WO2020038434A1 - Pharmaceutical composition of 2-aminopyrimidine compounds - Google Patents

Abstract

Disclosed is a pharmaceutical composition of 2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof. Specifically provided are a pharmaceutical composition comprising N-((5-((5-chlorine-4-((naphthalen-1-yl)amino))pyrimidin-2-yl)amino)-2-((N-methyl-N-dimethylaminoethyl)amino)-4-methoxy phenyl)acrylamide or pharmaceutically acceptable salts thereof. Also provided is a method for preparing the pharmaceutical composition.

Description

Pharmaceutical composition of 2-aminopyrimidine compound Technical field

The invention belongs to the field of pharmaceutical preparations, and in particular, the invention relates to a compound N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2 -((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preparing the same method.

Background technique

Epidermal growth factor receptor (EGFR), a receptor tyrosine protein kinase, regulates cell proliferation, survival, adhesion, migration, and differentiation. EGFR is over-activated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, and prostate cancer. Blocking the activation of EGFR and Erb-B2 has been clinically proven to be the leading method for targeted therapy of tumor cells. Two small molecule inhibitors targeting EGFR, gefitinib and erlotinib, have received rapid approval from the US FDA for the treatment of patients with advanced non-small cell lung cancer (NSCLC), who have already lost their response to conventional chemotherapy.

Patients with EGFR-activated mutation-positive NSCLC have significantly higher response rates to EGFR-TKI (EGFR-tyrosine kinase inhibitor) than patients with EGFR wild-type NSCLC, and their progression-free survival (PFS) and overall survival (OS) periods have also been significantly extended. . However, despite this, most patients with EGFR mutation-positive patients have PFS no longer than 12 to 14 months, that is, they have developed resistance to TKI. The mechanism of acquired resistance and its clinical coping strategies have become another research hotspot in the field of targeted therapy.

N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl-N-dimethylaminoethyl ) Amino) -4-methoxyphenyl) acrylamide, the chemical structure is shown in Formula I. The compound of formula I is an EGFR inhibitor that selectively inhibits the EGFR T790M mutation. It can overcome the resistance induced by the existing drugs gefitinib, erlotinib, etc., and has weak inhibitory activity against wild-type EGFR. However, there is still a lack of adaptation in the art to N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl- N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide A pharmaceutical composition for administration.

The unpublished Chinese invention patent application CN201710108703.X describes a pharmaceutical composition of a compound of formula I; the unpublished Chinese invention patent application CN201810332187.3 describes a pharmaceutically acceptable salt of a compound of formula I.

Summary of the Invention

The object of the present invention is to provide a suitable N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl -N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide or a pharmaceutical composition for administration thereof.

According to a first aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising an active ingredient, a filler, a lubricant, and a disintegrant, via Direct powder compression method;

The active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;

The disintegrant is crospovidone.

The pharmaceutical composition may further contain a glidant; the glidant is preferably talc or colloidal silica. In a preferred example, the weight ratio of the glidant to the active ingredient is 0.005: 1 to 0.2: 1, preferably 0.01: 1 to 0.1: 1.

The filler is selected from the group consisting of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, sorbitol, mannitol, or a combination thereof.

In a preferred example, the filler is a combination of a first filler and a second filler, the first filler is mannitol and / or lactose, and the second filler is microcrystalline cellulose.

In a preferred example, the weight ratio of the first filler and the second filler is preferably 9: 1 to 1: 9, and more preferably 9: 1 to 1: 3.

In a preferred example, the weight ratio of the filler to the active ingredient is 99: 1 to 1: 9, preferably 8: 1 to 1: 1, and more preferably 4: 1 to 2: 1.

The lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, Or a combination thereof; sodium stearyl fumarate is preferred.

In a preferred example, the weight ratio of the lubricant to the active ingredient is 1: 1 to 1: 200, preferably 1: 2 to 1:50, and more preferably 1: 5 to 1:15.

In a preferred example, the weight ratio of the disintegrant to the active ingredient is 1: 1 to 1:90, preferably 1: 1 to 1:30, and more preferably 1: 2 to 1:15.

In a preferred example, the pharmaceutical composition is used for preparing a medicament for treating cancer in a patient. Preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

In a preferred example, the pharmaceutical composition is used to treat cancer in a patient. Preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

According to a second aspect of the present invention, there is provided a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising an active ingredient, a filler, a lubricant, and a disintegrant, via Direct powder compression method;

The active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;

The pharmaceutical composition is free of colloidal silica.

The filler is selected from the group consisting of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, sorbitol, mannitol, or a combination thereof.

In a preferred example, the filler is a combination of a first filler and a second filler, the first filler is mannitol and / or lactose, and the second filler is microcrystalline cellulose.

In a preferred example, the weight ratio of the first filler and the second filler is preferably 9: 1 to 1: 9, and more preferably 9: 1 to 1: 3.

In a preferred example, the weight ratio of the filler to the active ingredient is 99: 1 to 1: 9, preferably 8: 1 to 1: 1, and more preferably 4: 1 to 2: 1.

The lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, Or a combination thereof; sodium stearyl fumarate is preferred.

In a preferred example, the weight ratio of the lubricant to the active ingredient is 1: 1 to 1: 200, preferably 1: 2 to 1:50, and more preferably 1: 5 to 1:15.

The disintegrant is crospovidone, low-substituted hydroxypropyl cellulose, or a combination thereof.

In a preferred example, the weight ratio of the disintegrant to the active ingredient is 1: 1 to 1:90, preferably 1: 1 to 1:30, and more preferably 1: 2 to 1:15.

In a preferred example, the pharmaceutical composition is used for preparing a medicament for treating cancer in a patient. Preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

In a preferred example, the pharmaceutical composition is used to treat cancer in a patient. Preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

According to a third aspect of the present invention, there is provided a method for preparing the pharmaceutical composition according to the first or second aspect of the present invention. The preparation method includes: (1) combining an active ingredient, a filler, a lubricant, and a The dissolving agent is mixed uniformly to obtain an intermediate powder; (2) tabletting is performed according to the tablet weight.

When the pharmaceutical composition contains a glidant, the preparation method includes: (1) mixing the active ingredient, filler, lubricant, disintegrant, and glidant uniformly to obtain an intermediate powder; (2) ) Compression according to tablet weight.

In a preferred example, the active ingredient is in a powder form.

In a preferred example, the active ingredient powder is obtained by mechanically pulverizing a drug substance of the compound of Formula I or a pharmaceutically acceptable salt thereof.

In a preferred example, the active ingredient powder is obtained by sieving a drug substance of Compound I or a pharmaceutically acceptable salt thereof.

In a preferred example, the active ingredient powder is obtained by mechanically pulverizing the drug substance of the compound of Formula I or a pharmaceutically acceptable salt thereof, and sieving the pulverized drug substance.

According to a fourth aspect of the present invention, a pharmaceutical tablet is provided, and the pharmaceutical tablet includes the pharmaceutical composition according to the first aspect or the second aspect of the present invention.

In a preferred example, the medicinal tablet includes a tablet core and a coating covering the tablet core, and the tablet core is the medicinal combination according to the first aspect or the second aspect of the present invention. Thing.

In a preferred example, the pharmaceutical tablet is used for preparing a medicament for treating cancer in a patient. Preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

In a preferred example, the pharmaceutical tablet is used for treating cancer in a patient. Preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

It should be understood that, within the scope of the present invention, the above technical features of the present invention and the technical features specifically described in the following (such as the embodiments) may be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a dissolution curve of three batches of 10 mg tablets in Comparative Example 1 in a pH 3.8 dissolution medium;

2 is a dissolution curve of three batches of 80 mg tablets in Comparative Example 1 in a pH 3.8 dissolution medium;

3 is a dissolution curve of the tablets of Group A, Group B, Group C, and Group D in a dissolution medium at pH 3.8 in Comparative Example 3;

FIG. 4 is a dissolution curve of the tablets in Examples 3 to 6 in a pH3.8 dissolution medium.

detailed description

The inventors have provided a suitable N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2 after long and intensive research. -((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide A pharmaceutical composition for administration of a pharmaceutically acceptable salt thereof. The pharmaceutical composition has excellent dissolution and chemical stability. Based on the above findings, the inventors have completed the present invention.

the term

As used herein, when used in reference to a particular recited value, the term "about" means that the value can vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the terms "containing" or "including (comprising)" may be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of" or "consisting of."

As used herein, the term "... standard core" or "... standard tablet" has the following meaning: each core or tablet contains a certain amount of a compound of formula I; for example, 10 mg standard core represents each core It contains about 10 mg of a compound of formula I. A pharmaceutically acceptable salt of a compound of formula I is converted according to a compound of formula I.

N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl-N-dimethylaminoethyl ) Amino) -4-methoxyphenyl) acrylamide

The pharmaceutically acceptable salt of Compound I is an inorganic or organic salt formed from Compound I and any acid. The salt may be selected from the group consisting of phosphate, hydrochloride, hydrobromide, sulfate, mesylate, p-toluenesulfonate, fumarate, tartrate, citrate, succinate, hexanoate Diacids, maleates, lactates, malates, camphor sulfonates, nitrates, acetates and benzoates.

The acid includes any of its optical isomers, racemates, and mesomers. For example, tartaric acid may be L-tartaric acid, D-tartaric acid, and DL-tartaric acid. The camphorsulfonic acid may be D-camphorsulfonic acid, L-camphorsulfonic acid, DL-camphorsulfonic acid, and the like.

The phosphate of the compound I is composed of a compound I with a phosphate molar ratio of about 3: 1, or about 2: 1, or about 1: 1. The sulfate of Compound I is composed of Compound I and sulfuric acid at a molar ratio of about 2: 1, or about 1: 1. Hydrochloride, citrate, acetate, maleate, tartrate, fumarate, camphorsulfonate, mesylate, malate, succinate, adipic acid The salts, benzoates, hydrobromides, lactates and nitrates consist of a compound with a molar ratio of about 1: 1 to the corresponding acid.

The method for preparing a pharmaceutically acceptable salt of Compound I may be a conventional salt formation method in the art, and includes a step of salting Compound I with a corresponding acid.

The pharmaceutically acceptable salt of Compound I is preferably a phosphate of Compound I (for example, a molar ratio of Compound I to phosphoric acid is about 1: 1, that is, a dihydrogen phosphate), a sulfate (for example, a molar ratio of Compound I to sulfuric acid is about It is 1: 1, ie, hydrogen sulfate), hydrobromide or camphorsulfonate, more preferably phosphate (such as dihydrogen phosphate) and sulfate (such as hydrogen sulfate).

N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl-N-dimethylaminoethyl ) Amino) -4-methoxyphenyl) acrylamide medicine or pharmaceutical composition thereof

An object of the present invention is to provide a compound N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl- N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide or a pharmaceutically acceptable salt thereof is a medicinal composition suitable for industrial production and meeting the requirements of clinical use.

The inventor of the present invention encountered a number of technical difficulties in the process of studying the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof suitable for industrial production and meeting the requirements of clinical use. For example, (1) the poor fluidity of the compound of formula I affects the uniformity of the content of the pharmaceutical composition, the consistency of the dissolution between batches, etc .; (2) the compound of formula I is easily oxidized, and the process needs to be fast and simple to minimize the preparation time (3) Patients with non-small cell lung cancer, especially advanced patients, have difficulty in swallowing the respiratory system, requiring drugs to be administered by nasal feeding, etc .; (4) Dissolution decreases after long-term storage.

It is known to those skilled in the art that, according to different tableting process routes, tableting methods can be divided into two categories, namely, pelletizing and direct tableting methods. Further, the granulation and tableting method can be divided into two categories: wet granulation and tableting method, dry granulation and tableting method, and direct tableting method into powder direct tableting method and semi-dry granule tableting method. Small class.

The direct compression method (direct compression method) is a method of directly compressing a mixture of a drug and an excipient without a granulation process. The direct compression method has the disadvantages of poor powder flowability, poor content uniformity, and large differences in tablet weight; therefore, the requirements for the fluidity of the drug substance are relatively high. The drug substance of the compound of formula I has poor fluidity, and research by the inventors shows that the poor fluidity has nothing to do with the crystal structure of the drug substance. For those skilled in the art, the direct powder tableting method is not suitable for manufacturing a pharmaceutical composition of the compound of formula I suitable for industrial production and meeting the requirements of clinical use.

However, the inventor made a lot of experiments on the four types of tableting methods, and surprisingly found that the invention can overcome the defect of poor fluidity, and use the powder direct tableting method to obtain a formula in the form of tablets with uniform content and stable tablet weight. A pharmaceutical composition of a compound I or a pharmaceutically acceptable salt thereof. More surprisingly, the pharmaceutical composition in the form of a tablet prepared by the direct compression method of the powder provided by the present invention has a short disintegration time and a fast dissolution rate. It has also been found that good dissolution performance can still be guaranteed after long-term storage.

Therefore, the present invention provides a pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof which is suitable for industrial production and meets the requirements of clinical use; the pharmaceutical composition is preferably in the form of a tablet. The pharmaceutical composition is prepared by a direct powder tableting method, and is composed of a compound of formula I or a pharmaceutically acceptable salt thereof, a filler, a lubricant, and a disintegrant.

The compound of formula I or a pharmaceutically acceptable salt thereof exists as an active ingredient in a pharmaceutical composition, and its content can generally be flexibly set according to the needs of the mode of administration.

The pharmaceutical composition of the present invention may be selected from one, two, three or more fillers. The filler, also known as a diluent, is mainly used to increase the weight and / or volume of the pharmaceutical composition; at the same time, it can reduce the dose deviation of the active ingredient and improve compression moldability. Pharmaceutical fillers include, but are not limited to, one or more of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, sorbitol, and mannitol.

In the present invention, the weight ratio of the filler to the active ingredient is 99: 1 to 1: 9, preferably 8: 1 to 1: 1, and more preferably 4: 1 to 2: 1

In the present invention, the filler is preferably a combination of a first filler and a second filler, the first filler is mannitol and / or lactose, and the second filler is microcrystalline cellulose. Among them, the weight ratio of the first filler and the second filler is preferably 9: 1 to 1: 9, and more preferably 9: 1 to 1: 3.

Suitable microcrystalline cellulose has an average particle size of 20-200 μm, and it is commercially available, such as Avicel PH-102, Avicel HFE-102, Avicel PH-301, Avicel PH-302, and Avicel PH-200 from FMC.

The "lubricant" used in the present invention refers to an auxiliary material added before tabletting to reduce the friction between particles or tablets and the die. Adding a lubricant can reduce the friction with the die and increase the sliding properties of the particles. The filling is good, the density distribution of the tablets is uniform, and the integrity of the ejected tablets is also guaranteed. The pharmaceutical composition of the present invention may be selected from one, two, three or more lubricants. Lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate. The lubricant of the present invention is preferably sodium stearyl fumarate. In the present invention, the weight ratio of the lubricant to the active ingredient is 1: 1 to 1: 200, preferably 1: 2 to 1:50, and more preferably 1: 5 to 1:15.

Disintegrants are excipients that promote the rapid fragmentation of tablets into fine particles in the gastrointestinal fluid. Common pharmaceutical disintegrants include, but are not limited to, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone. The present invention preferably uses low-substituted hydroxypropyl cellulose and / or crospovidone as a disintegrant; more preferably uses low-substituted hydroxypropyl cellulose or crospovidone; even more preferably uses crospovidone . In the present invention, the weight ratio of the disintegrant to the active ingredient is 1: 1 to 1:90, preferably 1: 1 to 1:30, and more preferably 1: 2 to 1:15.

The particle size distribution of the drug substance affects the dissolution of the tablet. In order to ensure the dissolution rate of the active ingredient, in the present invention, the particle diameter D90 of the active ingredient is preferably controlled to be 30 to 200 μm, and the particle diameter D90 of the active ingredient is preferably controlled to be 30 to 120 μm. The present invention can adopt methods known in the art to control the particle size of the compound of formula I or a pharmaceutically acceptable salt thereof. Preferably, the active ingredient is processed by pulverization and / or sieving; more preferably, the The treatment method is sieving 80-200 mesh (optionally, crushing before sieving).

The above medicinal composition is prepared through a direct powder tableting method, which includes: (1) mixing the active ingredients, fillers, lubricants, and disintegrating agents uniformly to obtain an intermediate powder; (2) according to Tablets are compressed. After the intermediate powder is obtained, the content can be detected, and the tablet weight can be calculated by calculating the tablet weight as a result of the content measurement.

Medicinal tablet and preparation thereof

The present invention also provides a pharmaceutical tablet comprising the pharmaceutical composition as described above. Preferably, in the present invention, based on the weight of the tablet, the absolute content of the compound of formula I or a pharmaceutically acceptable salt thereof in the tablet is 1-2000 mg / tablet; more preferably, the absolute content thereof is 10-500 mg / Tablets, for example, the absolute content of a compound of formula I or a pharmaceutically acceptable salt thereof in a tablet may be 10 mg / tablet, 20 mg / tablet, 40 mg / tablet, 80 mg / tablet, 100 mg / tablet, 160 mg / tablet, 240 mg / tablet .

In one embodiment of the present invention, there is provided a pharmaceutical tablet including a core comprising the pharmaceutical composition as described above, and the core further having a coating.

According to different coating materials, coated tablets can be mainly divided into sugar-coated tablets, film-coated tablets, and enteric-coated tablets. In the present invention, the coating is a suitable coating which is known not to adversely affect the dissolution of the final formulation, and is preferably a film coating. Through film coating, the tablet core can be provided with a sealed coating, so as to protect patients, clinical personnel, and block the tablet core from contact with air and moisture, and reduce the chance of drug degradation.

Suitable film coating materials include film-forming agents, such as film-forming polymers. Preferably, the film coating material also includes additional components, such as plasticizers, colorants, co-dispersants, and opacifiers. Plasticizers can be used to improve film flexibility and durability and adhesion properties of film coatings. Preferred film-forming polymers are selected from film-forming vinyl polymers (such as polyvinyl alcohol), film-forming acrylic polymers (such as methacrylic acid-methyl methacrylate copolymers), and esters of water-soluble cellulose ethers (such as One or more of hydroxypropyl methylcellulose phthalate). Suitable plasticizers include, for example, glycerol, acetylated monoglycerides, citrates, propylene glycol, polyethylene glycol, triglycerides or phthalates. Suitable sunscreens and colorants include, for example, titanium dioxide, iron oxide. Suitable co-dispersants include, for example, talc.

The weight gain of the coating may be 0.5% to 10%, preferably 1% to 6%, and more preferably 2.5% to 5% by weight of the pharmaceutical composition. A suitable film coating material may be a concentrate, and the coating solution is formulated with water or an organic solvent before spraying onto the tablet core. Such concentrates include the Opadry series coatings available from Colorcon.

Use of pharmaceutical composition

The present invention also provides the use of the above-mentioned pharmaceutical composition or tablet in the manufacture of a medicament for treating cancer in a patient. At the same time, the present invention also provides the use of the above pharmaceutical composition or tablet for treating cancer in a patient. Preferably, the cancer is lung cancer, more preferably, the cancer is non-small cell lung cancer, and particularly preferably, the cancer is EGFR-positive non-cell lung cancer. In one embodiment of the present invention, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

When a pharmaceutical composition is used, a safe and effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient (such as a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically considered effective dose for 60 kg For humans, the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health, etc., which are all within the skill of a skilled physician. The medicinal composition or tablet of the present invention is generally administered orally. For patients who have difficulty swallowing solids, the tablets can be disintegrated into a suspension by water and then administered orally or by nasal feeding. Dosing problems.

The pharmaceutical composition or tablet of the present invention may be administered alone or in combination with other therapeutic drugs such as a hypoglycemic agent.

The pharmaceutical composition or tablet of the present invention can be used in combination with other drugs known to treat or ameliorate similar conditions. When the combination is administered, the original drug is administered in the same manner and dosage, while the pharmaceutical composition or tablet of the present invention is taken simultaneously or subsequently. Drug combinations also include taking the pharmaceutical composition or tablet of the invention with one or more other known drugs over overlapping periods of time. When the pharmaceutical composition or tablet of the present invention is used in combination with one or more other drugs, the dosage of the pharmaceutical composition / tablet or known drug of the present invention may be lower than when they are used alone .

The drugs or active ingredients that can be used in combination with the pharmaceutical composition or tablet of the present invention include, but are not limited to: estrogen receptor modulators, androgen receptor modulators, retinal receptor modulators, cytotoxins / Cell inhibitors, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, inhibitors of cell proliferation and survival signals, interfering cells Cycle checkpoint drugs and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors Agent, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitor Agent, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, AKT inhibitor, integrin blocker, interferon-α, interleukin-12, COX-2 inhibitor, p53, p53 activator, VEGF antibody, EGF antibody, etc.

The main advantages of the invention are:

(1) The pharmaceutical composition of the present invention is easy to form, and a pharmaceutical composition of the compound of Formula I or a pharmaceutically acceptable salt thereof in the form of a tablet having a uniform content and a stable tablet weight can be obtained by a direct powder tableting method.

(2) The pharmaceutical composition of the present invention has a short disintegration time, a fast dissolution rate, and has very good chemical stability.

(3) The medicinal composition of the present invention is convenient to process, has short sieving time, and has fewer problems such as tableting difficulties and stickiness during the preparation process, which is very suitable for industrial production.

(4) The pharmaceutical composition of the present invention and the pharmaceutical tablets further prepared therefrom still have good dissolution performance after long-term storage.

The present invention will be further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are generally based on conventional conditions or conditions recommended by the manufacturer. Unless stated otherwise, percentages and parts are by weight.

Test Example 1 Study on fluidity of compound of formula I

The Brookfield engineering equipment was used to examine the fluidity of the compound of Formula I. The Flow Function Graph showed that the fluidity of the compound of Formula I was cohesive under low consolidation stress and consolidated in medium consolidation. The stress (consolidating stress) is between cohesive and easy flowing, which indicates that the compound of formula I has poor fluidity.

Observing the compound of formula I through an electron microscope, it was found that most of the compounds of formula I exhibited an irregular columnar structure and no needle-like crystal structure, so the crystal structure was not the cause of the poor fluidity of the powder.

Test Example 2 Study on Chemical Stability of Compounds of Formula I

Table 1 shows the test results of forced degradation of the compounds of formula I. The compounds of formula I are stable under high temperature and light conditions, relatively poor stability under acid and alkali conditions, and easily degrade under oxidizing conditions.

Table 1

project	Forced degradation conditions	Total miscellaneous
Unbroken	Unbroken	0.15%
Acid damage		HCl 60 ℃, 3h	2.37%
Alkali destruction		NaOH 60 ℃, 5h	1.28%
High temperature damage	100 ℃, 7h	0.17%
Light damage	6h	0.16%
Oxidative damage	1% H 2 O 2 , 1h	5.35%

Test Example 3 Study on the particle size change of the compound of formula I after different treatments

The raw materials of the compound of formula I were processed by mechanical crushing and sieving. The results are shown in Table 2. It is found that the material of the compound of formula I is very easy to pulverize. The mechanical pulverization for 10 seconds will make the particle size D90 of the raw material less than 30 μm.

Table 2

Comparative Example 1

Weigh 222.0 g of compound of formula I, 22.0 g of colloidal silica, 863.5 g of mannitol, 265.76 g of microcrystalline cellulose, 44.0 g of sodium stearyl fumarate, 51.26 g of croscarmellose sodium, and Substitute film-coated pre-mixed powder 61.6g. When weighing, check whether there are any particles or lumps in the raw materials.

First, colloidal silica, microcrystalline cellulose, and croscarmellose sodium are mixed and sieved; then the compound of formula I and mannitol are added sequentially, and after mixing, sodium stearyl fumarate is added, and the mixture is continued to be mixed uniformly To obtain intermediate powder.

The content of the intermediate powder is measured, and the tablet weight is calculated according to the intermediate product content determination result, and the tablet core is compressed. Monitor tablet weight and hardness regularly during tabletting. For example, it can be compressed into tablets with a size between 10 mg and 240 mg.

The qualified tablet cores were placed in a coating pan, and a coating premix (Opadry 85F640013, which was sampled at 1.3 to 1.4 times the theoretical core weight gain of 3%) was prepared to prepare a coating suspension. After the tablet core gains 3 to 4%, the coating is stopped.

Prepare 3 batches of 10mg standard tablets and 3 batches of 80mg standard tablets. Take the prepared 10mg and 80mg standard tablets in 6 batches for each batch and investigate the dissolution rate (dissolution medium pH = 3.8, 75rpm) The results are shown in Figures 1 and 2, and the dissolution in 30 minutes reached more than 90%; however, the dissolution of 6 tablets of 80 mg specifications in 30 minutes was slightly lower than that of 6 tablets of 10 mg specifications.

Comparative Example 2

Investigate the dissolution rate of the tablet after 30 minutes of stability setting out, including accelerated stability setting out (temperature 40 ° C ± 2 ° C, relative humidity 75% ± 5%), long-term stability setting out (temperature 25 ° C ± 2 ° C, relative humidity 60% ± 10%). Table 3 shows the dissolution data after settling with accelerated stability (dissolution medium pH = 3.8), and Table 4 shows the dissolution data after long-term stability setting out (dissolution medium pH = 3.8).

According to the data in Tables 3 and 4, it can be found that the dissolution rate of the 80 mg tablet is significantly lower than that of the 10 mg tablet after staking out.

table 3

Table 4

Comparative Example 3

Take the tablets prepared in Comparative Example 1 to determine the dissolution data in different combinations (Note: The relevant samples have been stored for about 15 months under long-term stable lofting conditions when the experiment was carried out); the average dissolution results are shown in Table 5 (each Group 3 parallel experiments were averaged and expressed as the cumulative percent dissolution rate); the data of Group A, Group B, Group C, and Group D were plotted in Figure 3. As can be seen from Table 5, as the tablet specifications increase, the average value of total dissolution shows a downward trend.

Group A (10 mg): 1 tablet of 10 mg specification (batch number 160702), pH of dissolution medium = 3.8.

Group B (80 mg): 80 mg, 1 tablet (batch number 160702), pH of dissolution medium = 3.8.

Group C (120 mg): 10 tablets of 4 tablets (batch number 160702) + 80 tablets of 1 tablet (batch number 160702), pH of dissolution medium = 3.8.

Group D (400 mg): 80 tablets of 5 tablets (batch number 160702), dissolution medium pH = 3.8.

Group E (400 mg): 80 tablets of 5 tablets (batch number 160701), pH of dissolution medium = 3.8.

Group F (400 mg): 80 tablets of 5 tablets (batch number 160701), pH of dissolution medium = 2.0.

table 5

Time / minute	Group A	Group B	Group C	Group D	Group E		Group F
5	89.10	84.83	67.06	58.00	57.23	101.46
10	96.57	93.10	79.24	68.64	69.05	99.11
20	96.97	95.40	83.96	75.51	75.47	98.56
30	96.37	92.90	83.39	75.67	76.69	98.42
45	Not sampled	93.37	83.78	78.15	77.32	98.79
60	Not sampled	94.08	83.99	78.12	77.32	100.32
90	Not sampled	Not sampled	Not sampled	78.35	76.86	Not sampled
120	Not sampled	Not sampled	Not sampled	79.29	78.53	Not sampled

Comparative Example 4 Wet granulation and tableting

Tablets were prepared by the conventional wet granulation and compression method according to the following prescription. The prescription is (w / w): 15.4% of the compound of formula I, 47% (manned) of mannitol, 18.5% of microcrystalline cellulose (added), 5.4% of low-substituted hydroxypropyl cellulose (added), 1% hydroxypropyl cellulose (3% solution for granulation), microcrystalline cellulose 6.2% (extra), low-substituted hydroxypropyl cellulose 4.3% (extra), sodium stearyl fumarate 2.3% (Plus).

Compared with the examples, wet granulation and tableting have good fluidity and hardness; but disintegration is slow, and the dissolution in 10 minutes is significantly smaller than that in the powder direct compression method. The dissolution in 10 minutes is only 7.6% (pH = 4.5, 75rpm) .

Example 1

Component	Proportion /%	1 tablet content / mg
Compound of formula I	25	80
lactose	16.75	53.60
Microcrystalline cellulose	50.25	160.80
Crospovidone	3.5	11.20
Sodium stearyl fumarate	3	9.60
Colloidal silica	1.5	4.80

Weighing: According to the scale of 500 tablets, accurately weigh the compound of formula I, lactose, microcrystalline cellulose (PH302), crospovidone, sodium stearyl fumarate (S96), and colloidal silica.

Mixing: Pre-mix other materials except sodium stearyl fumarate, then sieved 3 times through a 40 mesh stainless steel sieve, add sodium stearyl fumarate to the sieved material and mix thoroughly, take 9 samples at different positions , Determination of content uniformity.

Tableting: Calculate the standard tablet weight according to the determination results of the intermediate content, control the tablet weight ± 3%, hardness 90 ~ 120N, and tablet.

Coating: The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.

Example 2

Component	Proportion /%	1 tablet content / mg
Compound of formula I	25	80
Mannitol	50.25	160.80
Microcrystalline cellulose	16.75	53.60
Crospovidone	3.5	11.20
Sodium stearyl fumarate	3	9.60
Colloidal silica	1.5	4.80

Weighing: According to the scale of 500 tablets, accurately weigh the compound of formula I, mannitol, microcrystalline cellulose (PH302), crospovidone, sodium stearyl fumarate (S96), and colloidal silica.

Mixing: Pre-mix other materials except sodium stearyl fumarate, then sieved 3 times through a 40 mesh stainless steel sieve, add sodium stearyl fumarate to the sieved material and mix to determine the intermediate content.

Tableting: Calculate the standard tablet weight according to the determination results of the intermediate content, control the tablet weight ± 3%, hardness 90 ~ 120N, and tablet.

Coating: The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.

Example 3 to Example 6

Weighing: According to the scale of 1100 tablets, accurately weigh the compound of formula I, lactose, microcrystalline cellulose (PH302), crospovidone, and sodium stearyl fumarate (S96).

Mixing: Pre-mix other materials except sodium stearyl fumarate, then sieved 3 times through a 40 mesh stainless steel sieve, add sodium stearyl fumarate to the sieved material and mix to determine the intermediate content.

Tableting: Calculate the standard tablet weight according to the determination result of the intermediate content, control the tablet weight ± 3%, hardness 90 ~ 120N, and tablet.

Coating: The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.

Fifteen tablets of each example were taken and divided into three parts for dissolution examination (dissolution medium pH = 3.8). Samples were taken at 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, and 90 minutes, and the average cumulative dissolution percentage was calculated. The dissolution results are shown in Table 6 and Figure 4.

Table 6

Example 7

Component	Proportion /%	1 tablet content / mg
Compound of formula I	25	80
lactose	52.50	168.00
Microcrystalline cellulose	17.50	56.00
Low substituted hydroxypropyl cellulose	3	9.60
Sodium stearyl fumarate	2	6.40

Weighing: According to the scale of 500 tablets, weigh the compound of formula I, lactose, microcrystalline cellulose (PH302), low-substituted hydroxypropyl cellulose (L-HPC-B1), and sodium stearyl fumarate (S96).

Mixing: Pre-mix other materials except sodium stearyl fumarate, then sieved 3 times through a 40 mesh stainless steel sieve, add sodium stearyl fumarate to the sieved material and mix to determine the intermediate content.

Tableting: Calculate the standard tablet weight according to the determination results of the intermediate content, control the tablet weight ± 3%, hardness 90 ~ 120N, and tablet.

Coating: The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.

Example 8

Using low-substituted hydroxypropyl cellulose as a disintegrant, the first filler is mannitol, the second filler is microcrystalline cellulose, and the weight ratio of mannitol to microcrystalline cellulose is 7.6: 1 to 1.8: 1 A similar prescription and method as in Example 4 were used (the total amount of mannitol and microcrystalline cellulose in each tablet was about 222 mg, but the weight of the two was as described above). The pharmaceutical composition was prepared by a direct powder tableting method, and was similar to Example 4 in terms of fluidity, compressibility, and disintegrability.

Example 9

Weighing: According to the 80mg specification, weigh the material on a scale of 3500 tablets; 280g of the compound of formula I, 583.8g of lactose (Flow100), 194.6g of microcrystalline cellulose (PH302), 39.2g of crospovidone (KCL), and stearic acid 22.4 g of sodium maleate (S96), 47.04 g of Opadry film coating premix (85F640057) (weighing at 33.6 g of 3% coating weight, 140% of 33.6 g was taken into consideration, such as pipe residue); weighed Take 344.96g of purified water.

Mixing: Drymillu10 multi-directional motion mixer, using 5L mixing barrel for operation. Microcrystalline cellulose, lactose, and the compound of formula I were sequentially added to the mixing barrel and mixed at a rotation speed of 15 rpm for 15 minutes; crospovidone KCL was added to the mixing barrel and mixed at a speed of 15 rpm for 15 minutes. Weigh 44.8 g of the mixed material (twice the amount of sodium stearyl fumarate) and mix it with sodium stearyl fumarate, pass through a 40-mesh sieve, and then add it to the mixing tank for 10 minutes.

Tablet pressing: DPMODP020 tablet pressing machine, using 10mm round punch. Tablet weight 320mg, hardness control 105.00N ± 15.00N, compressed.

Coating: SOLID LAB 02 high-efficiency coating machine, 2.5L coating pan. The film coating premix was slowly added to the purified water to prepare a coating solution with a solid content of 12%. After the weight gain of the coating reached 3.0% ± 1%, the coating was stopped.

The prepared coated tablets were taken for dissolution examination. Samples were taken at 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, and 60 minutes, and the average cumulative dissolution percentage was calculated. See Table 7 for dissolution results. For each dissolution medium, 15 coated tablets were taken and divided into 3 portions.

Table 7

Example 10

Take the sample prepared in Example 9, and use high-density polyethylene (HDPE) and thick cold aluminum to simulate the packaging. After packaging, stake out at accelerated stability (temperature 40 ℃ ± 2 ℃, relative humidity 75% ± 5%), and examine The changes in the content and related substances are shown in Table 8.

Table 8

Example 11

Take the sample of accelerated stability setting out (HDPE simulation packaging) in Example 10, and examine the dissolution change (0 days, 18 days, February). Take 15 tablets each time and divide into 3 portions for dissolution evaluation (dissolution medium pH = 3.8). At 30 minutes, the average cumulative dissolution percentages reached 93.95% (0 days), 93.22% (18 days), and 97.95% (2 months).

Example 12

Five 80 mg tablets prepared in Example 9 were extracted and disintegrated into suspensions with 50 mL of water, and rapid disintegration was observed (all samples disintegrated within 3 minutes). The dissolution of the suspension after disintegration was measured, and the results showed that the dissolution of the suspension after disintegration was slightly faster than that of the same tablet under normal dissolution conditions in the first 5 minutes. ; F2 similarity factor is greater than 50, the dissolution behavior is consistent.

All documents mentioned in the present invention are incorporated by reference in this application, as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above-mentioned teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (14)

1. A pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof,

   

   It is characterized in that the medicinal composition comprises an active ingredient, a filler, a lubricant, and a disintegrant, and is prepared through a direct powder tableting method;

   The active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;

   The disintegrant is crospovidone.
2. A pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof,

   

   It is characterized in that the medicinal composition comprises an active ingredient, a filler, a lubricant, and a disintegrant, and is prepared through a direct powder tableting method;

   The active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;

   The pharmaceutical composition is free of colloidal silica.
3. The pharmaceutical composition according to any one of claims 1 or 2, wherein the filler is selected from the group consisting of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, Calcium sulfate, calcium hydrogen phosphate, sorbitol, mannitol, or a combination thereof.
4. The pharmaceutical composition according to claim 3, wherein the filler is a combination of a first filler and a second filler, the first filler is mannitol and / or lactose, and the second filler is micro Crystalline cellulose

   The weight ratio of the first filler and the second filler is preferably 9: 1 to 1: 9, and more preferably 9: 1 to 1: 3.
5. The pharmaceutical composition according to any one of claims 1 or 2, wherein the weight ratio of the filler to the active ingredient is 99: 1 to 1: 9, preferably 8: 1 to 1: 1, more preferably 4: 1 to 2: 1.
6. The pharmaceutical composition according to any one of claims 1 or 2, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, and sodium stearate. , Stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, or a combination thereof; sodium stearyl fumarate is preferred.
7. The pharmaceutical composition according to claim 6, wherein the weight ratio of the lubricant to the active ingredient is 1: 1 to 1: 200, preferably 1: 2 to 1:50, and more preferably 1: 5 to 1:15.
8. The pharmaceutical composition according to claim 2, wherein the disintegrant is crospovidone, low-substituted hydroxypropyl cellulose, or a combination thereof.
9. The pharmaceutical composition according to any one of claims 1 or 2, wherein a weight ratio of the disintegrant to the active ingredient is 1: 1 to 1:90, preferably 1: 1 to 1 : 30, more preferably 1: 2 to 1:15.
10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a glidant; the glidant is preferably talc or colloidal silica.
11. The pharmaceutical composition according to claim 10, wherein the weight ratio of the glidant to the active ingredient is 0.005: 1 to 0.2: 1, preferably 0.01: 1 to 0.1: 1.
12. A method for preparing the pharmaceutical composition according to any one of claims 1 or 2, wherein the method for preparing comprises:

    (1) Mix the active ingredients, fillers, lubricants and disintegrants uniformly to obtain intermediate powder;

    (2) Compression according to the weight of the tablet.
13. A medicinal tablet, the medicinal tablet comprises a tablet core and a coating covering the tablet core, and the tablet core is the pharmaceutical composition according to any one of claims 1 to 11.
14. The pharmaceutical composition according to any one of claims 1 to 11, or the pharmaceutical tablet according to claim 13, for use in the preparation of a medicament for treating cancer in a patient.

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