WO2013017100A1

WO2013017100A1 - Imatinib mesylate tablet

Info

Publication number: WO2013017100A1
Application number: PCT/CN2012/079644
Authority: WO
Inventors: 安晓霞; 张静; 李小强
Original assignee: 上海创诺制药有限公司
Priority date: 2011-08-04
Filing date: 2012-08-03
Publication date: 2013-02-07
Also published as: CN102302464A; CN102302464B

Abstract

Disclosed is an imatinib mesylate tablet. Said tablet consists of 40-60% alpha crystal form of imatinib mesylate, 5-20% antisticking agent, 20-50% disintegrating agent, and 0.2-1% lubricant. The invention effectively avoids defects of bad fluidity, bad compressibility, strong viscosity, static electricity and so on from alpha crystal form of imatinib mesylate by adding antisticking agent.

Description

Imatinib mesylate tablet

Technical field

The present invention relates to an imatinib mesylate tablet, and more particularly to an imatinib mesylate tablet prepared from the alpha form of imatinib mesylate. The field of preparation technology. Background technique

Imatinib mesylate, Novartis developed by the chemical name is 4- (4-methyl-1-piperazinyl) methyl -Ν-4- methyl _--3-4- ₍₃ - pyridyl) - ₂ -pyrimidinylaminophenyl-aniline methanesulfonate, the molecular formula is

C ₂₉ H ₃₁ N ₇ OCH ₄ S0 ₃ , molecular weight 589.7, chemical structural formula:

, can be used to treat chronic myeloid leukemia

(CML) Chronic patients after blast crisis, accelerated phase or a-interferon therapy failure; patients with malignant gastrointestinal stromal tumors (GIST) who cannot be surgically removed or metastasized.

International Patent Application WO 99/03854 discloses that there are two crystal forms of α and β in imatinib mesylate, and it is disclosed that the flowability, moisture resistance and thermal stability of the β crystal form are significantly better than those of the α crystal form, which is suitable for the final For the industrial production of the preparation, imatinib mesylate tablets (trade name "Gleevec") prepared by the beta form of imatinib mesylate have been marketed and applied. The α-form imatinib mesylate has a flocculent appearance, is light in weight, has poor fluidity, poor compressibility, strong viscosity, and static electricity, and is currently considered to be unsuitable as a raw material for preparation of pharmaceutical preparations. How to effectively prevent the α crystal form of imatinib mesylate from having poor fluidity, poor compressibility, strong viscosity, static electricity, etc., and preparing a stable and reliable quality from the α-form imatinib mesylate Imatinib sulfonate tablets are one of the problems to be solved in the art. Summary of the invention

The object of the present invention is to provide an imatinib mesylate tablet prepared from alpha form of imatinib mesylate to solve the current industrial preparation of imatinib mesylate tablets using β crystal The problem of defects in the type of imatinib mesylate as a raw material.

The present invention provides an imatinib mesylate tablet comprising alpha form of imatinib mesylate, Anti-adherent, disintegrant and lubricant; wherein the weight percentage of the above components is as follows:

Alpha form of imatinib mesylate 40~60%

Anti-adhesive agent 5~20%

Disintegrant 20~50%

Lubricant 0.2~1%.

In another preferred embodiment, the imatinib mesylate tablet further comprises a filler; preferably, the weight percentage of each component is as follows:

Alpha form of imatinib mesylate 50~60%

Filler 5~10%

Anti-adhesive agent 10~20%

Disintegrator 10~20%

Lubricant 0.4~0.8%.

In another preferred embodiment, the filler of the present invention comprises: lactose, microcrystalline cellulose, pregelatinized starch, or dextrin.

The invention provides an imatinib mesylate tablet which is composed of an alpha form of imatinib mesylate, an anti-adhesive agent, a disintegrating agent and a lubricant, wherein the weight percentage of each component is as follows :

Alpha form of imatinib mesylate 40~60%

Anti-adhesive agent 5~20%

Disintegrant 20~50%

Lubricant 0.2~1%

The sum of the weight percentages of the above components is 100%.

Preferably, the weight percentage of each component in the imatinib mesylate tablet is as follows:

Alpha form of imatinib mesylate 50~60%

Anti-adhesive agent 10~20%

Disintegrant 20~35%

Lubricant 0.4~0.8%

The sum of the weight percentages of the above components is 100%.

The anti-adhesive agent is preferably colloidal silica, calcium sulfate, magnesium carbonate or magnesium silicate; preferably magnesium carbonate. The disintegrant is preferably crosslinked polyvinylpyrrolidone, hydroxypropylcellulose or sodium carboxymethyl starch; preferably crosslinked polyvinylpyrrolidone, hydroxypropylcellulose.

The lubricant is preferably magnesium stearate.

The imatinib mesylate tablet is prepared by first mixing the alpha form of imatinib mesylate and an anti-adhesive agent, adding a disintegrant to make the mixture uniform, and then using a wetting agent. Granules, after drying, add lubricant to mix and compress.

The wetting agent is preferably isopropyl alcohol, ethanol or water; preferably ethanol.

The invention provides a preparation method of the imatinib mesylate tablet according to the invention, the method comprising the steps of: firstly mixing the alpha form of imatinib mesylate and the anti-adhesive agent uniformly, Further, a disintegrant is added to make the mixture uniform, and then granulated with a wetting agent, dried, and then added with a lubricant to be mixed, and finally tableted.

It should be understood that the tablets may also be treated with a coating agent. The coating agent may be a conventional film coat, sugar coat or casing, or the like. The coating agent is used in a conventional amount, preferably 2 to 3% by weight based on the weight of the tablet.

The present invention provides a composition comprising an alpha form of imatinib mesylate and an anti-adhesive; wherein the weight percentage of both is:

Alpha form of imatinib mesylate 40~60%

Anti-adhesive agent 5~20%.

The present invention provides a pharmaceutical composition comprising the aforementioned composition of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier includes: a disintegrating agent, a lubricant (such as stearic acid, magnesium stearate), a wetting agent (such as sodium dodecyl sulfate), a coloring agent, a flavoring agent, a stabilizer. , antioxidants, preservatives, fillers, coating agents, etc.

As a preferred embodiment, the pharmaceutical composition comprises an alpha form of imatinib mesylate, an anti-adherent, a disintegrant, and a lubricant; wherein the weight percentages of the above components are as follows:

Alpha form of imatinib mesylate 40~60%

Anti-adhesive agent 5~20%

Disintegrant 20~50%

Lubricant 0.2~1%

As another preferred embodiment, the pharmaceutical composition comprises an alpha form of imatinib mesylate, a filler, an anti-adhesive agent, a disintegrant, and a lubricant, wherein the weight percentage of each component is as follows: Α-form of imatinib mesylate 40~60%

Filler 5~20%

Anti-adhesive agent 5~20%

Disintegrant 10~30%

Lubricant 0.2~1%.

In another preferred embodiment, the sum of the weight percentages of the above components in the pharmaceutical composition is 诵%.

In another preferred embodiment, the weight percentage of each component in the above pharmaceutical composition is as follows: α-form of imatinib mesylate 50 to 60%

Filler 5~10%

Anti-adhesive agent 10~20%

Disintegrator 10~20%

Lubricant 0.4~0.8%.

The sum of the weight percentages of the above components is 100%. The invention effectively avoids the defects of poor flowability, poor compressibility, strong viscosity, static electricity, etc. of the α-form imatinib mesylate by adding an anti-adhesive agent, and the imatination of the α-form mesylate by the α-form The imatinib mesylate tablet prepared in the same manner as the original tablet prepared by the β crystal form has the same quality standards as hardness, disintegration and dissolution, and solves the current industrial preparation of imatinib mesylate tablets. The problem of defects in the use of β-form imatinib mesylate as a raw material. detailed description

The present invention will be further described in detail and in conjunction with the embodiments, without restricting the invention. The angle of repose was determined according to the USP32. The hardness, friability, disintegration time and dissolution of the obtained tablets were measured by a tablet four-meter. Example 1

Recipe:

Α-form imatinib mesylate 120g

Magnesium carbonate 30g Crosslinked polyvinylpyrrolidone 80g

Magnesium stearate 1.2g

Firstly, the formula amount of α-form imatinib mesylate and magnesium carbonate are uniformly mixed, and then the formulated amount of cross-linked polyvinylpyrrolidone is added to make the mixture uniform, and then 70 ml of ethanol is added for granulation, dried and then added. The magnesium stearate was mixed and pressed into 1000 pieces.

According to the USP32 method for determining the angle of repose, the angle of repose of the particles was measured to be 35°. The hardness, friability, disintegration time and dissolution of the obtained tablets were measured by a tablet four-meter. The measurement results were as follows: hardness 10 KG; friability 0.4%; disintegration time 2 min _; dissolution at each time point in a buffer of pH = 1.2 is shown in Table 1.

Example 2

Recipe:

Alpha-type imatinib mesylate

Magnesium carbonate

Crosslinked polyvinylpyrrolidone

Magnesium stearate

Firstly, the formula amount of α-form imatinib mesylate and magnesium carbonate are uniformly mixed, and then the formulated amount of cross-linked polyvinylpyrrolidone is added to make the mixture uniform, and then 50 ml of water is added for granulation, dried and then added. The magnesium stearate was mixed and pressed into 1000 pieces.

According to the USP32 method for determining the angle of repose, the angle of repose of the particles was measured to be 33 °. The hardness, friability, disintegration time and dissolution of the obtained tablets were measured by a tablet four-meter. The measurement results were as follows: hardness 12 KG; friability 0.5%; disintegration time 2.5 min _; dissolution at each time point in the buffer of pH = 1.2 is shown in Table 2. Time (minutes) 5 10 15 30 45 60 Dissolution (%) 70.5 80.8 91.7 98.0 99.6 100.2 Example 3

Recipe:

Α-form imatinib mesylate 120g

Magnesium carbonate 38g

Crosslinked polyvinylpyrrolidone 55g

Magnesium stearate 1.3g

Firstly, the formula amount of α-form imatinib mesylate and magnesium carbonate are uniformly mixed, and then the formulated amount of cross-linked polyvinylpyrrolidone is added to make the mixture uniform, and then 50 ml of isopropyl alcohol is added for granulation and drying. After adding magnesium stearate, it was mixed and pressed into 1000 pieces.

According to the USP32 method for determining the angle of repose, the angle of repose of the particles was measured to be 40°. The hardness, friability, disintegration time and dissolution of the obtained tablets were measured by a tablet four-meter. The measurement results were as follows: hardness 8 KG; friability 0.8%; disintegration time 1.5 min _; dissolution at each time point in the buffer of pH = 1.2 is shown in Table 3.

Example 4

The hardness, disintegration time and dissolution rate (buffer of ρ Η = 1.2) of the original tablet "Gleevec" prepared in the tablet of Example 3 and the β crystal form were measured by a tablet four-meter. The test results are shown in Table 4 Table 4

Time (minutes) 5 10 15 30 45 60

Example 3 75.2 84.6 95.1 99.2 100.6 101.2 Dissolution (%)

Gleevec 74.9 84.5 95.2 98.9 99.9 100.8 The imatinib mesylate tablet of Ming 1 is a good hardness.

Example 5 (Comparative Example)

Recipe:

Α-form imatinib mesylate 120g

Lactose 30g

Microcrystalline cellulose 30

Sodium Carboxymethyl Starch 40g

Magnesium stearate l -2g

First, the formula amount of α-form imatinib mesylate and lactose are mixed evenly, and then the microcrystalline cellulose and sodium carboxymethyl starch of the formula are added to make the mixture uniform, and then 70% isopropyl alcohol is added to granulate. After drying, magnesium stearate was added to mix and pressed into 1000 pieces.

The angle of repose of the particles was measured to be 36°.

The measurement results were as follows: hardness 6--8 KG; friability 0.3%; disintegration time 13.5 min _; and dissolution at each time point in the buffer of pH = 1.

The degree of performance is significantly reduced, reaching only 87% in the first 30 minutes. Example 6

Recipe:

Α-form imatinib mesylate 120g

Microcrystalline cellulose 20g

Magnesium silicate 30g

Low substituted hydroxypropyl cellulose 50g

Magnesium stearate l -2g

First, the formula] α crystal form of imatinib mesylate and magnesium silicate are mixed evenly, and then added to the formula. The amount of microcrystalline cellulose and low-substituted hydroxypropylcellulose were uniformly mixed, and then granulated by adding 60 ml of isopropyl alcohol, dried, and then added with magnesium stearate to be mixed, and pressed into 1000 pieces.

The angle of repose of the particles was measured to be 35 °.

The measurement results were as follows: hardness 6--8 KG; friability 0.4%; disintegration time 4.5 min _; and dissolution at each time point in the buffer of pH=1.2 as shown in Table 7.

7

Example 7

Recipe:

Α-form imatinib mesylate 120g

Lactose 20g

Calcium sulfate 40g

Sodium Carboxymethyl Starch 40g

Magnesium stearate 1.2g

Firstly, the formula amount of α-form imatinib mesylate and calcium sulfate are uniformly mixed, and then the formula amount of lactose and sodium carboxymethyl starch are uniformly mixed, and then 50 ml of purified water is added for granulation, and dried and then added with hard. The magnesium oleate was mixed and pressed into 1000 pieces.

The angle of repose of the particles was measured to be 42°.

The measurement results were as follows: hardness 6--8 KG; friability 0.5%; disintegration time 5.0 π; dissolution at each time point in the buffer of ρ Η = 1.2 is shown as 8.

Example 8

Recipe:

Α-form imatinib mesylate 120g

Microcrystalline cellulose 20g Magnesium carbonate 30g

Crosslinked polyvinylpyrrolidone 50g

Magnesium stearate l -2g

Firstly, the formula amount of α-form imatinib mesylate and magnesium carbonate are uniformly mixed, and then the formulated amount of cross-linked polyvinylpyrrolidone is added to make the mixture uniform, and then 80 ml of ethanol is added for granulation, dried and then added. The magnesium stearate was mixed and pressed into 1000 pieces.

The angle of repose of the particles was measured to be 33 °.

The measurement results were as follows: hardness 6--8 KG; friability 0.3%; disintegration time 5.2 min _; and dissolution at each time point in the buffer of pH=1.2 as shown in Table 9.

Table 9

Example 9

Recipe:

Alpha-type imatinib mesylate

Microcrystalline cellulose

Colloidal silica

Crosslinked polyvinylpyrrolidone

Magnesium stearate

First, mix the formula amount of α-form imatinib mesylate and colloidal silica uniformly, then add the formula amount of microcrystalline cellulose and cross-linked polyvinylpyrrolidone to make the mixture evenly, then add 50 % ethanol 80ml granulation, after drying, add magnesium stearate to mix, and press into 1000 pieces.

The angle of repose of the particles was measured to be 35 °.

The measurement results were as follows: hardness 6--8 KG; friability 0.4%; disintegration time 5.8 min _; and dissolution at each time point in the buffer of pH=1.2 as shown in Table 10.

Table 10

In summary, the invention effectively avoids the defects of the flowability of the α-form imatinib mesylate, the poor compressibility, the viscosity, the static electricity, etc. by adding an anti-adhesive agent. The imatinib mesylate tablet prepared by imatinib sulfonate is consistent with the quality standards of hardness, disintegration and dissolution of the original tablet prepared by the β crystal form, and solves the current industrial preparation of methanesulfonic acid IMA. The use of the beta form of imatinib mesylate as a raw material for the ani tablet requires a defect. It should be noted that the above embodiments are only used for further clarification of the technical solutions of the present invention, and are not to be construed as limiting the scope of the present invention. Some non-essential ones made by those skilled in the art according to the above-mentioned contents of the present invention. Improvements and adjustments are within the scope of the invention.

Claims

Rights request

An imatinib mesylate tablet comprising an alpha form of imatinib mesylate, an anti-adhesive agent, a disintegrant, and a lubricant; wherein the weight percentage of the above components is as follows :

Alpha form of imatinib mesylate 40~60%

Anti-adhesive agent 5~20%

Disintegrant 20~50%

Lubricant 0.2~1%.

2. An imatinib mesylate tablet characterized by comprising an alpha form of imatinib mesylate, an anti-adhesive agent, a disintegrant and a lubricant, wherein the weight of each component The percentages are as follows:

Alpha form of imatinib mesylate 40~60%

Anti-adhesive agent 5~20%

Disintegrant 20~50%

Lubricant 0.2~1%

The sum of the weight percentages of the above components is 100%.

The imatinib mesylate tablet according to claim 1 or 2, wherein the weight percentage of each component is as follows:

Alpha form of imatinib mesylate 50~60%

Anti-adhesive agent 10~20%

Disintegrant 20~35%

Lubricant 0.4~0.8%

The sum of the weight percentages of the above components is 100%.

The imatinib mesylate tablet according to claim 1 or 2, wherein the anti-adhesive agent is colloidal silica or calcium sulfate.

The imatinib mesylate tablet according to claim 1 or 2, which is characterized in that:

The disintegrant is crosslinked polyvinylpyrrolidone, hydroxypropylcellulose or sodium carboxymethyl starch.

6. The imatinib mesylate tablet according to claim 1 or 2, wherein:

The imatinib mesylate tablet according to claim 1 or 2, wherein the tablet is prepared by first mixing an alpha form of imatinib mesylate and an anti-adhesive agent. Evenly, then add disintegration The mixture is evenly mixed, and then granulated with a wetting agent, dried, and then added with a lubricant to be mixed, and finally compressed.

The imatinib mesylate tablet according to claim 7, wherein the moisturizing agent is isopropyl alcohol, ethanol or water.

9. A method for preparing imatinib mesylate tablet according to claim 1 or 2, characterized in that the method comprises the step of: first (immediate imatinib mesylate of form X) Mix well with the anti-adhesive agent, add the disintegrant to make the mixture evenly, then granulate with the wetting agent, add the lubricant after the drying to mix, and finally press.

A composition comprising an alpha form of imatinib mesylate and an anti-adhesive agent; wherein the weight percentage of the two is:

Alpha form of imatinib mesylate 40~60%

Anti-adhesive agent 5~20%.

A pharmaceutical composition comprising the composition of claim 10 and a pharmaceutically acceptable carrier.