CN110446701B

CN110446701B - Medicinal composition of 2-aminopyrimidine compounds and preparation method thereof

Info

Publication number: CN110446701B
Application number: CN201880014402.3A
Authority: CN
Inventors: 陈庆财; 丁健; 丁克; 金雪锋; 耿美玉; 谢华
Original assignee: Shanghai Institute of Materia Medica of CAS; Guangzhou Institute of Biomedicine and Health of CAS; Jiangsu Aosaikang Pharmaceutical Co Ltd
Current assignee: Shanghai Institute of Materia Medica of CAS; Guangzhou Institute of Biomedicine and Health of CAS; Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority date: 2017-02-27
Filing date: 2018-02-27
Publication date: 2022-09-30
Anticipated expiration: 2038-02-27
Also published as: WO2018153379A1; CN108498477A; CN110446701A

Abstract

A pharmaceutical composition comprising N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide and a process for preparing the pharmaceutical composition.

Description

Medicinal composition of 2-aminopyrimidine compounds and preparation method thereof

Technical Field

The present invention is in the field of pharmaceutical formulations, and in particular, relates to a pharmaceutical composition of the compound N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide, and a process for preparing the pharmaceutical composition.

Background

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, prostate cancer, and the like. Blocking the activation of EGFR and Erb-B2 has been clinically validated as the leading approach to target treatment of tumor cells. Two small molecule inhibitors targeting EGFR, gefitinib and erlotinib, have received rapid FDA approval in the united states for the treatment of advanced non-small cell lung cancer (NSCLC) patients who have lost response to conventional chemotherapy.

The response rate of the NSCLC patients positive to EGFR activating mutation to EGFR-TKI (EGFR-tyrosine kinase inhibitor) is obviously higher than that of EGFR wild type NSCLC patients, and the progression-free survival (PFS) phase and the total survival (OS) phase are also obviously prolonged. However, most patients positive for EGFR mutations have no more than 12-14 months of PFS, i.e., resistance to TKI. The mechanism of acquired drug resistance and its clinical coping strategy are another research hotspot in the field of targeted therapy.

N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide has a chemical structure shown in formula I. The compound shown in the formula I is an EGFR inhibitor for selectively inhibiting EGFR T790M mutation, can overcome drug resistance induced by the existing drugs of gefitinib, erlotinib and the like, and has weak inhibitory activity on wild type EGFR. However, there is a lack in the art of pharmaceutical compositions that accommodate administration of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide.

Disclosure of Invention

It is an object of the present invention to provide a pharmaceutical composition that is adapted to the administration of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide.

In a first aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I,

the pharmaceutical composition is prepared by a powder direct compression method, and comprises a compound shown in formula I, a filling agent, a glidant, a lubricant and a disintegrant.

In another preferred embodiment, 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; and/or

The glidant is talcum powder or colloidal silicon dioxide; preferably colloidal silica; and/or

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 combinations thereof; preferably sodium stearyl fumarate; and/or

The disintegrant is selected from the group consisting of: one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; preferably low-substituted hydroxypropyl cellulose and/or croscarmellose sodium; more preferably low substituted hydroxypropyl cellulose or croscarmellose sodium.

In another preferred embodiment, in said pharmaceutical composition, said compound of formula I has a particle size of 10-150 μm, preferably 30-100 μm.

In another preferred embodiment, the filler is mannitol and microcrystalline cellulose; preferably, the weight ratio of the mannitol to the microcrystalline cellulose in the filler is (1.5-9) to 1, preferably (1.8-8) to 1, and more preferably (3-7.6) to 1.

In another preferred embodiment, the weight ratio of the filler to the compound of formula I is 3-7: 1, preferably (4-6: 1), more preferably (4.5-5.5: 1; and/or

The weight ratio of the glidant to the compound of the formula I is (0.04-0.2) to 1, preferably (0.06-0.2) to 1, more preferably (0.08-0.15) to 1;

the weight ratio of the lubricant to the compound of formula I is (0.08-0.44) to 1, preferably (0.09-0.33) to 1, more preferably (0.1-0.22) to 1;

the weight ratio of the disintegrant to the compound of formula I is (0.15-0.8) to 1, preferably (0.18-0.7) to 1, and more preferably (0.2-0.65) to 1.

In another preferred embodiment, the pharmaceutical composition comprises:

in another preferred embodiment, the pharmaceutical composition comprises:

the filler comprises mannitol and microcrystalline cellulose, and the weight ratio of the mannitol to the microcrystalline cellulose is (1.8-8) to 1;

and the disintegrant is selected from the group consisting of: low substituted hydroxypropyl cellulose, or croscarmellose sodium.

In another preferred embodiment, the pharmaceutical composition consists of the following components:

In another preferred embodiment, the pharmaceutical composition is prepared by direct compression.

In a second aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition according to the first aspect of the present invention, said process comprising:

(1) mixing the glidant, the first part of filler and the disintegrant, and sieving;

(2) adding the compound shown in the formula I and a second part of filler, uniformly mixing, adding a lubricant, and continuously and uniformly mixing to obtain intermediate powder;

(3) and (4) detecting the content of the intermediate powder, calculating the tablet weight according to the content measurement result of the intermediate powder, and tabletting.

In another preferred embodiment, the compound of formula I is in the form of a powder.

In another preferred embodiment, the compound of formula I powder is obtained by mechanically pulverizing the compound of formula I drug substance.

In another preferred embodiment, the fillers are mannitol and microcrystalline cellulose, and the first part of the fillers are microcrystalline cellulose and the second part of the fillers are mannitol.

In another preferred embodiment, the pharmaceutical composition is used in the preparation of a medicament for treating cancer in a patient, preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

In a third aspect of the invention, there is provided a pharmaceutical tablet comprising a pharmaceutical composition according to the first aspect of the invention.

In another preferred embodiment, the pharmaceutical tablet comprises: a core comprising a pharmaceutical composition according to the first aspect of the invention and a coating over the core.

In another preferred embodiment, the weight ratio of coating to core is 2-5: 100, preferably 3-4: 100.

In another preferred embodiment, the pharmaceutical tablet is for use in the preparation of a medicament for treating cancer in a patient, preferably the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

In a fourth aspect of the invention, there is provided a kit comprising:

a pharmaceutical composition according to the first aspect of the invention; and

a second therapeutic agent for use in combination with said pharmaceutical composition.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and the technical features specifically described below (e.g., examples) may be combined with each other to constitute new or preferred technical solutions. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 is a dissolution profile of three batches of tablet cores prepared in example 1 in dissolution medium pH 1.2;

FIG. 2 is a dissolution profile of three batches of tablet cores prepared in example 1 in dissolution medium pH 4.5;

FIG. 3 is the dissolution profile of three batches of tablet cores prepared in example 1 in FASSIF dissolution medium;

FIG. 4 is a dissolution profile of three batches of 10mg sized tablets prepared in example 8 in dissolution medium at pH 3.8;

FIG. 5 is a dissolution profile of three batches of 80mg sized tablets prepared in example 8 in dissolution medium pH 3.8.

Detailed Description

The present inventors have conducted extensive and intensive studies for a long time to provide a pharmaceutical composition suitable for administration of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide. The medicinal composition has excellent dissolution rate and chemical stability. Based on the above findings, the inventors have completed the present invention.

Term(s) for

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

As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of or" consisting of.

As used herein, the term ". multidot.. normal tablet core" or ". multidot.. normal tablet" has the following meaning: each tablet core or each tablet contains a certain amount of the compound shown in the formula I; for example, a 10mg sized tablet core represents about 10mg of a compound of formula I per tablet core.

Pharmaceutical compositions of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide

The invention aims to provide a pharmaceutical composition which is suitable for industrial production and meets the requirements of clinical use and is prepared from a compound N- ((5- ((5-chloro-4- ((naphthalene-2-yl) amino)) pyrimidine-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide.

The inventor of the invention encounters a plurality of technical problems in the process of researching the pharmaceutical composition which is suitable for industrial production and meets the clinical use requirement of the compound shown in the formula I. For example, (1) the compound shown in the formula I has poor flowability, and the content uniformity, the batch dissolution consistency and the like of the pharmaceutical composition are influenced; (2) the compound shown in the formula I is easy to oxidize, the process is fast and simple, and the preparation time is shortened as much as possible; (3) in patients with non-small cell lung cancer, particularly in advanced stage patients, swallowing is difficult due to respiratory system disorders, and the drugs are required to be administered by nasal feeding and the like.

As known to those skilled in the art, the tabletting method can be divided into two main categories, namely granulation and direct compression, according to the different tabletting process routes. Furthermore, the granulation and tabletting method can be divided into a wet granulation and tabletting method and a dry granulation and tabletting method, and the direct tabletting method can be divided into a direct powder tabletting method and a semi-dry granule tabletting method.

The direct compression method is a method of directly compressing a mixture of a drug and an auxiliary material without a granulation process. The direct tabletting method has the defects of poor powder flowability, poor content uniformity and large tablet weight difference; therefore, the requirement on the flowability of the raw material medicine is higher. The compound shown in the formula I has poor flowability of the raw material medicine, and the research of the inventor shows that the poor flowability is independent of the crystal structure of the raw material medicine. For those skilled in the art, the direct powder compression method is not suitable for manufacturing pharmaceutical compositions suitable for industrial production and clinical use of the compounds of formula I.

However, after extensive attempts to perform the four subclasses of tableting methods, the inventors have surprisingly found that by the present invention, the disadvantage of poor flowability can be overcome and a pharmaceutical composition of the compound of formula I in the form of a tablet with a uniform content and a stable tablet weight can be obtained by direct powder tableting. More surprisingly, the pharmaceutical composition in the form of tablets prepared by the direct powder compression method provided by the invention has short disintegration time and high dissolution speed.

Therefore, the invention provides a pharmaceutical composition form of the compound shown in the formula I, which is suitable for industrial production and meets the clinical use requirement; the pharmaceutical compositions of the compounds of formula I are preferably in the form of tablets. The medicinal composition is prepared by a powder direct compression method, and comprises a compound shown in a formula I, a filling agent, a glidant, a lubricant and a disintegrant.

The compounds of formula I are present as active ingredients in pharmaceutical compositions in amounts which are generally flexible to the needs of the mode of administration.

The pharmaceutical composition of the present invention may select one, two, three or more fillers. Bulking agents, which may also be referred to as diluents, primarily serve to increase the weight and/or volume of the pharmaceutical composition; and can reduce dosage deviation of active ingredients and improve compression formability. Pharmaceutical fillers include, but are not limited to, one or more of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, dibasic calcium phosphate, sorbitol, mannitol.

In the present invention, the weight ratio of the filler to the compound of formula I is (3-7):1, preferably (4-6): 1, more preferably (4.5-5.5): 1.

In the present invention, mannitol and microcrystalline cellulose are preferably used as fillers. Wherein the weight ratio of the mannitol to the microcrystalline cellulose is (1.5-9) to 1; preferably, the weight ratio is (1.8-8) to 1; more preferably, the weight ratio is (3-7.6) to 1.

In the present invention, materials suitable for direct compression are preferably used.

Suitable mannitol has an average particle size of 50 to 200. mu.m, preferably 100 to 200. mu.m, and is commercially available, for example, as Pearlitol 100sd and Pearlitol 200sd from Roquette. The invention preferably uses Pearlitol 100sd, which has good fluidity and can meet the requirements of tabletting and content uniformity.

Suitable microcrystalline cellulose has an average particle size of 20 to 200 μm, preferably a particle size close to that of mannitol, and is commercially available, for example, from FMC, Avicel PH-102, Avicel HFE-102, Avicel PH-301, Avicel PH-302, and Avicel PH-200. The invention preferably uses Avicel PH-302, which has good fluidity, better compressibility than mannitol, and particle size and bulk density close to that of mannitol Pearlitol 100sd, and can avoid delamination in tabletting process.

The 'glidant' used in the invention is an auxiliary material added before tabletting to reduce the friction force between particles, and the glidant is added to improve the powder flowability so as to achieve the function of glidant. One, two, three or more glidants may be selected for the pharmaceutical composition of the present invention. Glidants include, but are not limited to, talc or colloidal silicon dioxide. In the invention, the weight ratio of the glidant to the compound of the formula I is (0.04-0.2) to 1, preferably (0.06-0.2) to 1, and more preferably (0.08-0.15) to 1.

The lubricant is added before tabletting to reduce the friction between the granules or the tablets and a punching die, and the lubricant can reduce the friction with the punching die and increase the sliding property of the granules, so that the filling is good, the density distribution of the tablets is uniform, and the integrity of the pushed tablets is ensured. The pharmaceutical composition of the present invention may select 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 glycols, sodium lauryl sulfate. Sodium stearyl fumarate is preferred as the lubricant of the present invention. In the invention, the weight ratio of the lubricant to the compound of the formula I is (0.08-0.44) to 1, preferably (0.09-0.33) to 1, and more preferably (0.1-0.22) to 1.

One, two, three or more disintegrants may be selected for the pharmaceutical composition of the invention. Disintegrants are excipients that facilitate rapid disintegration of tablets into fine particles in gastrointestinal fluids. Pharmaceutically acceptable disintegrants include, but are not limited to, dry starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone. The present invention preferably uses low-substituted hydroxypropyl cellulose and/or croscarmellose sodium as a disintegrant; more preferably, low-substituted hydroxypropyl cellulose or croscarmellose sodium is used. In the present invention, the weight ratio of the disintegrant to the compound of formula I is (0.15-0.8) to 1, preferably (0.18-0.7) to 1, and more preferably (0.2-0.65) to 1.

The particle size distribution of the raw material drug influences the dissolution rate of the tablet. In order to ensure the dissolution rate of the active drug compound shown in formula I, in the invention, the particle size D of the compound shown in formula I is preferably ₉₀ 30 to 120 μm; more preferably, the particle diameter D is controlled ₉₀ Is 30 to 85 μm. The present invention may employ means known in the art to control the particle size of the starting compound of formula I as one of the tablet ingredients, preferably by subjecting the compound of formula I to a sieving regime; more preferably, the compound shown in the formula I is processed by sieving with a sieve of 80-200 meshes.

The above pharmaceutical composition is prepared by a direct powder compression method comprising: (1) mixing the glidant, the first part of filler and the disintegrant, and sieving; (2) sequentially adding the compound shown in the formula I and a second part of filling agent, uniformly mixing, adding a lubricant, and continuously and uniformly mixing to obtain intermediate powder; (3) and detecting the content of the intermediate powder, calculating the tablet weight according to the content measurement result of the intermediate product after the intermediate powder is qualified, and tabletting. According to the invention, the filler of the second part in step (2) may be the same as or different from the filler of the first part in step (1). The first part of the filler is a part of the filler, and the part of the filler is added in the step (1); the second part of the filler refers to the remaining part of the filler, which is added in step (2). When the filler is a combination of microcrystalline cellulose and mannitol, preferably, the first portion of the filler is microcrystalline cellulose and the second portion of the filler is mannitol; more preferably, the microcrystalline cellulose and mannitol are both in the direct compression type.

In a second aspect, the present invention provides a process for the preparation of the above pharmaceutical composition. The preparation method comprises the following steps: (1) mixing the glidant, the first part of filler and the disintegrant, and sieving; (2) sequentially adding the compound shown in the formula I and a second part of filling agent, uniformly mixing, adding a lubricant, and continuously and uniformly mixing to obtain intermediate powder; (3) and (4) detecting the content of the intermediate powder, calculating the tablet weight according to the content measurement result of the intermediate product after the intermediate powder is qualified, and tabletting.

Preferably, according to one embodiment of the invention, the glidant is colloidal silicon dioxide; more preferred is colloidal silica having a particle size distribution comparable to that of the compound of formula I.

According to the invention, the second part of the filler in step (2) may be the same or different from the first part of the filler in step (1).

Preferably, according to one embodiment of the present invention, the first portion of filler is microcrystalline cellulose; more preferably, the microcrystalline cellulose is in the form of a direct tablet.

Preferably, according to one embodiment of the invention, the disintegrant is croscarmellose sodium.

According to the invention, the sieving step in the step (1) of mixing the glidant, the first part of filling agent and the disintegrant and sieving by using a 30-80-mesh sieve; preferably a 40-60 mesh screen is used.

Preferably, according to one embodiment of the invention, the particle size D of the compound of formula I is controlled by sieving ₉₀ Is 30 to 120 μm.

Preferably, according to one embodiment of the invention, the second portion of bulking agent is mannitol; more preferably, mannitol is in the form of a direct compression tablet.

Preferably, the compound shown in the formula I and the second part of the filler are sequentially added in the step (2), the mixture is uniformly mixed and then added into the lubricant, and the mixing time is 5-25 minutes, and the mixing speed is 10-25 revolutions per minute; more preferably, the mixing time is 10-20 minutes and the mixing speed is 15-20 revolutions per minute.

Preferably, according to one embodiment of the invention, the lubricant is sodium stearyl fumarate.

Preferably, the step (3) of mixing the intermediate powder continuously and uniformly to obtain the intermediate powder, wherein the mixing time is 5-15 minutes, and the mixing speed is 10-25 revolutions per minute; more preferably, the mixing time is 5 to 10 minutes and the mixing speed is 15 to 20 revolutions per minute.

According to the invention, the tabletting pressure is properly adjusted in the step (3), so that the friability and the disintegration of the pressed tablets are qualified, and the problem of cracking of the products in the transportation process is avoided.

Pharmaceutical tablets and their preparation

The invention also provides a pharmaceutical tablet comprising a pharmaceutical composition as described above. Preferably, in the present invention, the absolute content of the compound of formula I in the tablet is 1-2000 mg/tablet, based on the weight of the tablet; more preferably, the absolute content is 10-500 mg/tablet, for example, the absolute content of the compound of formula I in a tablet can 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 invention, there is provided a pharmaceutical tablet comprising a core comprising a pharmaceutical composition as described above, the core further having a coating.

Depending on the coating material, the coated tablets may be mainly classified into sugar-coated tablets, film-coated tablets, and enteric-coated tablets. In the present invention, the coating is a suitable coating, preferably a film coating, which is known not to negatively affect the dissolution of the final formulation. The tablet core can be provided with a seal coating through the film coating, so that the contact of patients and clinical personnel and the barrier of the tablet core with air and moisture is achieved, and the chance of degradation of the medicine is reduced.

Suitable film coating materials include film forming agents, such as film forming polymers. Preferably, the film coating material further comprises additional components, such as plasticizers, colorants, dispersion aids and opacifiers. Plasticizers may be used to improve the film flexibility and durability and adhesion characteristics of the film coating. Preferred film-forming polymers are selected from one or more of film-forming vinyl polymers (e.g., polyvinyl alcohol), film-forming acrylic polymers (e.g., methacrylic acid-methyl methacrylate copolymer), esters of water-soluble cellulose ethers (e.g., hydroxypropyl methylcellulose phthalate), and the like. Suitable plasticizers include, for example, glycerol, acetylated monoglycerides, citric acid esters, propylene glycol, polyethylene glycol, triglycerides or phthalates. Suitable opacifiers and colorants include, for example, titanium dioxide, iron sesquioxide. Suitable dispersion aids include, for example, talc.

The coating weight gain may be from 0.5% to 10%, preferably from 1% to 6%, more preferably from 2.5% to 5% by weight of the pharmaceutical composition. Suitable film coating materials may be concentrates, the coating being formulated with water or an organic solvent prior to spraying onto the core. Such concentrates include the Opadry series of coatings available from Calycon corporation (Colorcon).

Use of pharmaceutical compositions

Finally, the invention also provides the use of the above pharmaceutical composition or tablet for the manufacture of a medicament for the treatment of 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 mutant non-cell lung cancer. In one embodiment of the invention, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).

When the pharmaceutical composition is used, a safe and effective amount of the compound shown in the formula I is administered to a patient (such as a human) needing to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human with the weight of 60kg, the daily administration dose of the compound shown in the formula I is usually 1-2000mg, and preferably 20-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner. The pharmaceutical composition or tablet of the present invention is generally administered orally, and for patients with difficulty in swallowing solid, the problem of administration can be solved by first disintegrating the tablet with water to form a suspension and then administering orally or nasally.

The pharmaceutical composition or tablet of the present invention may be administered alone or in combination with other therapeutic agents (e.g., hypoglycemic agents).

The pharmaceutical compositions or tablets of the invention may be combined with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug is maintained, while the pharmaceutical composition or tablet of the present invention is administered simultaneously or subsequently. The pharmaceutical combination also includes administering the pharmaceutical composition or tablet of the present invention in an overlapping time period with one or more other known drugs. When the pharmaceutical composition or tablet of the present invention is administered in a pharmaceutical combination with one or more other drugs, the dosage of the pharmaceutical composition/tablet of the present invention or the known drug may be lower than when they are administered alone.

Drugs or active ingredients that may be combined with the pharmaceutical composition or tablet of the present invention include, but are not limited to: estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins/cytostatics, antiproliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, inhibitors of apoptosis, inhibitors of tumor growth, and the like, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, and the like.

The main advantages of the invention are:

(1) the medicinal composition is easy to form, and the medicinal composition of the compound shown in the formula I with uniform content and stable tablet weight can be obtained by a powder direct compression method.

(2) The medicinal composition has short disintegration time, high dissolution speed and very good chemical stability.

(3) The medicinal composition has the advantages of convenient processing, short sieving time, less phenomena of difficult tablet production, sticking and the like in the preparation process, and is very suitable for industrial production.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Test example 1 flowability study of Compound I

The flowability of the compound of formula I was examined using a Brookfield engineering instrument, and the Flow Function Graph (Flow Function Graph) shows that the flowability of the compound of formula I is cohesive (coherent) at low consolidation stress (coherent) and between cohesive (coherent) and easy flowing (easy flowing) at medium consolidation stress (coherent), indicating that the flowability of the compound of formula I is poor.

When the compound represented by the formula I is observed through an electron microscope, the compound represented by the formula I is mostly in an irregular columnar structure, and a needle-shaped crystal structure is not generated, so that the crystal structure is not a cause of poor powder flowability.

Test example 2 chemical stability of the Compound of formula I

Table 1 shows the results of the forced degradation of the compound of formula I, which is stable at high temperature and under light conditions, relatively poor in stability under acid and alkali conditions, and easily degradable under oxidation conditions.

TABLE 1

Item	Forced degradation conditions	Total miscellaneous
			Is not destroyed	Is not destroyed	0.15％
Acid destruction	HCl	60℃，3h				2.37％
			Alkali destruction	NaOH	60℃，5h		1.28％
High temperature destruction	100℃，7h	0.17％
			Photo damage	6h	0.16％
Oxidative destruction	1％H ₂ O ₂ ，1h	5.35％

EXAMPLE 1 Effect of particle size of drug substance on dissolution of formulation

The particle size distribution of 3 batches of the compound bulk drug shown in formula I was determined, and the results are shown in Table 2. The tablet cores (the content of the compound shown in the formula I in each tablet is 80mg) are prepared by powder direct compression method by using 3 batches of the compound shown in the formula I with the same prescription. The prescription composition of the tablet core is (w/w): 15% of a compound shown in formula I, 3% of colloidal silicon dioxide, 61.5% of mannitol, 8.1% of microcrystalline cellulose, 9.4% of low-substituted hydroxypropyl cellulose and 3% of sodium stearyl fumarate.

TABLE 2

Batch number of Compound of formula I	D ₅₀ μm	D ₉₀ μm	Tablet core batch number
				73-06S	18.1	37.8	20160106
74-05S	51.2	117	20160201
				81-01S	26.6	77.1	20160202

The dissolution curves of the tablet cores of each lot were measured in dissolution media of ph1.2 and 4.5 and fastif media by the slurry method at 75rpm, and the results are shown in fig. 1 to 3. From the dissolution rate results of the compound tablet cores shown in the formula I prepared with different particle sizes in 3 media with different pH values, it can be seen that:

in acidic media at ph1.2, there was little difference in the 3 dissolution profiles for different particle sizes due to the high solubility of the drug in this medium.

The dissolution medium with pH4.5 showed the slowest dissolution in the 74-05S group. The dissolution rates of the 81-01S group and the 73-06S group are respectively 74% and 68% in 30 minutes, and 79% and 75% in 45 minutes; the dissolution rates at 60 minutes are respectively 84% and 80%, and the difference between the two is not great.

In the artificial intestinal juice FASSIF medium at pH6.5, the 74-05S group was also slower than the other 2 groups. The dissolution rates of the 81-01S group and the 73-06S group at 45 minutes are 42% and 47% respectively; the dissolution rates at 60 minutes were 49% and 56%, respectively, and the dissolution rates were relatively close to each other.

Therefore, in a medium having a pH of 4.5 or more, the particle size of the raw material has an influence on the dissolution of the drug. Particle size D of the raw material in a period of 30 minutes to 60 minutes ₉₀ The drug dissolution curves at 37.8 μm and 77.1 μm are relatively close, while the particle size D of the starting material ₉₀ The elution was slow at 117 μm. But the particle diameter D of the raw material ₉₀ At 117 μm, the dissolution still satisfies the requirements of the present invention.

Example 2 content uniformity study

Taking 3 groups in example 1, taking the intermediate powder before tabletting, and inspecting the content uniformity of the compound shown in the formula I; the results are shown in Table 3. The result shows that the compound shown in the formula I is the bulk drug D ₉₀ The relative standard deviation RSD of the content measurement results is less than 5% at 37.8-117 mu m. Due to the adoption of proper auxiliary materials and a mixing process, the influence of the particle size distribution of the raw materials on the content uniformity can be reduced.

TABLE 3

Group of	Content (c) of	RSD
			73-06S	13.99％	2.55％
74-05S	14.86％	3.19％
			81-01S	14.10％	1.62％

Example 3 investigation of the mode of drug substance treatment

The compound of formula I was processed by mechanical crushing and sieving, and the results are shown in table 4. It was found that the compound of formula I was very easily comminuted, mechanical comminution for 10 seconds giving the starting material a particle size D ₉₀ Less than 30 μm.

TABLE 4

EXAMPLE 4 inspection of A core Filler

Tablet cores were prepared according to the recipe of example 1, wherein two different batches of the compound of formula I, 73-06S, 81-01S, were selected and mannitol, having an average particle size of 100 μm, 180 μm respectively, were selected.

When the compound of formula I is 73-06S (D) ₉₀ 37.8 μm), the mean mannitol particle size is 180 μm, 20 compressed tablet cores are taken and the tablets are weighed. The results show that: all tablet weights differed by less than 5%, 19 tablet weights differed by less than 4%, and 16 tablet weights differed by less than 3% compared to the average tablet weight. The compressed core 10 tablets were extracted and the content of the compound of formula I was determined with a relative standard deviation RSD of 2.55%.

When the compound of formula I is 81-01S (D) ₉₀ 77.1 μm), sweetWhen the average grain diameter of the dew alcohol is 180 mu m, 10 tablets of the tablet core at the beginning, the middle and the end of tabletting are respectively extracted, and the content of the compound shown in the formula I is respectively determined. The relative standard deviations RSD of the first, middle and end 3 phases are 0.8%, 0.4% and 2.8%, respectively.

When the compound of formula I is 81-01S (D) ₉₀ 77.1 μm), the mannitol has an average particle size of 100 μm, 10 tablet cores at the beginning, middle and end of the compression are extracted, and the content of the compound represented by formula I is determined. The relative standard deviations RSD of the first, middle and end 3 stages were 0.1%, 0.1% and 0.2%, respectively.

The results show that the formulation according to the invention allows the particle size and density of mannitol to have no significant effect on the tablet quality.

EXAMPLE 4B examination of the core Filler

The tablet core prescription is (w/w): 15% of compound shown in formula I, 3% of colloidal silicon dioxide, 9.4% of low-substituted hydroxypropyl cellulose, 3% of sodium stearyl fumarate, 69.6% of mannitol and microcrystalline cellulose (mass ratio is 7.6: 1-1.8: 1) or 69.6% of lactose premix. The lactose premix is commercial Cellactose 80 lactose cellulose, and the ratio of lactose to cellulose is about 3: 1.

The items of flowability, compressibility, disintegratability, etc. of the formulation were evaluated by a powder direct compression method. The results show that mannitol in combination with microcrystalline cellulose as a filler resulted in a similar result to most of the items of the lactose premix. However, the lactose premix formula has a hardness lower than that of the mannitol formula under the same compression force.

The effect of different ratios of mannitol and microcrystalline cellulose as fillers on dissolution was also examined and the results are shown in table 5. In the dissolution medium with pH4.5, the screening result of dissolution shows that: when the ratio of the mannitol to the microcrystalline cellulose is 36: 10 or 76: 10, the dissolution is not obviously changed, but when the ratio of the mannitol to the microcrystalline cellulose (w/w) is 18: 10, the dissolution is reduced to some extent, but the dissolution still reaches 57% at 20 min.

TABLE 5

Example 5 investigation of core glidants

Due to the poor flowability of the compound shown in formula I, the influence of the glidant on the production process of the tablet core is examined. When colloidal silicon dioxide is used as a flow aid, the flowability of the powder can be improved; but also the screen is blocked, so that the time for the first sieving of the mixed powder is prolonged.

Handbook of Pharmaceutical Excipients (fourth edition), 4 ^th edition, edited by Raymond C Rowe, Paul J Sheskey, and Paul J Weller) describes colloidal silicon dioxide as a glidant to improve dry powder flowability, typically in an amount of 0.1 to 0.5%.

The prescription of each batch of tablet cores is (w/w): 15% of a compound shown in formula I, 0-3% of colloidal silicon dioxide, 3% of croscarmellose sodium, 3% of sodium stearyl fumarate and the balance of mannitol and microcrystalline cellulose, wherein the mass ratio of the mannitol to the microcrystalline cellulose is 3.25: 1.

During tabletting, the compressibility of the formulation without glidant is reduced, and dead impact is easy to occur after the tabletting force is increased. When the amount of colloidal silica used was 0.6%, the recipe compressibility was significantly improved.

When the amount of colloidal silica was 1.5% or 3%, there was no significant difference in the sheet weight and the content uniformity. When the dosage of the silicon dioxide is 1.5%, 10 tablet cores with the specification of 10mg are extracted, and the relative standard deviation RSD of the tablet weight is 2.3%; at a dosage of 3%, the corresponding relative standard deviation RSD was 4.5%. The content measurement results of two tablet cores with different contents of colloidal silicon dioxide of the compound shown in the formula I show that the content uniformity is stable.

When the amount of colloidal silica used was 3%, the disintegration and dissolution were reduced from those of 1.5%, but the disintegration time was still less than 2 minutes, and the dissolution reached 57.4% in 20 minutes (dissolution medium pH4.5, 75 rpm).

When the dosage of the colloidal silicon dioxide is 1.5 percent, the mixed powder passes through a 60-mesh sieve, and the phenomenon of long sieving time does not occur; at a dosage of 3%, an extension of the first sieving time was observed, but still within the industrially acceptable range.

Example 6 examination of sodium stearyl fumarate

The prescription of each batch of tablet cores is (w/w): 15% of compound shown in formula I, 3% of colloidal silicon dioxide, 3% of croscarmellose sodium, 0.75% -3% of sodium stearyl fumarate and the balance of mannitol and microcrystalline cellulose, wherein the mass ratio of the mannitol to the microcrystalline cellulose is 3.25: 1.

Handbook of Pharmaceutical Excipients (fourth edition), 4 ^th edition, edited by ray Raymond C Rowe, Paul J Sheskey, and Paul J Weller) describes sodium stearyl fumarate as a lubricant for tablets or capsules, generally in an amount of 0.5 to 2.0%.

During tabletting, when the dosage of the sodium stearyl fumarate is 0.75%, the tablet is difficult to produce and the phenomenon of sticking occurs during tabletting. When the dosage of the sodium stearyl fumarate is 1.5 percent, the phenomena of difficult sheet discharging and sticking still occur, but the phenomena can be borne by the industrialized process. When the dosage of the sodium stearyl fumarate is 3 percent, the phenomena of difficult sheet forming and sticking do not occur.

Example 7 Effect of coating weight gain on tablets

The effect of different coating weight gains on the relevant substances of the tablets was examined, as well as the effect of the coating weight gain on dissolution. The opadry 85F640013 was chosen as the coating powder, and the results showed that the dissolution rates of the samples at different time points were very close to each other when the coating was increased by 3% and 4%, and the 20-minute dissolution rates were 89% and 88%, respectively, in the dissolution medium with pH 3.8. The change of related substances is also very similar when the mixture is placed for 10 days at 60 ℃ and 75% RH.

Example 8 exemplary Industrial recipes and Processes

222.0g of compound shown in formula I, 22.0g of colloidal silicon dioxide, 863.5g of mannitol, 265.76g of microcrystalline cellulose, 44.0g of sodium stearyl fumarate, 51.26g of croscarmellose sodium and 61.6g of Opadry film coating premixed powder are precisely weighed, whether granules or agglomeration phenomenon exists in the raw and auxiliary materials is checked during weighing, if yes, the raw and auxiliary materials are firstly sieved and weighed.

Mixing colloidal silicon dioxide, microcrystalline cellulose and croscarmellose sodium, and sieving; and sequentially adding the compound shown in the formula I and mannitol, uniformly mixing, adding sodium stearyl fumarate, and continuously and uniformly mixing to obtain intermediate powder.

And detecting the content of the intermediate powder, calculating the weight of the tablet according to the content detection result of the intermediate powder after the intermediate powder is qualified, and pressing the tablet core. The tablet weight and hardness were monitored periodically during the compression process. For example, tablet cores of between 10mg and 240mg size may be compressed.

And (3) placing the qualified tablet core into a coating pot, taking a coating premix (Opadry 85F640013, and sampling 1.3-1.4 times of the theoretical tablet core weight increment of 3%), and preparing a coating suspension. And stopping coating after the weight of the tablet core is increased by 3-4%.

Example 9 dissolution examination

Dissolution test was carried out on 6 tablets of 10mg and 80mg standard tablets prepared in example 8 (dissolution medium pH3.8, 75rpm) in each batch, and the results are shown in FIGS. 4 and 5. The dissolution of the tablet prepared in example 8 for 30 minutes was 90% or more.

10 tablets of 80mg size prepared in example 8 were withdrawn and disintegrated into suspensions with 50mL of water, respectively, and rapid disintegration was observed (all samples disintegrated completely within 3 minutes). The dissolution of the suspension after disintegration is measured, and the result shows that the dissolution of the suspension after disintegration is slightly faster than that of the same tablet in the initial 5 minutes under the normal dissolution condition, and the dissolution curves of the rest time points and the tablet are not different; f. of ₂ The similarity factor is 53, the dissolution rate is consistent.

Example 10 stability study

The stability of the film-coated tablets of the compound of formula I obtained in example 8 was examined. Placing the film-coated tablet in a high-density polyethylene bottle (with a bottle cover screwed and a paper bag in the bottle for filling with desiccant); the lofting condition is that the temperature is 40 plus or minus 2 ℃ and the relative humidity is 75 plus or minus 5 percent; the change in total impurity and content at the start (0M) and after 1 month (1M) was measured, and the results are shown in Table 6. Accelerated stability tests that have been completed show no significant change in both single and total impurities in all 6 samples, with 10mg of total impurities less than 0.6%, and 80mg of total impurities less than 0.4%; the dissolution rate change is less than 10%, and the product stability is good.

TABLE 6

Comparative example 1 Wet granulation tableting method

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

Compared with the tablet in the embodiment 8, the wet granulation tabletting has good flowability and high hardness; however, disintegration was slow, dissolution at 10 minutes was significantly less than powder direct compression, and dissolution at 10 minutes was only 7.6% (pH 4.5, 75 rpm).

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A pharmaceutical composition containing a compound of formula I,

the pharmaceutical composition is prepared by a powder direct compression method, and comprises a compound shown in formula I, a filling agent, a glidant, a lubricant and a disintegrant;

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;

the glidant is talcum powder or colloidal silicon dioxide;

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 combinations thereof;

the disintegrant is selected from the group consisting of: one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone;

the weight ratio of the filler to the compound of formula I is (3-7): 1;

the weight ratio of the glidant to the compound of the formula I is (0.04-0.2): 1;

the weight ratio of the lubricant to the compound of formula I is (0.08-0.44): 1;

the weight ratio of the disintegrant to the compound of formula I is (0.15-0.8): 1.

2. the pharmaceutical composition of claim 1, wherein the glidant is colloidal silicon dioxide.

3. The pharmaceutical composition of claim 1, wherein the lubricant is sodium stearyl fumarate.

4. The pharmaceutical composition of claim 1, wherein the disintegrant is low-substituted hydroxypropyl cellulose and/or croscarmellose sodium.

5. The pharmaceutical composition of claim 4, wherein the disintegrant is low-substituted hydroxypropyl cellulose or croscarmellose sodium.

6. The pharmaceutical composition of claim 1, wherein the filler is mannitol and microcrystalline cellulose.

7. The pharmaceutical composition according to claim 6, wherein the weight ratio of mannitol to microcrystalline cellulose in the filler is (1.5-9): 1.

8. the pharmaceutical composition of claim 6, wherein the weight ratio of mannitol to microcrystalline cellulose in the filler is (1.8-8): 1.

9. the pharmaceutical composition of claim 6, wherein the weight ratio of mannitol to microcrystalline cellulose in the filler is (3-7.6): 1.

10. the pharmaceutical composition of claim 1, wherein the weight ratio of the filler to the compound of formula I is (4-6): 1.

11. the pharmaceutical composition of claim 1, wherein the weight ratio of the filler to the compound of formula I is (4.5 to 5.5): 1.

12. the pharmaceutical composition of claim 1, wherein the weight ratio of the glidant to the compound of formula I is (0.06-0.2): 1.

13. the pharmaceutical composition of claim 1, wherein the weight ratio of the glidant to the compound of formula I is (0.08-0.15): 1.

14. the pharmaceutical composition of claim 1, wherein the weight ratio of lubricant to compound of formula I is (0.09-0.33): 1.

15. the pharmaceutical composition of claim 1, wherein the weight ratio of the lubricant to the compound of formula I is (0.1 to 0.22): 1.

16. the pharmaceutical composition according to claim 1, wherein the weight ratio of the disintegrant to the compound of formula I is (0.18 to 0.7): 1.

17. the pharmaceutical composition of claim 1, wherein the weight ratio of disintegrant to compound of formula I is (0.2 to 0.65): 1.

18. the pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises:

19. the pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises:

the filler comprises mannitol and microcrystalline cellulose, and the weight ratio of the mannitol to the microcrystalline cellulose is (1.8-8): 1;

and the disintegrant is selected from the group consisting of: low-substituted hydroxypropyl cellulose, or croscarmellose sodium.

20. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition consists of:

21. A process for preparing a pharmaceutical composition according to any one of claims 1 to 20, said process comprising:

(1) mixing the glidant, the first part of filling agent and the disintegrating agent, and sieving;

(2) adding the compound of formula I and a second part of filler, mixing uniformly, adding a lubricant, and continuously mixing uniformly to obtain intermediate powder;

22. The method of claim 21, wherein the fillers are mannitol and microcrystalline cellulose, and the first portion of the filler is microcrystalline cellulose and the second portion of the filler is mannitol.

23. A pharmaceutical tablet comprising the pharmaceutical composition of any one of claims 1 to 20.

24. The pharmaceutical tablet of claim 23, wherein the pharmaceutical tablet comprises: a tablet core being the pharmaceutical composition according to any one of claims 1 to 20, and a coating covering the tablet core.

25. A kit, comprising:

the pharmaceutical composition of any one of claims 1 to 20; and