KR101956586B1 - Pharmaceutical composition and preparation method thereof - Google Patents

Abstract

The present invention provides a process for the preparation of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- - < / RTI > amino) -benzamide hydrochloride, and a pharmaceutical composition comprising the compound.

Description

Pharmaceutical composition and preparation method thereof < RTI ID = 0.0 >

The present invention provides a process for the preparation of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- - < / RTI > amino) -benzamide hydrochloride, and a process for preparing the same.

Imatinib mesylate (Gleevec, Korean Patent Publication No. 1993-0021624), which is a therapeutic agent for chronic myelogenous leukemia, has an excellent effect on patients with chronic myelogenous leukemia but recently has a problem that drug resistance patients are caused.

Generally, the raw materials of conventional therapeutic agents for chronic myelogenous leukemia are extremely low in solubility in water and low solubility in the gastrointestinal tract due to low solubility, and thus the bioavailability is low. Also, it has a strong adhesive cohesiveness, and when it is made into tablets or capsules, there is a problem in that the formability is low due to adhesion to a mixer, a punch, a die and the like. In order to improve the disadvantages of the therapeutic compounds to provide the desired therapeutic effect, the therapeutic compound must be in the form of an aqueous solution and must have a water solubility. Compounds that are relatively insoluble exhibit incomplete irregular absorption and thus have a poor therapeutic effect and often exhibit imperfect absorption in poorly soluble drugs. Effective methods for increasing the solubility of highly-soluble drugs include chemical modifying methods such as salts or esters or soluble prodrugation, which are more soluble derivatives based on the chemical structure of the drug, and can be used to control (fine or nanoize) There may be physical formulas such as crystalline form, solid dispersion and complexation (inclusion) / dissolution. Representative methods for nanoparticulate active agent compositions for poorly soluble drugs are disclosed in U.S. Patent No. 5,145,684 and methods of making nanoparticulate active agent compositions are disclosed in U.S. Patent Nos. 5,518,187 and 5,862,999, U.S. Patents Nos. 5718, 388 and 5, < RTI ID = 0.0 > 510, 118. < / RTI >

Various problems have been raised in leukemia therapeutic compounds as described above. In order to solve such a problem, research has been conducted to find an N-phenyl-2-pyrimidine-amine derivative or a salt thereof exhibiting a drug efficacy superior to imatinib mesylate against chronic myelogenous leukemia.

As a result of repeated studies to solve the above problems, the present inventors have found that when 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride was found to be particularly suitable for oral pharmaceutical compositions with increased bioavailability. It is also believed that improved solubility and a significantly improved dissolution rate of the drug can be achieved by using the co-solvent with an organic solvent or co-solvent (water / organic solvent) or a surfactant when forming granules to improve the solubility of the material Respectively. Accordingly, it is an object of the present invention to provide an oral pharmaceutical composition with increased bioavailability and a method for producing the same.

The present invention relates to a process for the preparation of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- -Pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride, an oral pharmaceutical composition having increased bioavailability and a process for producing the same. This improves the solubility of the poorly soluble drug, and the pharmaceutical composition prepared therefrom has stability, can alleviate the electrostatic property and adsorption, and improve the dissolution rate and bioavailability.

FIG. 1 is a graph showing dissolution rates of drugs in In Vitro for Examples and Comparative Examples according to the present invention. FIG.
FIG. 2 is a graph showing PK absorption of drugs in beagle dogs according to Examples and Comparative Examples according to the present invention. FIG.
FIG. 3 is a graph showing dissolution rates of drugs in In Vitro for the examples according to the present invention. FIG.

The present invention relates to the use of the therapeutic compound 4-methyl-N- [3- (4-methylimidazol-1 -yl) -5-trifluoromethyl-phenyl] -3- Pyrimidin-2-ylamino) -benzamide hydrochloride and a pharmaceutically acceptable excipient.

The amount of therapeutic compound in the pharmaceutical composition may contain from 20 to 1000 mg and may be at least 40% by weight, preferably from 40 to 60% by weight, of the pharmaceutical composition. It is preferred that the average particle size of the N-phenyl-2-pyrimidine-amine derivative and its salt has an average particle size of about 50 mu m or less, preferably about 30 mu m or less.

The therapeutic compound of the present invention may be prepared in the form of a granule mixture including excipients, disintegrants, binders, lubricants, etc., and may be formulated into an oral dosage form filled in granules, powders, tablets and hard / soft capsules.

In the present invention, in order to improve the solubility, it is preferable to use a co-solvent containing an organic solvent or co-solvent (water / organic solvent) or a surfactant. It can be seen from the following experimental example of the present invention that such a characteristic improves the solubility.

As used herein, the term "therapeutic compound" refers to any compound, substance, drug, drug or active ingredient suitable for the administration of a mammal (e.g., a human) as a composition having therapeutic or pharmacological activity, it means. Such a therapeutic compound has an effect of inhibiting the activity of the increased tyrosine kinase enzyme and the phosphorylation of pCrkL, which is a cancer protein, Bcr-Abl protein, and is suitable for the manufacture of a pharmaceutical composition for the treatment of target anticancer drugs such as chronic myelogenous leukemia and proliferative diseases . The therapeutic compounds of the present invention are useful for the treatment and / or prophylaxis and treatment of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5- Pyrimidin-2-ylamino) -benzamide or a pharmaceutically acceptable salt thereof, particularly preferably 4-methyl-N- [3- (4-methylimidazol- Phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride.

In the present invention, the 4-methyl-N- [3- (4-methylimidazol-1 -yl) -5-trifluoromethyl-phenyl] -3- (4- -2-ylamino) -benzamide hydrochloride is an extremely soluble substance which is insoluble in organic solvents such as ethanol, methanol and the like, or a polar solvent, and has low solubility. The solubility is low and the benefits of this therapeutic compound are difficult to deliver to the patient (i. E., Bioavailability is low). Accordingly, there is a need for a pharmaceutical form which improves the solubility of the compound to increase the bioavailability, and the pharmaceutical composition of the present invention has enhanced bioavailability and a method for producing the same.

The therapeutic compound granules of the present invention can be prepared by using pharmaceutically acceptable excipients or surfactants, disintegrants, lubricants, alone, or by mixing them. The form of the preparation may be a physical mixture, but it has been found that granular form is useful by the following examples. For example, polyvinylpyrrolidone, macrogol glycerol hydroxystearate, lecithin can be used in combination with 4-methyl-N- [3- (4-methylimidazol-1-yl) -5- ] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride.

In the present invention, pharmaceutically acceptable surfactants include castor oil (e.g., macrogol glycerol hydroxystearate, cremophor RH 40, cremophor RH 60), lecithin (Egg), poly Oxyethylene-polyoxypropylene copolymer, polyoxyethylene sorbitan or mixtures thereof, sorbitol esters and polyoxyethylene sorbitan fatty acid esters (e.g., Polysorbate 80), sodium lauryl sulfate, glyceryl fatty acid esters , And fatty acid macrogol glyceride (e.g., Gelucire 44/14). However, the present invention is not limited thereto. Macrogol glycerol hydroxystearate is particularly useful. The surfactant may be used in an amount of preferably 1 to 50 parts by weight, more preferably 5 to 20 parts by weight based on 100 parts by weight of the active ingredient of the present invention. In addition, the surfactant may be contained at a concentration of 0.1 to 30 parts by weight based on the total weight of the pharmaceutical composition.

Examples of excipients in the present invention include microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, lactose hydrate and anhydrate, calcium hydrogenphosphate, light silicic anhydride, starch, mannitol , Polyvinyl pyrrolidone, polyethylene glycol, and ethyl lactate, but is not limited thereto. The excipient may be used in an amount of 0.01 to 60 parts by weight, preferably 1 to 50 parts by weight, based on 100 parts by weight of the active ingredient of the present invention.

In the present invention, the pharmaceutically acceptable disintegrant may be selected from the group consisting of crosslinked polyvinylpyrrolidone or crospovidone, croscarmellose sodium, sodium starch glycolate, starch, alginate, But is not limited thereto. The disintegrant may be used in an amount of about 1 to 40% by weight in the pharmaceutical composition.

In the present invention, the pharmaceutically acceptable lubricant may be selected from the group consisting of magnesium stearate, talc, light silicic anhydride, glyceryl behenate, stearic acid, and sodium stearyl fumarate. The lubricant may be used in an amount of 0 to 10% by weight, preferably 0.5 to 2% by weight, in the composition.

In embodiments of the present invention, one or more materials from the group described above may be selected to produce a mixture, and the process of a conventional wet granulation may be a mixing step, a coalescing step using a binding liquid, a drying step, . The wet process may begin with mixing the therapeutic compound with one or more pharmaceutically acceptable excipients using suitable pharmaceutical equipment. For example, a powder blend may be formed using a high-speed mixer or fluidized bed granulator / spray dryer / freeze dryer, but the granulation facility is not limited thereto. The solvent liquid of the wet granules may be used either alone or in combination of organic solvents such as ethanol, methanol, isopropanol, and acetone, which are polar solvents, including water, and organic solvents may be used alone or in combination. Drying of the wet granulation mixture may be carried out in a pharmaceutical granulating plant or in a suitable drying plant. In the drying step, the granulate is dried to a loss on drying value (LOD) of about 3% by weight or less, for example, 2% by weight or less. After the drying step a suitable granule size can be formed through sieving. Such a granular mixture may be prepared as tablets or as capsules by filling the capsules. Examples of capsules are hard gelatin capsules, hard HPMC capsules. The size of the capsule includes, but is not limited to, the size of No. 00 through No. 5. The therapeutic pharmaceutical composition may contain from 20 mg to 1000 mg in a capsule. In particular, it may contain from 20 mg to 800 mg of the therapeutic pharmaceutical composition, for example, more specifically, the capsule may contain the therapeutic pharmaceutical composition in an amount of 50 mg, 100 mg, 200 m. The amount of the additives used can ensure that the mixture of the therapeutic compound and the excipient is suitable for filling the capsule and the uniformity of the formulation. In order to improve the solubility of the therapeutic compound and ensure fast dissolution rate, the ratio of the disintegrant to the surfactant, which is a solubilizing agent, is important, and the ratio of the disintegrating / solubilizing agent should be 0.66 or more. (For example, crospovidone / macrogolglycerol hydroxystearate, 0.66 to 0.80)

The content of the excipient, surfactant, and retentive substance contained in the preferred pharmaceutical composition of the present invention, which can be prepared by the spray-drying technique, may vary depending on the characteristics of the composition to be obtained. The excipient or surfactant, It is important to control the concentration by controlling the amount of the substance. When the concentration is low, the production efficiency is low and the preparation of the granular composition is difficult. When the concentration is high, the viscosity becomes high and the dispersion is precipitated too quickly to easily clog the nozzle. The concentration of the excipient excluding the solvent is preferably 0.1 to 20 parts by weight in the composition, 0.1 to 50 parts by weight of the surfactant, and 0.1 to 5 parts by weight of the retentive substance.

In the present invention, for example, the excipient may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene glycol, and Eudragit. Phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -4-methyl-N- [3- ) -Benzamide hydrochloride in an amount of preferably 0.1 to 20 parts by weight, more preferably 1 to 10 parts by weight, based on 100 parts by weight of the hydrochloride salt.

Examples of the surfactant include surfactants such as castor oil (for example, macrogol glycerol hydroxystearate, chromophor RH 40, chromophor RH 60), lecithin (Egg), polyoxyethylene-polyoxy Propylene copolymers, polyoxyethylene sorbitan or mixtures thereof, sorbitol esters and polyoxyethylene sorbitan fatty acid esters (e.g., Polysorbate 80), sodium lauryl sulfate, glyceryl fatty acid esters, fatty acid macrogol glycerides (For example, Gelucire 44/14). The surfactant is used in an amount of preferably 1 to 60 parts by weight, preferably 5 to 50 parts by weight, based on 100 parts by weight of the N-phenyl-2-pyrimidine-amine derivative and the salt thereof.

In the present invention, the retentive substance may be selected from the group consisting of natural and animal oils (for example, soybean oil, fish oil, etc.), fatty acid triglycerides, hydrocarbons, polyethylene glycol 660 hydroxystearate and the like . N-phenyl-2-pyrimidine-amine derivatives and salts thereof is used in an amount of preferably 0.1 to 1 part by weight based on 100 parts by weight of the N-phenyl-2-pyrimidine-amine derivatives and salts thereof.

The pharmaceutical compositions of the present invention include methods of making wet granulation / dry granulation / melt granulation. Namely, the present invention relates to a method for preparing a composition dispersed in a surfactant, an excipient or a mixture thereof, a retentive substance, an N-phenyl-2-pyrimidine-amine derivative and a salt thereof, and a mixture of ethanol and purified water, A wet granulation preparation method, a surfactant, an excipient or a mixture thereof, a retentive substance of the present invention, an N-phenyl-2-pyrimidine-amine derivative or its salt as an active substance and a mixture of ethanol and purified water of 2% And the mixture can be prepared by a hot melt extrusion method by mixing the granules with a roller compacting method and compressing granulated granules containing 2% or more of ethanol and a purified water mixture, .

For example, the suspension is obtained by dissolving or suspending or wetting a mixture of ethanol and purified water into a surfactant, an excipient, or a mixture thereof, or a mixture thereof, and adding 4-methyl-N- [3- (4- -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2- ylamino) -benzamide hydrochloride .

In preparing the pharmaceutical composition, the suspension may be dried by spray drying, vacuum drying or freeze-drying using a drying method used in the field of pharmacy, and thermal drying and melting caused by pressure by roller compacting Thermal drying in the granulation process can also be performed. Examples of carriers which can be used in the drying step include pharmacologically acceptable excipients such as microcrystalline cellulose, calcium hydrogen phosphate, light silicic anhydride, crospovidone and its derivatives, povidone, starch glycolate sodium, croscarmellose, Disintegrating agents such as hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose and hydroxypropyl cellulose;

Methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4- pyrazin- -Ylamino) -benzamide or a pharmaceutically acceptable salt thereof, particularly 4-methyl-N- [3- (4-methylimidazol-1-yl) -5- trifluoromethyl- - (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride and an excipient or surfactant, a retentive material or a mixture thereof may be in the form of various formulations, , Capsules, tablets, solid preparations of powders or suspensions, preferably tablets or capsules.

For example 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin- -Aminoamino) -benzamide hydrochloride can be directly mixed with a pharmaceutically acceptable carrier to be filled in capsules, or compressed into tablets to make tablets, or to make tablets, , Film coating or enteric coating may be applied for safety and convenience.

In the present invention, the selection of a pharmaceutically acceptable carrier should ensure the stability of the therapeutic compound. As shown in the following Table 1, when the therapeutic compound (API) and the carrier were homogeneously mixed and stored at 40 ° C and 75% RH (6 weeks), discoloration of the carrier other than the lactose, reduction of the therapeutic drug content, Methyl-N- [3- (4-methylimidazol-l-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin- -Aminoamino) -benzamide hydrochloride is affected by the stability by humidity. When the water content of the carrier itself is high, such as lactose, there is a problem of discoloration and lowering of the content upon mixing.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not intended to be limited thereto.

Example

Example  One

Phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -4-methyl-N- [3- ) -Benzamide hydrochloride (A) and imatinib mesylate (B).

Examples 1-1 and 1-2: 18 g of castor oil 60 was put into a 100 mL beaker, and then 22.5 mL of water and 9 mL of ethanol were added thereto. The mixture was stirred for 1 hour to dissolve the mixture, and 0.5 g of each of A and B was added thereto for about 2 hours Lt; / RTI > After filtering about 5 mL using 0.45um GHP filter and syringe, 1 mL was taken and placed in a 100 mL volumetric flask and the solution (DMSO: MeOH = 3: 7) was adjusted to the mark. This was used as the sample solution.

Examples 1-5 and 1-6: 18 g of castor oil 60 was put into a 100 mL beaker, and 22.5 mL of water and 9 mL of acetone were added thereto. The mixture was stirred for 1 hour to dissolve the mixture, and 0.5 g of each of A and B was added thereto for about 2 hours Lt; / RTI > After filtering about 5 mL using 0.45um GHP filter and syringe, 1 mL was taken and placed in a 100 mL volumetric flask and the solution (DMSO: MeOH = 3: 7) was adjusted to the mark. This was used as the sample solution.

Examples 1-9, 1-10: 18 g of castor oil 60 was put into a 100-mL beaker, and 22.5 mL of water and 9 mL of IPA (isopropyl alcohol) were added to the beaker. After stirring for 1 hour, 0.5 g of A and B were added The mixture was sufficiently stirred for about 2 hours. After filtering about 5 mL using 0.45um GHP filter and syringe, 1 mL was taken and placed in a 100 mL volumetric flask and the solution (DMSO: MeOH = 3: 7) was adjusted to the mark. This was used as the sample solution.

Examples 1-3, 1-4: To a 100 mL beaker, 22.5 mL of water and 9 mL of ethanol were added and stirred for 10 minutes. Then, 0.5 g of each of A and B was added and stirred sufficiently for about 2 hours. After filtering about 5 mL using 0.45um GHP filter and syringe, 1 mL was taken and placed in a 100 mL volumetric flask and the solution (DMSO: MeOH = 3: 7) was adjusted to the mark. This was used as the sample solution.

Examples 1-7 and 1-8: To a 100 mL beaker, 22.5 mL of water and 9 mL of acetone were added, and the mixture was stirred for 10 minutes. Then, 0.5 g of each of A and B was added, and the mixture was sufficiently stirred for about 2 hours. After filtering about 5 mL using 0.45um GHP filter and syringe, 1 mL was taken and placed in a 100 mL volumetric flask and the solution (DMSO: MeOH = 3: 7) was adjusted to the mark. This was used as the sample solution.

Examples 1-11 and 1-12: To a 100 mL beaker, 22.5 mL of water and 9 mL of IPA (isopropyl alcohol) were added, and the mixture was stirred for 10 minutes. Then, 0.5 g of each of A and B was added thereto and stirred sufficiently for about 2 hours. After filtering about 5 mL using 0.45um GHP filter and syringe, 1 mL was taken and placed in a 100 mL volumetric flask and the solution (DMSO: MeOH = 3: 7) was adjusted to the mark. This was used as the sample solution.

Examples 1-13 and 1-14: To a 100 mL beaker, 31.5 mL of water was added, and 0.5 g of each of A and B was added, followed by sufficient stirring for about 2 hours. After filtering about 5 mL using 0.45um GHP filter and syringe, 1 mL was taken and placed in a 100 mL volumetric flask and the solution (DMSO: MeOH = 3: 7) was adjusted to the mark. This was used as the sample solution.

Examples 1-15 and 1-16: 0.5 g of each of A and B was added to a 100 mL beaker, and 5 mL of ethanol was added to the beaker, and the degree of melting was confirmed, and a total of 31.5 mL was added. The solution was filtered using a 0.45um GHP filter and syringe for 5mL, and then 1mL was taken into a 100mL volumetric flask, and the solution (DMSO: MeOH = 3: 7) was adjusted to the indicated value. This was used as the sample solution.

Examples 1-17 and 1-18: 0.5 g of each of A and B was added to a 100 mL beaker, and 5 mL of acetone was added to the beaker to confirm the degree of melting, and a total of 31.5 mL was added. The solution was filtered using a 0.45um GHP filter and syringe for 5mL, and then 1mL was taken into a 100mL volumetric flask, and the solution (DMSO: MeOH = 3: 7) was adjusted to the indicated value. This was used as the sample solution.

Examples 1-19 and 1-20: 0.5 g of each of A and B were added to a 100 mL beaker, and 5 mL of IPA (isopropyl alcohol) was added to the beaker. The solution was filtered using a 0.45um GHP filter and syringe for 5mL, and then 1mL was taken into a 100mL volumetric flask, and the solution (DMSO: MeOH = 3: 7) was adjusted to the indicated value. This was used as the sample solution.

Phenyl-3- (4-pyrazin-2-yl-pyrimidin-2-yl) Amino) -benzamide hydrochloride (A) Solubility analysis

Preparation of Standard Solution: Precisely weigh 106.8 mg of the standard product of A, place in a 50-mL volumetric flask and align with DMSO. Take 5 ml of this solution into a 50-mL volumetric flask and add a dilution (Dimethylsulfoxide: Methanol = 30:70) to the well. 10 mL of this solution was put into a 100-mL volumetric flask, and the solution was drawn with a diluent. Using this solution, 5, 10, 15, and 20 ppm were prepared and the calibration curve was confirmed. The amount of dissolution of the test sample was calculated using a linear equation of the calibration curve.

- Analysis conditions -

Column: Capsellpak MG II, C18 (4.6 × 150 mm, 5 μm) or similar column

Column temperature: 35 ° C

This phase was: ammonium acetate buffer solution (pH 4.0): methanol = 25: 75

Detector: UV 270 nm

Flow rate: 1.0 mL / min

Amount of injection: 10 μl

Preparation of buffer solution: 1.2 ml of acetic acid (100) and 0.25 g of ammonium acetate are added and filled with water

Make the total volume 1L. The pH is adjusted to 4.0 using 0.2 mol / L hydrochloric acid and 0.2 mol / L sodium hydroxide.

2) Solubility analysis of imatinib mesylate (B)

Standard solution preparation: Precisely weigh 20 mg of the standard product of A, put it in a 100 mL capacity flask and align the mark. 5 mL of this solution was placed in a 50 mL volumetric flask, and the solvent (methanol: 0.1 M hydrochloric acid = 6: 4) was added to the well. Using this solution, 5, 10, 15, and 20 ppm were prepared and the calibration curve was confirmed. The amount of dissolution of the imatinib test sample was calculated using a linear equation of the calibration curve.

- Analysis conditions -

ion pair reagent: 7.5 g of 1-octanesulfonic acid sodium salt monohydrate is dissolved in 800 mL of water, adjusted to pH 2.5 with 10% o-phosphoric acid, and diluted to 1000 mL.

Mobile phase A: ion pair reagent + methanol (420 + 580)

Mobile phase B: ion pair reagent + methanol (40 + 960)

Column: Symmetry C18, 5 μm (Waters), length 150 mm, internal diameter 3.9 mm or the like

Column temperature: 25 ° C

Detection: UV 268 nm

Flow rate: 1.2 ml / min

Injection volume: 10 μl

run time: 30 minutes

As can be seen in Table 2 above, 4-methyl-N- [3- (4-methylimidazol-1 -yl) -5-trifluoromethyl-phenyl] -3- (4- (A) is more insoluble in various water / organic solvents than the solubility of imatinib mesylate (B).

Example  2

Methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4- 2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride was formulated into a pharmaceutical composition of Example 2.

Methyl-N- [3- (4-methylimidazol-1 -yl) -5-trifluoromethyl-phenyl] -3- (4- pyrazin- -2-ylamino) -benzamide hydrochloride, microcrystalline cellulose, calcium hydrogenphosphate hydrate, light silicic anhydride, and crospovidone were mixed together to form a powder mixture. Separately, macrogolglycerol hydroxystearate was dissolved in a mixture of ethanol and water to prepare a liquid for granulation. The powder was wet-granulated by combining the liquid in a high-speed mixer with the previously prepared powder mixture. The granules were then dried for a suitable period of time under suitable conditions using a dryer. The dried granules were screened to form an optimal granule size, and then crospovidone and magnesium stearate were added to prepare a final granulation mixture. This granular mixture was filled into hard capsules.

Example  3

The mixture was granulated, dried, and lubricated in the same manner as in Example 2, followed by tableting / film coating to form tablets.

Example  4

A pharmaceutical composition except for the surfactant of Example 2 was formulated in the composition shown in Table 4 below.

The granular mixture was prepared by the same method as in Example 2 except that the surfactant macrogol glycerol hydroxystearate was excluded. And filled in capsules.

Comparative Example  One

Table 5 below compares the composition and the physical properties of the composition as in Example 4, but not the granulation.

The physically mixed powder of the composition shown in Table 4 was filled in the capsule

Comparative Example  2

Macrogolglycerol hydroxystearate was physically mixed and filled into capsules according to the same composition as in Example 2.

Comparative Example  3

Phenyl-3- (4-pyrazin-2-yl-pyrimidine-2- < / RTI > Amino) -benzamide hydrochloride was encapsulated in a co-encapsulated capsule.

Comparative Example  4

Phenyl-3- (4-pyrazin-2-yl-pyrimidine-2- < / RTI > Amino) -benzamide hydrochloride and macrogol glycerol hydroxystearate were made into a physical mixture to fill the capsules.

Test Example  1. Dissolution profile

The capsules prepared in Examples 2 to 4 and Comparative Examples 1 to 4 were subjected to the second method (paddle method) in the pharmacopoeial and dissolution test methods described above, and the dissolution temperature was tested using a sink at 37 ° C. The elution was carried out with 900 mL of pH 1.2 (with 1% SLS added) and a paddle speed of 100 rpm. The amount of dissolved drug substance was determined by HPLC. Methyl-N- [3- (4-methylimidazol-l-yl) -5-trifluoromethyl-phenyl] -3- (4- pyrazin- -1-amino) -benzamide hydrochloride was shown in FIG. 1 and Table 6.

As shown in Table 6 and Fig. 1, when Example 2 and Example 4 are compared, the non-ionic surfactant shows a faster dissolution when added. Comparing Example 2 and Comparative Example 4, it was found that the dissolution rate was significantly increased when prepared by the granulation method. Comparative Examples 1, 2, and 4, which were physical mixtures, exhibited slower dissolution rates than Comparative Example 3.

Example  5. With spray drying technology  Pharmaceutical composition manufacturing

20 g Macrogol glycerol hydroxystearate, 27 g Polyvinylpyrrolidone was dissolved in 1870 ml of a mixture of ethanol and purified water (1: 2.5), and 4-methyl-N- [3- Methyl-phenyl) -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride. The mixture was stirred at a rotation speed of 300 rpm or more for 3 hours, homogenized at a microfluidizer pressure of 10,000 to 15,000, and then a pharmaceutical composition was prepared using a spray dryer. The conditions of the spray dryer were inlet air temperature 100 ~ 120 ℃ and outlet air temperature 70 ~ 90 ℃.

A composition was prepared by the same procedure as in Example 5, with the components and contents shown in Table 7 below. The ethanol-purified water mixture was used in an amount of 10 ml per 1 g of the used components.

Example  15. Manufacture of pharmaceutical composition with fluidized bed granulation technology

30 g of macrogolglycerol hydroxystearate was dissolved in 234 ml of a mixture of ethanol and purified water, and 4-methyl-N- [3- (4-methylimidazol-1-yl) Phenyl-3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride was added and suspended. The mixture is homogenized by stirring at a rotation speed of 300 rpm or more for 3 hours, and then the carrier of 20 g of microcrystalline cellulose, 15 g of crospovidone, 5 g of light silicic anhydride and 25 g of calcium hydrogen phosphate is mixed well. The suspension was spray-dried while the mixture was placed in a fluidized bed granulator to prepare a granular pharmaceutical composition.

The pharmaceutical composition-containing granules were prepared in the same manner as in Example 15, with the ingredients and contents shown in Table 8 below. The ethanol-purified water mixture was used in an amount of 1.2 ml per 1 g of the total amount of the components used.

Example  24. Manufacture of capsules

After mixing 50 g of the pharmaceutical composition of Example 14 with 4% of microcrystalline cellulose, 6% of crospovidone, 6% of calcium hydrogen phosphate and 1.5% of magnesium stearate, 100 mg of 4-methyl-N- [3- 5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride was prepared.

Example  25. Manufacture of capsules

After mixing 50% of the pharmaceutical composition of Example 13 with 4% of microcrystalline cellulose, 4.2% of crospovidone, 6% of calcium hydrogen phosphate and 1.5% of magnesium stearate, 100 mg of 4-methyl-N- [3- 5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2- ylamino) -benzamide hydrochloride was prepared

Example  26. Manufacture of capsules

After mixing 5% of crospovidone and 1.5% of magnesium stearate in 100 g of the granules containing the pharmaceutical composition of Example 15, 100 mg of 4-methyl-N- [3- (4-methylimidazol- Fluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride was prepared.

Example  27. Manufacture of capsules

After mixing 5% of crospovidone and 1.5% of magnesium stearate in 100 g of the granules containing the pharmaceutical composition of Example 21, 100 mg of 4-methyl-N- [3- (4-methylimidazol- Fluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride was prepared.

Example  28. Manufacture of capsules

실시예 2와 같은 방법으로 제조하였으나 계면활성제인 마크로골글리세롤히드록시스테아레이트를 제외한 과립 혼합물이다. 캡슐 내에 충진하였다.

실시예 30
실시예 29와 같은 방법으로 제조된 계면활성제인 마크로골글리세롤히드록시스테아레이트를 제외한 과립 혼합물이다. 캡슐 내에 충진하였다.

실시예 31
실시예 29와 같은 방법으로 제조된 계면활성제인 마크로골글리세롤히드록시스테아레이트를 제외한 과립 혼합물이다. 캡슐 내에 충진하였다.

시험예 5. 용출 프로파일
상기의 실시예 29 ~ 31에서 제조된 과립 혼합물을 충진한 캡슐을 가지고 대한약전, 용출 시험법 중 제 2법(패들법)을 이용하였으며, 용출온도는 37℃에서 싱크를 사용하여 시험하였다. 용출액은 pH 1.2액 900mL(SLS 1% 첨가), 패들속도는 100 rpm으로 하여 용출시험을 수행하였다. 용해된 약물 물질의 양은 HPLC로 측정하였다. 시간에 따른 4-메틸-N-[3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-페닐]-3-(4-피라진-2일-피리미딘-2-일아미노)-벤즈아미드 염산염수화물 및 이염산염과 메탄설폰산염의 용출율(%)을 도 3 및 표 14에 나타내었다.

표 14 및 도 3에서 보여주듯이 실시예 29는 부가염이 염산염수화물로 실시예 30, 31 에 비하여 현저하게 빠른 용해 속도를 보였다. 또한, 실시예 4와 실시예 29를 비교하였을 때, 부가염이 염산염인 경우 더 우수한 용해 속도를 보였다.
After mixing 50 g of the pharmaceutical composition of Example 10 with 4% of microcrystalline cellulose, 4.2% of crospovidone, 6% of calcium hydrogen phosphate and 1.5% of magnesium stearate, 100 mg of 4-methyl-N- [3- 5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide hydrochloride was prepared.

Example 29
A pharmaceutical composition excluding the surfactant was formulated as in Example 4 with the composition shown in Table 13 below.

Was prepared in the same manner as in Example 2, except that it was a granule mixture except for the surfactant macrogol glycerol hydroxystearate. And filled in capsules.

Example 30
Is a granular mixture except for the macrogolglycerol hydroxystearate which is a surfactant prepared by the same method as in Example 29. [ And filled in capsules.

Example 31
Is a granular mixture except for the macrogolglycerol hydroxystearate which is a surfactant prepared by the same method as in Example 29. [ And filled in capsules.

Test Example 5: Dissolution profile
The capsules filled with the granule mixture prepared in Examples 29 to 31 were subjected to the second method (paddle method) in the Korean Pharmacopoeia and dissolution test method, and the dissolution temperature was tested using a sink at 37 캜. The elution was carried out with 900 mL of pH 1.2 solution (with 1% SLS added) and a paddle speed of 100 rpm. The amount of dissolved drug substance was determined by HPLC. Methyl-N- [3- (4-methyl-imidazol-l-yl) -5-trifluoromethyl-phenyl] -3- (4- (%) Of the hydrochloride salt of the hydrochloride and the salt of the dihydrochloride and the methanesulfonate are shown in FIG. 3 and Table 14.

As shown in Table 14 and FIG. 3, Example 29 showed a remarkably faster dissolution rate than that of Examples 30 and 31 as an addition salt hydrochloride hydrate. Further, when Example 4 and Example 29 were compared, the dissolution rate was better when the addition salt was a hydrochloride salt.

Test Example  2. Dissolution test

Phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -4-methyl-N- [3- ) -Benzamide hydrochloride and derivatives thereof, microcrystalline cellulose (20%), sodium starch glycolate (6%), light anhydrous silicic acid (1%) were added to the pharmaceutical composition of Example 5 in order to confirm the improvement in solubility of the pharmaceutical composition, %) And magnesium stearate (1.5%), and the lubricant containing the pharmaceutical composition of Examples 16 and 21 was mixed with the lubricant and filled in capsules. From Examples 24 to 28 And the release test of the drug was carried out. Methyl-N- [3- (4-methylimidazol-1 -yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin- (10%), light silicic acid (1%) and magnesium stearate (1.5%) were mixed to prepare capsules. The dissolution test conditions were analyzed by HPLC after elution test of 900 ml of the eluate for 45 minutes under the conditions of Korean Pharmacopoeia (Method 2). The results are shown in Table 9.

As shown in the above table, the pharmaceutical composition of the present invention can be confirmed that the release of the drug is remarkably improved due to the improvement of the solubility.

Test Example  3. Internal dynamics assessment test

Male beagle dogs weighing about 10 kg were selected and checked for body weight and wounds. The test substance was fasted for 16 hours before administration. And three groups per group. Methyl-N- [3- (4-methylimidazol-1 -yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin- 2-ylamino) -benzamide hydrochloride, microcrystalline cellulose, crospovidone, light silicic anhydride, and magnesium stearate were mixed and filled in capsules. The preparations of Example 24, Example 27, Example 28 and Example 2 were orally administered and analyzed by LC-MS / MS. As a result of the test, the area under the plasma concentration-time curve (AUC) was 922.0 ng / ml, 816.0 ng / ml and 1586.7 ng / ml in the Examples, 10 times higher than that of Comparative Example 5, and the maximum blood concentration (Cmax) was 4 to 18 times higher than that of Comparative Example 5. The results are shown in Fig.

The pharmacokinetic parameters are summarized in Table 10 below and the area under the plasma concentration-time curve (AUC) is calculated in a trapezoidal fashion.

Test Example  4. Stability test

Example 2 The capsules were subjected to a long-term stability test (25 ± 2 ° C, 60 ± 5% RH) and a high temperature stability test (60 ± 2 ° C) by PTP packing. The results of the long-term stability test (25 ± 2 ° C., 60 ± 5% RH) are shown in the following Table 11, and the results of the high temperature stability test (60 ± 2 ° C) The results of Table 11 and 12 show no significant change in the content and no change with time.

Claims (20)

Methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4- pyrazin- -Aminoamino) -benzamide hydrochloride in a mixture of water and an organic solvent in a granulation liquid prepared by dissolving a surfactant in a mixture of water and an organic solvent, followed by granulation by a wet granulation method,
Wherein the organic solvent is ethanol, methanol, isopropanol, acetone or a mixture thereof,
The surfactant is at least one selected from the group consisting of castor oil, lecithin, and fatty acid macrogol glyceride,
The pharmaceutical composition further comprises an excipient, a disintegrant, and a glidant,
The excipient is at least one selected from the group consisting of cellulose, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, calcium hydrogenphosphate, light silicic anhydride, polyvinylpyrrolidone, and polyethylene glycol ,
Wherein the disintegrant is at least one selected from the group consisting of crosslinked polyvinylpyrrolidone, crospovidone and sodium starch glycolate,
Wherein the lubricant is at least one selected from the group consisting of magnesium stearate and stearic acid. The pharmaceutical composition according to claim 1, wherein the organic solvent in the granulating liquid is ethanol. The pharmaceutical composition according to claim 1, wherein the solubility of the granulating liquid is 0.2 mg / mL or more. The pharmaceutical composition according to claim 1, wherein the castor oil is macroroglycerol hydroxystearate, Cremophor RH 40 or Cremophor RH 60. The pharmaceutical composition according to claim 1, wherein the fatty acid macrogol glyceride is Gelucire 44/14. The pharmaceutical composition according to claim 1, wherein the surfactant is contained in a concentration of 0.1 to 30 parts by weight of the total weight of the pharmaceutical composition. delete delete The pharmaceutical composition according to claim 1, wherein the excipient is contained in an amount of 0.01 to 60 parts by weight based on 100 parts by weight of the active ingredient. delete delete The pharmaceutical composition according to claim 1, wherein the weight ratio of disintegrant to surfactant is at least 0.66. delete The method according to claim 1, further comprising at least one retentive substance selected from the group consisting of natural and animal oils, fatty acid triglycerides, hydrocarbons and polyethylene glycol 660 hydroxystearate upon granulation by the wet granulation method ≪ / RTI > The pharmaceutical composition according to claim 1, wherein the content of the active ingredient is 20 mg to 1000 mg. The pharmaceutical composition according to claim 1, wherein the active ingredient has an average particle size of 50 탆 or less. A formulation comprising the granular pharmaceutical composition according to any one of claims 1 to 6, 9, 12 and 14 to 16. 18. A formulation according to claim 17, wherein the formulation is selected from the group consisting of granules, powders, tablets, capsules and suspensions. Methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4- pyrazin- - < / RTI > amino) -benzamide hydrochloride in a mixture of water and an organic solvent into a granulation liquid in which the surfactant is dissolved; And
Comprising the steps of forming granules by a wet granulation process,
A method for preparing a granular pharmaceutical composition according to any one of claims 1 to 6, 9, 12 and 14 to 16,
Wherein the organic solvent is ethanol, methanol, isopropanol, acetone or a mixture thereof,
The surfactant is at least one selected from the group consisting of castor oil, lecithin, and fatty acid macrogol glyceride,
The pharmaceutical composition further comprises an excipient, a disintegrant, and a glidant,
The excipient is at least one selected from the group consisting of cellulose, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, calcium hydrogenphosphate, light silicic anhydride, polyvinylpyrrolidone, and polyethylene glycol ,
Wherein the disintegrant is at least one selected from the group consisting of crosslinked polyvinylpyrrolidone, crospovidone and sodium starch glycolate,
Wherein the lubricant is at least one selected from the group consisting of magnesium stearate and stearic acid. Methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4- pyrazin- - < / RTI > amino) -benzamide hydrochloride with excipients and disintegrants to form a powder mixture;
Mixing the powder mixture into a granulation liquid in which a surfactant is dissolved in a mixture of water and an organic solvent;
Forming granules by wet granulation; And
And screening the formed granules.
A method for preparing a granular pharmaceutical composition according to any one of claims 1 to 6, 9, 12 and 14 to 16,
Wherein the organic solvent is ethanol, methanol, isopropanol, acetone or a mixture thereof,
The surfactant is at least one selected from the group consisting of castor oil, lecithin, and fatty acid macrogol glyceride,
The excipient is at least one selected from the group consisting of cellulose, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, calcium hydrogenphosphate, light silicic anhydride, polyvinylpyrrolidone, and polyethylene glycol ,
Wherein the disintegrant is at least one selected from the group consisting of crosslinked polyvinylpyrrolidone, crospovidone and sodium starch glycolate,
Wherein said pharmaceutical composition further comprises at least one lubricant selected from the group consisting of magnesium stearate and stearic acid.

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