KR20140065862A - Effervescent quick-dissoving imatinib preparation - Google Patents

Abstract

The present invention relates to an imatinib preparation whereby drug-taking convenience is enhanced. More specifically, the present invention relates to an effervescent super-disintegrating imatinib preparation comprising: 5-30 weight% of imatinib or a pharmaceutically acceptable salt thereof; 10-35 weight% of an effervescence agent; 10-35 weight% of an acidifying agent; and 0.1-5 weight% of a sweetening agent. The preparation of the present invention rapidly effervesces and becomes suspended in liquids and markedly reduces the inherent bitter taste of imatinib, thereby substantially promoting drug-taking convenience by overcoming problems of existing commercial preparations, namely inconvenience of drug-taking due to large size and inconvenience due to bitter taste.

Description

Effervescent quick-dissoving imatinib preparation < RTI ID = 0.0 >

The present invention relates to an imatinib preparation having increased ease of use, and more particularly, to an imatinib preparation comprising 5 to 30% by weight of imatinib or a pharmaceutically acceptable salt thereof, 10 to 35% by weight of a foaming agent, 10 to 35% 0.1 to 5% by weight based on the total weight of the composition.

Imatinib and its salts have been implicated in the pathogenesis of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit (CD117) benign unresectable and / or metastatic malignant gastrointestinal stromal tumor (GIST) It is prescribed for treatment.

And is commercially available as a film-coated tablet manufactured by Novartis Pharma Stein AG (Stein, Switzerland) and distributed by Novartis Pharmaceuticals Corporation (East Hanover, New Jersey) under the trade name Gleevec. Gleevec is available in strengths including imatinib methanesulfonate in an amount equal to 100 mg or 400 mg of imatinib free base. Gleevec is a colloidal silicon dioxide; Crospovidone; Hydroxypropylmethylcellulose; Magnesium stearate; And ferric oxide red; Ferric oxide yellow; Hydroxypropylmethylcellulose; Such as microcrystalline cellulose, with a polyethylene glycol and a tablet coating with talc.

Gleevec is generally administered at a dose of 400 mg / day as the imatinib free base for adult patients with chronic stage CML, and 600 mg / day for patients in accelerated or blast crisis . ≪ / RTI > In addition, Gleevec is recommended for doses of 400 mg / day or 600 mg / day for adult patients with unresectable and / or metastatic, malignant GIST.

Gleevec requires a very high dose of 400 mg or 600 mg as an imatinib free base at one time and, especially when taken in the esophagus at the time of administration, there is a risk of causing inflammation or ulceration by local irritation To prevent this, the dosage form of the product is prescribed to be administered together with a large amount of water.

However, a composition containing 400 mg of imatinib-free base has been very inconvenient to take in many patients as it is a very large dosage form to be taken by patients suffering from diseases. In order to solve this inconvenience, After being suspended, it can be taken.

Patent Application Publication Nos. WO 2001/47507, WO 2003/090720, US 2006/0275372, WO 2007/119601, US 2009/0087489 disclose oral dosage form compositions of imatinib.

WO 2003/090720 discloses a tablet containing about 30-80% w / w imatinib and produced by a wet granulation process, and is disclosed as being suitable for preparing small tablets despite containing high amounts of imatinib . However, this is represented by high abrasiveness and limited selection of suitable additives due to high drug content. In addition, the fluidity of the final mixture is poor and it is difficult to tablet in tablet form.

WO 01/47507 discloses compositions containing about 22% w / w of imatinib methane sulfonate, US 2006/0275372 and WO 2007/119601 disclose nanoparticulate compositions of imatinib methanesulfonate, US2009 / 008748 discloses a composition containing 23-29% w / w imatinib methanesulfonate, but it has been reported that there is a greater difficulty in taking into patients because of the significantly larger size of the tablet than Gleevec.

The above prior art describes techniques primarily focusing on compositions containing high doses of the active ingredient, and in particular, International Patent Publication Nos. US2009 / 008748 and WO 01/47507 disclose compositions that contain In the case of a composition which will contain at least 400 mg of imatinib, a composition which weighs more than 1.4 g has been disclosed, which is not suitable for patients who need to take it, especially for the elderly, children, severe patients and other dysphagic patients Lt; / RTI >

In addition, imatinib and its salts are very strong in taste, and even if they are suspended in beverages, the bitterness inherent in imatinib is expressed, making it difficult for the patient to take the medication. Especially, the time for suspending the tablet evenly in the beverage is considerable There is still the inconvenience of pulverizing the tablet to suspend or shake it strongly because of its long length.

Accordingly, the present inventors have found that when preparing imatinib as an effervescent preparation containing sweeteners, it is convenient to take it and can improve the bitter taste (problematic) which is a problem in conventional preparations, And confirmed the present invention.

It is therefore an object of the present invention to provide an effervescent disintegrating tablet comprising 5 to 30% by weight of imatinib or a pharmaceutically acceptable salt thereof, 10 to 35% by weight of a blowing agent, 10 to 35% by weight of an acidifying agent and 0.1 to 5% Tinib formulation.

Another object of the present invention is a pharmaceutical composition comprising a) mixing imatinib or a pharmaceutically acceptable salt thereof and a foaming agent to prepare granules; And b) mixing the granules with an acidifying agent and a sweetening agent to form a foamable quick disintegration-free imatinib preparation.

In order to achieve the above object, the present invention comprises 5 to 30% by weight of imatinib or a pharmaceutically acceptable salt thereof, 10 to 35% by weight of a foaming agent, 10 to 35% by weight of an acidifying agent and 0.1 to 5% by weight of a sweetener ≪ RTI ID = 0.0 > effervescent < / RTI >

In order to achieve another object of the present invention, the present invention relates to a pharmaceutical composition comprising a) mixing imatinib or a pharmaceutically acceptable salt thereof and a foaming agent to prepare granules; And b) mixing the granules with an acidifying agent and a sweetening agent to form a foamable quick disintegration-free imatinib preparation.

Hereinafter, the present invention will be described in detail.

The present invention relates to an emulsifiable, sustained-release pharmaceutical composition comprising 5 to 30% by weight of Imatinib or a pharmaceutically acceptable salt thereof, 10 to 35% by weight of a blowing agent, 10 to 35% by weight of an acidifying agent and 0.1 to 5% Tinib formulation.

Imatinib is a drug prescribed for the treatment of Philadelphia chromosome positive chronic myelogenous leukemia and Kit (Cd117) benign nonresectable and / or metastatic malignant gastrointestinal tract tumors. The formula of imatinib is as shown below.

≪ Formula 1 >

The imatinib of the present invention can be synthesized directly or purchased commercially and used. Imatinib or its salts are very strong in their properties.

Imatinib of the present invention may be used as such or in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable " as used herein refers to those which are physiologically acceptable and do not normally cause an allergic reaction or a similar reaction when administered to humans, wherein the salt is a pharmaceutically acceptable free acid, Lt; / RTI > is preferred. The free acid may be an organic acid or an inorganic acid. The organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, trifluroacetic, benzoic, gluconic, methanesulfonic, glycolic, succinic, Glutaric acid and aspartic acid. In addition, the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.

A preferred pharmaceutically acceptable salt of imatinib of the present invention may be imatinib methanesulfonate with methanesulfonic acid.

Imatinib or a pharmaceutically acceptable salt thereof of the present invention is preferably contained in an amount of 5 to 30% by weight based on the total weight of the preparation.

In general, when the content is less than 5% by weight, the total weight of the preparation increases, which makes it difficult to manufacture, distribute and store. When the content exceeds 30% by weight, the content of other foamable additives decreases, It can not be reduced or the high density of the active ingredient and the low flowability can not be improved and it may become difficult to produce the foamable preparation.

As the additive exhibiting foaming property, the agent of the present invention includes an acidifying agent and a foaming agent.

The foaming agent of the present invention may be an alkali metal carbonate, preferably sodium carbonate, sodium bicarbonate (sodium bicarbonate), potassium carbonate or potassium bicarbonate, alone or in combination, and most preferably sodium bicarbonate . The foaming agent of the present invention preferably comprises 10 to 35% by weight based on the total weight of the preparation. If it is contained in an amount of less than 10% by weight, the foaming performance may be deteriorated. If it is contained in an amount exceeding 35% by weight, the preparation may be difficult to manufacture due to a decrease in content of other components. Bubbles are generated even in a small amount of water exposure, which may indicate a decrease in stability.

As the acidifying agent, citric acid, succinic acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, acetylsalicylic acid and nicotinic acid may be used singly or in combination, and most preferably citric acid or tartaric acid. The acidifying agent of the present invention is preferably contained in an amount of 10 to 30% by weight based on the total weight of the preparation. If it is contained in an amount of less than 10% by weight, the foaming performance may be deteriorated. If it is contained in an amount exceeding 35% by weight, the content of other components may be lowered and the hardness of the preparation may be lowered.

The sweetener of the present invention is for improving bitter taste unique to the present invention imatinib or a pharmaceutically acceptable salt thereof. In general, any of the sweeteners used in pharmaceutical preparations can be used, and preferably, aspartame, Sardine, saccarin, sucrose, acesulfame potassium, tosin, ammonium glycyrrhizin acid and sucralose. Most preferably ammonium glycyrrhizic acid, aspartame and sucralose, or a mixture thereof. The ammonium glycyrrhizinic acid, aspartame and sucralose have a sweetness of about 100 times or more than that of sugar and are totally harmless to the human body. The present invention can also use a flavoring agent together with a sweetening agent. The flavoring agent can be adjusted within the content range of the sweetener.

The sweetener of the present invention is preferably contained in an amount of 0.1 to 5% by weight based on the total weight of the preparation. If it is contained in an amount of less than 0.1% by weight, the effect of removing imatinib is insufficient. If it is contained in an amount exceeding 5% by weight, the effect thereof may be insufficient as compared with the added sweetener.

The effervescent decolamizable imatinib formulation of the present invention may further comprise at least one member selected from the group consisting of a suspending agent, a buffering agent, a lubricant and an excipient.

Generally, as a constituent of the foaming agent, additional suspending agents other than the foaming agent and the acidifying agent may not be required. However, in the present invention, when the suspension agent is further constituted, the agent may be rapidly suspended in water to cause rapid foaming I will help you. The suspending agent of the present invention may be any suspending agent generally used in pharmaceutical preparations and may be any of the following: D-mannitol, sorbitol, xylitol, dextrin, maltodextrin, lactose, starch, microcrystalline cellulose, crospovidone, Calcium phosphate (Dibasic) alone or in combination of two or more is preferable. Most preferably, F-MELT from Fuji Chemical Co., Ltd. is the most preferable. F-MELT (manufactured by Fuji Chemical Co., Ltd.), which is used as a suspending agent, is capable of achieving rapid suspension of the tablet from water to provide rapid foaming, and also has excellent preparation of tablets, . F-MELT is composed of D-mannitol, xylitol, microcrystalline cellulose, crospovidone, calcium phosphate (Dibasic), and F-MELT Type C is most preferably used.

The suspending agent of the present invention is preferably contained in an amount of 10 to 35% by weight based on the total weight of the preparation. If it is contained in an amount of less than 10% by weight, the suspension effect of the preparation of the present invention may be lowered. If it is contained in an amount of more than 35% by weight, the effect thereof is insufficient as compared with the added suspension agent, Performance may be deteriorated.

The buffering agent is such that when the foaming agent is suspended in water, it exhibits a pH ranging from 2.0 to pH 7.0, preferably ranging from pH 3.0 to pH 5.0.

The buffering agent of the present invention is preferably at least one selected from the group consisting of potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, ammonium acetate, ammonium hydroxide, triethylamine, triethanolamine, sodium tartrate, potassium citrate and sodium citrate, Most preferably sodium citrate or sodium tartrate.

The buffering agent of the present invention is preferably contained in an amount of 5 to 25% by weight based on the total weight of the preparation. If it is contained in an amount of less than 5% by weight, the effect of pH buffering is insufficient. If it exceeds 25% by weight, an additional buffering effect may be insufficient as compared with a buffering agent added.

The lubricant does not cause caking of the powder, and when tableted, the tablets are discharged well from the tabletting die, and the tablets are hardened, thereby lowering the fatigue of the tablets.

Also, the lubricant is an important factor in tablet formulation, and it has a great effect on the hardness, disintegration time, and dissolution rate of tablets.

The lubricant of the present invention may be selected from the group consisting of PEG 4000-6000, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, glyceryl behenate, magnesium metasilicate magnesium, sodium stearate, sodium fumarate, sodium benzoate, sodium chloride, At least one selected from the group consisting of stearyl fumarate, sodium lauryl sulfate, L-leucine, and hydrogenated vegetable oils is preferable, and PEG 6000 or magnesium stearate alone or a mixture thereof is most preferable.

The number after the polyethylene glycol (PEG, polyethylene glycol) means the average molecular weight. The 'PEG 4000 to 6000' refers to polyethylene glycol having an average molecular weight of 4000 to 6000, and may specifically be PEG 4000, PEG 4500, PEG 5000 or PEG 6000.

The lubricant of the present invention is preferably contained in an amount of 0.3 to 3% by weight based on the total weight of the preparation. If it is contained in an amount of less than 0.3% by weight, the productivity is deteriorated due to insufficient lubricating effect, and if it exceeds 3% by weight, the disintegration and dissolution time of the preparation may be delayed due to hydrophobic properties.

The excipient of the present invention may be at least one water-soluble carbohydrate selected from the group consisting of saccharides including sugar alcohols having 4 to 12 carbon atoms, monosaccharides and disaccharides, and starch hydrolysates. The saccharide is preferably glucose, maltose, dextrose, sucrose, fructose, trehalose, sucralose and polydextrose, and the sugar is preferably mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol. Do. The starch hydrolyzate is preferably dextrin or maltodextrin.

The preparation of the present invention dissolves very quickly in water, and it is convenient to take, because the specific odor of imatinib is reduced.

The dose of the preparation of the present invention is such that 100 mg to 400 mg of the effective ingredient of the present invention is administered per day. However, the dosage of the present invention is not limited to various factors such as the degree of disease progression, the onset of disease, age, But it may be administered in the same or a smaller amount as the dosage of the conventional imatinib preparation. However, in case of severe complication or complication, the drug of the present invention can be administered in an increased amount up to a large dose in order to improve the therapeutic efficiency. The daily dose can be administered once or twice or 1-3 times, and can be appropriately adjusted depending on the situation.

The present invention also provides a process for preparing an effervescent decolorizing imatinib preparation.

The process for preparing the effervescent fast disintegrating imatinib formulation of the present invention comprises

a) mixing imatinib or a pharmaceutically acceptable salt thereof and a foaming agent to prepare granules; And

b) mixing the granules with an acidifying agent and a sweetener to form

And a control unit.

The manufacturing method of the present invention will be described step by step.

a) mixing imatinib or a pharmaceutically acceptable salt thereof and a foaming agent to prepare granules;

In step a), imatinib or a pharmaceutically acceptable salt thereof and a foaming agent are mixed to prepare granules.

Granulation is a dry granulation method in which a granulation is made by pulverizing a sludge or sheet material made by applying a mixture to a slug machine or a roller compressor, or by adding a liquid solvent to an active material to produce granules by extrusion granulation, And drying and sizing it, and preferably a wet granulation method is preferable.

The liquid solvent used in the wet granulation method does not affect the activity of the active ingredient imatinib, and any solvent generally used in the production of granules can be used, and these solvents are well known in the art. But is not limited to, water, ethanol, isopropyl alcohol, glycerin, propylene glycol, and polyethylene glycol, or a mixed solvent thereof. Preferably, the liquid solvent may be water.

The granules thus prepared are preferably granulated into granules having a uniform particle size distribution down to the sieve. Sieves 12 to 30 may be used, and preferably, sieves 18 may be used.

In addition, in the step (a) of the granule of the present invention, the granules can be prepared by further mixing suspending agents in addition to imatinib or its pharmaceutically acceptable salts and foaming agents.

The imatinib, the foaming agent and the suspending agent are as described above.

b) mixing the granules with an acidifying agent and a sweetening agent to form a mixture;

In step (b), an acidifying agent and a sweetener are mixed with the granules prepared in step (a). The acidifiers and sweeteners are as described above.

The acidifying agent and the sweetening agent may be separately granulated and mixed, or they may be mixed by direct mixing.

In the molding step b) of the present invention, at least one selected from the group consisting of a lubricant, an excipient, and a buffering agent may be mixed with an acidifying agent and a sweetening agent. The above-mentioned lubricants, excipients and buffering agents are as described above.

The form of the preparation may be a capsule containing a tablet, granule or granule, preferably a tablet. In the case of granules, granules may be prepared by pulverizing the granules of step a), mixing a foaming agent and a sweetener, and dry or wet granulation. The capsules can be prepared by filling the above-mentioned granules into a common co-capsule.

In the case of tablets, general tablets may be used to tablet the granules of step a), the direct mixture of the acidifying agent of step b) and the sweetener, or a mixture of granules.

In one embodiment of the present invention, the effervescent fast disintegrating imatinib formulation of the present invention is prepared in tablet form.

478 g of imatinib methanesulfonate, 972 g of F-Melt and 800 g of dried diatomaceous earth were placed in a high shear mixer (YC-SEP-SMG-3J, Yenchen) and uniformly mixed with 150 g of purified water. 18 (850 [mu] m) sieve to prepare granules. 640 g of anhydrous citric acid, 200 g of sodium citrate, 32 g of PEG 6000 and 8 g of magnesium stearate were mixed, and the other sweetening agents were added to the mixture, which was then weighed using a single-handed tableting machine (ERWEKA) The tablet was tableted with a circular tablet.

In another embodiment of the present invention, a common imatinib preparation was prepared (Comparative Example 1) for comparison of the characteristics of the present invention and other preparations, and as another comparative example, 100 mg of Glivec Film (manufactured by Novartis Korea) Coated Tab. 100 mg) (Comparative Example 2) was prepared and the time taken for complete suspension after administration to purified water was specified.

As a result, it was confirmed that the preparation of the present invention was suspended in less than 1 minute, while Comparative Example 1 took more than 4 minutes and Comparative Example 2 took 16 minutes or more. Thus, it was confirmed that the foam of the present invention was very excellent.

In another embodiment of the present invention, the effect of the improvement of the dullness was evaluated by sensory evaluation. The preparation of the present invention and the preparation of Comparative Example 2 were respectively suspended after refining and faded for 10 seconds in the mouth, and then the resulting dough was measured.

As a result of the experiment, it was confirmed that the preparation of the present invention significantly reduced the bitter taste as compared with the preparation of Comparative Example 2.

As described above, the present invention relates to a pharmaceutical composition comprising effervescent suds comprising 5 to 30% by weight of imatinib or a pharmaceutically acceptable salt thereof, 10 to 35% by weight of a foaming agent, 10 to 35% by weight of an acidifying agent and 0.1 to 5% Provides a solution of a solution of the sun-dried imatinib. The preparation of the present invention is rapidly foamed and suspended in a liquid phase, and the specific odor of imatinib is remarkably reduced, thereby solving the inconvenience caused by discomfort and bitter taste due to the large size which is a problem of the conventional commercial formulation.

Hereinafter, the present invention will be described in detail with reference to examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

< Example  1>

Imatinib Foamed tablets  Produce

The foamed tablets were prepared using imatinib methane sulfonate (Cheil Pharmaceutical Co., Ltd., Korea).

478 g of imatinib methanesulfonate, 972 g of F-melt and 800 g of dried sodium bicarbonate were placed in a high shear mixer (YC-SEP-SMG-3J, Yenchen) as shown in Table 1, and 150 g of purified water Granules were prepared by drying the granules with a No. 18 (850 μm) sieve. 640 g of anhydrous citric acid, 200 g of sodium citrate, 32 g of PEG 6000 and 8 g of magnesium stearate were mixed and the other sweeteners were added as shown in Table 1 below to obtain a final mixture. This was mixed with 800 mg of a single tablet machine (ERWEKA) The tablet was compressed into a circular tablet having a mass and constant hardness.

Preparations of the components as shown in Table 2 were prepared in the same manner as in Examples 1 to 4, except that 100 mg (Glivec Film Coated Tab. 100 mg, manufactured by Novartis Korea Co., ) Were used.

< Example  2>

Suspension time  Improvement test

Imatinib foam definition To determine the rapidity of the suspension time, tablets of Example 4 of Table 1, Comparative Example 1 of Table 2, and Comparative Example 2 were injected into a beaker containing 50 ml of purified water as described in the Gleevec Defined Dosage Capacity And then the time of foaming and the time at which the tablet disintegrated completely were measured.

As a result, as shown in Table 3, it was confirmed that the effervescent formulation containing imatinib of the present invention was very rapidly foamed and rapidly suspended.

< Example  3>

Improvement effect  exam

The tablets of Examples 1 to 4 were suspended in 50 ml of purified water as described in the Gleevec definition dosing dose of Comparative Example 2 in order to confirm the effect of improving the bitterness of imatinib containing imatinib and the tablets of Comparative Example 2 were pulverized to give 50 ml of purified water And the taste was compared.

10 adults in their twenties to 50 years old who had no impairment of bitter taste and arginine taste were selected as test subjects and the suspensions of Examples 1 to 4 and Comparative Example 2 were placed in the mouth for 10 seconds so that the bitterness (1): Gummy is not felt at all, ++ (2): Gummy is hardly felt, +++ (2) 3): Gummy feels very little, ++++ (4): Gummy feels slightly, +++++ (5): Gummy feels much, ++++++ (6) I feel a lot of pain.].

The above experiment was carried out after rinsing the mouth 1 with lemon water and then rinsing the mouth 3 with purified water before measuring the waxiness for each suspension.

As a result, as shown in [Table 4], the foamed tablet according to the present invention has a bitter taste unique to imatinib methanesulfonate, which is affected by the taste of sweetener, flavoring agent and carbon dioxide gas taste, Thus, it was confirmed that there was an excellent improvement effect on the hairiness as compared with the general tablet of Comparative Example 2, which is commercially available and sold.

Accordingly, the present invention relates to a process for the preparation of effervescent freeze-dried imatinib containing 5 to 30% by weight of imatinib or a pharmaceutically acceptable salt thereof, 10 to 35% by weight of a blowing agent, 10 to 35% by weight of an acidifying agent and 0.1 to 5% The formulation is provided. Since the preparation of the present invention is rapidly foamed and suspended in a liquid phase, the specific odor of imatinib is remarkably reduced, and the inconvenience caused by the discomfort and bitter taste due to the large size, which is a problem of the conventional commercial formulation, Is high.

Claims (13)

5 to 30% by weight of imatinib or a pharmaceutically acceptable salt thereof, 10 to 35% by weight of a foaming agent, 10 to 35% by weight of an acidifying agent and 0.1 to 5% by weight of a sweetener.
The preparation according to claim 1, wherein the foaming agent is at least one selected from the group consisting of sodium carbonate, sodium hydrogencarbonate (sodium bicarbonate), potassium carbonate, and potassium hydrogencarbonate.
The preparation according to claim 1, wherein the acidifying agent is at least one substance selected from the group consisting of citric acid, succinic acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, acetylsalicylic acid and nicotinic acid.
The method according to claim 1, wherein the sweetener is at least one substance selected from the group consisting of aspartame, stevioside, saccharin, sucrose, acesulfame potassium, tocaine, ammonium glycyrrhizin acid and sucralose Formulation.
The formulation according to claim 1, wherein the effervescent decolorizing agent further comprises at least one selected from the group consisting of a suspending agent, a buffering agent, a lubricant, and an excipient.
The method according to claim 5, wherein the suspending agent comprises D-mannitol, sorbitol, xylitol, dextrin, maltodextrin, lactose, starch, microcrystalline cellulose, crospovidone and calcium phosphate (Dibasic) By weight, based on the total weight of the composition.
6. The composition according to claim 5, wherein the buffering agent is at least one selected from the group consisting of potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, ammonium acetate, ammonium hydroxide, triethylamine, triethanolamine, sodium tartrate, potassium citrate and sodium citrate By weight based on the total weight of the preparation.
6. The composition of claim 5 wherein the lubricant is selected from the group consisting of PEG 4000-6000, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, glyceryl behenate, magnesium metasilicate magnesium, sodium stearate, sodium fumarate, sodium benzoate, At least one selected from the group consisting of sodium chloride, sodium chloride, sodium stearyl fumarate, sodium lauryl sulfate, L-leucine, and hydrogenated vegetable oil, in an amount of 0.3 to 3% by weight based on the total weight of the preparation.
[Claim 6] The preparation according to claim 5, wherein the excipient is at least one water-soluble carbohydrate selected from the group consisting of saccharides containing 4 to 12 carbon atoms, sugar alcohols, monosaccharides and disaccharides, and starch hydrolysates.
6. The pharmaceutical composition according to claim 5, wherein the excipient is selected from the group consisting of mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol as sugar alcohols; Examples of the saccharides include glucose, maltose, dextrose, sucrose, fructose, trehalose, sucralose and polydextrose; Wherein the starch hydrolyzate is at least one water-soluble carbohydrate selected from the group consisting of dextrin and maltodextrin.
a) mixing imatinib or a pharmaceutically acceptable salt thereof and a foaming agent to prepare granules; And
b) mixing the granules with an acidifying agent and a sweetener to form
&Lt; RTI ID = 0.0 &gt; 1. &Lt; / RTI &gt;
12. The method according to claim 11, wherein step a) is a step of mixing imatinib or a pharmaceutically acceptable salt thereof and a foaming agent together with a suspending agent to prepare granules.
[12] The method of claim 11, wherein the step b) comprises mixing at least one selected from the group consisting of a lubricant, an excipient, and a buffering agent with the granule, the foaming agent, and the sweetener.