preferably 10% -15%; the weight percentage of the other disintegrating agent in the pharmaceutical composition is 0% -20%, preferably 5% -15%, preferably 0% -10%, preferably 5% -10%, preferably 10% -20%;

the glidant is colloidal silicon dioxide.

In some embodiments, when the filler used comprises an ionic filler, the weight ratio of the nonionic filler to the ionic filler is from 1000 to 1:1; or 900-1:1; 800-1:1; or 700-1:1; or 600-1:1; or 500-1:1; or 300-1:1, or 200-1:1; or 100-1:1; or 50-1:1; or 20-1:1; or 10-1:1.

In some embodiments, in the aforementioned pharmaceutical compositions,

the glidant is colloidal silicon dioxide.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof:

active ingredients: 0.5% -80%; or 1% -75%; or 5% -70%; or 5% -65%; or 5% -60%; or 5% -55%; or 5% -50%;

filler: 10% -85%; or 10% -80%; or 10% -75%;

disintegrating agent: 5% -35%; or 5% -30%; or 5% -20%; or 6% -25%;

And (3) a lubricant: 1 to 6 percent; or 1% -5%; or 1% -4%; or 1% -3.5%; or 1% -3%;

glidant: 3% -8%; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%;

the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

active ingredients: 10% -70%; or 15% -70%; or 10% -55%; or 10% -50%; or 15% -55%; or 15% -50%; or 15% -45%;

filler: 15% -70%; or 15% -65%; or 15% -60%;

disintegrating agent: 5% -35%; or 5% -30%; or 5% -20%; or 7% -20%; or 7% -30%; or 7% -25%;

and (3) a lubricant: 1 to 6 percent; or 1% -5%; or 1.5% -5%; or 1% -4%; or 1.5% -4%; or 1% -3.5%; or 1.5% -3.5%; or 1% -3%; or 1.5% -3%; or 1% -2%;

glidant: 3% -8%; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%; or 3.5% -6%; or 3.5% -5.5%; or 3.5% -5%; or 4% -6%; or 4.5% -6%; or 5% -6%;

active ingredients: 16% -68%; or 16% -60%; or 20% -55%; or 20% -50%; or 20% -45%; or 20% -40%;

filler: 15% -68%; or 17% -68%; or 15% -60%; or 15% -55%; or 17% -50%;

disintegrating agent: 7% -20%; or 8% -20%; or 7% -18%; or 8% -18%; or 8% -15%;

and (3) a lubricant: 1% -4%; or 1.5% -4%; or 1% -3.5%; or 1.5% -3.5%; or 1% -3%; or 1.5% -3%; or 1% -2%;

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 5 to 70 percent of active ingredient, 10 to 85 percent of filler, 5 to 35 percent of disintegrating agent, 1 to 4 percent of lubricant and 3 to 8 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10 to 70 percent of active ingredient, 10 to 70 percent of filling agent, 7 to 30 percent of disintegrating agent, 1 to 3.5 percent of lubricant and 3 to 7 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15 to 70 percent of active ingredient, 15 to 70 percent of filler, 7 to 25 percent of disintegrating agent, 1 to 3.5 percent of lubricant and 3 to 7 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-70% of active ingredient, 15-70% of filler, 8-20% of disintegrating agent, 1-3% of lubricant and 3-7% of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above. In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 16 to 68 percent of active ingredient, 17 to 68 percent of filler, 8 to 20 percent of disintegrating agent, 1 to 3 percent of lubricant and 3 to 7 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 16 to 68 percent of active ingredient, 17 to 68 percent of filler, 8 to 15 percent of disintegrating agent, 1 to 3 percent of lubricant and 3 to 7 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-50% of active ingredient, 30-65% of filler, 8-15% of disintegrant, 1-3% of lubricant and 3-7% of glidant, wherein the active ingredient, filler, disintegrant, lubricant and glidant are defined as above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-45% of active ingredient, 30-65% of filler, 8-15% of disintegrant, 1-3% of lubricant and 3-7% of glidant, wherein the active ingredient, filler, disintegrant, lubricant and glidant are defined as above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-45% of active ingredient, 30-65% of filler, 8-15% of disintegrant, 1-3% of lubricant and 3.5-5% of glidant, wherein the active ingredient, filler, disintegrant, lubricant and glidant are defined as above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-70% of active ingredient, 15-70% of filler, 8-30% of disintegrating agent, 1-3% of lubricant and 3-7% of glidant;

the disintegrating agent is a nonionic disintegrating agent; preferably, the nonionic disintegrant comprises crospovidone;

the lubricant comprises a non-ionic lubricant, optionally further comprising an ionic lubricant;

the glidant is colloidal silicon dioxide;

wherein the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably 0% -0.5%, preferably less than or equal to 0.5%; preferably, when the weight percentage of active ingredient in the pharmaceutical composition is ≡40% (e.g. 40% -70%, 40% -68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ≡0.8%, preferably ≡0.7%, preferably ≡0.6%, preferably ≡0.5%; preferably, the nonionic lubricant comprises stearic acid; preferably, the ionic lubricant comprises magnesium stearate;

The nonionic disintegrants, nonionic lubricants, ionic lubricants, nonionic fillers and ionic fillers are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-70% of active ingredient, 15-70% of filler, 8-20% of disintegrating agent, 1-3% of lubricant and 3-7% of glidant;

the filler comprises a non-ionic filler comprising one or more of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose; preferably, the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or a combination selected from two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose;

the lubricant comprises a non-ionic lubricant, optionally further comprising an ionic lubricant; preferably, the nonionic lubricant comprises stearic acid; preferably, the ionic lubricant comprises magnesium stearate;

The glidant is colloidal silicon dioxide;

wherein the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably 0% -0.5%, preferably less than or equal to 0.5%; preferably, when the weight percentage of active ingredient in the pharmaceutical composition is ≡40% (e.g. 40% -70%, 40% -68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ≡0.8%, preferably ≡0.7%, preferably ≡0.6%, preferably ≡0.5%;

the nonionic disintegrants, nonionic lubricants, ionic lubricants and nonionic fillers are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 16 to 68 percent of active ingredient, 17 to 68 percent of filler, 8 to 20 percent of disintegrating agent, 1 to 3 percent of lubricant and 3 to 7 percent of glidant;

the glidant is colloidal silicon dioxide;

In some embodiments, the pharmaceutical composition comprises, by total weight thereof: 16 to 68 percent of active ingredient, 17 to 68 percent of filler, 8 to 15 percent of disintegrating agent, 1 to 3 percent of lubricant and 3 to 7 percent of glidant;

the disintegrant is a nonionic disintegrant comprising crospovidone;

the lubricant comprises a non-ionic lubricant, optionally further comprising an ionic lubricant; preferably, the non-ionic lubricant comprises stearic acid and the ionic lubricant comprises magnesium stearate;

the glidant is colloidal silicon dioxide;

In some embodiments, the pharmaceutical composition according to the first or second aspect is formulated as an oral formulation; preferably, the oral formulation is an oral solid formulation; further preferably, the oral solid formulation is selected from the group consisting of capsules, tablets, powders and granules; further preferred are capsules and tablets; still more preferably a tablet; still more preferably, the tablet is a coated tablet; still more preferably, the coated tablet is a film coated tablet.

In some embodiments, the coated tablet comprises a tablet core and a coating material, wherein the tablet core comprises the aforementioned pharmaceutical composition.

The coating material disclosed by the application can also be called coating powder, coating agent or coating premix, is a mixture of various medicinal auxiliary materials, and has the main effects of coloring, taste masking, light shielding, shelf life prolonging, appearance improving and the like. The "film-coated tablet" according to the present application, which may also be referred to as "film-coated tablet", refers to a tablet having a film (coated) coating over the core (which is made from the pharmaceutical composition of the present application by tabletting). The film coating material comprises one or more of film forming materials (or film forming agents and high polymer materials), plasticizers, pore forming agents, colorants (or lakes), opacifiers and certain solid materials; further, the coating material can be dissolved in a solvent to prepare a coating liquid. Wherein the film forming material can be selected from one or more of polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose, acrylic resin, ethyl cellulose, cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate and the like; the plasticizer is selected from glycerol, propylene glycol, polyethylene glycol, monoacetin, triacetin, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, castor oil, silicone oil, corn oil, liquid paraffin, etc.; the porogen (also called release rate modifier) may be selected from sucrose, sodium chloride, surfactants, etc.; the solid material can be selected from talcum powder, magnesium stearate, colloidal silicon dioxide, caprylic acid, capric acid, mono-diglyceride, etc.; shading device The gloss agent comprises titanium dioxide; colorants conventional in the art may also be used as appropriate, for example, the colorants being selected from one or more of red ferric oxide, amaranth, carmine, lemon yellow, soluble indigo, orange G, eosin, fuchsin, merocyanine, sudan yellow, or red mercuric. The coating material can also be directly selected from commercially available premixed coating powders, for exampleA series of coating powders,A series of coating powders,A series of coating powders,A series of coating powders,The series of coating powder can also be prepared by itself. The coating material may be a gastric soluble coating material or an enteric coating material, preferably a gastric soluble coating material. The film coating weight gain is 1-5%, preferably 1.5-4%, more preferably 1.5% -3%, and even more preferably 2% -3% of the weight of the tablet core. The coating solvent is selected from water and ethanol, preferably water, which can be removed during drying without remaining in the final product. For example, the number of the cells to be processed,the series of coating powder comprises the following components: 321A620034-CN、321A630026-CN、321A610052-CN, etc.

In some embodiments, the coating material comprises a film-forming material comprising a polyvinyl alcohol polyethylene glycol copolymer; preferably, the film-forming material is selected from polyvinyl alcohol polyethylene glycol copolymer, or a combination of polyvinyl alcohol polyethylene glycol copolymer and polyvinyl alcohol.

In a third aspect, the present application provides a pharmaceutical composition suitable for oral administration comprising as active ingredient a compound of formula 2, a filler, a disintegrant, a lubricant and a glidant, wherein the lubricant is an ionic lubricant, the disintegrant is a non-ionic disintegrant, the filler comprises a non-ionic filler, the glidant is a non-ionic glidant, the non-ionic filler, the non-ionic glidant, the ionic lubricant and the non-ionic disintegrant are as defined in the first and/or second aspects hereinbefore.

In some embodiments, the compound of formula 2 is as described above in the first aspect.

In some embodiments, the weight percentage of the active ingredient in the pharmaceutical composition is < 40% (preferably less than or equal to 35%, preferably less than or equal to 34%, for example 15% -35%, 15% -34%, 20% -35%, 20% -33.5%), the weight percentage of the ionic lubricant in the pharmaceutical composition is 1% -3%, preferably 1% -2.5%, preferably 1% -2%, preferably 1% -1.5%; preferably, the ionic lubricant is magnesium stearate or sodium stearyl fumarate; magnesium stearate is further preferred.

In some embodiments, the ionic lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate; magnesium stearate is further preferred.

In some embodiments, the nonionic disintegrant is selected from one or more of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose, or crospovidone; preferably crospovidone and/or low-substituted hydroxypropylcellulose.

In some embodiments, the ionic lubricant comprises magnesium stearate and the nonionic disintegrant comprises one or both of crospovidone or low substituted hydroxypropyl cellulose.

In some embodiments, the ionic lubricant is magnesium stearate and the nonionic disintegrant is selected from crospovidone or a combination of crospovidone and low substituted hydroxypropylcellulose.

In some embodiments, the weight percentage of the active ingredient in the pharmaceutical composition is < 40%, preferably < 35%; preferably less than or equal to 34%, such as 15-38%, 15-37%, 15-36%, 15-35%, 15-34%, 16-35%, 18-35%, 16-34%, 18-34%, 20-35%, 20-33.5%.

In some embodiments, the weight percentage of the ionic lubricant in the pharmaceutical composition is 1% to 3%, preferably 1% to 2.5%, preferably 1% to 2%, preferably 1% to 1.5%.

In some embodiments, the weight percentage of the active ingredient in the pharmaceutical composition is < 40%, preferably < 35%; preferably less than or equal to 34%, such as 15-38%, 15-37%, 15-36%, 15-35%, 15-34%, 16-35%, 18-35%, 16-34%, 18-34%, 20-35%, 20-33.5%; the weight percentage of the ionic lubricant in the pharmaceutical composition is 1% -3%, preferably 1% -2.5%, preferably 1% -2%, preferably 1% -1.5%.

In some embodiments, the weight percentage of the nonionic disintegrant in the pharmaceutical composition is 8% to 40%; preferably 10% -40%; preferably 10% -35%; preferably 10% -30%; preferably 15% -40%; preferably 15% -30%; preferably 20% -30%; preferably 20% -40%; preferably 25% -40%; preferably 30 to 40%.

In some embodiments, the filler comprises a non-ionic filler selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose; preferably, the non-ionic filler comprises one or more of microcrystalline cellulose, lactose, mannitol, or pregelatinized starch; further preferably, the nonionic filler is selected from one of microcrystalline cellulose, lactose, mannitol, starch or pregelatinized starch; or a combination selected from two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose; preferably, the nonionic filler is selected from microcrystalline cellulose.

In some embodiments, the filler is a nonionic filler; preferably, the non-ionic filler comprises one or more of microcrystalline cellulose, lactose, mannitol, or pregelatinized starch; further preferably, the non-ionic filler comprises microcrystalline cellulose, optionally further comprising one or more of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose;

In some embodiments, the weight percentage of the active ingredient in the pharmaceutical composition is 5% to 45%; preferably 5% -40%; preferably 5% -35%; preferably 5% -30%; preferably 10% -40%; preferably 10% -35%; preferably 15% -35%; preferably 10% -30%; preferably 10% -27%; preferably 10% -25%; preferably 10% -20%; preferably 10% -24%; preferably 10% -23%; preferably 10% -22%; preferably 10% -21%; preferably 15% -25%; preferably 15% -20%; preferably 20% -35%; preferably 20% -30%; preferably 15% to 38%, preferably 15% to 37%, preferably 15% to 36%, preferably 15% to 35%, preferably 15% to 34%, preferably 16% to 35%, preferably 18% to 35%, preferably 16% to 34%, preferably 18% to 34%, preferably 20% to 35%, preferably 20% to 33.5%.

In some embodiments, the weight percentage of the nonionic filler in the pharmaceutical composition is 25% to 70%; preferably 28% -60%; preferably 28% -55%; preferably 28% -50%; preferably 30% -60%; preferably 35% -55%; preferably 38% -55%; preferably 25% -55%; preferably 30% -70%; preferably 35% -70%; preferably 40% -70%; preferably 40% -65%; preferably 40% -60%; preferably 40% -55%; preferably 40% -50%; preferably 35% -45%; preferably 30% -45%; preferably 30% -44%; preferably 35% to 50%.

In some embodiments, the glidant is a non-ionic glidant; preferably, the nonionic glidant is selected from colloidal silicon dioxide. Preferably, the colloidal silica is present in the pharmaceutical composition in a weight percentage of: 0% -8%; or 0% -7%; or 0.5% -7%; or 1% -7%; or 1.5% -7%; or 2% -7%; or 2.5% -7%; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10 to 35 percent of active ingredient, 30 to 65 percent of filler, 20 to 40 percent of disintegrating agent, 1 to 3 percent of lubricant and 0.5 to 5 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10-35% of active ingredient, 30-60% of filler, 20-40% of disintegrating agent, 1-2% of lubricant and 3-5% of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10 to 35 percent of active ingredient, 30 to 55 percent of filler, 20 to 40 percent of disintegrating agent, 1 to 1.5 percent of lubricant and 3 to 5 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15 to 35 percent of active ingredient, 30 to 50 percent of filler, 30 to 40 percent of disintegrating agent, 1 to 1.5 percent of lubricant and 3 to 5 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 18-35% of active ingredient, 30-50% of filler, 20-40% of disintegrating agent, 1-3% of lubricant and 3-7% of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 20-35% of active ingredient, 30-45% of filler, 20-40% of disintegrating agent, 1-3% of lubricant and 3-7% of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 20-34% of active ingredient, 30-45% of filler, 20-40% of disintegrating agent, 1-3% of lubricant and 3-7% of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 20-35% of active ingredient, 30-45% of filler, 20-40% of disintegrating agent, 1-2% of lubricant and 3-7% of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10 to 30 percent of active ingredient, 30 to 60 percent of filler, 20 to 40 percent of disintegrating agent, 1 to 1.5 percent of lubricant and 3 to 5 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10 to 35 percent of active ingredient, 28 to 50 percent of filler, 20 to 40 percent of disintegrating agent, 1 to 1.5 percent of lubricant and 3 to 5 percent of glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10-35% of active ingredient, 30-50% of filler, 20-40% of disintegrating agent, 1-2% of lubricant and 3-5% of glidant;

The disintegrating agent is a nonionic disintegrating agent; preferably, the nonionic disintegrant comprises crospovidone, optionally; further comprising a low substituted hydroxypropylcellulose;

the lubricant is magnesium stearate;

the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from the group consisting of colloidal silicon dioxide,

wherein the non-ionic disintegrant and the non-ionic glidant are as defined in the second aspect above.

Preferably, the nonionic disintegrant is selected from crospovidone or a combination of crospovidone and low substituted hydroxypropylcellulose.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10 to 35 percent of active ingredient, 30 to 55 percent of filler, 20 to 40 percent of disintegrating agent, 1 to 1.5 percent of lubricant and 3 to 5 percent of glidant;

the lubricant is magnesium stearate;

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15 to 35 percent of active ingredient, 30 to 50 percent of filler, 30 to 40 percent of disintegrating agent, 1 to 1.5 percent of lubricant and 3 to 5 percent of glidant;

the lubricant is magnesium stearate;

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 20-35% of active ingredient, 30-45% of filler, 20-40% of disintegrating agent, 1-3% of lubricant and 3-5% of glidant;

the filler comprises a non-ionic filler comprising one or more of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose; preferably, the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or a combination selected from two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose; preferably, the nonionic filler is microcrystalline cellulose;

the lubricant is magnesium stearate or sodium stearyl fumarate;

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 20-34% of active ingredient, 30-45% of filler, 20-40% of disintegrating agent, 1-2% of lubricant and 3-5% of glidant;

the lubricant is magnesium stearate or sodium stearyl fumarate;

In some embodiments, the pharmaceutical composition is formulated as an oral formulation; preferably, the oral formulation is an oral solid formulation; further preferably, the oral solid formulation is selected from the group consisting of capsules, tablets, powders and granules; further preferred are capsules and tablets; still more preferably a tablet; still more preferably, the tablet is a coated tablet.

In some embodiments, the coated tablet comprises a tablet core comprising the aforementioned pharmaceutical composition and a coating material as defined in the second aspect above.

In a fourth aspect, the present application provides a pharmaceutical composition suitable for oral administration comprising as active ingredient a compound of formula 2, a filler and a disintegrant, optionally further comprising a glidant and/or a lubricant, wherein the disintegrant is a non-ionic disintegrant, and the filler, glidant and non-ionic disintegrant are as defined in the first, second or third aspects above.

In some embodiments, when the lubricant comprises both a non-ionic lubricant and an ionic lubricant, wherein the weight percentage of the non-ionic lubricant in the pharmaceutical composition is 1% to 4%, preferably 1% to 3.5%, further preferably 1% to 3%, further preferably 1% to 2%; and, in addition, the processing unit,

(i) When the weight percentage of active ingredient in the pharmaceutical composition is equal to or greater than 40% (e.g., 40% -70%, 40% -68%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably equal to or less than 0.8%, preferably equal to or less than 0.7%, preferably equal to or less than 0.6%, preferably equal to or less than 0.5%;

(ii) The weight percentage of the active ingredient in the pharmaceutical composition is less than 40% (e.g., 15% or less than 40% by weight of the active ingredient, 16% to 35%,16% to 34%), and the weight percentage of the ionic lubricant in the pharmaceutical composition is less than or equal to 2%, preferably less than or equal to 1.5%, preferably less than or equal to 1%, preferably less than or equal to 0.8%, more preferably less than or equal to 0.7%, more preferably less than or equal to 0.6%, even more preferably less than or equal to 0.5%.

In some embodiments, when the lubricant is an ionic lubricant, the weight percentage of the active ingredient in the pharmaceutical composition is < 40% (preferably less than or equal to 35%, preferably less than or equal to 34%, for example 15% to 35%,15% to 34%,20% to 35%,20% to 33.5%), the weight percentage of the ionic lubricant in the pharmaceutical composition being 1% to 3%; preferably 1 to 2.5%, preferably 1 to 2%, preferably 1 to 1.5%; preferably, the ionic lubricant is magnesium stearate or sodium stearyl fumarate; magnesium stearate is further preferred.

In some embodiments, the lubricant comprises a non-ionic lubricant, optionally, further comprising an ionic lubricant; preferably, the lubricant is a nonionic lubricant; the non-ionic lubricant and the ionic lubricant are as defined in the second aspect hereinbefore.

Preferably, the weight percentage of the nonionic lubricant in the pharmaceutical composition is 0% to 3%, preferably 0% to 2%, preferably 0% to 1%, preferably 0.5% to 2.5%, further preferably 1% to 2%; the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably 0% -0.5%, preferably less than or equal to 0.5%.

In some embodiments, the lubricant comprises stearic acid, optionally, further comprising another lubricant selected from magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols; wherein the weight percentage of the stearic acid in the pharmaceutical composition is 1% -4%, preferably 1% -3.5%, more preferably 1% -3%, still more preferably 1% -2%; the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably between 0% and 0.5%, preferably less than or equal to 0.5%.

In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols. Preferably, the weight percentage of the lubricant in the pharmaceutical composition is 0.1% -3%; preferably 0.1% -2%; preferably 0.1 to 1.5%; preferably 0.1 to 1%.

In some embodiments, the filler comprises a non-ionic filler, optionally, further comprising an ionic filler; preferably, the filler is a nonionic filler; the non-ionic filler and the ionic filler are as defined in the second aspect hereinbefore.

In some embodiments, the non-ionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose; preferably, the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose, or the nonionic filler is a combination of two nonionic fillers, including a combination of microcrystalline cellulose and starch, or microcrystalline cellulose and pregelatinized starch, or microcrystalline cellulose and lactose, or microcrystalline cellulose and mannitol, or pregelatinized starch and lactose, or microcrystalline cellulose and dextrin, or microcrystalline cellulose and powdered sugar, or microcrystalline cellulose and sucrose; further preferably, the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose, or a combination of microcrystalline cellulose and starch, or a combination of microcrystalline cellulose and pregelatinized starch, or a combination of microcrystalline cellulose and lactose, or a combination of microcrystalline cellulose and mannitol, or a combination of pregelatinized starch and lactose. Preferably, the nonionic filler is microcrystalline cellulose.

In some embodiments, the nonionic disintegrant comprises crospovidone; preferably, the nonionic disintegrant is crospovidone.

In some embodiments, the weight percent of the disintegrant in the pharmaceutical composition is: 5% -35%; or 8% -40%; or 8% -35%; or 8% -30%; or 10% -40%; or 10% -35%; or 10% -30%; or 15% -40%; or 15% -30%; or 20% -30%; or 20% -40%; or 25% -40%; or 30% -40%; or 5% -30%; or 5% -25%; or 6% -25%; or 7% -20%; or 8% -20%; or 8% -18%; or 8% -10%; or 8% -15%; or 10% -15%.

In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols; preferably, the lubricant comprises stearic acid; preferably, the lubricant is stearic acid.

In some embodiments, the weight percent of the lubricant in the pharmaceutical composition is: 0% -6%; or 0% -5%; or 0% -4%; or 0% -3.5%; or 0% -3%; or 0% -2.5%; or 0% -2%; or 0% -1.5%; or 0% -1%.

In some embodiments, the glidant is a non-ionic glidant; preferably, the nonionic glidant is selected from colloidal silicon dioxide. Preferably, the colloidal silica is present in the pharmaceutical composition in a weight percentage of: 0% -8%; or 0% -7%; or 0% -6%; or 0% -5.5%; or 0% -5%; or 0% -4%; or 0% -3%; or 0% -2%; or 0% -1.5%; or 0% -1%; or 0% -0.5%.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 10 to 70 percent of active ingredient, 15 to 80 percent of filler, 8 to 30 percent of disintegrating agent, 0 to 3 percent of lubricant and 0 to 6 percent of glidant.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15 to 70 percent of active ingredient, 15 to 75 percent of filling agent, 8 to 20 percent of disintegrating agent, 0 to 3 percent of lubricant and 0 to 5 percent of glidant.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 16 to 68 percent of active ingredient, 17 to 75 percent of filler, 8 to 20 percent of disintegrating agent, 0 to 2 percent of lubricant and 0 to 5 percent of glidant.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 16 to 68 percent of active ingredient, 17 to 75 percent of filler, 8 to 15 percent of disintegrating agent, 0 to 2 percent of lubricant and 0 to 5 percent of glidant;

the lubricant comprises a non-ionic lubricant, optionally further comprising an ionic lubricant; preferably, the non-ionic lubricant comprises stearic acid, the ionic lubricant comprises magnesium stearate or sodium stearyl fumarate, further preferably comprises magnesium stearate;

the glidant is colloidal silicon dioxide;

wherein the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably 0% -0.5%, preferably less than or equal to 0.5%;

the non-ionic filler, non-ionic disintegrant, non-ionic lubricant or ionic lubricant is as defined in the previous (second aspect).

Preferably, the non-ionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose.

Preferably, the non-ionic filler comprises microcrystalline cellulose, or one or more of pregelatinized starch, mannitol, or lactose; preferably, the nonionic filler is selected from microcrystalline cellulose, or one of pregelatinized starch, mannitol or lactose; or a combination selected from two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose; preferably, the nonionic filler is selected from microcrystalline cellulose.

Preferably, the filler is a nonionic filler.

the glidant is colloidal silicon dioxide;

the non-ionic filler, and non-ionic disintegrant are as defined in the second aspect above.

Preferably, the non-ionic filler comprises microcrystalline cellulose, or one or more of pregelatinized starch, mannitol, or lactose; preferably, the nonionic filler is selected from microcrystalline cellulose, or one of pregelatinized starch, mannitol or lactose; or a combination selected from two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose; preferably, the nonionic filler is microcrystalline cellulose.

Preferably, the filler is a nonionic filler.

In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols; preferably, the lubricant comprises stearic acid.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-70% of active ingredient, 15-75% of filler, 8-30% of disintegrating agent, 0-3% of lubricant and 0-6% of glidant;

the filler comprises a non-ionic filler, optionally further comprising an ionic filler; the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose; the ionic filler is one or more selected from calcium sulfate, calcium hydrophosphate or calcium phosphate; preferably, the nonionic filler comprises microcrystalline cellulose;

The disintegrant is selected from nonionic disintegrants; preferably, the nonionic disintegrant comprises crospovidone;

the lubricant comprises stearic acid, optionally, further comprises another lubricant selected from one or more of magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate or polyethylene glycols;

the glidant is colloidal silicon dioxide;

wherein the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably 0% to 0.5%; preferably not more than 0.5%.

In some embodiments, the pharmaceutical composition comprises the following components by total weight thereof: 15-70% of active ingredient, 15-75% of filler, 8-20% of disintegrating agent, 0-3% of lubricant and 0-5% of glidant;

the filler is a non-ionic filler comprising microcrystalline cellulose, optionally further comprising one or more of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose; preferably, the nonionic filler is microcrystalline cellulose;

The disintegrant is a nonionic disintegrant comprising crospovidone, optionally further comprising another nonionic disintegrant selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low substituted hydroxypropyl cellulose; preferably, the nonionic disintegrant is crospovidone;

the lubricant comprises stearic acid, optionally, further comprises another lubricant selected from one or more of magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate or polyethylene glycols; preferably, the lubricant is stearic acid;

the glidant is colloidal silicon dioxide;

wherein the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably between 0% and 0.5%, preferably less than or equal to 0.5%.

In some embodiments, the pharmaceutical composition is formulated as an oral formulation, preferably the oral formulation is an oral solid formulation; preferably, the oral solid preparation is a tablet or capsule; preferably, the oral solid preparation is a capsule.

In some embodiments, each of the oral preparation or oral solid preparation of the first to fourth aspects may contain 1 to 500mg of the active ingredient, or 10 to 450mg, or 25 to 400mg, or 50 to 350mg, or 100 to 300mg, or 150 to 200mg, or 25 to 200mg; for example, a single dose form of the medicament contains 5mg, 10mg, 20mg, 25mg, 30mg, 50mg, 60mg, 100mg, 150mg, 200mg, 250mg, 300mg, 400mg, 500mg, etc. of the active ingredient; wherein the active ingredient is calculated as a compound represented by formula 2, i.e., dihydrochloride. Preferably, the dose is calculated on the compound of formula 2; further preferably, the dose is calculated as the crystalline form (anhydrous and solvent-free form) of the compound of formula 2; still more preferably, the dose is calculated as form I of the compound of formula 2.

In some embodiments, the oral preparation, oral dosage form or oral solid preparation of the foregoing first to fourth aspects contains a therapeutically effective amount of a compound represented by formula 2, which is administered in the following dosage amounts: 25mg-900mg per dose; preferably, 200mg to 800mg per administration; further preferably, 300mg to 700mg per administration; further preferably, 300mg to 600mg per administration; further preferably, 400mg to 600mg per administration; further preferably, 450mg to 600mg per administration; exemplary doses of administration include 25mg, 50mg, 100mg, 200mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, or 900mg per administration. The administration dose is calculated by the compound shown in the formula 2. Preferably, the administration dose is calculated on the compound of formula 2; further preferably, the administration dose is calculated as the crystalline form (anhydrous and solvent-free form) of the compound represented by formula 2; still more preferably, the administered dose is calculated as form I of the compound of formula 2.

In some embodiments, the oral formulation or oral solid formulation of the foregoing first to fourth aspects is administered daily at a dosage frequency of: once daily, twice daily, three times daily or four times daily; preferably once daily.

In some embodiments, the oral preparation or the oral solid preparation of the first to fourth aspects contains a therapeutically effective amount of the compound shown in formula 2, and the daily administration dose of the compound is 25mg to 900mg; preferably 200mg to 800mg; further preferably 300mg to 700mg; further preferably 300mg to 600mg; further preferably 400mg to 600mg; further preferably 450mg to 600mg; exemplary daily dosing amounts include daily dosing of 25mg, 50mg, 100mg, 200mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, or 900mg. The doses were calculated as anhydrous form of compound 2. Preferably, the administration dose is calculated on the compound of formula 2; further preferably, the administration dose is calculated as the crystalline form (anhydrous and solvent-free form) of the compound represented by formula 2; still more preferably, the administered dose is calculated as form I of the compound of formula 2.

In some embodiments, the oral preparation or the oral solid preparation of the foregoing first to fourth aspects contains a therapeutically effective amount of a compound represented by formula 2, which is administered in a dose and a dose frequency of: the medicine is administrated once a day, and 25mg-900mg is administrated each time; preferably, the administration is once daily, each time 200mg-800mg; further preferably, the administration is once daily, 300mg to 700mg per administration; further preferably, the administration is once daily, 300mg to 600mg per administration; further preferably, the administration is once daily, each time 400mg-600mg; further preferably, the administration is once daily, each time 450mg-600mg; exemplary dosages and frequencies of administration include once daily administration of 25mg, 50mg, 100mg, 200mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, or 900mg per administration. The doses are calculated as compound 2. Preferably, the administration dose is calculated on the compound of formula 2; further preferably, the administration dose is calculated as the crystalline form (anhydrous and solvent-free form) of the compound represented by formula 2; still more preferably, the administered dose is calculated as form I of the compound of formula 2.

In some embodiments, the oral preparation or the oral solid preparation of the foregoing first to fourth aspects contains a therapeutically effective amount of a compound represented by formula 2, and the administration dosage frequency is as follows: once daily for 21 days, and stopping for 7 days, wherein every 28 days is a period. In some embodiments, the oral formulation or oral solid formulation may be administered in a single dose or in divided doses; preferably, the administration is in a single dose. Preferably, the compound represented by formula 2 is in a crystalline form; further preferably, the crystalline form of the compound of formula 2 is form I.

In a fifth aspect, the present application provides the use of a pharmaceutical composition of the first to fourth aspects, an oral formulation or an oral solid formulation of the first to fourth aspects, as hereinbefore described, for inhibiting one or more activities of RET, FGFR, VEGFR, FLT, EGFR kinase or a mutant thereof.

In a sixth aspect, the present application provides a pharmaceutical composition of the first to fourth aspects, an oral formulation of the first to fourth aspects or a use of an oral solid formulation for the manufacture of a medicament.

In some embodiments, the medicament is for treating or preventing a protein kinase mediated disease, the protein kinase selected from the group consisting of: RET, FGFR, VEGFR, FLT, EGFR or mutants thereof.

In a seventh aspect, the present application provides a pharmaceutical composition of the first to fourth aspects, an oral formulation or an oral solid formulation of the first to fourth aspects, for use in the treatment of a protein kinase mediated disease, the protein kinase selected from the group consisting of: RET, FGFR, VEGFR, FLT, EGFR or mutants thereof.

In an eighth aspect, the application provides a method of treating a protein kinase mediated disease comprising: administering to a subject in need thereof a pharmaceutical composition of the first to fourth aspects, an oral formulation of the first to fourth aspects, or an oral solid formulation of the first to fourth aspects, the protein kinase selected from the group consisting of: RET, FGFR, VEGFR, FLT, EGFR or mutants thereof.

In some embodiments, the disease in the sixth, seventh, eighth aspects described above is a cell proliferative disease. Preferably, the cell proliferative disease is a tumor or cancer. Preferably, the tumor comprises thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, renal cancer, liver cancer, lung cancer or ovarian cancer. Preferably, the thyroid cancer is medullary thyroid cancer, the lung cancer is non-small cell lung cancer, and the biliary tract cancer is intrahepatic cholangiocarcinoma. Preferably, the non-small cell lung cancer is RET fusion non-small cell lung cancer.

In a ninth aspect, the present application provides a kit comprising the pharmaceutical composition of the first to fourth aspects, the oral formulation of the first to fourth aspects or the oral solid formulation of the first to fourth aspects.

In one embodiment, the kit comprises one or more containers comprising the pharmaceutical composition of the first to fourth aspects, the oral formulation of the first to fourth aspects, or the oral solid formulation of the first to fourth aspects.

In one embodiment, the kit comprises the pharmaceutical composition of the first to fourth aspects, the oral formulation of the first to fourth aspects or the oral solid formulation of the first to fourth aspects.

In a tenth aspect, the present application provides a process for the preparation of the pharmaceutical composition of the first to fourth aspects, comprising: (1) weighing: weighing the active ingredients and excipients in the prescribed amounts; (2) mixing: mixing the active ingredients and excipients in a mixing container.

In some embodiments, the pharmaceutical composition is formulated as a tablet, the method of making comprising: (1) weighing the active ingredient and excipients in prescribed amounts; (2) Adding the active ingredient and excipient 1 to a mixing vessel for mixing to produce a premix; (3) granulating; (4) total mixing: mixing the granules prepared in the step (3) with excipient 2; and (5) tabletting.

Preferably, the granulation is dry granulation.

Preferably, excipient 1 comprises a filler and a glidant, and excipient 2 comprises a disintegrant and a lubricant, optionally further comprising a filler and/or a glidant.

In some embodiments, the pharmaceutical composition is encapsulated, and the method of making comprises: (1) weighing the active ingredient and excipients in prescribed amounts; (2) Adding the active ingredient and excipient 1 to a mixing vessel for mixing to produce a premix; (3) granulating; (4) total mixing: mixing the granules prepared in the step (3) with excipient 2; and (5) filling the capsules.

Preferably, the granulation is selected from direct compression granulation or dry granulation.

[ define and explain ]

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular phrase or terminology, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

All percentages are given in weight percent of the total weight of the pharmaceutical composition and its oral formulation, unless otherwise indicated.

The term "oral formulation" or "oral dosage form" as used herein refers to a pharmaceutical formulation for oral administration.

The term "oral solid preparation" as used herein refers to a pharmaceutical preparation in a solid state for oral administration.

In embodiments of the application, the subject may be a human or non-human mammal, more preferably a human.

In embodiments of the present application, the terms "comprising," including, "and" containing "generally mean open-ended, but also include within their scope the closed-ended case defined by" consisting of … …. For example, "a pharmaceutical composition comprising: the "compound and excipient shown in formula 2" as an active ingredient also includes "a pharmaceutical composition composed of the compound and excipient shown in formula 2 as an active ingredient".

Within the scope of the present application, the various options of any feature may be combined with the various options of other features to form a number of different embodiments. The application is intended to include all possible embodiments consisting of the various options of all technical features.

The terms "optional," "optional," or "optionally" used herein mean that the subsequently described event, circumstance or circumstance may, but need not, occur, and that the event, circumstance or circumstance occurs or is not to be involved. For example, "optionally further comprising an ionic filler" means that an ionic filler may be, but is not necessarily, present, and the description includes cases where the pharmaceutical composition comprises an ionic filler and cases where it does not.

In the scope of the present application, the amount of the compound represented by formula 2 in the prescription may be appropriately adjusted, or the ratio (mass ratio) with the excipient may be adjusted to obtain pharmaceutical compositions or oral preparations containing different specifications or different drug weights, which also fall within the scope of the present application.

The terms "2θ", "2θ angle" or "2θ angle" as used herein refer to diffraction angles in degrees or degrees, and the error range of 2θ may be ±0.5°, ±0.4°, ±0.3°, ±0.2°, or ±0.1°, unless otherwise specified; in some embodiments of the application, the error range of 2θ is ±0.2°.

The term "substantially as shown in the figures" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure. Further, as the content of a certain crystal form in a product gradually decreases, some diffraction peaks ascribed to the crystal form in the powder X-ray diffraction pattern thereof may be reduced due to factors of the detection sensitivity of the instrument.

The term "characteristic diffraction peak" refers to a diffraction peak useful in representing the crystalline form in an X-ray powder diffraction pattern, which is related to the peak position, peak shape, and relative peak intensity of the diffraction peak, e.g., a small angle peak, sharp peak shape, and a diffraction peak having a relative peak intensity of at least 3% or more, or at least 5% or more, or at least 10% or more, or at least 20% or more, or at least 30% or more, or at least 40% or more, or at least 50% or more, or at least 60% or more, or at least 70% or more, or at least 75% or more.

Reference herein to "crystalline form" refers to a compound of formula 2 in crystalline form, including anhydrous and solvent-free forms, hydrated forms, and solvated forms of the compound of formula 2.

The term "solvate" or "solvate" refers to an association of a stoichiometric or non-stoichiometric ratio of a solvent molecule with a compound of formula 2 of the present application, and includes an association containing both water molecules and one or more other solvent molecules, as well as an association containing only one or more other solvent molecules.

The term "hydrate" refers to an association of water molecules in stoichiometric or non-stoichiometric proportions with the compound of formula 2 of the present application.

The "anhydrous and solvent-free form" means that no water molecules or solvent molecules are contained, or water molecules or solvent molecules coexist with the compound represented by formula 2 in a non-intermolecular force-bonded manner, for example, in an adsorption manner.

[ technical Effect ]

The pharmaceutical composition and/or the oral preparation in the application has one or more of the following beneficial technical effects:

(1) Has good dissolution effect; (2) having a acceptable active ingredient content; (3) The preparation method is simple and convenient, the preparation process is smooth, and the adopted instruments and equipment and operation process have no harsh requirements, so that the preparation method is more suitable for industrial production; (4) has good stability.

Drawings

FIG. 1 shows the XRPD patterns of form I of the dihydrochloride salt of Compound 1 from preparation 2;

figure 2 shows the XRPD pattern of form I of the dihydrochloride salt of compound 1 from preparation 2 in test example 3 after long term stability testing.

Detailed Description

The technical scheme of the application will be further described in detail below with reference to specific preparation examples and examples. The following preparations and examples are illustrative of the present application and should not be construed as limiting the scope of the application. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible and can be made without departing from the scope of the application. Unless otherwise indicated, the starting materials, reagents (e.g., organic solvents, inorganic solvents, buffers, excipients, etc.), used in the following preparation examples and examples, are all commercially available, or may be prepared or formulated by known methods or reagent specifications.

In the following preparation examples, the analytical detection conditions were as follows:

1. content or related substance testing

Detection instrument: agilent 1260 (LC 1260-3-DAD) high performance liquid chromatograph

Column: c18 4.6X105 mm,5 μm

Test conditions: a wavelength of 252nm; column temperature 40+ -5 ℃.

2. Solubility (Water, pH2.0 buffer)

Detection instrument: agilent 1260 high performance liquid chromatograph

Detection medium: purified water, pH2.0 phosphate-disodium hydrogen phosphate buffer

Preparing a reference substance solution: taking a proper amount of the compound of formula 1 as a reference substance, precisely weighing, adding a solvent to completely dissolve the compound, diluting the compound to prepare a solution of 100 mug/mL, precisely weighing 10uL, and measuring the content of the compound 1 in the reference substance solution by using HPLC.

3. X-ray powder diffraction (X-RayPowderDiffraction, XRPD)

Detection instrument: bruker D2PHASER powder X-ray diffractometer

Test conditions:

type of light pipe: a Cu target, a ceramic X-ray tube;

x-ray wavelength: the composition of cukα,1.5406；

voltage current: 30kV,10mA;

scanning range: 3-40 degrees 2 theta;

scanning total time: for 40min;

scanning speed: 0.5 seconds/step;

sample dosage: 3mg of

And (3) acquisition software: diffrac Plus XRD Commander

Analysis software: MDI Jade 6.0.

4 differential scanning calorimeter-thermogravimetric analysis (Dimrentila ScanningCalorimetric-ThermogravimetricAnalysis, DSC-TGA)

Detection instrument: NETZSCH STA449F3 synchronous thermal analyzer

The testing method comprises the following steps: the sample (about 3 mg) was weighed and placed in an alumina crucible for testing, and the sample was heated from 20℃to 340℃at a heating rate of 10K/min under a condition of 20mL/min of dry nitrogen (shielding gas).

Instrument control software: NETZSCH-protein

Analysis software: protein Analysis.

5. Chlorides (CPS)

Detection instrument: dynamics-900 ion chromatograph

Column: dionex Ion Pac AS11-HC anion chromatographic column (specification: 4X 250 mm)

Experimental operation:

sample solution preparation: taking a proper amount of the test sample, precisely weighing, dissolving with a leaching solution (12.5 mmol/L sodium hydroxide solution) and quantitatively diluting to obtain a solution containing about 0.5mg of the test sample in each 1mL, and shaking uniformly to obtain the test sample solution.

Preparing a reference substance solution: proper amount of sodium chloride (corresponding to 18mg of chloride ions) is taken, precisely weighed, placed in a 250mL measuring flask, dissolved by leacheate, fixed in volume and shaken uniformly to serve as a reference substance solution.

Assay: precisely measuring 10 mu L of each of the reference solution and the sample solution, respectively injecting into an ion chromatograph, recording the chromatograms, and calculating the chloride ion content according to an external standard method by using the peak area.

6. Nuclear magnetic hydrogen spectrum

Instrument model: bruker Advance 600 type nuclear magnetic resonance spectrometer

Measurement conditions: the test was carried out at room temperature (. About.25 ℃) using DMSO-d6 as solvent.

7. Determination of solubility in biological menstruum

The formulation procedure of the biological vehicle media (SGF, feSSIF and FaSSIF) for the solubility determination is shown in table 1 below:

TABLE 1

The testing method comprises the following steps: and adding the sample to be tested into a biological solvent medium to prepare a solution or suspension with the target concentration of 10 mg/mL. The resulting solution or suspension was continuously shaken at 37℃at 200 rpm. The suspension was filtered at 0.5 hours and the concentration of compound in the filtrate was determined using HPLC.

8. Dissolution measurement

Dissolution medium: 1000ml of water

The dissolution method comprises the following steps: second method for preparing 0931 of four parts of Chinese pharmacopoeia 2020 edition

Rotational speed: 50rpm

Preparation example 1 preparation of Compound 1

Compound 1 was prepared using the procedure in CN106660970B (example 22).

Preparation example 2 preparation of dihydrochloride salt of Compound 1

Compound 1 (10 g,21.58 mmol) obtained in preparation example 1 was weighed into a eggplant-type bottle, methanol solvent (110 mL) was added, the temperature was raised to 55±5 ℃, hydrochloric acid (3.7 mL,44.4 mmol) was added dropwise to the solution, stirring was carried out for 20 minutes, 200mL of ethyl acetate was slowly added, the temperature was lowered to 5±5 ℃, stirring was carried out for 2±1 hour, suction filtration was carried out, and the filter cake was washed with ethyl acetate (20 mL), thus obtaining dihydrochloride (11 g) of compound 1 in white color, yield 94.8%.

¹ H-NMR(600MHz,DMSO-d ₆ )δ:15.41(s,1H),11.78(s,1H),10.44(s,1H),8.80(s,1H),8.42(s,1H),7.78(dd,J＝9.6Hz，J＝2.4Hz,1H),7.58-7.52(m,2H),7.47(s,1H),4.24(t,J＝6Hz,2H),4.03(s,3H),3.15-3.14(m,2H),2.76-2.75(m,6H),1.90-1.88(m,4H).

The chloride ion content was determined by ion chromatography and the stoichiometric ratio of the hydrochloride salt was calculated (see table 2 below) and it was concluded that the alkali/acid ratio of the hydrochloride salt was 1:2.

TABLE 2

The obtained hydrochloride sample was subjected to X-ray powder diffraction, which showed good crystallinity, and was designated as form I of dihydrochloride, whose XRPD characterization pattern is shown in fig. 1, and diffraction peak data is shown in table 3. Samples were taken for DSC-TGA testing, with two endothermic peaks, endothermic peak 1: having an endothermic peak onset at 219.1 ℃ and peak around 231.0 ℃; endothermic peak 2: an endothermic peak at 235.1℃was initiated, a peak was reached around 284.2℃and decomposition occurred around 205 ℃. The PLM plot shows that the crystalline particles are in a regular morphology.

TABLE 3 XRPD diffraction peak data for Crystal form I of dihydrochloride obtained in preparation example 2

Test example 1 solubility test

The sample of preparation 2 was taken and subjected to solubility test in water and pH2.0 buffer, and the test results are shown in Table 4 below:

TABLE 4 solubility results

Results: the sample of preparation 2 has high solubility in both water and pH2.0 buffer, and although the solubility of preparation 2 is reduced compared with the solubility in water under acidic conditions, the sample still has a solubility of >10mg/mL, which meets the preparation requirements.

According to the general requirement of the drug formulation on the solubility of the bulk drug, the solubility of the solid oral formulation in water is required to be more than 0.1g/L, and the solubility of the drug is required to be more than 10g/L for solution preparations such as injection or oral liquid, and more importantly, the solubility of the drug is required to meet the clinically required dosage concentration. Based on the solubility results of Table 4, the dihydrochloride of preparation example 2 can be considered for preparing solid oral dosage forms, and can be further considered for preparing solution preparations such as injections or oral liquids.

Test example 2 solubility test in biological Medium

A sample (20 mg) of preparation 2 was weighed, and a different biological vehicle (2 mL) was added to conduct a solubility test, and the results are shown in Table 5.

TABLE 5 solubility of samples in different biological vehicles

Results: the sample obtained in the preparation example 2 can keep good solubility in different biological solvents and has high dissolution speed.

Test example 3 stability test

Taking a proper amount of salt sample obtained in preparation example 2, placing a polyethylene film seal for 5 months at 40+/-2 ℃ and 75+/-5% RH, and testing the salt sample, wherein the result is as follows:

TABLE 6 stability results and Crystal form detection results of samples

TABLE 7 XRPD data sheet for the crystal samples of PREPARATIVE EXAMPLE 2 after stability testing

XRPD patterns of crystalline form I of the dihydrochloride salt of compound 1 from preparation example 2 after stability testing are shown in fig. 2.

Results: the dihydrochloride salt of the compound 1 obtained in the preparation example 2 can maintain chemical stability and crystal form stability, and accords with the storage regulations as a raw material medicine.

Test example 4 solid stability test

The dihydrochloride salt of preparation 2 was taken and placed under 40 ℃/75% RH (open) conditions for 7 days, respectively, and stability test was performed, and the results are shown in Table 8.

TABLE 8 stability results and Crystal form detection results

Results: the dihydrochloride of the compound 1 obtained in the preparation example 2 can maintain chemical stability and crystal form stability after being placed for 7 days under the condition of 40 ℃/75% RH (opening), so that the sample obtained in the preparation example 2 has better thermal stability and meets the requirement of being stored as a bulk drug.

Test example 5 mechanical stability test

The appropriate amount of dihydrochloride in preparation example 2 was taken and subjected to mechanical grinding for 5 minutes, and then subjected to X-ray powder diffraction, and the result shows that the crystal form was unchanged.

Example 1 tablets of Compound 2

Table 9. Prescription of example 1 (1000 tablets)

The dry granulation process is used, and the specific method comprises the following steps: 1) Weighing or preparing materials: weighing an active ingredient (API) compound 2 and corresponding fillers, disintegrants, glidants and lubricants according to the prescription amount; 2) Premixing: adding the active ingredients, the filling agent and the glidant into a mixing container for premixing to obtain premixed powder; 3) Granulating: dry granulating with premixed powder; 4) Total mixing: mixing the granules obtained by dry granulation with a disintegrating agent and a lubricant to obtain total mixed powder; 5) Tabletting: the total mixed powder is tabletted by a tablet press.

As a result, the tablet has the advantages of smooth tabletting process, no sticking and punching, qualified content of the prepared tablet core, quick dissolution and qualified prescription.

Example 2 tablets of Compound 2 (composition and/or weight ratio of Lubricant was adjusted)

With reference to the preparation method of example 1, the amount or composition of the lubricant was adjusted to obtain tablets of examples 2-1 to 2-6.

Table 10. Prescription of example 2 (1000 tablets)

The tablet has the advantages of smooth tabletting process, no sticking and punching, qualified content of the prepared tablet core, quick dissolution, and qualified prescription, and meets the preparation requirement.

Table 10-1. Prescription of example 2 (1000 tablets)

Example 3 examination of Compound 2 tablet (Ionic Lubricant)

With reference to the preparation method of example 1, magnesium stearate was used as a lubricant, and the amount of magnesium stearate was adjusted to obtain examples 3-1, 3-2 and 3-3.

Table 11. Prescription of example 3 (1000 tablets)

As a result, the formulations of example 3-1 and example 3-2 failed, and the dissolution was slow; further reduction of magnesium stearate yields examples 3-3, which, although dissolution was satisfactory, exhibited sticking during tabletting, and failed the formulation of examples 3-3.

With reference to the preparation method of example 1, attempts were made to adjust the disintegrant on the basis of the prescription of example 3-1, resulting in examples 3-4, 3-5 and 3-6.

Table 12. Prescription of example 3 (1000 tablets)

As a result, the obtained prescription tablet has smooth tabletting process, no sticking and punching, the prepared tablet core content meets the requirements, the dissolution is quick, and the prescription is qualified. It is understood that, in addition to the prescription of example 3-2, a satisfactory prescription can be obtained by adjusting the disintegrant with reference to the prescription of example 3-6.

Referring to the preparation method of example 1, the kinds of lubricants were changed on the basis of example 1, resulting in examples 3 to 7 and examples 3 to 8.

Table 13. Prescriptions for examples 3-7 and examples 3-8 (1000 tablets)

As a result, on the basis of the prescription of example 1, sodium stearyl fumarate was used as a lubricant, but the amount was kept unchanged, and the obtained prescriptions (examples 3-7) showed significant sticking during tabletting, and the prescriptions were unacceptable; the dosage proportion of the sodium stearyl fumarate is further improved, the obtained prescription (examples 3-8) still has the sticking phenomenon in the tabletting process, and the prescription is unqualified.

With reference to the formulations of examples 3-6 and the preparation method of example 1, the kinds of lubricants were changed to obtain examples 3-9.

Table 13-1. Prescriptions for examples 3-9 (1000 tablets)

And finally, the obtained prescription is qualified.

Example 4 tablets of Compound 2 (Conditioning of the amount of glidant)

With reference to the preparation method of example 1, the amount of lubricant was reduced to give example 4-1, and further, based on example 4-1, the amount of glidant was adjusted to give examples 4-2 and 4-3.

Table 14. Prescription of example 4 (1000 tablets)

As a result, the lubricant consumption is reduced to 1 percent (example 4-1), the tabletting process is smooth, the content and the dissolution meet the requirements, and the prescription is qualified; based on the embodiment 4-1, the proportion of the glidant is reduced to 3 percent to obtain the embodiment 4-2, the tabletting process is smooth, the content and the dissolution meet the requirements, and the prescription is qualified; and (3) improving the glidant to 7%, so as to obtain the embodiment 4-3, wherein the obtained prescription tablet has smooth process, and the content and the dissolution meet the requirements, and the prescription is qualified.

Example 5 tablets of Compound 2 (examination of disintegrants)

With reference to the prescription and preparation method of example 1, the amount of the disintegrant or the composition of the disintegrant was adjusted to obtain examples 5-1, 5-2 and 5-3.

Table 15. Prescription of example 5 (1000 tablets)

As a result, on the basis of the prescription of example 1, the dosage of the disintegrating agent is reduced (example 5-1) or the dosage of the disintegrating agent is increased (example 5-2), the obtained prescription is smooth in tabletting process, the content and the dissolution meet the requirements, and the prescription is qualified. Further, a combination of two disintegrants was used (examples 5-3), and the resulting formulation was acceptable.

Referring to the preparation method of example 1, the kinds of disintegrants were changed to obtain examples 5 to 4 and examples 5 to 5.

Table 16. Prescriptions for examples 5-4 and examples 5-5 (1000 tablets were prepared)

As a result, when a plasma disintegrant such as croscarmellose sodium (examples 5 to 4) or sodium carboxymethyl starch (examples 5 to 5) was used, the content of the active ingredient (API) in the obtained formulation was significantly reduced and the formulation was not acceptable although the tabletting process was smooth.

With reference to the formulations of examples 5-3 and the preparation method of example 1, the amounts of disintegrants were adjusted to obtain examples 5-6 and examples 5-7.

Table 15-1. Prescription of example 5 (1000 tablets)

As a result, on the basis of the prescription of the embodiment 5-3, the dosage of the disintegrating agent is reduced, the tabletting process of the obtained prescription is smooth, the content and the dissolution meet the requirements, and the prescription is qualified.

Example 6 tablets of Compound 2 (Single filler, type adjustment)

With reference to the prescription and preparation method of example 1, the types of fillers were adjusted using a single filler, to obtain examples 6-1, 6-2 and 6-3.

Table 17. Prescription of example 6 (1000 tablets)

As a result, when a single filler was used, microcrystalline cellulose was replaced with lactose (example 6-1), pregelatinized starch (example 6-2) or mannitol (example 6-3), respectively, and the obtained tablets were subjected to a smooth process, and were qualified in content and dissolution, and the formulation was qualified.

Example 7 tablets of Compound 2 (combination of two fillers)

With reference to the formulation and preparation method of example 1, a combination of two fillers was used to give examples 7-1, 7-2 and 7-3.

Table 18. Prescription of example 7 (1000 tablets)

As a result, the single filler (microcrystalline cellulose) is replaced by the combination of the two fillers, the obtained prescription tablet is smooth in the process, and the content and the dissolution are qualified, and the prescription is qualified.

Example 8 tablets of Compound 2 (adjustment of the amount of active ingredient)

The amounts of the active ingredients (APIs) were adjusted with reference to the preparation method of example 1 and the formulation of example 2-3 to obtain examples 8-1, 8-2 and 8-3.

Table 19. Prescription of example 8 (1000 tablets each)

As a result, the dosage of the active ingredients is regulated, the obtained prescription tablet is smooth in the process, the content and the dissolution are qualified, and the prescription is qualified.

Example 9 tablets of Compound 2 (with different coating materials)

With reference to the preparation method of example 1 and the formulation of examples 2-3, tablet cores were prepared and coated with different coating materials to give examples 9-1, 9-2, 9-3 and 9-4.

Table 20 coating materials and results of example 9 (1000 tablets each)

As a result, the coated tablet has good appearance, high coating speed and high coating efficiency, and is beneficial to reducing production cost.

Example 10 Capsule of Compound 2

Table 21. Prescription of example 10-1 (1000 granules)

The preparation method comprises the following steps of 1) weighing or preparing materials: weighing an active ingredient (API) compound 2 and corresponding fillers, disintegrants, glidants and lubricants according to the prescription amount; 2) Premixing: adding the active ingredients, the filling agent and the glidant into a mixing container for premixing to obtain premixed powder; 3) Granulating: dry granulating with premixed powder; 4) Total mixing: mixing the granules obtained by dry granulation with a disintegrating agent and a lubricant to obtain total mixed powder; 5) Filling capsules: and filling the total mixed powder into capsules.

As a result, the content was found to be acceptable and the dissolution was rapid, and the obtained formulation of example 10-1 was found to be acceptable.

Table 22. Prescriptions (1000 grains) of examples 10-2, 10-3 and 10-4

As a result, when the lubricant was not used (example 10-2) on the basis of the prescription of example 10-1, the obtained prescription was acceptable; when the glidant proportion was further reduced based on the prescription of example 10-2 (example 10-3), the obtained prescription was also acceptable; on the basis of the prescription of example 10-3, no glidant was added (example 10-4), and the obtained prescription was acceptable.

Example 11 Capsule of Compound 2

With reference to the prescriptions of examples 10-1, 10-2 and 10-4 and the preparation method of example 10-1, the amounts of the active ingredients were changed to obtain examples 11-1 to 11-9, respectively.

Table 23. Prescriptions for examples 11-1, 11-2 and 11-3 (1000 granules were prepared)

Table 24. Prescriptions for examples 11-4, 11-5 and 11-6 (1000 granules were prepared)

Table 25. Prescriptions for examples 11-7, 11-8 and 11-9 (1000 granules were prepared)

Results: the prescriptions corresponding to the examples in tables 23, 24 and 25 were all acceptable.

Test example 6 compatibility test of active ingredient with auxiliary Material

The compatibility test is carried out by using the active ingredient and different excipients, and the content of the relevant substances is respectively detected under the conditions of light 4500lx, high temperature 60 ℃, high humidity 75%RH + -5%RH and high humidity 92.5%RH + -5%RH, so that the result shows that the active ingredient (the compound shown in the formula 2) has good compatibility with the detected excipients (especially non-ionic excipients) and the relevant substances have no obvious increase.

Test example 7 accelerated stability test

The oral formulations obtained in each example were individually subjected to aluminum blister packaging and stability testing (accelerated conditions, temperature 40 ℃ + -2 ℃ C., relative humidity 75% + -5%) with the stability results of the exemplary examples shown in the following table.

TABLE 26 results of stability data for acceleration (40 ℃ C.)

TABLE 27 results of stability data for acceleration (40 ℃ C.)

TABLE 27-1 results of stability data for acceleration (40 ℃ C.)

Conclusion that the oral formulations (tablets or capsules) obtained in the four examples in Table 26, table 27 and Table 27-1 all have the characteristic of good stability, the related substances are not obviously increased, the dissolution in water is maintained stable, and the content meets the requirements. Other qualified prescriptions in the application also have the characteristic of good stability, and the dissolution rate and the content in water at the inspection time point meet the requirements.

Test example 8 Long term stability test

The oral formulations obtained in each example were individually subjected to aluminum blister packaging and stability testing (30 ℃ + -2 ℃/65% RH+ -5% RH), the stability results of the exemplary examples are shown in the following table.

TABLE 28 stability data results

TABLE 29 stability data results

Conclusion that the oral formulations (tablets) obtained in the three examples in Table 28 and Table 29 have the characteristics of good long-term stability, no obvious increase of related substances, stable dissolution in water and satisfactory content. Other qualified prescriptions in the application also have the characteristic of good stability, and the dissolution rate and the content in water at the inspection time point meet the requirements.

Claims

A pharmaceutical composition which is suitable for oral administration and comprises a compound represented by formula 2 as an active ingredient and an excipient,

wherein the excipient comprises a disintegrant and a filler, the disintegrant being a non-ionic disintegrant, optionally the excipient further comprising a glidant and/or a lubricant.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated in an oral formulation; preferably, the oral formulation is an oral solid formulation; more preferably, the oral solid preparation is a tablet or capsule.
The pharmaceutical composition according to claim 1 or 2, wherein each formulation unit of the oral formulation comprises 1mg to 500mg, or 10 to 450mg, or 25 to 400mg, or 50 to 350mg, or 100 to 300mg, or 150 to 200mg, or 25 to 200mg of active ingredient.
A pharmaceutical composition according to any one of claims 1 to 3, wherein the active ingredient is present in an amount of 0.5% to 80% by weight, based on the total weight of the pharmaceutical composition; or 1% -75%; or 5% -70%; or 10% -70%; or 15% -70%; or 16% -68%; or 16% -67%; or 20% -70%; or 20% -67%; or 5% -65%; or 5% -60%; or 5% -55%; or 5% -50%; or 10% -55%; or 10% -50%; or 15% -55%; or 15% -50%; or 15% -45%; or 20% -50%; or 20% -45%; or 20% -40%.
The pharmaceutical composition of any one of claims 1 to 4, wherein the weight percentage of the nonionic disintegrant in the pharmaceutical composition is 8% -40%; preferably 8% -30%; preferably 10% -40%; preferably 10% -35%; preferably 10% -30%; preferably 15% -40%; preferably 15% -30%; preferably 20% -30%; preferably 20% -40%; preferably 25% -40%; preferably 30 to 40%.
The pharmaceutical composition of any one of claims 1 to 5, wherein the filler is present in the pharmaceutical composition in a weight percentage of: 10% -85%; or 10% -80%; or 15% -75%; or 17% -68%; or 15% -70%; or 15% -65%; or 20% -65%; or 30% -65%; or 30% -60%; or 30% -55%; or 30% -50%; or 35% -50%; or 40% -55%.
The pharmaceutical composition of any one of claims 1 to 6, wherein the weight percent of lubricant in the pharmaceutical composition is: 0% -6%; or 0% -5%; or 0% -4%; or 0% -3.5%; or 0% -3%; or 0% -2.5%; or 0% -2%; or 0% -1.5%; or 0% -1%; or,

The weight percentage of the lubricant in the pharmaceutical composition is as follows: 1 to 6 percent; or 1% -5%; or 1.5% -5%; or 1% -4%; or 1.5% -4%; or 1% -3.5%; or 1.5% -3.5%; or 1% -3%; or 1% -2%; or 1.5% -3%; or 2% -3.5%.
The pharmaceutical composition of claim 7, wherein:

(1) The lubricant is an ionic lubricant, the weight percentage of the active ingredient in the pharmaceutical composition is less than 40%, and the weight percentage of the ionic lubricant in the pharmaceutical composition is 1% -3%; preferably 1 to 2.5%, preferably 1 to 2%, preferably 1 to 1.5%; or alternatively

(2) The lubricant comprises a nonionic lubricant and an ionic lubricant, wherein the weight percentage of the nonionic lubricant in the pharmaceutical composition is 1-4%, preferably 1-3.5%, more preferably 1-3%, and even more preferably 1-2%; and is also provided with

(i) The weight percentage of the active ingredient in the pharmaceutical composition is greater than or equal to 40%, the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8%, preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably less than or equal to 0.5%; or alternatively

(ii) The weight percentage of the active ingredient in the pharmaceutical composition is less than 40%, the weight percentage of the ionic lubricant in the pharmaceutical composition is less than or equal to 2%, preferably less than or equal to 1.5%, preferably less than or equal to 1%, preferably less than or equal to 0.8%, more preferably less than or equal to 0.7%, more preferably less than or equal to 0.6%, more preferably less than or equal to 0.5%.
The pharmaceutical composition of any one of claims 1 to 8, wherein the glidant is present in the pharmaceutical composition in weight percent: 0% -8%; or 0% -7%; or 0% -6%; or 0% -5.5%; or 0% -5%; or 0% -4%; or 0% -3%; or 0% -2%; or 0% -1.5%; or 0% -1%; or 0% -0.5%; or,

the glidant accounts for 3 to 8 percent of the weight of the pharmaceutical composition; or 3% -7%; or 3% -6%; or 3% -5.5%; or 3% -5%; or 3.5% -7%; or 4% -7%; or 4.5% -7%; or 5% -7%; or 4% -7%; or 4% -6%.
The pharmaceutical composition of any one of claims 1 to 9, wherein the non-ionic disintegrant is selected from one or more of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropylcellulose, or crospovidone;

Preferably, the nonionic disintegrant is selected from one of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose, or crospovidone, or a combination of crospovidone and one or more of dry starch, microcrystalline cellulose, polyvinylpyrrolidone, corn starch, pregelatinized starch, or low substituted hydroxypropyl cellulose;

more preferably, the nonionic disintegrant is selected from the group consisting of crospovidone, and low substituted hydroxypropylcellulose.
The pharmaceutical composition of any one of claims 1 to 10, wherein the filler comprises a non-ionic filler, optionally further comprising an ionic filler;

preferably, the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose;

further preferably, the nonionic filler is selected from microcrystalline cellulose, or one of pregelatinized starch, mannitol, or lactose; or a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose, or a combination of microcrystalline cellulose and dextrin, or a combination of microcrystalline cellulose and powdered sugar, or a combination of microcrystalline cellulose and sucrose.
The pharmaceutical composition of any one of claims 1 to 11, wherein the pharmaceutical composition comprises a lubricant, when the lubricant comprises a non-ionic lubricant, the non-ionic lubricant is selected from one or more of stearic acid, palmitic acid, glyceryl palmitostearate, glyceryl behenate, hydrogenated vegetable oil, talc or polyethylene glycols; preferably stearic acid; and/or

When the lubricant comprises an ionic lubricant, the ionic lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate; more preferably magnesium stearate.
The pharmaceutical composition of any one of claims 1 to 12, wherein the pharmaceutical composition comprises a glidant, and wherein the glidant is a non-ionic glidant; preferably, the nonionic glidant is selected from colloidal silicon dioxide.
The pharmaceutical composition of any one of claims 1 to 13, the excipient comprising a filler, a disintegrant, a lubricant and a glidant, wherein the disintegrant is a non-ionic disintegrant, the lubricant comprising a non-ionic lubricant, optionally further comprising an ionic lubricant.
The pharmaceutical composition of any one of claims 1 to 14, wherein the excipient comprises a filler, a disintegrant, a lubricant and a glidant, wherein the disintegrant is a non-ionic disintegrant, the lubricant is an ionic lubricant, the filler comprises a non-ionic filler, and the glidant is a non-ionic glidant.
Use of a pharmaceutical composition according to any one of claims 1 to 15 for the preparation of a medicament.
The use of claim 16, wherein the medicament is for the treatment or prevention of a protein kinase mediated disease, the protein kinase being selected from the group consisting of: RET, FGFR, VEGFR, FLT, EGFR and mutants thereof.
The use of claim 17, wherein the disease is a cell proliferative disease;

preferably, the cell proliferative disease is a tumor or cancer;

more preferably, the tumor comprises thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, renal cancer, liver cancer, lung cancer, and ovarian cancer;

more preferably, the thyroid cancer is medullary thyroid cancer, the lung cancer is non-small cell lung cancer, and the biliary tract cancer is intrahepatic cholangiocarcinoma;

Further preferably, the non-small cell lung cancer is RET fusion non-small cell lung cancer.