WO2022042738A1 - Pharmaceutical composition containing cdk4/6 inhibitor - Google Patents

Abstract

Disclosed is a pharmaceutical composition containing 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-N-(5-(1-methylpiperidine-4-yl)pyridine-2-yl)pyrimidine-2-amine as an active ingredient or a pharmaceutically acceptable salt thereof and a diluent. The pharmaceutical composition is quick to dissolve, has improved solubility, stability and fluidity, has reduced moisture absorption and food effect risks, and has stable and controllable quality. In addition, the pharmaceutical composition has a simple preparation formula and process and is more suitable for industrial mass production.

Description

A kind of pharmaceutical composition containing CDK4/6 inhibitor technical field

The invention belongs to the field of pharmaceutical preparations, in particular to a kind of 5-fluoro-4-(7'-fluoro-2'-methyl spiro[cyclopentane-1,3'-indol]-5'-yl)-N A pharmaceutical composition of -(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine or a pharmaceutically acceptable salt thereof.

Background technique

The cell cycle is an important part of cell life activities. In the normal cell growth process, the realization of the cell cycle process depends on the precise and tight regulation of the cell cycle by various regulatory factors. The core of these regulatory factors is cyclin-dependent protein kinase (Cyclin Dependent Kinase, CDK) and its positive and negative regulators - cyclin (Cyclin) and cyclin-dependent protein kinase inhibitor (CDI). The CDK-Cyclin complex formed by cyclin-dependent protein kinases and cyclins is involved in cell growth, proliferation, dormancy or entering apoptosis. During the cell cycle, cyclins are periodically and continuously expressed and degraded, and respectively bind to their transiently activated CDKs. Through CDK activity, they catalyze the phosphorylation of different substrates to achieve the advancement of different phases of the cell cycle. and transformation.

At present, 13 members of the CDK family have been found, namely CDK1-CDK13; CDK1, CDK2, CDK3, CDK4 and CDK6 are involved in regulating cell proliferation, and CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13 are involved in regulating transcription.

Cyclin is divided into A-L subtypes, and different CDKs are connected to different subtypes of Cyclin. Among them, Cyclin D family (Cyclin D1, D2, D3) begins to express in G1 phase, binds and activates CDK4 and CDK6, and forms CDK4/6-Cyclin D complex, including retinoblastoma protein (Rb) phosphorylation of a series of substrates. After Rb is phosphorylated, it releases the proteins that bind to it and are inhibited by it, mainly transcription factors E2F, etc. E2F activates and transcribes some genes necessary for entering the S phase (Ma Ke, Research Progress in Anti-tumor Effects of CDK4/6 Inhibitors, "Foreign Studies" Medicine and Antibiotics Volume, 2013, 34(5): 197-202). If the balance is disturbed due to various factors, whether the signal that promotes cell proliferation is increased, or the signal that inhibits cell proliferation is weakened to a certain extent, cell proliferation will be out of control, and tumors will appear. Studies have found that about 80% of human tumors have abnormalities in the Cyclin D-CDK4/6-INK4-Rb pathway (1.Malumbres M, Barbacid M., To cycle or not to cycle: a critical decision in cancer[J]. Nature Reviews Cancer, 2001, 1(3): 222; 2. Shapiro GI., Cyclin-dependent kinase pathways as targets for cancer treatment [J]. J Clinical Oncology, 2006, 24(11): 1770). Alteration of this pathway accelerates the G1 phase process, allowing tumor cells to proliferate faster and gain a survival advantage. Therefore, its intervention has become a therapeutic strategy, and CDK4/6 has thus become one of the potential anti-tumor targets.

The advantages of CDK4/6 as an anti-tumor target are: (1) Most proliferating cells depend on CDK2 or CDK4/6 for proliferation, but CDK4/6 inhibitors do not show the cytotoxicity of "pan-CDK inhibitors", such as Myelosuppression and intestinal reaction; (2) Preclinical experiments have shown that if the level of Cyclin D in cells is increased or p16INK4a is inactivated, the sensitivity of cells to drugs can be increased. increased drug targeting.

The applicant applied for a series of new substituted 2-(pyridin-2-yl)aminopyrimidine compounds (WO2017/092635A1), which showed good and highly selective activities against CDK4/6. Among them, the patent document WO2017/092635A1 discloses the compound of formula (I)

Its chemical name is: 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1 -Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (hereinafter referred to as "Compound 1"), the synthesis method is specifically described in Example 17.

However, the above-mentioned patent documents do not disclose how to obtain a pharmaceutical composition with rapid dissolution and stability. Compound 1 has poor solubility. At the same time, some salts of compound 1 have the characteristics of hygroscopicity, and have the defects of poor fluidity and low bulk density, so it is necessary to provide a compound that dissolves rapidly and has improved solubility, stability, fluidity and reduced hygroscopicity. Pharmaceutical compositions, thereby solving the process problems of their application, storage and scale-up production.

SUMMARY OF THE INVENTION

A technical problem to be solved by the present invention is to provide a pharmaceutical composition based on compound 1 as an active ingredient that meets the needs of oral administration.

Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved solubility properties and lower risk of food effects.

Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with reduced hygroscopicity.

Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved fluidity.

Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved dissolution properties.

Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved stability.

Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient having two or more of the above properties (preferably having all of the above properties).

Another technical problem to be solved by the present invention is to provide a solid oral pharmaceutical preparation made from the above-mentioned pharmaceutical composition.

In the course of research to obtain the desired pharmaceutical composition based on Compound 1 as an active ingredient and solid oral pharmaceutical preparations thereof, the inventors have carried out careful screening experiments on the formulation of the pharmaceutical composition, and have found that the The formula composition of the specific pharmaceutical composition can solve the above technical problems, thus completing the present invention. Accordingly, the present invention provides a pharmaceutical composition using Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient, the pharmaceutical composition dissolves rapidly, has improved solubility, stability, fluidity and reduced moisture absorption Sexual and food effect risks, and the quality is stable and controllable.

Specifically, the present invention provides a pharmaceutical composition containing, as an active ingredient, 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3] '-Indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine or a pharmaceutically acceptable salt thereof and dilution It is characterized in that the diluent is selected from one or more of microcrystalline cellulose, lactose or its hydrate, and sugar alcohol.

The inventors found that when the diluent of the present invention is used, the fluidity of the obtained pharmaceutical composition powder can be significantly improved, and the obtained pharmaceutical composition has a larger bulk density and smaller Carr's index and angle of repose , and the powder color of the pharmaceutical composition is uniform and no color difference.

In one embodiment, the pharmaceutically acceptable salt is selected from 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate, maleate, adipate and succinic acid one or more of the salts. In another embodiment, the pharmaceutically acceptable salt is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate (hereinafter referred to as "Compound A").

The inventors have found that when the salts of the present invention are used, the solubility of the pharmaceutical compositions of the present invention will be significantly improved relative to the use of the free base of Compound 1, while allowing the pharmaceutical compositions of the present invention to have a reduced risk of food effects , and compared to the use of other salts of compound 1 such as hydrochloride and mesylate, the obtained pharmaceutical composition can also have improved hygroscopicity.

In one embodiment, based on the content of the free base of Compound 1, the content of Compound 1 or a pharmaceutically acceptable salt thereof is 3.0% or more, preferably 4.0% or more, preferably 4%- 80%, preferably 5%-62%, preferably 6%-50%, more preferably 6%-25%, most preferably 8%-23%. The pharmaceutical composition of the present invention contains different dosages of active pharmaceutical ingredients, which can meet the needs of different patients, and choose different dosages of medicines according to the severity of different diseases, which is helpful for individualized treatment and avoids adverse effects caused by improper medication.

In one embodiment, the diluent is selected from one or more of microcrystalline cellulose, lactose monohydrate, mannitol and sorbitol. In a more preferred embodiment, the diluent is a mixture of microcrystalline cellulose and lactose monohydrate, or a mixture of microcrystalline cellulose and mannitol. Preferably, the microcrystalline cellulose is microcrystalline cellulose PH101 or microcrystalline cellulose PH102; preferably, the lactose monohydrate is lactose monohydrate FlowLac 100 or lactose monohydrate Tablettose 80; preferably, the mannitol It is mannitol 100SD. In a further preferred embodiment, the diluent is a mixture of mannitol 100SD and microcrystalline cellulose PH101, a mixture of lactose monohydrate Tablettose 80 and microcrystalline cellulose PH102, or a mixture of microcrystalline cellulose PH102 and lactose monohydrate FlowLac 100 mixture.

In one embodiment, the weight ratio of lactose monohydrate and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably Preferably it is 1:1; or the weight ratio of the mannitol and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1. The further selection of the diluent and the dosage ratio of the diluent in the present invention is beneficial to improve the dissolution rate of the pharmaceutical composition and has good dissolution consistency.

In one embodiment, the content of the diluent is more than 20% of the total weight of the pharmaceutical composition, preferably more than 30%, preferably more than 40%, preferably 20-90%, preferably 50-90% , preferably 60-90%, more preferably 60%-85%, further preferably 65%-80%.

In one embodiment, the pharmaceutical composition may further include a glidant, the glidant is selected from one or both of talc and colloidal silicon dioxide, more preferably, the glidant For colloidal silica.

In one embodiment, the content of the glidant is 0.5%-15% of the total weight of the pharmaceutical composition, preferably 1%-10%, more preferably 1%-3%, most preferably 1% , 2% or 3%. The addition of the glidant in the invention is beneficial to improve the fluidity of the pharmaceutical composition, improve the stability of the filling amount of the filling capsule, and the difference in the filling amount is small.

In one embodiment, the pharmaceutical composition may further comprise a disintegrant, preferably, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low Substituting one or more of hydroxypropyl cellulose, more preferably, the disintegrant is croscarmellose sodium.

In one embodiment, the content of the disintegrant is 0.5%-15% of the total weight of the pharmaceutical composition, preferably 1%-10%, more preferably 1%-5%, more preferably 1% -3%, most preferably 1%, 2%, 3%, 4%, or 5%. The disintegrant and the selection of the dosage of the present invention help to improve the dissolution rate of the pharmaceutical composition and have good dissolution consistency.

In one embodiment, the pharmaceutical composition may further include a lubricant, preferably, the lubricant is selected from one of magnesium stearate, stearic acid, sodium stearoyl fumarate and zinc stearate One or more, more preferably, the lubricant is magnesium stearate.

In one embodiment, the content of the lubricant is 0.1%-5% of the total weight of the pharmaceutical composition, preferably 0.5%-3%, more preferably 1%-2%, most preferably 1%. The selection of the lubricant and its dosage of the present invention further reduces the friction between the powders and between the powders and the mold wall, and is helpful for filling capsules or tableting.

As a preferred embodiment, the present invention provides a pharmaceutical composition containing the following components by weight:

(1) 5%-40%, preferably 8%-35%, more preferably 10%-30% as active ingredient 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane] -1,3'-Indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate;

(2) 50%-90%, preferably 60%-90%, preferably 60%-85%, more preferably 65%-80% diluent, preferably, the diluent is a mixture of microcrystalline cellulose and lactose monohydrate a mixture, or a mixture of microcrystalline cellulose and mannitol;

(3) 0.5%-15%, preferably 1%-10%, more preferably 1%-3%, more preferably 1%, 2%, or 3% of a glidant, preferably, the glidant is colloidal silica;

(4) 0.5%-15%, preferably 1%-10%, more preferably 1%-5%, more preferably 1%-3%, more preferably 1%, 2%, 3%, 4%, Or 5% disintegrant, preferably, the disintegrant is selected from one of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose or various; and

(5) 0.1%-5%, preferably 0.5%-3%, more preferably 1%-2%, most preferably 1% lubricant, preferably the lubricant is selected from magnesium stearate, stearic acid , one or more of sodium stearoyl fumarate and zinc stearate.

In one embodiment, in the pharmaceutical composition, the weight ratio of lactose monohydrate and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5 : 1-1: 1.5, most preferably 1: 1; or the weight ratio of the mannitol and microcrystalline cellulose is 5: 1-1: 5, preferably 3: 1-1: 3, more preferably 1.5: 1-1:1.5, most preferably 1:1.

In one embodiment, in the pharmaceutical composition, 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'- yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base, the pharmaceutical composition comprises 0.1-1000 mg, preferably 1- 100 mg, more preferably 8 to 50 mg of active ingredient.

The present invention also provides a solid oral pharmaceutical preparation made from the pharmaceutical composition, preferably a powder, a capsule, a tablet or a granule, more preferably a capsule, wherein the capsule is made of the pharmaceutical composition as filler.

In one embodiment, in the solid oral pharmaceutical formulation, 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base content, the solid oral pharmaceutical preparation comprises 0.1～1000mg, preferably 1 to 100 mg, more preferably 8 to 50 mg of active ingredient.

In one embodiment, the capsules are prepared using a powder direct filling process.

The capsules of the present invention are loaded according to the free base content of compound 1, and a capsule filling machine is used to fill the medicinal powder, that is, the pharmaceutical composition of the present invention, into hard capsule shells of different specifications, and the differences in the loading of the capsules are investigated to avoid Affect product content and uniformity.

The present invention also provides the pharmaceutical composition of the present invention or the solid oral pharmaceutical preparation of the present invention, which is used for the treatment of CDK4/6-mediated disorders or diseases.

The present invention also provides the use of the pharmaceutical composition of the present invention or the solid oral pharmaceutical preparation of the present invention in preparing a medicament for treating CDK4/6-mediated disorders or diseases.

The present invention also provides a method for treating a CDK4/6-mediated disorder or disease, comprising administering the pharmaceutical composition of the present invention or the solid oral pharmaceutical formulation of the present invention to a subject in need thereof.

In one embodiment, the CDK4/6 mediated disorder or disease is cancer, AIDS, atherosclerosis or restenosis after stent implantation, wherein the cancer is preferably a malignant solid tumor or a malignant non-solid tumor, more Breast cancer, lung cancer, prostate cancer, leukemia, brain cancer or gastric cancer are preferred, and glioma is even more preferred.

Beneficial effects of the present invention:

1) The present invention can significantly improve the fluidity of the obtained pharmaceutical composition powder, the obtained pharmaceutical composition has a larger bulk density, a smaller Carr index and an angle of repose, and the pharmaceutical composition powder has a uniform color and no color difference. .

2) The pharmaceutical composition of the present invention dissolves rapidly and has good dissolution consistency.

3) When the salt of the present invention is used, the solubility of the pharmaceutical composition of the present invention will be further improved relative to the use of the free base of compound 1, and the pharmaceutical composition of the present invention will have a reduced risk of food effects, and is relatively The use of other salts of Compound 1, such as hydrochloride and mesylate, also results in improved hygroscopicity of the obtained pharmaceutical composition.

4) The pharmaceutical composition of the present invention has high stability under the experimental conditions of high temperature (60°C), high humidity (75%RH), strong light (5000lux) and acceleration (40°C/75%RH).

5) The pharmaceutical composition of the present invention can realize the preparation of capsules by directly filling the capsules with powder, the process is simple, the filling volume stability of the capsules prepared by filling is good, and the filling volume difference is small.

Description of drawings

Figure 1 is a ¹ H-NMR chart of the fumarate salt of compound 1 in CD ₃ OD.

Figure 2 is a ¹ H-NMR chart of the maleate salt of compound 1 in CD ₃ Cl.

Figure 3 is a ¹ H-NMR chart of the adipate salt of Compound 1 in CD ₃ OD.

Figure 4 is a ¹ H-NMR chart of the succinate salt of compound 1 in CDCl ₃ .

Figure 5 is a ¹ H-NMR chart of the mesylate salt of Compound 1 in CD ₃ OD.

Figure 6 is the dissolution curve of the 10 mg specification pilot batch of Test Example 11 in pH 1.2 hydrochloric acid buffer.

Figure 7 is the dissolution curve of the 50 mg specification pilot batch of Test Example 11 in pH 1.2 hydrochloric acid buffer.

detailed description

The present invention will be further described in detail below through specific embodiments, but it should not be understood that the scope of the present invention is limited to the following examples. Without departing from the idea of the above solutions of the present invention, various substitutions or changes made according to common technical knowledge in the art and conventional means should all be included within the scope of the present invention.

abbreviation or definition

Mannitol 100SD: Mannitol

100SD.

Microcrystalline Cellulose PH101: Microcrystalline Cellulose

Microcrystalline Cellulose PH102: Microcrystalline Cellulose

Lactose Monohydrate FlowLac 100: Lactose Monohydrate

Lactose Monohydrate Tablettose 80: Lactose Monohydrate

Colloidal Silica 200: Colloidal Silica

The term "diluent" as used herein refers to an excipient used to increase the weight and/or volume of a pharmaceutical composition to facilitate molding and sub-dosing. The diluent described in the present invention is selected from one or more of microcrystalline cellulose, lactose or its hydrate, and sugar alcohol, preferably selected from one or more of microcrystalline cellulose, lactose monohydrate, mannitol and sorbitol one or more. The diluent may be a single diluent or a mixture of two diluents. When the diluent is a mixture of two diluents, it is preferably microcrystalline cellulose (eg, microcrystalline cellulose PH101 or microcrystalline cellulose PH102) and lactose monohydrate (eg, lactose monohydrate FlowLac 100 or lactose monohydrate). Tablettose 80), or a mixture of microcrystalline cellulose (eg, microcrystalline cellulose PH101 or microcrystalline cellulose PH102) and mannitol (eg, mannitol 100SD), and the weight of the lactose monohydrate and microcrystalline cellulose The ratio is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1; or the weight ratio of the mannitol and microcrystalline cellulose It is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1.

The "glidant" in the present invention refers to an excipient used to increase the fluidity of a material. The glidant of the present invention is selected from one or both of talc and colloidal silicon dioxide, more preferably, the glidant is colloidal silicon dioxide.

The "disintegrant" in the present invention refers to an excipient used to promote the disintegration of the pharmaceutical composition in the gastrointestinal tract and increase the dissolution of the active ingredient. The disintegrant of the present invention is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose, more preferably, The disintegrating agent is croscarmellose sodium.

The "lubricant" used in the present invention refers to an excipient used to reduce the frictional force between particles of a pharmaceutical composition and improve the transmission and distribution of force. The lubricant of the present invention is selected from one or more of magnesium stearate, stearic acid, sodium stearoyl fumarate and zinc stearate, more preferably, the lubricant is stearic acid magnesium.

The pharmaceutical compositions of the present invention may also contain other excipients other than diluents, glidants, disintegrants and lubricants. Specific examples thereof include binders, flavoring agents, dispersing agents, coloring agents, fragrances, and the like.

The "solid oral pharmaceutical preparation" in the present invention refers to a solid pharmaceutical preparation for oral administration. The present invention relates to a solid oral pharmaceutical preparation made from the above-mentioned pharmaceutical composition, and its specific dosage form is preferably powder, capsule, tablet or granule, more preferably capsule, wherein the capsule is filled with the pharmaceutical composition .

The pharmaceutical composition of the present invention or its solid oral pharmaceutical preparation may contain 0.1-1000 mg, preferably 1-100 mg, more preferably 8-50 mg of active ingredients in the form of 5-fluoro-4-(7'-fluoro-2'-methylspiro) [Cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base content meter. For example, the content of the active ingredient in the pharmaceutical composition of the present invention or its solid oral pharmaceutical preparation can be 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 8 mg, 10 mg, 20 mg, 25 mg, 40mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 500mg, 1000mg, etc.

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

In the present invention, the administration subject may be a human or a non-human mammal, more preferably a human.

In the present invention, the term "comprising" or similar terms "comprising" and "comprising" generally express an open meaning, but also includes a closed meaning defined by "consisting of" within its scope. condition. For example, "a pharmaceutical composition comprising..." also includes the case of "a pharmaceutical composition consisting of".

Within the scope of the present invention, various options of any one feature can be combined with each other with various options of other features to form many different embodiments. The present invention is intended to include all possible embodiments consisting of various options of all technical features.

Example 1

The preparation methods of different salt forms of compound 1 are as follows:

(1) Preparation of Compound 1 Fumarate

Under nitrogen protection, at room temperature, dichloromethane (22.0 vol) and ethanol (22.0 vol) were added to the reaction kettle, and 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane] was added while stirring. Alkyl-1,3'-indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (2.070kg), Heat up to 30-40 degrees Celsius, stir until all dissolved, cool to room temperature, and transfer the solution to a solvent bucket for later use. Under nitrogen protection, the above solution was filtered through a microporous filter, and transferred to the reactor, stirred, and dichloromethane and ethanol were distilled off at normal pressure, and then the temperature of the reactor was kept to 80 ± 5 degrees Celsius, and the fumaric acid ( 1.0eq) of ethanol solution (12 volumes) was slowly dropped into the reaction kettle through a microporous filter, and kept stirring overnight. Cool to 20-30 degrees Celsius, continue stirring for at least 1 hour, centrifuge, and collect the filter cake. The filter cake was placed in a vacuum oven and dried overnight to obtain 1.605 kg of 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate (compound A), yield 63.6%. Its ¹ H-NMR data are shown in FIG. 1 .

(2) Preparation of compound 1 maleate

Weigh out 353.5 mg of 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1- Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine to a 20 mL glass bottle, add 5 mL isopropanol (IPA)/ _H2O (19:1, v/v), A solution of IPA/H ₂ O (19:1, v/v; 3.75 ml) containing 83.7 mg of maleic acid was dropped into a glass bottle, stirred at room temperature for 4 days, centrifuged to separate the solid, and dried at 50 degrees Celsius for 5 hours to obtain 405.1 mg Maleate, yield 92.7%. Its ¹ H-NMR data are shown in FIG. 2 .

(3) Preparation of Compound 1 Adipate

Weigh out 350.6 mg of 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1- Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine to a 20 mL glass bottle, add 5 mL of tetrahydrofuran (THF), drop a solution of 105.4 mg of adipic acid in THF (3.75 mL) put into a glass bottle, stirred at room temperature for 4 days, centrifuged to separate the solid, and dried at 50 degrees Celsius for 5 hours to obtain 362.4 mg of adipate with a yield of 79.5%. Its ¹ H-NMR data are shown in FIG. 3 .

(4) Preparation of Compound 1 Succinate

351.6 mg of 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methyl) Piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine and 5 ml of acetone were added to the reaction flask, stirred magnetically, and then 3.75 ml of acetone solution containing 85.1 mg of succinic acid was added dropwise to the reaction flask, It was stirred at room temperature for 4 days, the solid was separated by centrifugation, and dried at 50 degrees Celsius for 5 hours to obtain 377.7 mg of solid, namely succinate, with a yield of 86.5%. Its ¹ H-NMR data are shown in FIG. 4 .

(5) Preparation of compound 1 mesylate

61.1 mg of methanesulfonic acid and 305.3 mg of 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-( 5-(1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine was added to the reaction flask, 10 mL of ethyl acetate was added, stirred at room temperature for 3 days, centrifuged to separate the solid, and dried at 50 degrees Celsius After 3 hours, 370.2 mg of solid, the mesylate salt, was obtained in 101.0% yield. Its ¹ H-NMR data are shown in FIG. 5 .

(6) Preparation of Compound 1 Hydrochloride

Weigh out 352.2 mg of 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1- Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine was added to a 20 mL glass vial and 5 mL of THF was added to give a suspension of compound 1 free base. 60 μl of 37% hydrochloric acid was weighed and diluted with 3.75 ml of THF, and the resulting acid solution was gradually added to the free base suspension and stirred at room temperature for 4 days. The solid was separated by centrifugation, dried at 50° C. for 5 hours, and 361.4 mg of the solid was collected to obtain the hydrochloride salt with a yield of 83.3%.

Test Example 1 Solubility Test

The purpose of this test example is to compare the solubility of various salts (also called salt forms) and free bases obtained by the present invention.

Test Methods: Solubility tests were performed in three vehicles, water, simulated fasting intestinal fluid (FaSSIF) and simulated fed intestinal fluid (FeSSIF), to assess the solubility and food effect risk of the salts of the present invention.

In the test, the sample and the solvent were mixed in a centrifuge tube (the initial feeding amount was 10 mg/ml), and then the centrifuge tube was sealed and fixed on a rotating disk with a rotation speed of 25 rpm, and rotated and mixed at 37 °C. Samples were taken after 24 hours. The turbid samples were centrifuged, and the filtered supernatant was used to measure the HPLC concentration. If the sample dissolves, test the concentration of the resulting solution.

Test subjects: free base, maleate, fumarate, adipate and succinate of compound 1.

Test results: See Tables 1-3, solubility of different salt forms and free bases in water, simulated fasting intestinal fluid (FaSSIF) and simulated fed intestinal fluid (FeSSIF).

Table 1 Solubility of different salt forms and free bases of compound 1 in water

sample name	Solubility (mg/ml)
Free base of compound 1	0.075
Maleate of Compound 1	12.9
Fumarate of compound 1	6.3
Adipate salt of compound 1	6.5
Succinate of Compound 1	7.5

As shown in Table 1, the solubility of maleate, fumarate, adipate and succinate of compound 1 in water was 12.9, 6.3, 6.5 and 7.5 mg/ml, respectively, which was significantly higher than that of the free base in water. Solubility in water (0.075 mg/ml). This suggests that when the above-mentioned salt of the present invention is used to formulate the pharmaceutical composition of the present invention, the solubility of the active ingredient Compound 1 can be significantly improved.

Table 2 Solubility of different salt forms and free bases of compound 1 in simulated fasting intestinal fluid (FaSSIF)

sample name	Solubility (mg/ml)
Free base of compound 1	0.19
Maleate of Compound 1	7.1
Fumarate of compound 1	7.6
Adipate salt of compound 1	6.8
Succinate of Compound 1	6.4

As shown in Table 2, the solubility of maleate, fumarate, adipate and succinate of compound 1 in simulated fasting intestinal fluid (FaSSIF) was significantly higher than that of free base in simulated fasting intestinal fluid (FaSSIF), respectively ( FaSSIF) (0.19 mg/ml).

Table 3 Solubility of different salt forms and free bases of compound 1 in simulated fed intestinal fluid (FeSSIF)

sample name	Solubility (mg/ml)
Free base of compound 1	10.2
Maleate of Compound 1	7.8
Fumarate of compound 1	8.0
Adipate salt of compound 1	11.6
Succinate of Compound 1	10.7

As shown in Table 3, the solubility of maleate, fumarate, adipate and succinate of Compound 1 in simulated fed intestinal fluid (FeSSIF) was comparable to the free base of Compound 1 in simulated fed intestinal fluid (FeSSIF) The solubility of these salts in simulated fasting intestinal fluid (FaSSIF) and simulated fed intestinal fluid (FeSSIF) is similar relative to the free base, suggesting that the above salts of the present invention have lower food effect risk.

Test Example 2 Hygroscopicity Test

This test example compares the hygroscopicity of various salt forms and free bases of compound 1 provided by the present invention.

Under the condition of 25°C, the dynamic moisture adsorption (DVS) test was used to test the moisture adsorption capacity of the salt and free base of compound 1 of the present invention when the humidity reached 80% RH, so as to compare the hygroscopicity.

Test subjects: Compound 1 free base, maleate, fumarate, adipate, succinate, mesylate and hydrochloride.

Experimental results: The test results are shown in Table 4. Among them, hygroscopicity (measured by the amount of moisture absorbed by the test object when the humidity reaches 80%RH)>15% is very hygroscopic, 2-15% is hygroscopic, 0.2-2% is slightly hygroscopic, <0.2% is almost hygroscopic Not hygroscopic.

Table 4 Hygroscopicity of different salt forms and free bases of compound 1

sample name	Hygroscopicity (%)
Free base of compound 1	0.10
Maleate of Compound 1	2.00
Fumarate of compound 1	0.35
Adipate salt of compound 1	0.22
Succinate of Compound 1	0.33
Mesylate of Compound 1	12.02
Compound 1 hydrochloride	9.12

The results showed that the water adsorption capacity of maleate, fumarate, adipate and succinate of compound 1 was 0.10-2.00% under the condition of 25℃/80%RH. The hygroscopicity of the free base is comparable; while the hydrochloric acid salt and the mesylate salt have higher hygroscopicity at 25℃/80%RH, the water adsorption capacity is 9.12% and 12.02%, respectively. This suggests that when the maleate, fumarate, adipate and succinate of Compound 1 are used as active ingredients in the pharmaceutical composition, significant improvements will be seen relative to the methanesulfonate and hydrochloride of Compound 1 Hygroscopicity of pharmaceutical compositions.

Example 2-3

The preparation method of the pharmaceutical composition powder of embodiment 2-3 is as follows:

(1) according to the formula consumption in table 5, take by weighing compound A, mannitol 100SD, microcrystalline cellulose PH101, colloidal silicon dioxide 200 and magnesium stearate respectively;

(2) compound A and colloidal silica 200 are mixed and sieved to obtain pretreated powder;

(3) sieve mannitol 100SD, microcrystalline cellulose PH101, magnesium stearate respectively, for subsequent use;

(4) the pretreatment powder obtained in step (2) is mixed with mannitol 100SD, microcrystalline cellulose PH101, and the winner is mixed powder for subsequent use;

(5) adding magnesium stearate to the main mixed powder prepared in step (4) and mixing to obtain a total mixed powder of pharmaceutical composition powder.

table 5

*Note: Compound A is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-( The fumarate salt of 1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine.

Test Example 3 Fluidity Test

The angle of repose of the active ingredient raw material Compound A and the pharmaceutical compositions of Examples 2-3 was measured by an intelligent powder characteristic tester (in compliance with the national standard GB11986-89 on "Measurement of the angle of repose of surfactant powders and particles") , bulk density, tap density, and Carr's index. Wherein, Carr's index=(tap density-bulk density)/tap density*100%, and the results are shown in Table 6.

Table 6

As can be seen from the data in Table 6, the bulk density of the pharmaceutical composition of Example 2-3 is significantly increased compared to the single active ingredient raw material Compound A, and the angle of repose and Carr's index are significantly reduced, indicating that the pharmaceutical composition of Example 2-3 is combined. Compared with the single active ingredient raw material Compound A, the fluidity of the powder is significantly improved, and it can realize the preparation of capsules by a simple powder direct filling process, reduce the risk of large differences in the filling volume of the capsules, and meet the requirements of capsule filling and industrialization. production requirements.

Examples 4-6

According to the formulation dosage in Table 7, the pharmaceutical composition powders of Examples 4-6 were prepared by adopting the steps similar to those in Example 2-3.

Table 7

Test Example 4 Fluidity Test

According to the method of Test Example 3, the angle of repose, bulk density, tap density and Carr's index of the pharmaceutical composition powder obtained in Examples 4-6 were measured, and the results are shown in Table 8 below.

Table 8

As can be seen from the data in Table 8, the bulk density of the pharmaceutical composition powder of Example 4-6 is significantly increased compared to the single active ingredient raw material Compound A, and the angle of repose and Carr's index are significantly reduced, indicating that the medicine of Example 4-6 Compared with the single active ingredient compound A, the fluidity of the composition powder is significantly improved, and when it is subsequently used to prepare a preparation in the form of capsules, it will be able to reduce the risk of large differences in the filling volume of the capsules, and meet the requirements and requirements of capsule filling. requirements for industrial production.

Examples 7-9

The preparation method of the capsule of embodiment 7-9 is as follows:

(1) according to the consumption in table 9, take by weighing compound A, microcrystalline cellulose PH102, lactose monohydrate FLOWLAC100, croscarmellose sodium, colloidal silicon dioxide 200 and magnesium stearate respectively;

(2) compound A and colloidal silica 200 are mixed and sieved to obtain pretreated powder;

(3) sieving microcrystalline cellulose PH102, lactose monohydrate FLOWLAC100, croscarmellose sodium, magnesium stearate, respectively, for subsequent use;

(4) mixing the pretreated powder obtained in step (2) with microcrystalline cellulose PH102, lactose monohydrate FLOWLAC100 and croscarmellose sodium, and the winner is mixed powder for subsequent use;

(5) adding magnesium stearate to the main mixed powder prepared in step (4) and mixing to obtain a total mixed powder of pharmaceutical composition powder.

(6) Filling the pharmaceutical composition powder blend powder into empty capsules using a capsule filling machine.

Table 9

*Note: 50mg capsules are based on 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-N-( The content of the free base of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine. Compound A is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methyl) The fumarate salt of ylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine, the molecular weight is 604.66, the molecular weight of its free base is 488.59, and the conversion factor is 1.24.

Test Example 5 Dissolution Test

According to the first method (basket method) of "Chinese Pharmacopoeia" 2015 Edition Part Four 0931 Dissolution Determination Method, the dissolution rate of the prepared capsules of Examples 7-9 was determined. Using 900 ml of PH1.2 hydrochloric acid buffer as the medium, the water temperature was 37±0.5 °C, and the rotation speed was 50 rpm, and samples were taken at 6 time points such as 5 min, 15 min, 30 min, 45 min, 60 min, and 75 min, respectively. Each sampling volume was 10 ml and was filtered with a PFS filter (0.45 μm to 10 μm). For each dissolution test, repeat 3 capsules or 6 capsules. The dissolution results are shown in Table 10 below.

Table 10

*Note: RSD stands for "relative standard deviation".

From the data in Table 10, it can be seen that the capsules obtained in Examples 7-9 of the present invention, in the dissolution medium of pH 1.2, Compound A has a faster dissolution rate and good dissolution consistency, and there is no significant difference in dissolution behavior.

Examples 10-13

According to the formulations in Table 11, the pharmaceutical composition powders of Examples 10-13 were obtained by the steps similar to those of Examples 2-3.

Table 11

Test Example 6 Fluidity Test

According to the method of Test Example 3, the angles of repose of the pharmaceutical composition powders obtained in Examples 10-13 were measured, and the test results are shown in Table 12.

Table 12

formula	Angle of repose (°)
Example 10	41.97
Example 11	40.41
Example 12	40.05
Example 13	40.86

As can be seen from the data in Table 12, compared to the pharmaceutical composition of Example 10 without colloidal silicon dioxide, the pharmaceutical compositions of Examples 11-13 with colloidal silicon dioxide added to the formula, the angle of repose is further reduced. , the fluidity is further improved, and when the amount of colloidal silicon dioxide is in the range of about 1% to 3%, the fluidity of the pharmaceutical composition powder has no significant change.

Examples 14-15

Following the steps similar to those of Examples 7-9, capsules of Examples 14-15 whose formulations are shown in Table 13 were obtained.

Table 13

Test Example 7 Dissolution Test

The dissolution rate of the capsules obtained in Examples 14-15 was measured according to the method of Test Example 5, and the test results are shown in Table 14 below.

Table 14

It can be seen from the data in Table 14 that the capsules obtained in Examples 14-15 of the present invention, in the dissolution medium of pH 1.2, Compound A has a relatively fast dissolution rate and good dissolution consistency.

Example 1610mg specification capsule

Following the steps similar to those in Examples 7-9, 10 mg capsules with the formula shown in Table 15 were obtained.

Table 15

*Note: 10mg capsules are based on 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-N-( The content of the free base of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine. Compound A is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methyl) The fumarate salt of ylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine, the molecular weight is 604.66, the molecular weight of its free base is 488.59, and the conversion factor is 1.24.

Test Example 8 Dissolution Test

The dissolution rate of the capsules obtained in Example 16 was measured according to the method of Test Example 5, and the test results are shown in Table 16.

Table 16 Dissolution results of 10mg specification

It can be seen from the above results that the 10 mg capsules of the present invention have good dissolution behavior.

Test Example 9 Capsule weight test results

In the three stages before, during and after the capsule filling of Example 7 (50mg specification) and Example 16 (10mg specification), 10 capsules were sampled respectively, and the weight of a single capsule was detected (the first, middle and last three stages respectively) Refers to 5 minutes after the start of capsule filling, about half of the filling is completed, and 5 minutes before the end of filling), according to the "Chinese Pharmacopoeia" 2015 edition four 0103 capsules under the difference inspection method detection, the test results are shown in Tables 17 and 18.

Table 17 Weight test results of 50mg capsules

Table 18 10mg specification capsule weight test results

From the experimental results of Tables 17 and 18, it can be known that the capsule filling process is stabilized by using the pharmaceutical composition formula of the present invention, and the difference of the obtained capsule filling is less, and the difference in the filling is all significantly less than the limit of the difference in the filling (±7.5%), and in Product content and content uniformity are not significantly affected during capsule filling.

Test Example 10 Stability of the pharmaceutical composition of the present invention

In order to investigate the stability of the pharmaceutical composition obtained by the present invention, the capsules of Example 7 (50 mg strength) and Example 16 (10 mg strength) were used for stability experiments. The two specifications of the samples were placed under the same conditions for 10 days and 30 days under accelerated conditions of 40°C/75%RH (opening), respectively. The free base content of compound A in the capsules was determined by HPLC, and the method of Test Example 5 was used. Determination of dissolution; respectively at 60°C (open), 25°C/75%RH (open), light (intensity 5000lux) (open), 40°C/75%RH (open), 40°C/75%RH (closed) After 10 days and 30 days under the conditions, the changes of related substances were determined by HPLC. The test results of changes in capsule content, dissolution results and related substances are as follows:

Table 19 Results of changes in capsule content

*Note: Capsule content means "free base content of compound A in capsules".

Table 20 Capsule dissolution results

It can be seen from the above data that the active substance content of the capsules of 2 specifications is stable after being placed under the accelerated conditions of 40°C/75%RH (opening) for 30 days, and the accelerated conditions (40°C/75%RH) are effective for the dissolution of the capsules of 2 specifications. No effect.

Test Example 11 Research on the dissolution test and stability test of the pilot scale-up sample of the present invention

Capsules were prepared using the formulations of Example 7 (50 mg strength) and Example 16 (10 mg strength), and 10,000 capsules were prepared each, and were divided into three batches. The packaging adopts oral solid medicinal high density polyethylene bottle and oral solid medicinal child safety cap.

1. Dissolution test

6 capsules were randomly selected from each batch, and the dissolution rate was measured by the method of Test Example 5. The dissolution result curve is shown in Figure 6-7. , the dissolution is greater than 95% in 15 minutes, and the complete dissolution can be achieved within 30 minutes.

2. Stability test

For the samples amplified in the pilot scale, under the conditions of high temperature (60°C), strong light (illumination 5000 lux), and high humidity (75% RH), the drug properties, content and changes in related substances, dissolution rate, moisture absorption and weight gain were determined. The stability of the pharmaceutical composition of the present invention under scaled-up production conditions was further confirmed. Among them, the drug properties were observed by visual observation, the free base content of Compound A and the changes of related substances were determined by HPLC, the dissolution was determined by the first method (basket method) of "Chinese Pharmacopoeia" 2015 Edition Part Four 0931 Dissolution Determination Method, and the "Chinese Pharmacopoeia" 2015 Edition Chinese Pharmacopoeia 2015 edition four 0832 moisture determination method first method (Fischer's method) to measure moisture absorption weight gain, the result is shown in table 23-26.

The test results show that the capsules of the present invention obtained through enlarged production are stable after long-term storage under the conditions of high temperature (60° C.), strong light (illumination 5000 lux), and high humidity (75% RH), and the results of each test item are not significant. changes to meet quality standard limits. It is further proved that under the conditions of scaled-up production, the obtained pharmaceutical composition of the present invention also has high stability, and the preparation production process adopted in the present invention is simple and stable, and can meet the needs of large-scale industrial production.

Table 24 10mg specification capsule stability test (high humidity 75%RH)

Table 26 Stability test of 50mg capsules (high humidity 75%RH)

Claims (21)

1. A pharmaceutical composition containing 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' as an active ingredient -yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine or a pharmaceutically acceptable salt thereof and a diluent, wherein the The diluent is selected from one or more of microcrystalline cellulose, lactose or its hydrate, and sugar alcohol.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1, 3'-Indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate, maleic acid one or more of salts, adipates and succinates; preferably, the pharmaceutically acceptable salt is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopenta] Alk-1,3'-indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate.
3. The pharmaceutical composition according to any one of claims 1-2, characterized in that, with 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indone] Indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base content, 5-fluoro-4-( 7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridine- The content of 2-yl)pyrimidin-2-amine or its pharmaceutically acceptable salt is 3.0% or more, preferably 4.0% or more, preferably 4%-80%, preferably 5%-62% of the total weight of the pharmaceutical composition , preferably 6%-50%, more preferably 6%-25%, most preferably 8%-23%.
4. The pharmaceutical composition of any one of claims 1-3, wherein the diluent is selected from one or more of microcrystalline cellulose, lactose monohydrate, mannitol and sorbitol;

   Preferably, the diluent is a mixture of microcrystalline cellulose and lactose monohydrate, or a mixture of microcrystalline cellulose and mannitol;

   Preferably, the microcrystalline cellulose is microcrystalline cellulose PH101 or microcrystalline cellulose PH102;

   Preferably, described lactose monohydrate is lactose monohydrate FlowLac 100 or lactose monohydrate Tablettose 80;

   Preferably, the mannitol is mannitol 100SD;

   Further preferably, the diluent is a mixture of mannitol 100SD and microcrystalline cellulose PH101, a mixture of lactose monohydrate Tablettose 80 and microcrystalline cellulose PH102, or a mixture of microcrystalline cellulose PH102 and lactose monohydrate FlowLac 100.
5. The pharmaceutical composition according to any one of claims 1-4, wherein the weight ratio of lactose monohydrate and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1: 3, more preferably 1.5:1 to 1:1.5, most preferably 1:1; or

   The weight ratio of mannitol and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the content of the diluent is 20% or more, preferably 30% or more, preferably 40% or more of the total weight of the pharmaceutical composition , preferably 20-90%, preferably 50-90%, preferably 60-90%, more preferably 60-85%, further preferably 65-80%.
7. The pharmaceutical composition according to any one of claims 1-6, wherein the pharmaceutical composition further comprises a glidant, preferably, the glidant is selected from talc and colloidal silicon dioxide One or both of the above, more preferably, the glidant is colloidal silica.
8. The pharmaceutical composition according to claim 7, wherein the content of the glidant is 0.5%-15% of the total weight of the pharmaceutical composition, preferably 1%-10%, more preferably 1% -3%, most preferably 1%, 2%, or 3%.
9. The pharmaceutical composition according to any one of claims 1-8, wherein the pharmaceutical composition further comprises a disintegrating agent, preferably, the disintegrating agent is selected from croscarmellose sodium, One or more of sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone and low-substituted hydroxypropyl cellulose, more preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose.
10. The pharmaceutical composition of claim 9, wherein the content of the disintegrant is 0.5%-15%, preferably 1%-10%, preferably 1%-15% of the total weight of the pharmaceutical composition 5%, more preferably 1%-3%, more preferably 1%, 2%, 3%, 4%, or 5%.
11. The pharmaceutical composition according to any one of claims 1-10, wherein the pharmaceutical composition further comprises a lubricant, preferably, the lubricant is selected from magnesium stearate, stearic acid, stearic acid One or more of sodium acyl fumarate and zinc stearate, more preferably, the lubricant is magnesium stearate.
12. The pharmaceutical composition according to claim 11, wherein the content of the lubricant is 0.1%-5% of the total weight of the pharmaceutical composition, preferably 0.5%-3%, more preferably 1%- 2%, most preferably 1%.
13. A pharmaceutical composition, characterized in that the pharmaceutical composition contains the following components by weight:

    (1) 5%-40%, preferably 8%-35%, more preferably 10%-30% as active ingredient 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane] -1,3'-Indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate;

    (2) 50%-90%, preferably 60%-90%, preferably 60%-85%, more preferably 65%-80% diluent, preferably, the diluent is microcrystalline cellulose and lactose monohydrate a mixture, or a mixture of microcrystalline cellulose and mannitol;

    (3) 0.5%-15%, preferably 1%-10%, more preferably 1%-3%, more preferably 1%, 2%, or 3% of a glidant, preferably, the glidant is colloidal silica;

    (4) 0.5%-15%, preferably 1%-10%, more preferably 1%-5%, more preferably 1%-3%, more preferably 1%, 2%, 3%, 4%, Or 5% disintegrant, preferably, the disintegrant is selected from one of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose or various; and

    (5) 0.1%-5%, preferably 0.5%-3%, more preferably 1%-2%, most preferably 1% lubricant, preferably the lubricant is selected from magnesium stearate, stearic acid , one or more of sodium stearoyl fumarate and zinc stearate.
14. The pharmaceutical composition of claim 13, wherein the weight ratio of lactose monohydrate to microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1; or the weight ratio of the mannitol and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5 :1-1:1.5, most preferably 1:1.
15. The pharmaceutical composition of any one of claims 1-14, wherein 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]- 5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base content, the pharmaceutical composition comprises 0.1-1000mg, Preferably 1 to 100 mg, more preferably 8 to 50 mg of active ingredient.
16. A solid oral pharmaceutical preparation made from the pharmaceutical composition of any one of claims 1-15, preferably powder, capsule, tablet or granule, more preferably capsule, wherein the capsule is in the form of the Pharmaceutical compositions as fillers.
17. The solid oral pharmaceutical formulation of claim 16, wherein 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl )-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base content, the solid oral pharmaceutical preparation comprises 0.1～1000mg, preferably 1～ 100 mg, more preferably 8 to 50 mg of active ingredient.
18. The solid oral pharmaceutical preparation according to claim 16 or 17, wherein the capsule is prepared by a powder direct filling process.
19. The pharmaceutical composition of any one of claims 1-15 or the solid oral pharmaceutical formulation of any one of claims 16-18, for use in the treatment of a CDK4/6 mediated disorder or disease.
20. Use of the pharmaceutical composition according to any one of claims 1-15 or the solid oral pharmaceutical preparation according to any one of claims 16-18 in the manufacture of a medicament for the treatment of CDK4/6 mediated disorders or diseases .
21. A method for treating a CDK4/6-mediated disorder or disease, comprising administering the pharmaceutical composition according to any one of claims 1-15 or any one of claims 16-18 to a subject in need thereof solid oral pharmaceutical preparations.

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