CN116113628A

CN116113628A - Pharmaceutical composition containing CDK4/6 inhibitor

Info

Publication number: CN116113628A
Application number: CN202180053613.XA
Authority: CN
Inventors: 尹磊; 姚郑林
Original assignee: Gan and Lee Pharmaceuticals Co Ltd
Current assignee: Gan and Lee Pharmaceuticals Co Ltd
Priority date: 2020-08-31
Filing date: 2021-08-31
Publication date: 2023-05-12
Also published as: WO2022042738A1

Abstract

A pharmaceutical composition comprising 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine or a pharmaceutically acceptable salt thereof as an active ingredient and a diluent. The pharmaceutical composition has rapid dissolution, improved solubility, stability, flowability, reduced hygroscopicity and risk of food effect, and stable and controllable quality. In addition, the preparation formula of the pharmaceutical composition has simple process and is more suitable for industrial mass production.

Description

Pharmaceutical composition containing CDK4/6 inhibitor

Technical Field

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indole ] -5' -yl) -N- (5- (1-methylpiperidine-4-yl) pyridin-2-yl) pyrimidine-2-amine or pharmaceutically acceptable salts thereof.

Background

The cell cycle is an important part of the life activities of cells, and in the normal cell growth process, the implementation of the cell cycle process depends on the accurate and tight regulation of the cell cycle by each level of regulatory factors. Central to these regulatory factors are Cyclin-dependent protein kinases (Cyclin Dependent Kinase, CDKs) and their positive and negative regulatory factors, cyclin (Cyclin) and Cyclin-dependent protein kinase inhibitors (CDI). Cyclin dependent protein kinases and Cyclin form a CDK-Cyclin complex that is involved in cell growth, proliferation, dormancy, or entry into apoptosis. During the course of the cell cycle, cyclin proteins are expressed and degraded cyclically and bind to the CDKs transiently activated by them, respectively, catalyzing the phosphorylation of different substrates by CDK activity, effecting propulsion and transformation of different phases of the cell cycle.

Currently 13 members of the CDK family have been found, CDK1-CDK13 respectively; wherein 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.

The Cyclin is divided into A-L subtype, and different CDKs are respectively connected with the Cyclin of different subtype. Wherein the Cyclin D family (Cyclin D1, D2, D3) begins to express in the G1 phase, binds to and activates CDK4 and CDK6, forming CDK4/6-Cyclin D complexes, phosphorylating a range of substrates including retinoblastoma proteins (Rb). Rb is phosphorylated and releases proteins bound to and inhibited by it, mainly transcription factors E2F and the like, some genes necessary for E2F activation and transcription into S phase (Ma Ke, development of anti-tumor effect research by CDK4/6 inhibitors, foreign medicine & antibiotics division, 2013, 34 (5): 197-202). If the balance is disturbed due to various factors, the signal for promoting the cell proliferation is enhanced or the signal for inhibiting the cell proliferation is weakened to a certain extent, the cell proliferation is out of control, and thus a tumor appears. It was found that abnormalities in the Cyclin D-CDK4/6-INK4-Rb pathway are present in approximately 80% of human tumors (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). The change of the path accelerates the G1 phase progress, so that the proliferation of tumor cells is accelerated to obtain survival advantage. Thus, intervention into it is a therapeutic strategy, and CDK4/6 is therefore one of the potential anti-tumor targets.

The CDK4/6 has the advantages as an anti-tumor target: (1) Most proliferating cells proliferate dependent on CDK2 or CDK4/6, but inhibitors of CDK4/6 do not exhibit cytotoxicity of "pan-CDK inhibitors", such as myelosuppression and intestinal responses; (2) Preclinical experiments show that if the level of Cyclin D in cells is increased or p16.sup.INK4a is inactivated, the sensitivity of the cells to the drug can be increased, and the targeting of the drug is increased to a certain extent because of the phenomenon that tumor cells exist relative to normal cells.

Applicants have filed a series of novel substituted 2- (pyridin-2-yl) aminopyrimidines (WO 2017/092635 A1) which show good activity with high selectivity towards CDK 4/6. Wherein patent document WO2017/092635A1 discloses compounds of formula (I)

The chemical name is: 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ 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 is described in detail in example 17.

However, the above patent documents do not disclose how to obtain a pharmaceutical composition which dissolves rapidly and stably. Compound 1 has poor solubility. Meanwhile, some salts of the compound 1 have the characteristic of hygroscopicity and have the defects of poor flowability, small bulk density and the like, so that it is required to provide a pharmaceutical composition which is rapidly dissolved and has improved solubility, stability, flowability and reduced hygroscopicity, thereby solving the technical problems of application, storage and scale-up production thereof.

Disclosure of Invention

The technical problem to be solved by the present invention is to provide a pharmaceutical composition based on compound 1 as active ingredient which satisfies the need for oral administration.

Another technical problem underlying the present invention is to provide a pharmaceutical composition based on compound 1 as active ingredient with improved dissolution properties and lower risk of food effects.

Another technical problem underlying the present invention is to provide a pharmaceutical composition based on compound 1 as active ingredient with reduced hygroscopicity.

Another technical problem underlying the present invention is to provide a pharmaceutical composition based on compound 1 as active ingredient with improved flowability.

Another technical problem underlying the present invention is to provide a pharmaceutical composition based on compound 1 as active ingredient with improved dissolution properties.

Another technical problem underlying the present invention is to provide a pharmaceutical composition based on compound 1 as 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 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 of the pharmaceutical composition.

In an effort to obtain a desired pharmaceutical composition based on compound 1 as an active ingredient and a solid oral pharmaceutical formulation thereof, the inventors have conducted a careful screening experiment on the formulation of the pharmaceutical composition, and have found that the formulation composition of the specific pharmaceutical composition according to the present invention can solve the above technical problems, thereby completing the present invention. Accordingly, the present invention provides a pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient, which is rapidly dissolved, has improved solubility, stability, fluidity, and reduced hygroscopicity and risk of food effect, and is stable and controllable in quality.

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

The inventors found that when the diluent of the present invention is used, the flowability of the obtained pharmaceutical composition powder can be significantly improved, the obtained pharmaceutical composition has a large bulk density and a small karl index and angle of repose, and the pharmaceutical composition powder has uniform color and no color difference.

In one embodiment, the pharmaceutically acceptable salt is selected from one or more of fumarate, maleate, adipate and succinate salts of 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine. In another embodiment, the pharmaceutically acceptable salt is 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -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 using the salts of the present invention, the solubility of the pharmaceutical composition of the present invention will be significantly improved relative to the use of the free base of compound 1, while allowing the pharmaceutical composition of the present invention to have a reduced risk of food effects, and also allowing the resulting pharmaceutical composition to have improved hygroscopicity relative to the use of other salts of compound 1, such as hydrochloride and mesylate salts.

In one embodiment, the content of compound 1 or a pharmaceutically acceptable salt thereof is more than 3.0%, preferably more than 4.0%, preferably 4% -80%, preferably 5% -62%, preferably 6% -50%, more preferably 6% -25%, most preferably 8% -23% of the total weight of the pharmaceutical composition, based on the content of the free base of compound 1. The pharmaceutical composition contains different amounts of the pharmaceutical active ingredients, can be used by different patients, and can be used for selecting different amounts of the medicines according to different disease severity, thereby being beneficial to personalized treatment and avoiding 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 tabletose 80; preferably, the mannitol 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 tab 80 and microcrystalline cellulose PH102, or a mixture of microcrystalline cellulose PH102 and lactose monohydrate FlowLac 100.

In one embodiment, the weight ratio of lactose monohydrate to microcrystalline cellulose is from 5:1 to 1:5, preferably from 3:1 to 1:3, more preferably from 1.5:1 to 1:1.5, most preferably 1:1; or the weight ratio of mannitol to microcrystalline cellulose is from 5:1 to 1:5, preferably from 3:1 to 1:3, more preferably from 1.5:1 to 1:1.5, most preferably 1:1. The invention further selects the diluent and the dosage proportion thereof, is beneficial to improving the dissolution rate of the pharmaceutical composition, and has good dissolution consistency.

In one embodiment, the diluent is present in an amount of 20% or more, preferably 30% or more, preferably 40% or more, preferably 20-90%, preferably 50-90%, preferably 60-90%, more preferably 60% -85%, even more preferably 65% -80% of the total weight of the pharmaceutical composition.

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

In one embodiment, the glidant is present in an amount of 0.5% to 15%, preferably 1% to 10%, more preferably 1% to 3%, most preferably 1%, 2% or 3% of the total weight of the pharmaceutical composition. The addition of the glidant is beneficial to improving the fluidity of the pharmaceutical composition, improves the stability of the filling quantity of the filled capsules, and has small filling quantity difference.

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

In one embodiment, the disintegrant is present in an amount of 0.5% to 15%, preferably 1% to 10%, more preferably 1% to 5%, more preferably 1% to 3%, most preferably 1%, 2%, 3%, 4%, or 5% of the total weight of the pharmaceutical composition. The disintegrating agent and the selection of the dosage of the disintegrating agent are beneficial to improving the dissolution rate of the pharmaceutical composition and have good dissolution consistency.

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

In one embodiment, the lubricant is present in an amount of 0.1% to 5%, preferably 0.5% to 3%, more preferably 1% to 2%, most preferably 1% of the total weight of the pharmaceutical composition. The lubricant and the dosage thereof are selected to further reduce friction between powders and mold walls, thereby facilitating capsule filling or tabletting.

As a preferred embodiment, the present invention provides a pharmaceutical composition comprising the following ingredients by weight:

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

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

(3) From 0.5% to 15%, preferably from 1% to 10%, more preferably from 1% to 3%, more preferably 1%, 2%, or 3% of a glidant, preferably colloidal silicon dioxide;

(4) 0.5% -15%, preferably 1% -10%, more preferably 1% -5%, more preferably 1% -3%, more preferably 1%, 2%, 3%, 4%, or 5% of a disintegrant, preferably selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and low substituted hydroxypropylcellulose; and

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

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

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

The invention also provides a solid oral pharmaceutical preparation, preferably powder, capsule, tablet or granule, more preferably capsule, prepared from the pharmaceutical composition, wherein the capsule takes the pharmaceutical composition as a filling.

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

In one embodiment, the capsule is prepared using a powder direct fill process.

The capsule of the invention is prepared by converting the content of the free alkali of the compound 1 into the content, filling the medicinal powder, namely the medicinal composition of the invention, into hard capsule shells of different specifications by using a capsule filling machine, and examining the difference of the content of the capsules, thereby avoiding influencing the content and uniformity of the product.

The invention also provides a pharmaceutical composition according to the invention or a solid oral pharmaceutical formulation according to the invention for use in the treatment of a CDK4/6 mediated disorder or disease.

The invention also provides the use of a pharmaceutical composition according to the invention or a solid oral pharmaceutical formulation according to the invention in the manufacture of a medicament for the treatment of a CDK4/6 mediated disorder or disease.

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

In one embodiment, the CDK4/6 mediated disorder or disease is cancer, aids, atherosclerosis or restenosis following vascular stent implantation, wherein the cancer is preferably a malignant solid tumor or a malignant non-solid tumor, more preferably breast cancer, lung cancer, prostate cancer, leukemia, brain cancer or gastric cancer, even more preferably glioma.

The invention has the beneficial effects that:

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

2) The medicine composition provided by the invention is quick in dissolution and has good dissolution consistency.

3) With the salts of the present invention, 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, while allowing the pharmaceutical composition of the present invention to have a reduced risk of food effects, and also allowing the resulting pharmaceutical composition to have improved hygroscopicity relative to the use of other salts of compound 1, such as hydrochloride and mesylate salts.

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

5) The pharmaceutical composition can realize the preparation of capsules by a powder direct capsule filling process, has simple process, good stability of the filling quantity of the prepared capsules, and small filling quantity difference.

Drawings

FIG. 1 is a fumarate salt of Compound 1 in CD ₃ In OD ¹ H-NMR chart.

FIG. 2 shows the maleate salt of Compound 1 in CD ₃ In Cl ¹ H-NMR chart.

FIG. 3 is a plot of adipic acid salt of Compound 1 on CD ₃ OD (optical axis) ¹ H-NMR chart.

FIG. 4 is a chart showing the presence of compound 1 succinate in CDCl ₃ In (a) and (b) ¹ H-NMR chart.

FIG. 5 is a graph showing the presence of methanesulfonate salt of Compound 1 in CD ₃ In OD ¹ H-NMR chart.

FIG. 6 is a dissolution profile of a test batch in pH 1.2 hydrochloric acid buffer in a 10mg specification of test example 11.

FIG. 7 is a dissolution profile of a test batch in 50mg format of test example 11 in pH 1.2 hydrochloric acid buffer.

Detailed Description

The present invention will be described in further detail by way of the following specific embodiments, but the scope of the present invention should not be construed as being limited to the following examples. Various substitutions and alterations are also within the scope of the present invention, as will be apparent to those of ordinary skill in the art and by routine experimentation, without departing from the spirit of the invention as defined by the foregoing description.

Abbreviations or definitions

Mannitol 100SD: mannitol (mannitol)

100SD。

Microcrystalline cellulose PH101: microcrystalline cellulose

Microcrystalline cellulose PH102: microcrystalline cellulose

Lactose water flow lac 100: lactose monohydrate

Lactose monohydrate tab 80: lactose monohydrate

Colloidal silica 200: colloidal silica

"diluents" as used herein refers to excipients used to increase the weight and/or volume of a pharmaceutical composition to facilitate shaping and dosing. The diluent is selected from one or more of microcrystalline cellulose, lactose or a hydrate thereof, and sugar alcohol, preferably from one or more of microcrystalline cellulose, lactose monohydrate, mannitol, and sorbitol. 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 a mixture of microcrystalline cellulose (e.g., microcrystalline cellulose PH101 or microcrystalline cellulose PH 102) and lactose monohydrate (e.g., lactose monohydrate FlowLac 100 or lactose monohydrate Tablettose 80), or a mixture of microcrystalline cellulose (e.g., microcrystalline cellulose PH101 or microcrystalline cellulose PH 102) and mannitol (e.g., mannitol 100 SD), and the weight ratio of lactose monohydrate to microcrystalline cellulose is 5:1 to 1:5, preferably 3:1 to 1:3, more preferably 1.5:1 to 1:1.5, most preferably 1:1; or the weight ratio of mannitol to microcrystalline cellulose is from 5:1 to 1:5, preferably from 3:1 to 1:3, more preferably from 1.5:1 to 1:1.5, most preferably 1:1.

The "glidant" as used herein refers to an excipient that is used to increase the flowability of a material. The glidant is selected from one or two of talcum powder and colloidal silicon dioxide, and more preferably, the glidant is colloidal silicon dioxide.

The "disintegrant" as used herein refers to an excipient for promoting the disintegration of the pharmaceutical composition in the gastrointestinal tract and increasing the dissolution of the active ingredient. The disintegrating agent is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose, and more preferably, the disintegrating agent is cross-linked sodium carboxymethyl cellulose.

The "lubricant" as used herein refers to an excipient that is used to reduce the inter-particle friction of a pharmaceutical composition, improving the transmission and distribution of forces. The lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate and zinc stearate, and more preferably, the lubricant is magnesium stearate.

The pharmaceutical compositions of the present invention may also contain other excipients in addition to diluents, glidants, disintegrants and lubricants. As specific examples thereof, there may be mentioned: binders, flavoring agents, dispersants, colorants, fragrances, and the like.

The term "solid oral pharmaceutical formulation" as used herein refers to a pharmaceutical formulation in solid form for oral administration. The invention relates to a solid oral pharmaceutical preparation prepared from the pharmaceutical composition, and the specific dosage form of the solid oral pharmaceutical preparation is preferably powder, capsule, tablet or granule, more preferably capsule, wherein the capsule takes the pharmaceutical composition as a filling material.

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

All percentages are given as 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 non-human mammal, more preferably a human.

In the present invention, the terms "comprising" or similar terms "including" and "comprising" and the like generally mean open-ended, but also include within their scope the case of a closure defined by "consisting of. For example, "a pharmaceutical composition containing the case of" a pharmaceutical composition consisting of "a pharmaceutical composition" is also included.

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

Example 1

The preparation method of the different salt forms of the compound 1 is as follows:

(1) Preparation of Compound 1 fumarate salt

Under the protection of nitrogen, methylene chloride (22.0 volumes) and ethanol (22.0 volumes) are added into a reaction kettle at room temperature, and 5-fluoro-4- (7 ' -fluoro-2 ' -methyl spiro [ cyclopentane-1, 3' -indole) is added under stirring]-5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (2.070 kg), heating to 30-40 ℃, stirring until all is dissolved, cooling to room temperature, and transferring the solution into a solvent tank for use. The solution was filtered through a microporous filter under nitrogen protection and transferred to a reaction kettle, stirred, methylene dichloride and ethanol were distilled off at normal pressure, then the temperature of the reaction kettle was maintained to 80.+ -. 5 ℃, and an ethanol solution (12 volumes) of fumaric acid (1.0 eq) was slowly dropped into the reaction kettle through the microporous filter, and stirred at an insulation temperature overnight. Cooling to 20-30 ℃, continuously stirring for at least 1 hour, centrifuging, and collecting a filter cake. The filter cake was placed in a vacuum oven and dried overnight to give 1.605kg of 5-fluoro-4- (7 ' -fluoro-2 ' -methyl spiro [ cyclopentane-1, 3' -indole) ]-5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine fumarate (compound a) in 63.6% yield. Which is a kind of ¹ The H-NMR data are shown in FIG. 1.

(2) Preparation of Compound 1 maleate salt

353.5 mg of 5-fluoro-4- (7 ' -fluoro-2 ' -methyl spiro [ cyclopentane-1, 3' -indole) was weighed out]-5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine to a 20 ml glass bottle was added 5 ml isopropyl alcohol (IPA)/H ₂ O (19:1, v/v), IPA/H containing 83.7 mg of maleic acid ₂ A solution of O (19:1, v/v;3.75 ml) was added dropwise to a glass bottle, stirred at room temperature for 4 days, the solid was centrifuged and dried at 50℃for 5 hours to give 405.1 mg of maleate in 92.7% yield. Which is a kind of ¹ The H-NMR data are shown in FIG. 2.

(3) Preparation of Compound 1 adipate

350.6 mg of 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole) were weighed out]-5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine into a 20 ml glass bottle, 5 ml of Tetrahydrofuran (THF) was added, a THF solution (3.75 ml) containing 105.4 mg of adipic acid was added dropwise to the glass bottle, stirred at room temperature for 4 days, and the solid was centrifuged and dried at 50℃for 5 hours to give 362.4 mg of adipic acid salt in a yield of 79.5%. Which is a kind of ¹ The H-NMR data are shown in FIG. 3.

(4) Preparation of Compound 1 succinate

351.6 mg of 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine and 5 ml of acetone were added to the reaction flask, magnetically stirred, then 3.75 ml of acetone solution containing 85.1 mg of succinic acid was added dropwise to the reaction flask, stirred at room temperature for 4 days, and the solid was separated by centrifugation and dried at 50 degrees celsius for 5 hours to give 377.7 mg of solid, i.e., succinate, in 86.5% yield. Which is a kind of ¹ The 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 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-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, the solid was centrifuged and dried at 50 ℃ for 3 hours to give 370.2 mg of a solid, i.e. methanesulfonate, in 101.0% yield. Which is a kind of ¹ The H-NMR data are shown in FIG. 5.

(6) Preparation of Compound 1 hydrochloride

352.2 mg of 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine were weighed into a 20 ml glass bottle 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, then 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 and dried at 50℃for 5 hours, and 361.4 mg of the solid was collected to give the hydrochloride salt in 83.3% yield.

Test example 1 solubility test

The purpose of this test example is to compare the solubility of various salts (also referred to as salt forms) and the free base obtained in accordance with the present invention.

The test method comprises the following steps: solubility tests were performed in three vehicles, water, simulated fasted intestinal fluid (FaSSIF) and simulated fed intestinal fluid (FeSSIF) to assess the solubility of the salts of the invention and the risk of food effects.

In the test, the sample and the solvent are mixed in a centrifuge tube (initial feeding amount is 10 mg/ml), the centrifuge tube is sealed and fixed on a rotating disc with the rotating speed of 25 revolutions per minute, and the mixture is sampled after rotating and mixing for 24 hours at 37 ℃. The turbid sample was centrifuged, and the filtered supernatant was taken to determine the HPLC concentration. If the sample is clear, the resulting solution concentration is tested.

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

Test results: see tables 1-3 for solubility of different salt forms and free base in water, simulated fasted intestinal fluid (FaSSIF) and simulated fed intestinal fluid (FeSSIF).

Table 1 solubility of different salt forms and free base of compound 1 in water

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

As shown in table 1, the solubility of the maleate, fumarate, adipate and succinate salts of compound 1 in water was 12.9, 6.3, 6.5 and 7.5 mg/ml, respectively, which is significantly higher than the solubility of the free base in water (0.075 mg/ml). This suggests that the dissolution properties of the active ingredient compound 1 are significantly improved when the pharmaceutical composition of the present invention is formulated using the above-described salts of the present invention.

Table 2 solubility of different salt forms and free base of compound 1 in simulated fasted bowel fluid (FaSSIF)

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

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

Table 3 solubility of different salt forms and free base of compound 1 in simulated feeding intestinal fluid (FeSSIF)

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

As shown in table 3, the solubility of the maleate, fumarate, adipate and succinate salts of compound 1 in the simulated feeding broth (FeSSIF) was comparable to the solubility of the free base of compound 1 in the simulated feeding broth (FeSSIF) (10.2 mg/ml), but the solubility of these salts in the simulated fasted broth (FaSSIF) and the simulated feeding broth (FeSSIF) was close relative to the free base, suggesting that the above salts of the invention have a lower risk of food effects.

Test example 2 hygroscopicity test

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

The moisture adsorption amount of the salt and the free base of the compound 1 of the present invention at a humidity of 80% rh was tested by a dynamic moisture adsorption (DVS) test at 25 ℃ to conduct hygroscopicity comparison.

Test object: the free base of compound 1, maleate, fumarate, adipate, succinate, mesylate and hydrochloride.

Experimental results: the test results are shown in Table 4. Wherein, the hygroscopicity (based on the moisture adsorption amount of the test object when the humidity reaches 80% RH) is more than 15% and is very hygroscopic, 2-15% is hygroscopic, 0.2-2% is slightly hygroscopic, and < 0.2% is almost no hygroscopicity.

Table 4 hygroscopicity of the different salt forms and free base of compound 1

Sample name	Hygroscopicity (%)
Free base of Compound 1	0.10
Maleate salt of compound 1	2.00
Fumarate salt of Compound 1	0.35
Adipic acid salt of compound 1	0.22
Succinate salt of Compound 1	0.33
Methanesulfonic acid salt of Compound 1	12.02
Hydrochloride salt of compound 1	9.12

The results show that: the maleate, fumarate, adipate and succinate salts of the compound 1 have moisture adsorption amounts of 0.10-2.00% at 25 ℃/80% RH, and have only slight hygroscopicity, almost equivalent to that of the free base; the water adsorption amounts of the hydrochloride and the mesylate are respectively 9.12% and 12.02% under the condition of 25 ℃/80% RH, and the hydrochloride and the mesylate have higher hygroscopicity. This suggests that the use of the maleate, fumarate, adipate and succinate salts of compound 1 as active ingredients of the pharmaceutical composition significantly improves hygroscopicity of the pharmaceutical composition relative to the mesylate and hydrochloride salts of compound 1.

Examples 2 to 3

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

(1) Compound a, mannitol 100SD, microcrystalline cellulose PH101, colloidal silicon dioxide 200, and magnesium stearate were weighed according to the formulation amounts in table 5, respectively;

(2) Uniformly mixing the compound A with colloidal silicon dioxide 200, and sieving to obtain pretreatment powder;

(3) Sieving mannitol 100SD, microcrystalline cellulose PH101 and magnesium stearate respectively for standby;

(4) Uniformly mixing the pretreatment powder obtained in the step (2) with mannitol 100SD and microcrystalline cellulose PH101, and mainly mixing the powder for later use;

(5) And (3) adding magnesium stearate into the main mixed powder prepared in the step (4) and mixing to obtain the total mixed powder of the medicine composition powder.

TABLE 5

* And (3) injection: compound a is the fumarate salt of 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine.

Test example 3 flowability test

The angle of repose (in accordance with the national standard GB11986-89 for measurement of angle of repose of surfactant powder and particles), bulk Density, tap Density and Cal index of the active ingredient raw material Compound A and the pharmaceutical compositions of examples 2-3 were measured with an Intelligent powder Property tester. The result of the karl index= (tap density-bulk density)/tap density 100% is shown in table 6.

TABLE 6

As can be seen from the data in table 6, the pharmaceutical compositions of examples 2-3 have significantly increased bulk density and significantly reduced repose angle and karr index relative to the single active ingredient raw material compound a, which indicates that the pharmaceutical composition powders of examples 2-3 have significantly improved flowability relative to the single active ingredient raw material compound a, and can realize the preparation of capsules by a simple powder direct filling process, reduce the risk of large difference in filling amount when filling capsules, and meet the requirements of capsule filling and industrial production.

Examples 4 to 6

The pharmaceutical composition powders of examples 4-6 were prepared according to the formulation amounts in Table 7 using procedures similar to those used in examples 2-3.

TABLE 7

Test example 4 flowability test

The angle of repose, bulk density, tap density and karl index of the pharmaceutical composition powders obtained in examples 4 to 6 were measured in accordance with the method of test example 3, and the results are shown in the following table 8.

TABLE 8

As can be seen from the data in table 8, the bulk density of the pharmaceutical composition powders of examples 4 to 6 is significantly increased and the repose angle and the karl index are significantly reduced with respect to the single active ingredient raw material compound a, which indicates that the pharmaceutical composition powders of examples 4 to 6 are significantly improved in flowability with respect to the single active ingredient raw material compound a, and when used for preparing a capsule-form formulation in the subsequent step, the risk of large variation in the filling amount of the filled capsules can be reduced, and the requirements of capsule filling and the requirements of industrial production can be satisfied.

Examples 7 to 9

The capsules of examples 7-9 were prepared as follows:

(1) Compound a, microcrystalline cellulose PH102, lactose monohydrate FLOWLAC ac100, croscarmellose sodium, colloidal silicon dioxide 200, and magnesium stearate were weighed according to the amounts in table 9, respectively;

(3) Sieving microcrystalline cellulose PH102, lactose monohydrate FLOWLAC100, crosslinked sodium carboxymethylcellulose and magnesium stearate respectively for use;

(4) Uniformly mixing the pretreatment powder obtained in the step (2) with microcrystalline cellulose PH102, lactose monohydrate FLOWLAC100 and crosslinked sodium carboxymethylcellulose, and mainly mixing the powder for later use;

(6) The pharmaceutical composition powder total mix is filled into empty capsules using a capsule filling machine.

TABLE 9

* And (3) injection: 50mg of the standard capsule, based on the free base content of 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine. Compound a was a fumarate salt of 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine, having a molecular weight of 604.66, its free base molecular weight of 488.59, and a conversion factor of 1.24.

Test example 5 dissolution test

The dissolution of the capsules of examples 7 to 9 thus prepared was determined according to the first method (basket method) of dissolution determination method of four parts 0931 of the 2015 edition of chinese pharmacopoeia. 900 ml of PH1.2 hydrochloric acid buffer solution is adopted as a medium, and the water temperature is 37+/-0.5 ℃ and the water is sampled at 6 time points of 5min, 15min, 30min, 45min, 60min, 75min and the like at the rotating speed of 50 rpm. Each sample volume was 10 ml and was filtered through a PFS filter (0.45 μm to 10 μm). 3 capsules or 6 capsules were repeated for each dissolution test. The elution results are shown in Table 10 below.

Table 10

* And (3) injection: RSD stands for "relative standard deviation".

As can be seen from the data in Table 10, the capsules obtained in examples 7 to 9 of the present invention have a relatively high dissolution rate and good dissolution uniformity in the dissolution medium at pH1.2, and no significant difference in dissolution behavior.

Examples 10 to 13

Following the formulation in Table 11, similar procedures to those used in examples 2-3 were followed to give the pharmaceutical composition powders of examples 10-13.

TABLE 11

Test example 6 flowability test

The repose angles of the pharmaceutical composition powders obtained in examples 10 to 13 were measured in accordance with the method of test example 3, and the test results are shown in Table 12.

Table 12

Formulation of	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, the pharmaceutical compositions of examples 11 to 13, in which colloidal silica was added to the formulation, had a further reduced angle of repose and improved flowability, compared to the pharmaceutical composition of example 10, in which colloidal silica was not added, and the flowability of the pharmaceutical composition powder did not significantly change when the amount of colloidal silica was in the range of about 1% to 3%.

Examples 14 to 15

Following a procedure similar to examples 7-9, capsules of examples 14-15 were obtained having formulations as shown in Table 13.

TABLE 13

Test example 7 dissolution test

The dissolution rates of the capsules obtained in examples 14 to 15 were measured according to the method of test example 5, and the test results are shown in Table 14 below.

TABLE 14

As is clear from the data in Table 14, the capsules obtained in examples 14 to 15 of the present invention have a relatively high dissolution rate and good dissolution uniformity in the dissolution medium having a pH of 1.2.

EXAMPLE 1610mg Standard Capsule

Following a procedure similar to examples 7-9, 10mg specification capsules were obtained with the formulations shown in Table 15.

TABLE 15

* And (3) injection: the 10mg size capsule is based on the free base content of 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine. Compound a was a fumarate salt of 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine, having a molecular weight of 604.66, its free base molecular weight of 488.59, and a conversion factor of 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 elution results of 10mg

From the above results, it was found that the capsule of the present invention has excellent dissolution behavior.

Test example 9 results of weight detection of capsules

10 capsules were sampled at the front, middle and rear three stages of capsule filling in example 7 (50 mg standard) and example 16 (10 mg standard), and the weight of each capsule was measured (the front, middle and rear three stages refer to 5 minutes after starting capsule filling, about half of capsule filling, and 5 minutes before filling), and the test results were shown in tables 17 and 18 according to the "chinese pharmacopoeia" 2015 edition four-part 0103 capsule item difference test method.

TABLE 17 weight detection results of 50mg specification capsules

Table 18 weight detection results of 10mg specification capsules

As shown in the experimental results of tables 17 and 18, the capsule filling process is stable by using the pharmaceutical composition formula of the invention, the obtained capsule filling quantity difference is small, the filling quantity difference is obviously smaller than the filling quantity difference limit (+ -7.5%), and the product content and content uniformity cannot be obviously influenced in the capsule filling process.

Test example 10 stability of the pharmaceutical composition of the present invention

To examine the stability of the pharmaceutical composition obtained in the present invention, stability experiments were performed using the capsules of example 7 (50 mg specification) and example 16 (10 mg specification). The two standard samples are placed under the same conditions, and are placed under the acceleration condition of 40 ℃/75% RH (open) for 10 days and 30 days respectively, the content change of free alkali of the compound A in the capsule is measured by adopting an HPLC method, and the dissolution rate is measured by adopting the method of test example 5; the samples were left for 10 days and 30 days under 60℃and 25℃and 75% RH (open), light (intensity 5000 lux) (open), 40℃and 75% RH (open) and 40℃and 75% RH (closed), respectively, and then the changes in the substances were measured by HPLC. The detection results of the capsule content change, the dissolution result and the related substance change are as follows:

TABLE 19 results of Capsule content variation

* And (3) injection: the capsule content means "free base content of compound a in capsule".

Table 20 results of capsule dissolution

From the above data, it was found that the active material content was stable after 2-sized capsules were left for 30 days under acceleration conditions of 40 ℃/75% rh (open), and that the acceleration conditions (40 ℃/75% rh) had no effect on the dissolution of the 2-sized capsules.

Test example 11 dissolution test and stability test study of pilot-scaled-up samples of the invention

Capsules were prepared using the formulations of example 7 (50 mg format) and example 16 (10 mg format), 10000 pellets each, and each in three batches. The package adopts an oral solid medical high-density polyethylene bottle and an oral solid medical child safety cap.

1. Dissolution test

For each batch, 6 capsules were randomly selected, and the dissolution rate was determined by the method of test example 5, and the dissolution results are shown in fig. 6 to 7, which show that: the pharmaceutical compositions with two specifications can be dissolved out more than 95% in a hydrochloric acid buffer solution with pH of 1.2 in 15 minutes, and can be completely dissolved out in 30 minutes.

2. Stability test

For the samples obtained by pilot scale-up, the pharmaceutical properties, content and related substance changes, dissolution and moisture absorption and weight gain were measured under conditions of high temperature (60 ℃), intense light (5000 lux) and high humidity (75% RH) to further confirm the stability of the pharmaceutical composition of the present invention under scale-up production conditions. Wherein, the medicine property is observed by visual inspection, the content of free alkali and the change of related substances of the compound A are measured by an HPLC method, the dissolution rate is measured by a first method (basket method) of a four-part 0931 dissolution rate measurement method of the 2015 edition of Chinese pharmacopoeia, the moisture absorption and weight gain is measured by a first method (Fei Xiushi method) of a four-part 0832 moisture measurement method of the 2015 edition of Chinese pharmacopoeia, and the results are shown in tables 23-26.

The test result shows that the capsule obtained by the amplification production is stable after being placed for a long time under the conditions of high temperature (60 ℃), strong light (illumination 5000 lux) and high humidity (75%RH), and the results of all detection items are not changed obviously and meet the requirements of quality standard limits. Further proved by the invention, the obtained pharmaceutical composition has higher stability under the condition of amplified production, and the preparation adopted by the invention has simple and stable production process and can meet the requirement of industrial mass production.

TABLE 24 stability test of 10mg Capsule with high humidity 75% RH

TABLE 26 stability test of 50mg Capsule with high humidity 75% RH

Claims

A pharmaceutical composition containing 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine or a pharmaceutically acceptable salt thereof as an active ingredient and a diluent, characterized in that the diluent is selected from one or more of microcrystalline cellulose, lactose or a hydrate thereof, and a sugar alcohol.
The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from one or more of fumarate, maleate, adipate, and succinate salts of 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine; preferably, the pharmaceutically acceptable salt is 5-fluoro-4- (7 '-fluoro-2' -methyl spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine fumarate.
Pharmaceutical composition according to any one of claims 1-2, characterized in that the content of 5-fluoro-4- (7 '-fluoro-2' -methylparaben [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine free base, 5-fluoro-4- (7 '-fluoro-2' -methylparaben [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine or a pharmaceutically acceptable salt thereof, based on the content of free base, is more than 3.0%, preferably more than 4.0%, preferably 4% -80%, preferably 5% -62%, preferably 6% -50%, more preferably 6% -25% and most preferably 8% -23% of the total weight of the pharmaceutical composition.
A pharmaceutical composition according to any one of claims 1 to 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, the lactose monohydrate is lactose monohydrate FlowLac 100 or lactose monohydrate tabletose 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.
Pharmaceutical composition according to any of claims 1 to 4, wherein the weight ratio of lactose monohydrate to microcrystalline cellulose is 5:1 to 1:5, preferably 3:1 to 1:3, more preferably 1.5:1 to 1:1.5, most preferably 1:1; or (b)

The weight ratio of mannitol to microcrystalline cellulose is 5:1 to 1:5, preferably 3:1 to 1:3, more preferably 1.5:1 to 1:1.5, most preferably 1:1.
The pharmaceutical composition according to any one of claims 1 to 5, wherein the diluent is present in an amount of 20% or more, preferably 30% or more, preferably 40% or more, preferably 20-90%, preferably 50-90%, preferably 60-90%, more preferably 60-85%, even more preferably 65-80% of the total weight of the pharmaceutical composition.
The pharmaceutical composition according to any one of claims 1-6, further comprising a glidant, preferably the glidant is selected from one or both of talc and colloidal silicon dioxide, more preferably the glidant is colloidal silicon dioxide.
The pharmaceutical composition according to claim 7, wherein the glidant is present in an amount of 0.5% to 15%, preferably 1% to 10%, more preferably 1% to 3%, most preferably 1%, 2%, or 3% of the total weight of the pharmaceutical composition.
The pharmaceutical composition according to any one of claims 1 to 8, further comprising a disintegrant, preferably selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low substituted hydroxypropyl cellulose, more preferably the disintegrant is croscarmellose sodium.
Pharmaceutical composition according to claim 9, wherein the content of disintegrant is 0.5% to 15%, preferably 1% to 10%, preferably 1% to 5%, more preferably 1% to 3%, more preferably 1%, 2%, 3%, 4%, or 5% of the total weight of the pharmaceutical composition.
The pharmaceutical composition according to any one of claims 1 to 10, further comprising a lubricant, preferably the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate and zinc stearate, more preferably the lubricant is magnesium stearate.
Pharmaceutical composition according to claim 11, wherein the lubricant is present in an amount of 0.1% to 5%, preferably 0.5% to 3%, more preferably 1% to 2%, most preferably 1% of the total weight of the pharmaceutical composition.
A pharmaceutical composition, characterized in that it comprises the following ingredients by weight:

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

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

(3) From 0.5% to 15%, preferably from 1% to 10%, more preferably from 1% to 3%, more preferably 1%, 2%, or 3% of a glidant, preferably colloidal silicon dioxide;

(4) 0.5% -15%, preferably 1% -10%, more preferably 1% -5%, more preferably 1% -3%, more preferably 1%, 2%, 3%, 4%, or 5% of a disintegrant, preferably selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and low substituted hydroxypropylcellulose; and

(5) From 0.1% to 5%, preferably from 0.5% to 3%, more preferably from 1% to 2%, most preferably 1%, of a lubricant, preferably the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate and zinc stearate.
Pharmaceutical composition according to 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 mannitol to microcrystalline cellulose is from 5:1 to 1:5, preferably from 3:1 to 1:3, more preferably from 1.5:1 to 1:1.5, most preferably 1:1.
The pharmaceutical composition according to any one of claims 1-14, wherein the pharmaceutical composition comprises 0.1-1000 mg, preferably 1-100 mg, more preferably 8-50 mg of active ingredient, based on the content of 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine free base.
A solid oral pharmaceutical formulation, preferably a powder, capsule, tablet or granule, more preferably a capsule, made from the pharmaceutical composition of any one of claims 1-15, wherein the capsule has the pharmaceutical composition as a fill.
The solid oral pharmaceutical formulation according to claim 16, wherein the solid oral pharmaceutical formulation comprises 0.1-1000 mg, preferably 1-100 mg, more preferably 8-50 mg of active ingredient, based on the content of 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine free base.
The solid oral pharmaceutical formulation according to claim 16 or 17, wherein the capsule is prepared using a powder direct fill process.
A pharmaceutical composition according to any one of claims 1 to 15 or a solid oral pharmaceutical formulation according to any one of claims 16 to 18 for use in the treatment of a CDK4/6 mediated disorder or disease.
Use of a pharmaceutical composition according to any one of claims 1 to 15 or a solid oral pharmaceutical formulation according to any one of claims 16 to 18 in the manufacture of a medicament for the treatment of a CDK4/6 mediated disorder or disease.
A method for treating a CDK4/6 mediated disorder or disease comprising administering to a subject in need thereof a pharmaceutical composition according to any one of claims 1-15 or a solid oral pharmaceutical formulation according to any one of claims 16-18.