CN115581678B

CN115581678B - Repetinib tablet composition and preparation method thereof

Info

Publication number: CN115581678B
Application number: CN202211375236.4A
Authority: CN
Inventors: 刘立媛; 郭婷婷; 赵苗静; 霍志强; 吕永磊; 段丽颖; 戴信敏
Original assignee: Beijing Xinkaiyuan Pharmaceuticals Co Ltd
Current assignee: Beijing Xinkaiyuan Pharmaceuticals Co Ltd
Priority date: 2022-11-04
Filing date: 2022-11-04
Publication date: 2023-09-12
Anticipated expiration: 2042-11-04
Also published as: CN115581678A

Abstract

The invention relates to a repatinib tablet composition and a preparation method thereof, belonging to the technical field of medicines. The repairanib tablet composition comprises 5-15% of repairanib, 2-10% of solid dispersing agent, 40-80% of filling agent, 4-10% of disintegrating agent and 0.5-2% of lubricant. The invention develops a repatinib tablet composition taking repatinib as an active ingredient, wherein the repatinib is prepared into a solid dispersion by adopting a hot-melt extrusion process, and then the repatinib tablet composition is prepared by adopting a direct tabletting method. The dissolution rate of the repatinib tablet composition in vitro for 30min can reach more than 85%, the dissolution rate is high, the dissolution effect is good, the bioavailability is high, the in vivo absorption is facilitated, and the stability is good.

Description

Repetinib tablet composition and preparation method thereof

Technical Field

The invention relates to a repatinib tablet composition and a preparation method thereof, belonging to the technical field of medicines.

Background

Repidinib (Ripritinib) is a tyrosine kinase inhibitor useful in the treatment of cancer patients with abnormal mutations in KIT and PDGFRA kinases. The chemical name of the repitinib is: 1- (4-bromo-5- [ 1-ethyl-7- (methylamino) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-3-yl]-2-fluorophenyl) -3-phenylurea of formula C ₂₄ H ₂₁ BrFN ₅ O ₂ The molecular weight is 510.36, the CAS is 1442472-39-0, and the chemical structure is as follows:

the repatinib is a lipophilic weak alkaline insoluble drug, is almost insoluble in aqueous medium, and is unfavorable for the absorption of the drug in vivo. Researches show that the dissolution rate of the Repetinib original grinding preparation (the trade name is Optic book Lev/QINLOCK, national drug standard HJ 20210022) is slower and can reach more than 85% within 60 min; in addition, the stability was also poor, and the increase of the relevant substances was more than 34% after 3 months of acceleration test compared with 0 day.

Therefore, in order to better meet the clinical and market demands, a repatinib tablet composition with higher dissolution rate and better stability is developed, and the repatinib tablet composition has important economic and social benefits.

Disclosure of Invention

The invention aims to provide a repairanib tablet composition and a preparation method thereof, wherein repairanib is taken as an active ingredient of the repairanib tablet composition, the repairanib is prepared into a solid dispersion by adopting a hot-melt extrusion process, and then the repairanib tablet composition is prepared by adopting a direct tabletting method, and the specific technical scheme is as follows:

in one aspect, the invention provides a repatinib tablet composition, which comprises the following components in percentage by weight:

the sum of the weight percentages of the components is 100 percent.

Further, the solid dispersing agent is one or more of povidone, hydroxypropyl methylcellulose acetate succinate, copovidone and cholesterol stearate.

Further, the solid dispersing agent consists of hydroxypropyl methylcellulose acetate succinate and cholesterol stearate, wherein the mass ratio of the hydroxypropyl methylcellulose acetate succinate to the cholesterol stearate is 1 (1-2).

In the solid dispersing agent, cholesterol stearate is used, so that the dissolution effect is improved; in addition, the drug loading rate of the repatinib can be improved to more than 60% by combining the repatinib and hydroxypropyl methylcellulose acetate succinate, and meanwhile, the stability of the drug can be obviously improved.

As is known in the art: in general, the larger the amount of the solid dispersant used, the larger the API (active ingredient) dispersed in the solid dispersant, the smaller the risk of amorphous molecules converging with each other, the more stable the amorphous solid dispersion, and particularly for an API in which amorphization of the API is difficult. Therefore, the drug loading of the general solid dispersion is 10-30%, mainly for balancing the stability of the solid dispersion and the feasibility of subsequent formulation development. The solid dispersing agent is used too little, and the solid dispersing agent is unstable; the solid dispersant is too much to use, the preclinical animal test formulation cannot be formulated, and in the later formulation development, the weight of the formulation is large and patient compliance is reduced.

For example: in comparison of dissolution behavior of ritonavir/copovidone solid dispersion in the study with the drug and carrier (solid dispersing agent) at different drug loading rates, the study found that: when the drug loading rate is improved to 50%, the dissolution rates of the drug and the carrier are very low; and when the drug loading is 10%, the drug and the carrier can maintain a higher dissolution level. In addition, the dissolution rate of the drug can be influenced by selecting different carrier materials, and the selection of a proper carrier based on API properties is important because different carriers have different crystallization inhibiting abilities.

Further, the filler is one or more of spray-dried lactose, mannitol, microcrystalline cellulose and corn starch.

Further, the filler is composed of spray-dried lactose and microcrystalline cellulose, and the mass ratio of the spray-dried lactose to the microcrystalline cellulose is 1 (5-8).

Microcrystalline cellulose has both filling, binding and disintegrating properties and also has good compressibility, adhesion and flowability, and is preferred as a filler when a direct compression method is used. In addition, in the present invention, a part of spray-dried lactose is used as the filler, which can promote drug dissolution. The content (mass percent) of spray-dried lactose cannot be too high, otherwise it tends to cause deterioration of compressibility, and the yield of the final repatinib tablet composition is significantly lowered. Therefore, it is necessary to control the mass ratio between the spray-dried lactose and the microcrystalline cellulose, which is preferably 1 (5 to 8).

Further, the disintegrating agent is one or more of sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose. In the present invention, the disintegrating agent is preferably crospovidone, and its disintegrating effect is good.

Further, the lubricant is one or more of magnesium stearate, calcium stearate, micro silica gel and hard sodium fumarate.

Preferably, the lubricant consists of magnesium stearate and aerosil according to the mass ratio of (1-2): 1.

The repatinib and the solid dispersing agent are prepared into a solid dispersion by adopting a hot-melt extrusion process, and the solid dispersion has certain viscosity.

Further, the repatinib raw material is crushed to obtain the repatinib with D90 smaller than 20 mu m, so that the repatinib is in order to meet the in vivo absorption requirement, has large granularity, has poor in vitro dissolution effect and is not beneficial to absorption.

In another aspect, the invention provides a method for preparing a repatinib tablet composition, comprising the steps of:

s1, crushing a repatinib raw material, and separating to obtain the repatinib with D90 less than 20 mu m for later use;

s2, adding the Repetitinib with the D90 less than 20 mu m and the solid dispersing agent into hot-melt extrusion equipment to perform hot-melt extrusion operation to obtain an extrusion material, and crushing the extrusion material to obtain a solid dispersion;

step S3, uniformly mixing the solid dispersion, the filler, the disintegrating agent and the lubricant to obtain a mixture;

and S4, tabletting the mixture to obtain the repatinib tablet composition.

Further, in the step S1, the air flow pulverizer is used for pulverizing the raw materials of the repitinib, the feeding speed is 0.5-1.5 kg/h, the pulverizing pressure is 0.7-0.9 Mpa, and a cyclone separator is used for separating to obtain the repitinib with D90 less than 20 mu m;

in the step S2, when the hot-melt extrusion equipment performs hot-melt extrusion operation, the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h; crushing the extruded material, and sieving with a 50-70 mesh sieve to obtain a solid dispersion;

in the step S3, when the lubricant consists of magnesium stearate and aerosil, firstly adding the solid dispersion, the filler, the disintegrating agent and the aerosil into three-dimensional mixing equipment for mixing for 30-60 min, then adding the magnesium stearate, and mixing for 5-10 min to obtain a mixture;

in step S4, the mixture is compressed by a rotary tablet press, and the compression hardness is 6kgf to 9kgf.

If the hot melt extrusion temperature is too high, a part of the solid dispersing agent can be disintegrated and degraded; if too low, the dispersion in the molten state is poor, resulting in uneven dispersion, ultimately affecting the stability of the drug. The hot melt extrusion temperature may be 130 ℃, 140 ℃, 150 ℃, 160 ℃, 170 ℃, 180 ℃, etc.

In hot melt extrusion operation, the screw speed, feeding speed, particle size of the solid dispersion and the like affect the properties of the solid dispersion, thereby affecting the dissolution and stability of the solid dispersion in medicines.

The invention has the beneficial effects that:

1) The invention develops a repatinib tablet composition taking repatinib as an active ingredient, wherein the repatinib is prepared into a solid dispersion by adopting a hot-melt extrusion process, and then the repatinib tablet composition is prepared by adopting a direct tabletting method. The repatinib tablet composition is useful for treating cancer patients with KIT and PDGFRA kinase abnormal mutations.

2) The dissolution rate of the repatinib tablet composition in vitro for 30min can reach more than 85%, the dissolution rate is high, the dissolution effect is good, the bioavailability is high, and the in vivo absorption is more facilitated.

3) After the accelerated test for 3 months, the dissolution rate of the original preparation was 8.7% and the increase of the relevant substances was 34.2% compared with 0 day. Compared with the original developer, the Repetinib tablet composition has lower growth speed of related substances and better stability.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

Example 1

Formula 1 (components in wt.%)

The preparation method of the repatinib tablet composition comprises the following steps:

and 1, crushing the repatinib raw material by using an air flow crusher, wherein the feeding speed is 0.5-1.5 kg/h, the crushing pressure is 0.7-0.9 Mpa, and separating by using a cyclone separator to obtain the repatinib with the D90 of 16+/-1 mu m for later use.

And 2, adding the Repettinib with the D90 of 16+/-1 mu m, hydroxypropyl methylcellulose acetate succinate and cholesterol stearate into hot-melt extrusion equipment to carry out hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, the feeding speed is 0.8-1.2 kg/h, so as to obtain an extrusion material, crushing the extrusion material, and sieving the crushed extrusion material with a 60-mesh sieve, thus obtaining the solid dispersion. Wherein the drug loading of the solid dispersion is 62.5%.

And 3, adding the solid dispersion, the spray-dried lactose, the microcrystalline cellulose, the crosslinked povidone and the micro-powder silica gel into three-dimensional mixing equipment for mixing for 30-60 min, and then adding the magnesium stearate for mixing for 5-10 min to obtain the mixture.

And 4, tabletting the mixture by using a rotary tabletting machine, wherein the hardness of tabletting is 6 kgf-9 kgf, and obtaining the repairanib tablet composition.

Example 2

Formula 2 (components in wt.%)

and 1, crushing the repatinib raw material by using an air flow crusher, wherein the feeding speed is 0.5-1.5 kg/h, the crushing pressure is 0.7-0.9 Mpa, and separating by using a cyclone separator to obtain the repatinib with the D90 of 10+/-1 mu m for later use.

And 2, adding the Repettinib with the D90 of 10+/-1 mu m, the hydroxypropyl methylcellulose acetate succinate and the cholesterol stearate into hot-melt extrusion equipment to carry out hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, the feeding speed is 0.8-1.2 kg/h, so as to obtain an extrusion material, and crushing the extrusion material and sieving the extrusion material with a 60-mesh sieve to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 63.2%.

Example 3

Formula 3 (components in wt.%)

and 1, crushing the repatinib raw material by using an air flow crusher, wherein the feeding speed is 0.5-1.5 kg/h, the crushing pressure is 0.7-0.9 Mpa, and separating by using a cyclone separator to obtain the repatinib with the D90 of 6+/-1 mu m for later use.

And 2, adding the Repettinib with the D90 of 6+/-1 mu m, hydroxypropyl methylcellulose acetate succinate and cholesterol stearate into hot-melt extrusion equipment to carry out hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, the feeding speed is 0.8-1.2 kg/h, so as to obtain an extrusion material, crushing the extrusion material, and sieving the crushed extrusion material with a 60-mesh sieve, thus obtaining the solid dispersion. Wherein the drug loading of the solid dispersion is 61.5%.

Example 4

Formula 4 (components in wt.%)

And 2, adding the repitinib with the D90 of 16+/-1 mu m and the hydroxypropyl methylcellulose acetate succinate into hot-melt extrusion equipment to carry out hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, the feeding speed is 0.8-1.2 kg/h, so as to obtain an extrusion material, and after the extrusion material is crushed, sieving the extrusion material with a 60-mesh sieve, thus obtaining the solid dispersion. Wherein the drug loading of the solid dispersion is 62.5%.

Example 5

Formula 5 (components in wt.%)

And 2, adding the Repettinib with the D90 of 10+/-1 mu m and the cholesterol stearate into hot-melt extrusion equipment for hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, the feeding speed is 0.8-1.2 kg/h, so as to obtain an extrusion material, and crushing the extrusion material and sieving the extrusion material with a 60-mesh sieve to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 63.2%.

Example 6

Formulation 6 (components in wt.%)

And 2, adding the Repettinib and povidone with D90 of 6+/-1 mu m into hot-melt extrusion equipment to perform hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, the feeding speed is 0.8-1.2 kg/h, so as to obtain an extrusion material, and crushing the extrusion material and sieving the extrusion material with a 60-mesh sieve to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 61.5%.

Example 7

Dissolution test

Dissolution test tests were performed on the formulations corresponding to examples 1 to 6 and the original grinding formulation (national drug standard HJ 20210022).

Dissolution was measured by the dissolution and release rate measurement method (second method of the fourth edition of chinese pharmacopoeia 2020, rule 0931).

Instrument: high performance liquid chromatograph and dissolution tester.

Dissolution medium: ph=4.5 acetate buffer containing 0.25% sodium dodecyl sulfate.

Volume of dissolution medium: 900mL.

Rotational speed: 75 revolutions per minute.

Sampling time: 10min, 15min, 20min, 30min, 45min, 60min.

The corresponding preparation and the original preparation in examples 1 to 6 were taken, 900mL of a buffer solution containing 0.25% sodium dodecyl sulfate and having ph=4.5 acetate as a dissolution medium was taken according to a dissolution rate and release rate measurement method (second method of the fourth edition of chinese pharmacopoeia 2020 edition, general rule 0931), the paddle method was operated at 75 revolutions per minute, the solution was taken according to the sampling time, and the dissolution curve measurement data are shown in table 1:

TABLE 1

		10min	15min	20min	30min	45min	60min
								Example 1	Self-made product (%)	31.1	51.5	71.6	88.3	94.0	96.2
Example 2	Self-made product (%)	36.1	57.3	72.4	89.6	95.4	97.5
								Example 3	Self-made product (%)	42.2	65.1	78.1	92.4	97.3	98.3
Example 4	Self-made product (%)	36.1	50.2	64.2	81.2	88.6	90.2
								Example 5	Self-made product (%)	29.1	49.2	67.8	79.9	85.5	91.1
Example 6	Self-made product (%)	24.2	42.5	59.1	75.3	82.4	90.1
								Original developer	Commercial (%)	28.6	48.3	64.1	77.2	84.1	90.4

Conclusion: the corresponding formulations in examples 1-3 can reach more than 85% in vitro in 30min, and have better dissolution rate than the original formulation [ the original formulation reaches more than 85% in 60min (90.4%) ]. The corresponding preparations in examples 1-3 have high dissolution rate, good dissolution effect and higher bioavailability, and are more beneficial to in vivo absorption.

Stability test

Taking the corresponding preparations and original grinding preparations in examples 1-6, placing for 3 months under the condition of 40 ℃/RH75% according to the requirements of the raw material medicaments and the stability test guidelines of the preparations (four guidelines 9001 of Chinese pharmacopoeia 2020 edition), and carrying out accelerated test investigation, wherein the dissolution and related substances are detected as shown in Table 2:

TABLE 2

Conclusion: the formulations corresponding to examples 1 to 3 showed good stability, and the dissolution rate and the change of the relevant substances were not large (compared with 0 day) after the 3-month acceleration test, and the relevant substances were grown at a lower rate than the original developer, and were better in stability than the original developer. The dissolution rate of the original preparation after 3 months of accelerated test was 8.7% and the increase of the relevant substances was 34.2% compared with 0 day.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims

1. The repatinib tablet composition is characterized by comprising the following components in percentage by weight:

5-15% of repatinib;

2-10% of a solid dispersing agent;

40-80% of filler;

4-10% of a disintegrating agent;

0.5-2% of a lubricant;

the sum of the weight percentages of the components is 100 percent;

the solid dispersing agent consists of hydroxypropyl methylcellulose acetate succinate and cholesterol stearate, wherein the mass ratio of the hydroxypropyl methylcellulose acetate succinate to the cholesterol stearate is 1 (1-2);

the filler consists of spray-dried lactose and microcrystalline cellulose, wherein the mass ratio of the spray-dried lactose to the microcrystalline cellulose is 1 (5-8);

the disintegrating agent is crospovidone, the lubricant is magnesium stearate and micro-powder silica gel, and the repairanib is obtained by crushing the repairanib raw material to obtain the repairanib with D90 less than 20 mu m.

2. A process for the preparation of a repatinib tablet composition according to claim 1, characterized by the steps of:

and S4, tabletting the mixture to obtain the repatinib tablet composition.

3. The method for preparing the repatinib tablet composition according to claim 2, wherein the method comprises the following steps:

in the step S1, crushing the repatinib raw material by using an airflow crusher, wherein the feeding speed is 0.5-1.5 kg/h, the crushing pressure is 0.7-0.9 mpa, and separating by using a cyclone separator to obtain the repatinib with D90 less than 20 mu m;

and/or the number of the groups of groups,

in the step S3, when the lubricant consists of magnesium stearate and micro silica gel, adding the solid dispersion, the filler, the disintegrating agent and the micro silica gel into three-dimensional mixing equipment for mixing for 30-60 min, and then adding the magnesium stearate for mixing for 5-10 min to obtain a mixture;

and/or the number of the groups of groups,

in the step S4, the mixture is pressed by a rotary pressing machine, and the pressing hardness is 6 kgf-9 kgf.