BR102012027409A2 - pharmaceutical composition and its method of preparation - Google Patents

Abstract

Summary pharmaceutical composition and method of preparation thereof disclosed a method of solubilizing an insoluble drug including 4-methyl-n- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- ( 4-Pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide, and a pharmaceutical composition including the compound.

Description

PHARMACEUTICAL COMPOSITION AND ITS PREPARATION METHOD

Background of the Invention 1. Field of the Invention The present invention relates to a pharmaceutical composition including 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- ( 4-Pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide, and their method of preparation. 2. Description of the Prior Art Imatinib Mesylate (gleevec, Korean Open Patent No. 1993-0021624), which has been conventionally used as a therapeutic agent for chronic medullary leukemia, shows an excellent effect on patients with chronic medullary leukemia, but has a problem that drug-resistant patients have recently experienced.

Generally speaking, the raw materials for conventional medullary leukemia therapeutic agents have extremely low solubility in water, and have a low release rate within the gastrointestinal tract due to low solubility. Thus, its bioabsorbability is low. Similarly, they have strong adhesive cohesion. Correspondingly, when formulated into tablets or capsules, they are adhered to a mixer, a perforator, a paint, etc. For this reason, they have a problem of low formulation processability. In order to show a preferable therapeutic effect by ameliorating the disadvantages of a therapeutic compound, the therapeutic compound must be in the form of an aqueous solution, and must necessarily have water solubility. A relatively insoluble compound shows an incomplete and irregular absorption rate and thus has a low therapeutic effect. Similarly, an insoluble drug sometimes shows an incomplete absorption rate. In order to efficiently increase the solubility of an extremely insoluble drug based on a chemical structure characteristic of the drug, a chemical modification method, such as production of more soluble derivatives (eg salt, ester or pro soluble drug), or a method of physical modification such as particle size adjustment (refinement, natural size), crystalline modification, solid dispersion and complexity (inclusion) / dissolution can be used. U.S. Patent No. 5,145,684 discloses a representative method of preparing a nanoparticle type of activator composition for an insoluble treatment drug. Similarly, U.S. Patent Nos. 5,518,187 and 5,862,999, and U.S. Patent Nos. 5718,388 and 5,510,118 disclose a method for preparing a nanoparticle type of the activator composition.

Summary of the Invention As described above, in the prior art, several problems with therapeutic leukemia compounds have been raised. In order to solve the aforementioned problems, the inventors of the present invention have researched the N-phenyl-2-pyrimidine amine derivative or salt thereof, which shows a higher efficacy of the drug on chronic medullary leukemia than immatinib mesylate. In order to solve the problems through repetitive research, the inventors found that 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4 -pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide is especially suitable for an oral pharmaceutical composition with improved bioavailability. Similarly, they found that when this material is formulated into granules using an organic solvent or a cosolvent (aqueous / organic solvent) or a surfactant containing cosolvent, it is possible to increase solubility and significantly improve the drug release rate of this material. .

Correspondingly, an object of the present invention is to provide an improved bioavailability oral pharmaceutical composition and method of preparation thereof.

In the present invention 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -hydrochloride Benzamide increased solubility and a significantly improved drug release rate. Thus, it is possible to obtain an oral pharmaceutical composition including the material, with increased bioavailability, and its method of preparation. Likewise, it is possible to improve the solubility of an insoluble drug and thus the pharmaceutical composition including the drug has stability, and a reduction in a static electrical characteristic and absorptivity, and is improved in a release rate and bioavailability.

Brief Description of the Drawings The above objects and other objects, features and advantages of the present invention will be more apparent from the following detailed description taken in conjunction with the accompanying drawings in which: FIG. 1 shows a graph illustrating a drug release rate (In Vitro) in the Examples and Comparative Examples according to the present invention; and FIG. 2 shows a graph illustrating a PK absorption rate of a drug in a beagle in the Examples and Comparative Examples according to the present invention. FIG. 3 is a graph illustrating the dissolution rate of a drug as measured in vitro for the examples according to the present invention.

Detailed Description Of Preferred Embodiments Hereinafter, a preferred embodiment of the present invention will be described with reference to the accompanying drawings. In the following description and drawings, the same reference numerals are used to designate the same or similar components, and then the repetition of the description about the same or similar components will be omitted. The present invention relates to a pharmaceutical composition including the N-phenyl-2-pyrimidine amine derivative or its salt, preferably 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl. phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide or its pharmaceutically acceptable salt, especially preferably 4-methyl-N- [3- (4-methylimidazole-1-yl) hydrochloride ) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide as a therapeutic compound, and a pharmaceutically acceptable excipient. The pharmaceutical composition may include the therapeutic compound in an amount of from 20 to 1000 mg. Likewise, the therapeutic compound may be included in an amount of 40 wt% or more, and preferably 40-60 wt%, with respect to the pharmaceutical composition. The N-phenyl-2-pyrimidine amine derivative or salt thereof preferably has an average particle size of about 50 µm or less, and preferably about 30 µm or less. The inventive therapeutic compound may be prepared as a granular mixture with an excipient, a disintegrating agent, a binder, a lubricant, etc., and may be formulated into oral administration forms such as granules, powders, tablets, capsules. rigid / flexible (by filling).

In the present invention, for purposes of improving solubility, an organic solvent, a cosolvent (aqueous / organic solvent), or a surfactant-containing cosolvent is preferably used. Improvement of solubility through the use of such material has been identified in the Examples below in the present invention.

In this specification, the term "therapeutic compound" denotes a therapeutically or pharmacologically active composition suitable especially for oral administration, and specifically denotes any active compound, material, drug, drug or ingredient suitable for administration to a mammal (e.g. eg human). Such a therapeutic compound has an effect of inhibiting the enzymatic activity of Bcr-Abl (oncoprotein) increased protein tyrosine kinase, and pCrkL phosphorylation, and is suitable for the preparation of a pharmaceutical composition for targeted cancer therapy in chronic spinal cord leukemia. and myeloproliferative disease. The inventive therapeutic compound is derived from N-phenyl-2-pyrimidine amine or its salt, preferably 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-Pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide or its pharmaceutically acceptable salt, and especially preferably 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-one trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide.

In the present invention, 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -hydrochloride Benzamide is an extremely insoluble material that is insoluble in an organic solvent, such as ethanol, methanol or a polar solvent, such as water, and has low solubility. Due to the low solubility, it is difficult to transfer the advantage of the therapeutic compound to a patient (in other words, the therapeutic compound has low bioabsorbability). Correspondingly, it is required to formulate the compound in a form with improved solubility and increased bioavailability. The present invention provides a pharmaceutical composition with increased bioavailability and method of preparation thereof.

Granules of the inventive therapeutic compound may be prepared using a pharmaceutically acceptable excipient. Further, in preparation, a surfactant, a disintegrating agent or a lubricant may be used alone or in combination. The compound may be formulated as a physical mixture, but it has been found that from the Examples below, a granular form is advantageous. For example, polyvinyl pyrrolidone, macrogolglycerol hydroxystearate or lecithin may be wet granulated with 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3-4-pyrazine hydrochloride particles -2-yl-pyrimidin-2-ylamino) -benzamide to prepare the granules.

In the present invention a pharmaceutically acceptable surfactant may be at least one type of material selected from the group consisting of surfactants such as castor oil (e.g. macroglycerol hydroxystearate, cremofor RH 40, cremofor RH 60), lecithin (Egg), polyoxyethylene polyoxypropylene copolymer, polyoxyethylene sorbitans or mixtures thereof, sorbitol ester and polyoxyethylene sorbitan fatty acid ester (e.g. polysorbate 80), sodium lauryl sulfate, glyceryl fatty acid ester, macrogolglyceride fatty acid (e.g. Gelucire 44/14), but the present invention is not limited thereto. Especially macrogolglycerol hydroxystearate is useful. The surfactant may preferably be used in an amount of from 1 to 50 parts by weight, and more preferably from 5 to 20 parts by weight, with 100 parts by weight of the inventive active ingredient. Similarly, the surfactant may be included at a concentration of 0.1 part by weight to 30 parts by weight with respect to the total weight of the pharmaceutical composition.

In the present invention, an excipient may be at least one type of material selected from the group consisting of cellulose or its derivative (such as myocrystalline cellulose), hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose, lactose hydrate and anhydrate, calcium hydrogen, light silicic acid anhydride, starch, mannitol, polyvinyl pyrrolidone, polyethylene glycol, eudragit, but the present invention is not limited thereto. The excipient may be used in an amount from 0.01 to 60 parts by weight, and preferably from 1 to 50 parts by weight, with respect to 100 parts by weight of the inventive active ingredient.

In the present invention, a pharmaceutically acceptable disintegrating agent may be at least one type of material selected from the group consisting of cross-linked polyvinyl pyrrolidone or crospovidone, croscarmellose sodium, sodium starch glycolate, starch and alginate, but the present invention does not. is limited to that. The disintegrating agent may be used in an amount of about 1 to 40 wt% with respect to the pharmaceutical composition.

In the present invention, a pharmaceutically acceptable lubricant may be at least one type of material selected from the group consisting of magnesium stearate, talc, light silicic acid anhydride, glyceryl behenate, stearic acid and sodium stearyl fumarate. The lubricant may be used in an amount from 0 to 10 wt%, and preferably from 0.5 to 2 wt% with respect to the composition.

In the Examples according to the present invention, for the preparation of a mixture, at least one type of material may be selected from the group described above. In general, a wet granulation process includes a mixing step, a coupling step using a liquid, a drying step and an adjustment step. In the wet process, first, a step of mixing a therapeutic compound with at least one pharmaceutically acceptable excipient may be conducted using the appropriate pharmaceutical facilities. For example, a high speed mixer, a fluid bed granulator, a spray dryer or a freeze dryer may be used to form a powder mixture, but the present invention is not limited to such granulation facilities. In wet granulation as a liquid solvent water as a polar solvent and organic solvents such as ethanol, methanol, isopropanol and acetone alone or in combination may be used and the organic solvent may be used alone or in combination. . The wet granulate mixture may be dried in pharmaceutical granulation facilities or suitable drying facilities. In the drying step, the granules are dried at an LOD of about 3 wt% or less, for example 2 wt% or less. After the drying step, an appropriate granule size can be obtained through a sieve. Such granular mixture may be formulated into tablets or formulated into capsules by being loaded into a capsule. Capsule Examples include a rigid gelatin capsule, and a rigid HPMC capsule. Capsule size ranges from # 00 to # 5, but the present invention is not limited to that. The therapeutic pharmaceutical composition may be included in an amount of from 20 mg to 1000 mg within a capsule. Specifically, a capsule may include a therapeutic pharmaceutical composition in an amount of from 20 mg to 800 mg. For example, more specifically, a capsule may include a therapeutic pharmaceutical composition in an amount of 50 mg, 100 mg or 200 mg. Depending on the amount of additives used, the mixture of the therapeutic compound and the excipient may have flowability and uniformity of formulation such that it can be adequately filled into a capsule. In order to improve the dissolution rate of the therapeutic compound, and to ensure a high release rate of the therapeutic compound, a ratio of a disintegrating agent to a solubilizing agent (i.e. a surfactant) is important. The ratio of disintegrating agent / solubilizing agent should be 0.66 or more (eg crospovidone / macrogolglycerol hydroxystearate, 0.66 ~ 0.80).

Similarly, in the present invention, in a preferred pharmaceutical composition prepared by a spray drying technology, the content of an excipient, a surfactant or an oily material may vary according to the characteristic of a composition obtained. It is important to adjust the amounts of the excipient, surfactant, oily material and inventive active materials to adjust the concentration. When the concentration is low, the preparation efficiency is reduced, and it is difficult to prepare a particulate composition. When the concentration is high, the viscosity is increased, and a precipitate is produced at a very high speed during dispersion. This way, a mouthpiece can be facially blocked. Preferably, within the composition, an excipient excluding a solvent has a concentration of 0.1 to 20 parts by weight, the surfactant has a concentration of 0.1 to 50 parts by weight, and the oily material has a concentration of 0.1 to 5 parts by weight.

In the present invention, for example, the excipient may be at least one type of material selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene glycol and eudragit. It is preferably used in an amount from 0.1 to 20 parts by weight, and more preferably from 1 to 10 parts by weight, with respect to 100 parts by weight of 4-methyl-N- [3- (4-methylimidazole hydrochloride]. -1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide.

In the present invention the surfactant may be at least one type of material selected from the group consisting of castor oil (eg macrogolglycerol hydroxystearate, chromophore RH 40, cremofor RH 60), lecithin (Egg), polyoxyethylene copolymer polyoxypropylene, polyoxyethylene sorbitans or mixtures thereof, sorbitol ester and polyoxyethylene sorbitan fatty acid ester (e.g. polysorbate 80), sodium lauryl sulfate, glyceryl fatty acid ester, eg fatty acid maerogolglyceride (e.g. Gelucire 44/14). The surfactant is preferably used in an amount of 1 to 60 parts by weight, and more preferably 5 to 50 parts by weight, with respect to 100 parts by weight of a N-phenyl-2-pyrimidine amine derivative or salt thereof. .

In the present invention, the oily material may be at least one type of material selected from the group consisting of natural and animal oils (e.g. soybean oil, fish oil, etc.), fatty acid triglycerides, hydrocarbons. , polyethylene glycol 660 hydroxystearate and the like. It is preferably used in an amount from 0.1 to 1 part by weight with respect to 100 parts by weight of an N-phenyl-2-pyrimidine amine derivative or salt thereof. The inventive pharmaceutical composition may be prepared by preparation methods such as wet granulation / dry granulation / melt granulation. In other words, the inventive composition may be prepared by a wet granulation preparation method, a dry granulation preparation method or a melt granulation preparation method (hot melt extrusion method). In the wet granulation preparation method, a composition is obtained by suspending, drying and dispersing from a mixing liquid including a surfactant, an excipient or mixture thereof, an oily material, an active material (an N-phenyl derivative). Pyrimidine amine or its salt), ethanol and pure water. In the method of preparing dry granulation, the composition may be prepared by mixing a surfactant, an excipient or mixture thereof, an oily material, an active material (an N-phenyl-2-pyrimidine amine derivative or salt thereof), by adding a mixture liquid of ethanol and pure water in an amount of 2% or more with respect to the mixture, and compressive granulation of the resulting mixture by cylinder compaction. In the melt granulation preparation method, the composition is prepared by mixing the derivative mixture with a mixture liquid of ethanol and pure water in an amount of 2% or more relative to the mixture.

For example, in order to obtain the suspension liquid, a surfactant, an excipient or mixture thereof, and an oily material are added with a mixture liquid of ethanol and pure water, followed by stirring, and then the resulting mixture is subjected. to dissolution, suspension or soaking, and lightly added to 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl) hydrochloride pyrimidin-2-ylamino) benzamide.

In preparing the pharmaceutical composition, the suspension liquid may be dried by a drying method generally used in the field of pharmacology, such as spray drying, vacuum drying, freeze drying or it may be heat dried by pressure drying. in cylinder compaction or heat drying in the melt granulation preparation method. A carrier that may be used in the drying step is a pharmaceutically acceptable material, and may include an excipient (such as microcrystalline cellulose, calcium hydrogen phosphate, light silicic acid anhydride), a disintegrating agent (such as crospovidone or its derivative, povidones, sodium starch glycolate, croscarmellose, low substituted hydroxyl cellulose), a lubricant (such as magnesium stearate, stearic acid) and a surfactant (such as sodium lauryl sulfate). The pharmaceutical composition including 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide or pharmaceutically acceptable salt thereof, especially 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-hydrochloride) ylamino) benzamide, together with an excipient or a surfactant, an oily material or a mixture thereof may be formulated into various forms. It may be formulated in a solid preparation such as granules, capsules, tablets, powders, or may be formulated in a suspension preparation. Preferably, it may be formulated into tablets or capsules.

For example, the granulated pharmaceutical composition by the granulation method, including 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazine-2-hydrochloride) (pyrimidine-2-ylamino) benzamide, may be directly mixed with a pharmaceutically acceptable carrier. Then, the mixture may be filled into a capsule, may be compressed into a tablet by a tableting machine, or may be film-coated or enteric-coated for appearance, taste, safety and convenience.

In the present invention, the pharmaceutically acceptable carrier should be selected such that the stability of the therapeutic compound can be guaranteed. As noted in Table 1 below, when a homogeneous mixture of a therapeutic compound (API) and a carrier were stored at 40 ° C, 75% RH (6 weeks}, discoloration, reduction of therapeutic drug content or production. related substances was not observed in all carriers except lactose In one case of 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-Pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide, stability is influenced by moisture.In a case of a carrier having high moisture retention by itself such as lactose, some problems such as , discoloration, and content reduction may occur during a mixing process.

[Table 1] Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples. However, the Examples and Comparative Examples are illustrative only, and do not limit the present invention.

Example Example 1 4-Methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -hydrochloride benzamide (A) and imatinib mesylate (B), solubility was tested.

Example 1-1, 1-2: In a 100 mL beaker, castor oil 60 (18 g) was charged, and water (22.5 mL) and ethanol (9 mL) were added thereto, followed by stirring. for 1 hour. After the materials were dissolved, A and B each was added in an amount of 0.5 g to the resulting mixture, followed by sufficient stirring for about 2 hours. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting product was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-5, 1-6: In a 100 mL beaker, castor oil 60 (18 g) was charged, and water (22.5 mL) and acetone (9 mL) were added thereto, followed by stirring. for 1 hour. After the materials were dissolved, A and B each was added in an amount of 0.5 g to the resulting mixture, followed by sufficient stirring for about 2 hours. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting product was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-9, 1-10: In a 100 mL beaker, castor oil 60 (18 g) was charged, and water (22.5 mL) and IPA (isopropyl alcohol, 9 mL) were added thereto, followed by stirring for 1 hour. After the materials were dissolved, A and B each was added in an amount of 0.5 g to the resulting mixture, followed by sufficient stirring for about 2 hours. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting product was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-3, 1-4: In a 100 mL beaker, water (22.5 mL) and ethanol (9 mL) were charged, followed by stirring for 10 minutes. The resulting mixture was added with A and B each in an amount of 0.5 g, followed by sufficient stirring for about 2 hours. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting product was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-7, 1-8: In a 100 mL beaker, water (22.5 mL) and acetone (9 mL) were charged, followed by stirring for 10 minutes. The resulting mixture was added with A and B each in an amount of 0.5 g, followed by sufficient stirring for about 2 hours. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting product was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-11, 1-12: In a 100 mL beaker, water (22.5 mL) and IPA (isopropyl alcohol, 9 mL) were charged, followed by stirring for 10 minutes. The resulting mixture was added with A and B each in an amount of 0.5 g, followed by sufficient stirring for about 2 hours. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting product was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-13, 1-14: In a 100 mL beaker, water (31.5 mL) was charged, and A and B each in an amount of 0.5 g were added thereto, followed by sufficient stirring for about of 2 hours. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting product was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-15, 1-16: In a 100 mL beaker, A and B each in an amount of 0.5 g was charged. Then ethanol (5 mL each time) was added there while dissolved in the mixture. In other words, ethanol was added there to a total amount of 31.5 mL. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting solution was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-17, 1-18: In a 100 mL beaker, A and B each in an amount of 0.5 g were charged. Then acetone (5 mL each time) was added there while dissolved in the mixture. In other words, acetone was added there to a total amount of 31.5 mL. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting solution was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test.

Example 1-19, 1-20: In a 100 mL beaker, A and B each in an amount of 0.5 g were charged. Then, IPA (isopropyl alcohol, 5 mL each time) was added there while dissolved in the mixture. In other words, IPA was added there to a total amount of 31.5 mL. Using a 0.45 æm GHP filter and syringe, 5 mL of the resulting solution was filtered. Then 1 mL of the product was collected and loaded into a 100 mL flask, and a dissolution liquid (DMSO: MeOH = 3: 7) was added there to a reference point. This liquid was used as a test. 1) Analysis on the solubility of 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl) -3- (4-pyrazin-2-yl-pyrimidin-2-hydrochloride) (A) Preparation of a standard solution: A reference standard (106.8 mg) of A was accurately measured and loaded into a 50 mL vial, and DMSO was added there to a reference point. 5 ml of this liquid was collected and loaded into a 50 ml flask, and a diluent (dimethyl sulfoxide: methanol = 30: 70) was added there to a reference point. 10 mL of this liquid was refilled into a 100 mL vial, and a diluent added thereto to a reference point. This liquid was prepared at concentrations of 5, 10, 15 and 20 ppm, and its calibration curve was analyzed. Using a linear equation of the calibration curve, the dissolution amount of a test sample was calculated. - Analysis Condition - Column: Capsellpak MG II, Cl8 (4.6 χ 150mm, 5μιτϊ) or similar column column temperature: 35 ° C mobile phase: ammonium acetate buffered solution (pH 4.0): methanol = 25: 75 detector: UV 270 nm flow rate: 1.0 mL / min injection amount: 10 µL buffered solution preparation method: acetic acid (100) (1.2 mL) and ammonium acetate (0, 25 g) were charged and water was added there to make a total volume of 1 L. Using 0.2 mol / l hydrochloric acid and 0.2 mol / l sodium hydroxide, the pH was adjusted to 4.0. 2) Solubility Analysis of Imatinib Mesylate (B) Preparation of a Standard Solution: A reference standard (20 mg) of A was accurately measured and loaded into a 100 mL vial to a reference point. 5 ml of this liquid was collected and loaded into a 50 ml flask, and a solvent (methanol: 0.1M hydrochloric acid = 6: 4) was added there to a reference point. This liquid was prepared at concentrations of 5, 10, 15 and 20 ppm, and its calibration curve was analyzed. Using a linear equation of the calibration curve, the dissolution amount of an imatinib test sample was calculated. - Condition of Analysis - ion pair reagent: 1-octanesulfonic acid sodium salt monohydrate (7.5 g) was dissolved in 800 mL of water. The resulting solution was acidified with 10% o-phosphoric acid to pH 2.5, and then 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 pm (Water-s), length 150 mm, 3.9 mm internal diameter or similar column column temperature: 25 ° C detector: ÜV 268 nm flow rate: 1.2 ml / min injection amount: 10 μΐ run time: 30 minutes [Table 2] As noted in Table 2 above it can be found that 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidine) hydrochloride -2-ylamino) -benzamide (A) is more insoluble in various types of aqueous / organic solvent than imatinib mesylate (B).

Example 2 According to the composition observed in Table 3 below, the inventive pharmaceutical composition containing 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4 -pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide was formulated.

[Table 3] Using a high-speed mixer, 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl) hydrochloride -pyrimidin-2-ylamino) -benzamide, microcrystalline cellulose, calcium hydrogen phosphate hydrate, light silicic acid anhydride and crospovidone were mixed to form a powder mixture. Additionally, in an ethanol: water mixing liquid, macrogolglycerol hydroxystearate was dissolved to provide a granulating liquid. The liquid was mixed with the powder mixture prepared within a high speed mixer to wet granulate the powder mixture. Then, the powder mixture was dried under a suitable condition for a suitable time using a dryer, and then formulated into granules. The dried granules were sieved to an ideal granule size by sorting, and then further added with crospovidone and magnesium stearate to provide a final granular mixture. This granulated mixture was filled into a rigid capsule.

In the same manner as described in Example 2, the inventive composition was compressed by mixing, granulating, drying, lubricating, tableting and film coating steps.

According to the composition observed in Table 4 below, the inventive pharmaceutical composition was formulated, wherein the surfactant used in Example 2 was excluded.

Similarly as described in Example 2, the inventive composition was formulated as a granular mixture, and filled into a capsule, in which macrogolglycerol hydroxystearate as a surfactant was excluded.

Comparative Example 1 According to the same composition as in Example 4, seen in Table 5 below, the ingredients were not granulated but physically mixed to provide a powder mixture. Then, the role of a surfactant and the release rate according to the preparation methods were comparatively analyzed.

According to the same composition as in Table 4, the ingredients were simply physically mixed and the resulting powder was filled into a capsule.

[Table 5] Comparative Example 2 According to the same composition as in Example 2, macrogolglycerol hydroxystearate was physically mixed and the resulting mixture was filled into a capsule.

Comparative Example 3 213.6 mg 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) hydrochloride ) -benzamide were formulated in a capsule form when loaded into an empty capsule.

Comparative Example 4 213.6 mg of 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) hydrochloride ) -benzamide and macrogolglycerol hydroxystearate were prepared in a physical mixture, and filled into a capsule.

Test Example 1. Dissolution Profile The capsules of Example 2 ~ 4, and Comparative Example 1 ~ 4 were tested according to method 2 (paddle method) within the Korean Pharmacopoeia release testing methods, where the temperature The release pressure was set to 37 ° C by a sink. The release test was conducted using a dissoulution medium (pH 1.2) in an amount of 900 mL (added with 1% SLS) at a paddle rate of 100 rpm. The amount of a dissolved drug material was measured by HPLC. Over time, the release rate (%) of 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazine-2) hydrochloride -yl-pyrimidin-2-ylamino) -benzamide was shown and observed in FIG. 1 and Table 6.

[Table 6] As shown in FIG. 1 and Table 6, when the capsules of Example 2 and Example 4 were compared to each other, it can be found that the addition of a nonionic surfactant increased the release rate. Similarly, when the capsules of Example 2 and Comparative Example 4 were compared to each other, it can be found that the granulation method significantly increased the release rate. Physical mixtures of Comparative Examples 1, 2 and 4 showed a low dissolution rate as compared to the capsule of Comparative Example 3.

Example 5. Preparation of a pharmaceutical composition by spray-drying technology 20 g macrogolglycerol hydroxystearate, and 27 g polyvinyl pyrrolidone were dissolved in 1870 ml of a mixed liquid of ethanol and pure water (1: 2.5). The resulting product was stirred by a mechanical stirrer while 100 g of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- {4-pyrazine-2-hydrochloride 1-pyrimidin-2-ylamino) benzamide was added thereto and suspended. The resulting product was stirred for 3 hours at a rotation speed of 300 rpm or more and homogenized at a pressure of 10,000 to 15,000 by a microfluidizer. Then, using a spray dryer, a pharmaceutical composition was prepared. The spray drying process was conducted with an inlet air temperature of 100-120 ° C and an outlet air temperature of 70 to 90 ° C.

According to the ingredients and contents noted in Table 7 below, a composition was prepared in the same process as described in Example 5. The mixed liquid of ethanol and pure water was in an amount of 10 ml relative to 1 g of the sum of all. the ingredients used.

[Table 7] Example 15. Preparation of a pharmaceutical composition by fluid bed granulation technology 30 g macrogolglycerol hydroxystearate were dissolved in 234 ml of a mixed liquid of ethanol and pure water. The resulting product was stirred by a mechanical stirrer while 100 g of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazine-2-hydrochloride). (pyrimidin-2-ylamino) -benzamide were added thereto and suspended. The resulting product was stirred for 3 hours at a rotation speed of 300 rpm or more and homogenized. Then the carriers such as microcrystalline cellulose (20 g), crospovidone (15 g), light silicic acid anhydride (5 g) and calcium hydrogen phosphate (25 g) were sufficiently mixed. fluid bed granulator and fluidized while the suspension liquid was spray dried to prepare a granule type of the pharmaceutical composition.

According to the ingredients and contents noted in Table 8 below, granules containing a pharmaceutical composition were prepared in the same process as described in Example 15. The mixed liquid of ethanol and pure water was in an amount of 1.2 ml relative to 1 g of the sum of all ingredients used.

[Table 8] m. . . 200 222 210 200 221 190 181 205 | Total () () 1.5 1.5 1.0 1.0 1.0 1.0 1.0 1.0 Example 24. Preparation of a capsule 50 g of the pharmaceutical composition of Example 14 were mixed with 4% microcrystalline cellulose, 6% crospovidone, 6% calcium hydrogen phosphate and 1.5% magnesium stearate to prepare a capsule containing 100 mg of 4-methyl-N-hydrochloride. [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide.

Example 25. Preparation of the capsule 50 g of the pharmaceutical composition of Example 13 were mixed with 4% microcrystalline cellulose, 4.2% crospovidone, 6% calcium hydrogen phosphate and 1.5% magnesium stearate to prepare a capsule containing 100 mg of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-hydrochloride) ylamino) benzamide.

Example 26. Preparation of the capsule 100 g of the granules containing the pharmaceutical composition of Example 15 were mixed with 5% crospovidone and 1.5% magnesium stearate to prepare a capsule containing 100 mg 4-methyl-N hydrochloride. - [3- (4-Methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- {4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide.

Example 27. Preparation of the capsule 100 g of granules containing the pharmaceutical composition of Example 21 were mixed with 5% crospovidone and 1.5% magnesium stearate to prepare a capsule containing 100 mg of 4-methyl-N hydrochloride. - [3- (4-Methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide.

Example 28. Preparation of the capsule 50 g of the pharmaceutical composition of Example 10 were mixed with 4% microcrystaline cellulose, 4.2% crospovidone, 6% calcium hydrogen phosphate and 1.5% magnesium stearate to prepare a capsule containing 100 mg of 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-hydrochloride) ylamino) benzamide.

Test Example 2. Dissolution Test For the purpose of determining the improvement of solubility of a pharmaceutical composition including 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -chloride. 3- (4-Pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide or its derivative, a drug release test was conducted in a capsule prepared by mixing the pharmaceutical composition of Example 5 with microcrystalline cellulose (20%). , sodium starch glycolate (6%), light silicic acid anhydride (1%) and magnesium stearate (15%), a capsule prepared by dissolving the granules containing the pharmaceutical composition of each of Example 16 and Example 21. with a lubricant, and fill the mixture into the capsule, and one capsule of each of Examples 24 to 28.

In Comparative Example 5, a capsule was prepared by mixing 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl) hydrochloride. -pyrimidin-2-ylamino) -benzamide (67.5%), with microcrystalline cellulose (20%), crospovidone (10%), light silicic acid anhydride (1%) and magnesium stearate (1.5%). The dissolution test was conducted under the condition according to a Korean Pharmacopoeia dissolution test method (method 2) using 900 ml of an average dissoulution. After dissolution testing for 45 minutes, HPLC analysis was conducted. The results are observed in Table 9.

[Table 9] As noted in Table above, it can be found that the drug release rate of the inventive pharmaceutical composition was significantly improved due to improved solubility.

Test Example 3. A pharmacokinetic test Male beagles (about 10 kg) were selected and weighed, and were checked for any injuries. Before administering a test material, they fasted for 16 hours. Each group included 3 beagles. The capsule of Comparative Example 5, which is obtained by mixing 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazine-2-hydrochloride). (pyrimidin-2-ylamino) -benzamide, with microcrystalline cellulose, crospovidone, light silicic acid anhydride and magnesium stearate, and filling the mixture into the capsule was used. The drugs of Example 24, Example 27, Example 28 and Example 2 were orally administered, and analyzed by LC-MS / MS. As a result, Comparative Example 5 showed the area under plasma concentration versus time curve (AÜC) of 137.4 ng / ml, while other Examples showed AUC of 922.0 ng / ml, 816.0 ng / ml and 1586.7 ng / ml. In other words, as compared to Comparative Example 5, the Examples showed an AUC of 5 to 10 times or higher. Likewise, it was found that the Examples showed a 4 to 18-fold higher maximum blood concentration (Cmax) than Comparative Example 5. The results are seen in FIG. 2.

Pharmacokinetic parameters are observed in Table 10 below, and the area under plasma concentration versus time curve (AUC) was calculated by a trapezoidal method.

[Table 10] Test Example 4. A Stability Test The capsule of Example 2 was packaged in a PTP package, and subjected to a long term stability test (25 ± 2 ° C, 60 ± 5% RH) and a High temperature stability test (60 ± 2 ° C). Long term stability test results (25 ± 2 ° C, 60 ± 5% RH) are shown in Table 11 below, and high temperature stability test results (60 ± 2 ° C) are shown in Table 12 below. From the results of Tables 11 and 12, a significant change in content and a change over time were not observed.

[Table 11] [Table 12] Example 29 According to the following composition noted in Table 13 below, a pharmaceutical composition without surfactant was formulated as in Example 4.

This composition is a granular mixture which was prepared in the same manner as described in Example 2, but from which surfactant (macrogolglycerolhydroxystearate) was excluded. This was filled in capsules.

Example 30 A granular blend surfactant excluding (macrogolglycerolhydroxystearate) was prepared in the same manner as described in Example 29. This was filled into capsules.

Example 31 A granular blend surfactant excluding (macrogolglycerolhydroxystearate) was prepared in the same manner as described in Example 29. This was filled into capsules.

Test Example 5. Dissolution Profile Capsules filled with the granular mixtures prepared in Examples 29-31 were tested using a sink at a dissolution temperature of 37 ° C according to method 2 (paddle method), among the methods of the Korean Pharmacopoeia dissolution test. 900 mL pH 1.2 buffer solution (added with 1% SLS) was used as dissolution medium, and dissolution test was performed at a paddle speed of 100 rpm. The amount of a dissolved drug material was measured by HPLC. The dissolution rates (%) of hydrochloride hydrochloride, dihydrochloride, methanesulfonate and, as a function of time are shown in FIG. 3 and Table 14.

Table 14__________________________________________________________ As shown in Table 14 and FIG. 3, Example 29, using hydrochloride hydrate as an addition salt showed a significantly high dissolution rate compared to Examples 30 and 31. In addition, compared between Example 4 and Example 29, the use of hydrochloride as a addition salt resulted in a more excellent dissolution rate.

While a preferred embodiment of the present invention has been described for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible without departing from the scope and spirit of the invention as disclosed in the appended claims.

CLAIM

Claims (19)

1. A pharmaceutical composition comprising 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2) hydrochloride. (amino) benzamide as an active ingredient and a pharmaceutically acceptable excipient. The pharmaceutical composition as claimed in claim 1, characterized in that the pharmaceutical composition is formulated in granules, powders, tablets, capsules or a suspension liquid while comprising the active ingredient in an amount of 20 mg to 1000 mg. The pharmaceutical composition as claimed in claim 1, characterized in that the active ingredient has an average particle size of about 50 μηη or less. The pharmaceutical composition as claimed in claim 1, characterized in that the excipient is at least one type of material selected from the group consisting of cellulose, its derivative comprising microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, lactose hydrate, lactose anhydrate, calcium hydrogen phosphate, light silicic acid anhydride, starch, mannitol, polyvinyl pyrrolidone, polyethylene glycol and eudragit. The pharmaceutical composition as claimed in claim 4, characterized in that the excipient is used in an amount of 0.01 to 60 parts by weight with respect to 100 parts by weight of the active ingredient. The pharmaceutical composition as claimed in claim 1, further comprising a surfactant, a disintegrating agent, a lubricant or a mixture thereof. The pharmaceutical composition as claimed in claim 6, characterized in that the surfactant is at least one type of material selected from the group consisting of castor oil (e.g. macroglycerol hydroxystearate, cremofor RH 40 or cremofor RH 60), lecithin (Egg), polyoxyethylene polyoxypropylene copolymer, polyoxyethylene sorbitans, a mixture of polyoxyethylene polyoxypropylene and polyoxyethylene sorbitan copolymer, sorbitol ester, polyoxyethylene sorbitan fatty acid ester (e.g. polysorbate 80 sulfate, sodium lauryl sulfate 80), sodium lauryl sulfate 80 glyceryl fatty acid and fatty acid macrogolglyceride (eg Gelucire 44/14). Pharmaceutical composition as claimed in claim 7, characterized in that the surfactant is included in a concentration of 0.1 part by weight to 30 parts by weight with respect to the total weight of the composition. The pharmaceutical composition as claimed in claim 6, characterized in that the disintegrating agent is at least one type of material selected from the group consisting of cross-linked polyvinyl pyrrolidone, crospovidone, croscarmellose sodium, sodium starch glycolate, starch and alginate. . The pharmaceutical composition as claimed in claim 6, characterized in that the surfactant disintegrating agent ratio is 0.66 or more. 11. The pharmaceutical composition containing 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -acetamide benzamide or its pharmaceutically acceptable salt as an active ingredient, the pharmaceutical composition comprising: a. a disintegrating agent selected from the group consisting of crospovidone, croscarmellose sodium, alginate and mixture thereof; B. an excipient selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, light silicic acid anhydride, lactose, starch, mannitol and a mixture thereof; and c. a lubricant selected from the group consisting of magnesium stearate, talc, stearic acid, sodium stearyl fumarate and a mixture thereof. A method for preparing a pharmaceutical composition comprising 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidine (2-ylamino) benzamide or a pharmaceutically acceptable salt thereof, the method comprising a wet / dry granulation step using a surfactant, an organic solvent or a cosolvent (aqueous / organic solvent) as a solubilizing agent of an active ingredient of the pharmaceutical composition. . The method as claimed in claim 12, further comprising the step of forming a granulation liquid when using the surfactant with a pharmaceutically acceptable liquid. The method as claimed in claim 12, characterized in that, among the granulating liquids, the cosolvent comprises water and organic solvents such as ethanol, methanol, isopropanol, acetone, alone or in combination. The method as claimed in claim 14, characterized in that a granulation liquid having a solubility of 0.2mg / ml or more is used. The method as claimed in any one of claims 12 to 15, characterized in that the active ingredient is 4-methyl-N- [3- (4-methylimidazole-1-yl) -5-trifluoromethylphenyl] -hydrochloride. 3- (4-Pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide. 17. A method for preparing a pharmaceutical composition, the method comprising the steps of: forming a powder mixture using 4-methyl-N- [3- (4-methylimidazole-1-yl) -5- trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzamide and at least one type of pharmaceutically acceptable excipient; forming the wet granules by combining the powder mixture with a surfactant, an organic solvent or a cosolvent (aqueous / organic solvent) as a granulation liquid; forming the granules by drying the wet granules; and perform a screening process. The method as claimed in claim 17, characterized in that at the stage of forming the granules, an oily material is further included. 19. Composition comprising 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethylphenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-hydrochloride) ylamino) benzamide.