CN106913529B

CN106913529B - Preparation method of pharmaceutical composition of neratinib or pharmaceutically acceptable salt thereof

Info

Publication number: CN106913529B
Application number: CN201611187268.6A
Authority: CN
Inventors: 郭辰宁; 潘凯; 刘凯; 刘通
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Shanghai Maijin Biomedical Technology Co Ltd; Jiangsu Hengrui Medicine Co Ltd
Priority date: 2015-12-24
Filing date: 2016-12-20
Publication date: 2020-12-04
Anticipated expiration: 2036-12-20
Also published as: CN106913529A

Abstract

The invention relates to a preparation method of a pharmaceutical composition of neratinib or a pharmaceutically acceptable salt thereof. In particular, in the process of preparing the neratinib-containing granules, the maximum water content of the granules during granulation is kept below 10%, or/and the water content of the final granules or the pharmaceutical composition is controlled below 2%, so that the pharmaceutical preparation with good stability can be prepared, and meanwhile, the pharmaceutical preparation shows good dissolution property.

Description

Preparation method of pharmaceutical composition of neratinib or pharmaceutically acceptable salt thereof

Technical Field

According to the preparation method of the medicinal composition containing the active pharmaceutical ingredients such as the neratinib, the maximum water content of the granules in the granulation preparation process is controlled to be less than 10%, or/and the water content of the final granules or the composition is controlled to be less than 2%, so that a medicinal preparation with good stability can be prepared, and meanwhile, the medicinal composition prepared by the method has good dissolution property.

Background

(E) -N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino-3-cyano-7-ethoxyquinolin-6-yl) -4- (dimethylamino) but-2-enamide, also known as lenatinib, has the following specific structure and is a specific protein kinase inhibitor.

Studies have shown that there is high or abnormal expression of EGFR in many solid tumors. EGFR is involved in the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. Overexpression of EGFR plays an important role in the evolution of malignant tumors, and EGFR overexpression exists in tissues such as glial cells, kidney cancer, lung cancer, prostate cancer, pancreatic cancer and breast cancer. Increased concentrations of EGFR and HER2 can be found in more than 30% of breast cancer patients.

Neratinib is an irreversible HER2/EGFR inhibitor and can effectively inhibit HER1 and HER2 tyrosine kinase activities. Thereby inhibiting the growth of tumor cells.

The lenatinib has a good effect of inhibiting the growth of tumor cells, but the lenatinib is easy to degrade and has poor stability, particularly after the lenatinib is prepared into a pharmaceutical composition, the degradation of the lenatinib is accelerated due to the existence of various auxiliary materials, and the specific structural formula of the degraded impurities is as follows. In clinical applications, because the side effects of the impurity of neratinib are large, generally speaking, the content of the degradation impurity of a neratinib preparation needs to be controlled to be less than 0.2%, and therefore, providing a stable neratinib preparation is a challenge for those skilled in the art.

Patent CN 102724970 discloses a method for preparing a tablet formulation of maleic acid salt of neratinib, but the method is only aimed at improving the caking property of neratinib during the granulation process. Namely, the physical characteristics of the neratinib which are shown in the granulating process and influence the granulation are improved. Without addressing the unstable, readily degradable chemistry of neratinib itself. And merely improving the cohesiveness during granulation does not guarantee good stability and good dissolution properties of the final formulation.

Disclosure of Invention

The invention discloses a preparation method of a neratinib pharmaceutical composition, which can remarkably improve the stability and dissolution property of active ingredients in the neratinib pharmaceutical composition by keeping the maximum water content of granules below 10% during granulation or/and the maximum water content of finally obtained granules below 2% in the preparation process. Specifically, in the process of preparing the neratinib-containing granules, the maximum water content of the granules during granulation is kept below 10 percent

(A) Neratinib or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a maleate salt thereof,

(B) one or more fillers selected from sugar alcohols and water-swellable additives,

(C) a disintegrating agent, a disintegrating agent and a carrier,

(D) an adhesive agent is added to the mixture of the components,

and (4) granulating. The obtained granule contains active components such as neratinib with good stability and dissolution property.

In order to further improve the stability of the active ingredient in the granules, the maximum water content of the finally obtained granules may be controlled to 2% or less (preferably 2%, 1.8%, 1.6%, 1.4%, 1.2%, 1.0%, 0.8%, 0.6%, 0.4%, 0.2%).

The invention also provides a preparation method of the neratinib-containing pharmaceutical composition, wherein the neratinib-containing pharmaceutical composition is prepared by the steps of (A) neratinib or pharmaceutically acceptable salt thereof or solvate thereof, (B) one or more fillers selected from sugar alcohol and water swelling additives, (C) disintegrating agent, (D) binding agent, granulating, drying, compressing the obtained granules and the like under the condition that the maximum water content of the granules during granulation is below 10%. The maximum water content of the finally obtained pharmaceutical composition is controlled to be 2% or less (preferably 2%, 1.8%, 1.6%, 1.4%, 1.2%, 1.0%, 0.8%, 0.6%, 0.4%, 0.2%), thereby further improving the stability of the pharmaceutical composition and the dissolution property thereof.

The preparation method of the neratinib-containing pharmaceutical composition further comprises a coating step after the granulation step.

The filler of the present invention is selected from sugar alcohols, water swellable additives or combinations thereof. The sugar alcohol used for improving the stability of the compound neratinib is selected from mannitol, erythritol, xylitol and the like, and preferably mannitol. The water-swellable filler is pregelatinized starch, gelatinized starch, microcrystalline (crystalline) cellulose, corn starch, hydroxypropylmethyl cellulose (HPMC-K100LV), calcium sulfate, sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose), calcium carboxymethyl cellulose, croscarmellose sodium (croscarmellose sodium), soybean lecithin, low-substituted hydroxypropyl cellulose, tragacanth powder, and bentonite.

The disintegrant described in the present invention includes adipic acid, alginic acid, gelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydrated silicon dioxide, calcium citrate, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose (microcrystalline cellulose), synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, corn starch, tragacanth powder, potato starch, hydroxyethyl methyl cellulose, hydroxypropyl starch, pregelatinized starch, monosodium fumarate, povidone, anhydrous citric acid, methyl cellulose, or calcium dihydrogen phosphate. Among them, crospovidone or sodium carboxymethyl starch is preferably the disintegrant according to the present invention, and more preferably crospovidone.

The binder of the present invention may be polyvinyl acetate resin, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, hydroxypropyl methyl cellulose 2208, hydroxypropyl methyl cellulose 2906, hydroxypropyl methyl cellulose 2910, hydroxypropyl methyl cellulose phthalate, vinylpyrrolidone-vinyl acetate copolymer, povidone, preferably povidone or hydroxypropyl cellulose, more preferably povidone.

The pharmaceutical excipients used in the invention are known to those skilled in the art, and are one or more of glidants, lubricants and coatings.

Glidants used in the present invention may be hydrated silicon dioxide (colloidal silicon dioxide), light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch or magnesium aluminum metasilicate.

The lubricant used in the present invention may be cocoa fat, carnauba wax, hydrated silicon dioxide (colloidal silica), aluminum hydroxide xerogel, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium fumarate stearate, stearyl alcohol, polyethylene glycol 40 stearate, preferably sodium fumarate stearate, magnesium stearate.

The coating agent used in the present invention may be hypromellose, methylcellulose, ethylcellulose, methylcellulose or hydroxypropylcellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin or polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer dispersion), saccharides, including the sugar alcohols sucrose, mannitol, and opadry (trade name), preferably opadry.

The maximum water content of the granules during granulation according to the present invention is 10% or less (preferably 10% or less, 9% or less, 8.5% or less, 8% or less, 7.5% or less, 7.0% or less, 6.5% or less, 6% or less, or 5% or less), or/and the final water content of the final granules or composition is 2% or less (preferably 2%, 1.8%, 1.6%, 1.4%, 1.2%, 1.0%, 0.8%, 0.6%, 0.4%, 0.2%), so that the stability of the active ingredient in the pharmaceutical composition can be significantly increased, the generation of degradation impurities can be reduced, and the elution of neratinib can be improved.

In the present invention, "the step of granulating the components under the condition of keeping the maximum water content of the granules during granulation at 10% or less" means granulating with a mixture containing the compound nateglinide or a pharmaceutically acceptable salt thereof, or a solvate thereof, an excipient and other suitable additives while adjusting the granulation conditions so that the maximum water content of the mixture and/or granules is kept at 10% or less from the start to the completion of granulation, for example, while adjusting the granulation conditions in which a sample is taken from the granulator so that the water content of the mixture and/or granules sampled from the granulator is kept at 10% or less. The parameters of the granulator (such as inlet air temperature, spray rate, spray pressure or inlet air volume) used to maintain the maximum moisture content of the granules below 10% during granulation may vary depending on the apparatus and environment in which granulation is carried out. As for the condition of "keeping the maximum water content of the granules during granulation below 10%", the person skilled in the art of pharmacy can easily set the respective parameter conditions of each granulator in order to achieve this condition and granulation environment at the granulator. In the present invention, the term "the final water content of the granules is 2% or less" means the water content of the finally obtained/used granules (or referred to as pharmaceutical composition) after the granules are prepared and dried; similarly, "the final water content of the composition is less than 2%" means that the dosage form of the present invention, such as tablet, powder, capsule, etc., is prepared, and the amount of water contained in the tablet and powder and the amount of water contained in the pharmaceutical composition in the capsule are the same.

The method for measuring the moisture of the granules or the compositions is an infrared rapid moisture meter (measuring temperature is 105 ℃), belongs to a common method for measuring the moisture which is well known by a person skilled in the art, and is widely applied to the moisture content measurement in granules, tablets, powder and the like.

The moisture content (%) of the granules was measured at any stage of the start of granulation, during granulation and at the completion of granulation. To measure the moisture content (%) of the granules at some midpoint during granulation, the granules may be collected by interrupting the granulation operation and may be collected through a sampling port (if any) of the granulator. From the moisture content (%) of the granules measured at certain granulation stages, it is expected that continuous granulation would result in a moisture content (%) of the granules of more than 10% without changing the granulation conditions, in which case the skilled person can adjust the maximum moisture content (%) of the granules to not more than 10% by adjusting the conditions affecting the moisture content of the granules (such as the inlet temperature, the spraying speed, the spraying pressure or the inlet volume for fluid bed granulation, or the amount of water added for high speed stirring granulation). Therefore, if the parameters of the pelletizer (such as the inlet air temperature, the spraying speed, the spraying air pressure or the inlet air volume) are not provided as "the condition for keeping the maximum moisture content (%) of the pellets during the pelletization to 10% or less", the skilled person can set the parameters (such as the inlet air temperature, the spraying speed, the spraying air pressure or the inlet air volume) suitable for the pelletizer to be used, using the maximum moisture content (%) of the pellets during the pelletization as an index, thereby practicing the present invention. The aforementioned setting of the parameters of the granulator by sampling, such as the inlet air temperature, the spraying speed, the spraying air pressure or the inlet air volume, may be carried out each time granulation is carried out, or may be carried out at least once. It will be appreciated that once the skilled person in the pharmaceutical arts has found that the maximum moisture content of the granules during granulation is maintained below 10% in the granulator used (e.g. inlet temperature, spray rate, spray pressure or inlet volume), they can use this set value in the next granulation to carry out the granulation step without sampling.

The granulation method of the present invention may be wet granulation. The wet granulation is fluidized bed granulation and high-speed stirring granulation, and preferably fluidized bed granulation. In the granulating process, the maximum moisture in the granulating process is ensured to be less than 10 percent by controlling the spraying speed of the adhesive and the drying temperature; in addition, during the coating process, the spray rate of the coating agent and the drying temperature are controlled to ensure that the maximum water content of the composition during the coating process is less than 10%.

In the case of fluidized bed granulation, the compound neratinib or a pharmaceutically acceptable salt thereof, or a solvate thereof or the like, an excipient, a disintegrant or the like, as a pharmaceutical adjuvant, are mixed, and the mixture can be granulated by spraying an aqueous binder solution thereon. Taking the maximum water content (%) of the granules during granulation as an index, the skilled person can appropriately set various parameters of the granulator, for example, the inlet air temperature, the spraying speed, the spraying air pressure or the inlet air volume, depending on the granulator used. For example, when granulation is performed at a laboratory level (about 1kg granulation scale) (fluid bed granulator DPL-ii (manufactured by seiko pharmaceutical machinery ltd)), the inlet air temperature may be set to about 70 ℃ to 90 ℃; the spraying speed may be set to 6rpm to 10 rpm; the spraying pressure can be set to 0.6 to 1.5 bar. Alternatively, when granulation is performed at a commercial scale production level (100kg scale) (FL-120 (manufactured by shanghai huafa pharmaceutical machinery, ltd)), the intake air temperature may be set to about 70 ℃ to 90 ℃; the spraying speed can be set to 400g/min to 600 g/min; the gas injection volume may be set to 500 to 750 NL/min.

In the case of high-speed stirring granulation, pure water is added to neratinib, excipient, disintegrant, binder, etc. with stirring with a stirring paddle, and then the mixture can be granulated by kneading. Taking the maximum water content (%) of the granules during granulation as an index, the skilled person can appropriately set various parameters of the granulator, for example, the addition rate of pure water, depending on the granulator used.

The granules or compositions thus obtained are subjected to a drying step, if necessary. The drying method is not particularly limited, and may be vacuum drying, forced air drying, oven drying or oven drying. The granules may be dried until the final moisture content (dry weight method) is 2.0% or less. For example, the drying temperature is from room temperature to 100 ℃, preferably from 70 ℃ to 90 ℃, and the drying time is of the order of tens of minutes to hours, preferably from 10 minutes to 30 minutes.

The dosage form of the pharmaceutical composition provided by the invention is a solid preparation, preferably tablets, granules and powder (including fine granules), or capsules, more preferably capsules and tablets. The solid preparation can be obtained by widely known preparation method, the maximum water content of the final dry granule after granulation is controlled below 2%, and then the solid preparation is filled into capsules or directly packaged into granules. When the dosage form is a tablet, the humidity of the tabletting environment is controlled during tabletting to ensure that the water content of the final tablet is less than 2% (below 2%), and the vacuum drying treatment is adopted on the final composition to ensure that the water content of the final composition is less than 2%.

When the pharmaceutical composition of the present invention is a tablet, it can be prepared by compressing the granules obtained as described above. The pressure of the compression can be determined within a suitable range, and the pressure is preferably 5 to 15 kN. Further, the tablet shape is not particularly limited, and is preferably a lenticular shape, a disc shape, a circular shape, an oval shape (e.g., a caplet), a teardrop shape or a polygonal shape (e.g., a triangle or a diamond shape). The tablets prepared may be coated by spraying a suspension/solution of the coating agent through a pan coater. After coating, the moisture content of the final tablet is controlled within 2% by drying process. The drying temperature can be selected from 40-80 deg.C, preferably 50-60 deg.C. The drying method can adopt common oven drying or vacuum drying, and preferably vacuum drying.

When the pharmaceutical composition of the present invention employs granules, the granules obtained as described above may be used directly or may be granulated into desired granules by an appropriate technique. Alternatively, the granules thus prepared may be coated with a coating agent by spraying a suspension/solution of the coating agent.

When a powder is used as the pharmaceutical composition of the present invention, the desired powder or fine particles can be prepared from the granules obtained as described above by an appropriate technique. Alternatively, the powder or granules thus prepared may be coated with a coating agent by spraying a suspension/solution of the coating agent.

When the pharmaceutical composition of the present invention is in the form of a capsule, the aforementioned granules or powders may be filled with the capsule.

The neratinib provided by the invention can be a solvate (including a hydrate) or a pharmaceutically acceptable salt or a solvate of a salt (including a hydrate). Pharmaceutically acceptable salts are the hydrochloride, sulfate, hydrobromide, citrate, hydroiodide, phosphate, nitrate, benzoate, methanesulfonate, benzenesulfonate, 2-hydroxyethanesulfonate, p-toluenesulfonate, acetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, fumarate, malate and mandelate salts. Among them, maleic acid salts are preferable, and anhydride of maleic acid salts is particularly preferable, and the structure thereof is as follows.

The neratinib or a pharmaceutically acceptable salt or solvate thereof and the like according to the present invention can be obtained according to the methods described in US6002008, US6288082, US6297258, US6384051, and US7399865, or commercially available.

The pharmaceutical composition prepared by the method of the invention shows good stability, and particularly, the growth rate of the degradation impurities of the neratinib is obviously reduced. In the long-term stability test, the lenatinib degradation impurity in the composition increased by less than 0.2% when placed at 40 ℃ and 75% Relative Humidity (RH) for 6 months. And when the composition is placed for 24 months at the temperature of 25 ℃ and the Relative Humidity (RH) of 50 percent, the degradation impurity of the neratinib in the composition increases by less than 0.1 percent; meanwhile, the pharmaceutical composition prepared by the method of the invention also shows better dissolution property and faster dissolution rate (80% is dissolved 10min after the start of the dissolution experiment).

The invention also provides a pharmaceutical composition, which contains the neratinib or the pharmaceutically acceptable salt thereof or the solvate thereof, a filling agent, a disintegrating agent, a binding agent and a lubricant which is sodium stearate fumarate. Compared with the prior art, the stability of the pharmaceutical composition is obviously improved, and the degradation impurities are obviously reduced.

Drawings

FIG. 1: the dissolution contrast curves for the lenatinib maleate capsule formula B1 of example 1 are shown versus formula a 1.

FIG. 2: the dissolution profile of the lenatinib maleate tablet formulation D1 of example 4 is shown.

Detailed Description

Example 1

And granulating the neratinib maleate, the mannitol, the microcrystalline cellulose, the crospovidone and the silicon dioxide by adopting a fluidized bed according to the proportion in the table 1, spraying 5% of polyvinylpyrrolidone as a binding agent for granulation, stopping spraying the binding agent after the granulation is finished, and drying the granules. Sodium stearyl fumarate was added in the proportions indicated in table 1. Mixing with a rotary mixer. And (4) filling the obtained total mixed particles into capsules to prepare capsules.

Table 1: lenalitinib maleate capsule prescription

Composition (I)	Unit dose (mg)	Ratio (%)
			Lenalinib maleate (anhydrous)	290	48.33
Mannitol	202	33.67
			Microcrystalline cellulose	36	6.00
Cross-linked polyvidone	18	3.00
			Colloidal silica	12	2.00
Polyvinylpyrrolidone	30	5.00
			Stearic acid sodium fumarate	12	2.00
Total up to	600	100

According to the above formulation, granulation was carried out using a DPL-II fluidized bed (manufactured by Chongqing Seiki pharmaceutical machinery, Ltd.) in accordance with the parameter settings shown in Table 2.

Table 2: fluid bed granulation parameters

The granules granulated under different conditions were further dried using the same drying parameters as shown in table 3, by controlling the drying time to obtain a final granule with a water content of between 0 and 2%, i.e. formulations a1 and B1 and C in table 3 below. Or the water content of the final granules is 1-2%, namely formulas A2 and B2 in the following table 3.

Table 3: final moisture content of differently formulated granules

The granules thus granulated and dried under the respective conditions were mixed with sodium stearyl fumarate in an amount prescribed in table 1, and the mixture was filled into capsules. The neratinib maleate capsules are filled into high-density polyethylene bottles, and the increase of degradation products is inspected by a standing stability test. The results are given in table 4 below:

table 4: stability study of Lenalitinib maleate capsules

As a result, it can be seen from the comparison of a1 with a2 and B1 with B2 that the stability of the formulation can be significantly improved and the amount of degradation products can be reduced by controlling the moisture content of the final pharmaceutical composition. Compared with A1 and B1, the preparation method of the invention controls the maximum water content in the granulation process to be 10 percent and simultaneously controls the water content of the final preparation to be less than 2 percent, and the stability of the prepared preparation is obviously improved. The lenatinib capsule prepared by the preparation method provided by the invention is proved to have good stability.

Example 2

Dissolution rate test results

Dissolution tests were performed on the neratinib maleate capsules of formula B1 and formula a1 of example 1. In the second method of Chinese pharmacopoeia dissolution test method, dissolution test of capsules was performed using 900mL of hydrochloric acid solution with pH1.0 as a dissolution medium, the dissolution medium temperature was 37. + -. 0.5 ℃ and the paddle speed was 50 rpm. Samples were taken at 5, 10, 15, 30, 45min and measured by UV spectrometer at 266 nm.

The dissolution rate measurement results and the dissolution curve of the neratinib maleate capsule prepared by the method of the present invention are shown in fig. 1. The ordinate shows the dissolution rate of neratinib, and the abscissa shows time (min). The result shows that the lenatinib capsule (B1) prepared by the method is quick in dissolution, can dissolve more than 80% in 15min, is remarkably superior to the capsule of the formula A1, and shows better dissolution and faster dissolution rate.

Example 3

Granulating the neratinib, the mannitol, the microcrystalline cellulose, the crospovidone and the silicon dioxide by adopting a fluidized bed according to the proportion in the table 1, spraying 5% of polyvinylpyrrolidone as a binding agent for granulation, stopping spraying the binding agent after the granulation is finished, and drying the granules. Sodium stearyl fumarate was added in the proportions indicated in table 1. Mixing with a rotary mixer. And (4) filling the obtained total mixed particles into capsules to prepare capsules.

Table 5: lenalitinib maleate tablet prescription

Composition (I)	Unit dose (mg)	Ratio (%)
			Lenalinib maleate (anhydrous)	290	36.25
Mannitol	335	41.88
			Microcrystalline cellulose	60	7.50
Cross-linked polyvidone	25	3.13
			Colloidal silica	16	2.00
Polyvinylpyrrolidone	42	5.25
			Cross-linked polyvidone	16	2.00
Stearic acid sodium fumarate	16	2.00
			Total up to	800	100

Table 6: fluid bed granulation parameters

	Granulation Condition C	Granulation Condition D
			Temperature of inlet air	70℃	80℃
Speed of rotation of the spray	8rpm	8rpm
			Spray gun atomization pressure	1.0bar	1.2bar
Maximum moisture content of the granulation process	12.33％	6.42％

The granules granulated under different conditions were further dried, using the same drying parameters as shown in table 7, by controlling the drying time to make the final water content of the granules between 0-2%, the final water content of the granules is shown in table 3.

Table 7: final moisture content of differently formulated granules

	High moisture conditioned particles	Low moisture conditioned particles
			Temperature of inlet air	70℃	70℃
Temperature of the material	40℃	40℃
			Drying time	13min	9min
Content of dried particles	0.40％	0.33％

The dried granules were mixed with the extragranular components crospovidone and sodium stearyl fumarate and the mixture was compressed into tablets using a single punch tablet press (19.2mm 10mm profile punch). Subsequently, these tablets were each film-coated with 15 w/v% coating agent suspension (OPADRY) composed mainly of polyvinyl alcohol by using a high-performance coating machine (manufactured by O' hara, Canada) so that the amount of coating in each tablet was 20 mg.

During the coating process, the coating process was controlled according to the parameters of table 8 such that the maximum water content of the tablets during the coating process was controlled to be below 10%.

Table 8: parameter setting during coating process

	Coating parameters
		Temperature of inlet air	50℃
Speed of spray	6g/min
		Temperature of outlet air	40℃
Maximum moisture content during coating	3.5％

The coated tablets were dried using a small rotary vacuum dryer at 50 ℃ to a final moisture content of 0-2% by controlling the drying time, as shown in tables 9, C1 and D1. Or the water content of the final tablet is between 1 and 2 percent, namely C2 and D2 in the following table 9.

Table 9: final moisture content of tablets of different formulations

The dried neratinib tablets were filled into high density polyethylene bottles and placed in a stability test to investigate the increase of degradation products. The results are given in table 10 below:

table 10: stability study of lenatinib maleate tablets

As a result, it can be seen from the comparison of C1 with C2 and D1 with D2 that the stability of the formulation can be significantly improved and the amount of degradation products can be reduced by controlling the moisture content of the final pharmaceutical composition. Compared with the C1 and the D1, by adopting the preparation method, the water content in the granulating process is controlled to be 6.42 percent, the water content of the final preparation is controlled to be less than 1 percent, the stability of the prepared preparation is obviously improved, and the stability of the neratinib tablet prepared by adopting the preparation method is proved to be good.

Example 4

Dissolution rate test results

The neratinib tablets of example 3 were subjected to dissolution rate examination. In the second method of Chinese pharmacopoeia dissolution test method, dissolution test of capsules was performed using 900mL of hydrochloric acid solution with pH1.0 as a dissolution medium, the dissolution medium temperature was 37. + -. 0.5 ℃ and the paddle speed was 50 rpm. Samples were taken at 5, 10, 15, 30, 45min and measured by UV spectrometer at 266 nm.

The dissolution rate measurement results and the dissolution curve of the neratinib tablets prepared by the method of the present invention are shown in fig. 2. The ordinate shows the dissolution rate of neratinib, and the abscissa shows time (min). The result shows that the neratinib capsule prepared by the method is quick in dissolution, can dissolve more than 80% in 15min, and shows better dissolution and faster dissolution rate.

Claims

1. A process for preparing granules containing neratinib or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising maintaining the maximum water content of the granules during granulation below 10%

A) Neratinib or a pharmaceutically acceptable salt thereof, or a solvate thereof,

B) a filler, a filler and a filler,

C) a disintegrating agent, a disintegrating agent and a carrier,

D) an adhesive agent is added to the mixture of the components,

a step of granulating, wherein the final water content of the granules is less than 2%.

2. The method of claim 1, wherein the final moisture content of the pellets is less than 1.8%.

3. The method of claim 1, wherein the final moisture content of the pellets is less than 1.6%.

4. A method according to claim 1, characterized in that the maximum moisture content of the granules during granulation is below 8.5%.

5. A method according to claim 1, characterized in that the maximum moisture content of the granules during granulation is below 6.5%.

6. A process according to any one of claims 1 to 3, characterised in that the filler is one or more additives selected from sugar alcohols and water-swellable additives.

7. Process according to claim 6, characterized in that the filler is chosen from at least one or more sugar alcohols and at least one or more water-soluble additives.

8. Process according to claim 6, characterized in that the sugar alcohol is selected from mannitol, xylitol, erythritol and the water-swellable additive is selected from microcrystalline cellulose, pregelatinized starch, lactose, starch.

9. Process according to claim 8, characterized in that the sugar alcohol is chosen from mannitol and the water-swellable additive is chosen from microcrystalline cellulose.

10. The method according to claim 1, characterized in that the disintegrant is crospovidone or sodium croscarmellose.

11. The method according to claim 10, characterized in that the disintegrant is selected from crospovidone.

12. The method according to claim 1, characterized in that the binder is povidone or hydroxypropyl cellulose.

13. The method according to claim 12, characterized in that the binder is selected from povidone.

14. The method according to claim 1, characterized in that the pharmaceutically acceptable salt of neratinib is the maleate salt.

15. A process for the preparation of a pharmaceutical composition, characterized in that it comprises the step of preparing granules according to any one of claims 1 to 14.

16. The method of claim 15, further comprising the step of tableting or encapsulating the granules.

17. The method of claim 15, further comprising a coating step after the granulating step, wherein the coating agent is selected from the group consisting of opadry, hypromellose, ethylcellulose and polyvinyl alcohol.

18. The method according to claim 17, wherein the coating agent is selected from the group consisting of opadry.

19. A pharmaceutical composition comprising neratinib or a pharmaceutically acceptable salt thereof, or a solvate thereof, a filler, a disintegrant, a binder, a lubricant, prepared by a process according to any one of claims 15 to 18, characterized in that the lubricant is sodium fumarate stearate.