Apixaban-containing particle, pharmaceutical composition containing the same, and method for producing them

Abstract

To provide an apixaban-containing particle that achieves improved amorphous stability of apixaban using simplified means or a pharmaceutical composition containing the same, or methods for producing an apixaban-containing particle having improved amorphous stability of apixaban or a pharmaceutical composition containing the same.SOLUTION: An apixaban-containing particle comprises amorphous apixaban, and porous silicate as a carrier. The apixaban-containing particle may comprise the porous silicate of 100 wt.% or more relative to the weight of the amorphous apixaban as a carrier.SELECTED DRAWING: None

Description

[Technical Field]

[0001] One embodiment of the present invention relates to apixaban-containing particles, or to a pharmaceutical composition comprising apixaban-containing particles, or to a method for producing apixaban-containing particles, or to a method for producing a pharmaceutical composition comprising apixaban-containing particles. [Background technology]

[0002] Apixaban (1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) is an oral anticoagulant that reversibly inhibits blood coagulation activation factor X (FXa) and is effective in the treatment of thromboembolic diseases (Patent Document 1). Because apixaban is a poorly soluble drug, Patent Document 1 improves the solubility of apixaban by using a solid amorphous dispersion containing amorphous apixaban and a polymer selected from hydroxypropylmethylcellulose acetate succinate or hydroxypropylmethylcellulose. However, Patent Document 1 addresses the issue of controlled release of apixaban from an apixaban-containing formulation, and does not describe the stability of amorphous apixaban, nor has it been examined at all whether apixaban is maintained in an amorphous state in the formulation.

[0003] According to the description in Patent Document 1, apixaban is a poorly soluble drug, and the use of an apixaban solid dispersion is expected to improve the solubility of apixaban. However, as a result of studies by the present inventors, it has become clear that apixaban has low stability in an amorphous form and is prone to crystallization even in a solid dispersion.

[0004] Furthermore, Patent Document 1 discloses a method for producing a solid amorphous dispersion of apixaban, but it indicates that the production process requires a special machine called a spray dryer and takes a long time. The longer the production time, the smaller the production quantity. Therefore, there is a need for the development of a pharmaceutical composition with improved amorphous stability of apixaban that can be produced by a simpler production method other than solid dispersion.

[0005] For example, the method of adsorbing a drug substance onto a porous body can be produced in a shorter time using commonly used machines such as a high-speed agitating granulator, and is therefore easier than a solid dispersion. When adsorbing a drug substance onto a porous body, the solvent remains in the adsorbate, so purified water or the like is usually used as the solvent. However, since apixaban is a poorly soluble drug, a large amount of solvent is required to dissolve it in such a solvent, exceeding the adsorption limit of the porous body. For this reason, the porous body adsorption method has not been applied to apixaban to date. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 5775071 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to solve the above problems and provides apixaban-containing particles or pharmaceutical compositions containing the same in which the amorphous stability of apixaban has been improved using a simple means other than a solid dispersion. Alternatively, in one embodiment, the present invention aims to provide a method for producing apixaban-containing particles or pharmaceutical compositions containing the same in which the amorphous stability of apixaban has been improved. [Means for solving the problem]

[0008] According to one embodiment of the present invention, there is provided an apixaban-containing particle comprising amorphous apixaban and a porous silicate as a carrier.

[0009] The carrier may contain 100% by weight or more of porous silicate relative to the weight of amorphous apixaban.

[0010] The porous silicate may be one or more porous silicates selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.

[0011] According to one embodiment of the present invention, there is provided an apixaban-containing pharmaceutical composition comprising any of the apixaban-containing particles described above and one or more pharmaceutically acceptable additives.

[0012] According to one embodiment of the present invention, there is provided a method for producing apixaban-containing particles, which comprises preparing a solution of apixaban dissolved in a solvent containing acetic acid, adding the solution to a porous silicate, and removing the solvent to obtain particles containing amorphous apixaban and the porous silicate as a carrier.

[0013] Particles containing amorphous apixaban and a porous silicate carrier may be prepared so that the porous silicate carrier accounts for 100% by weight or more of the weight of amorphous apixaban contained in the apixaban-containing particles.

[0014] The porous silicate may be one or more porous silicates selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.

[0015] According to one embodiment of the present invention, there is provided a method for producing an apixaban-containing pharmaceutical composition, which comprises mixing apixaban-containing particles produced by any of the above-described methods for producing apixaban-containing particles with one or more pharmaceutically acceptable additives, followed by tableting. [Effects of the Invention]

[0016] According to one embodiment of the present invention, there is provided apixaban-containing particles in which the amorphous stability of apixaban is improved using a simpler means, or a pharmaceutical composition containing the same, or a method for producing apixaban-containing particles in which the amorphous stability of apixaban is improved, or a pharmaceutical composition containing the same. DETAILED DESCRIPTION OF THE INVENTION

[0017] The apixaban-containing particles and pharmaceutical compositions containing the same according to the present invention are described in detail below. However, the apixaban-containing particles and pharmaceutical compositions containing the same according to the present invention should not be construed as being limited to the following embodiments and examples.

[0018] The apixaban-containing particles according to the present invention comprise amorphous apixaban and a porous silicate as a carrier. As used herein, the term "porous silicate" refers to silicate particles having numerous pores formed on the surface and capable of adsorption. In one embodiment, the porous silicate is a pharmaceutically acceptable porous silicate selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.

[0019] In one embodiment, the apixaban-containing particles are particles in which amorphous apixaban is adsorbed on the surface and / or inside the pores of a porous silicate. In this embodiment, the apixaban-containing particles are adsorbents in which amorphous apixaban is adsorbed on the surface and / or inside the pores of a porous silicate, thereby allowing apixaban to remain amorphous in the apixaban-containing particles.

[0020] In one embodiment, the apixaban-containing particles contain 100% by weight or more of porous silicate as a carrier relative to the weight of amorphous apixaban contained in the apixaban-containing particles. In one embodiment, the apixaban-containing particles may contain 900% by weight or less of porous silicate as a carrier relative to the weight of amorphous apixaban contained in the apixaban-containing particles. On the other hand, if the porous silicate is less than 100% by weight relative to the amorphous apixaban contained in the apixaban-containing particles, it is difficult to obtain apixaban-containing particles. Furthermore, although it is possible to increase the porous silicate content to 1000% by weight or more relative to the amorphous apixaban contained in the apixaban-containing particles, this is not preferred because the silicate content per tablet increases, resulting in a low tablet hardness and causing problems during tableting.

[0021] [Pharmaceutical composition] The apixaban-containing pharmaceutical composition of the present invention comprises the apixaban-containing particles described above. The apixaban-containing pharmaceutical composition of the present invention may be in the form of tablets, capsules, granules, powder, etc., and is not particularly limited. In one embodiment, the apixaban-containing pharmaceutical composition of the present invention contains one or more pharmaceutically acceptable additives. The apixaban-containing pharmaceutical composition contains 2.5 mg or 5 mg of apixaban per tablet, but is not limited thereto, and the formulation can be changed as needed.

[0022] Pharmaceutically acceptable additives contained in the apixaban-containing pharmaceutical composition include, but are not limited to, excipients, binders, disintegrants, stabilizers, flavoring agents, lubricants, and flavoring agents. Apixaban-containing tablets can be prepared by selecting one or more of these additives. Additionally, the tablets may contain a premixed additive comprising two or more of these additives.

[0023] The excipient can be selected from, for example, sugars, sugar alcohols, starches, celluloses, carmelloses, gum arabic, dextran, pullulan, phosphates, carbonates, sulfates, etc. Examples of sugars include lactose, sucrose, glucose, trehalose, maltose, etc. Examples of sugar alcohols include mannitol, erythritol, xylitol, sorbitol, isomalt, etc. Examples of starches include corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, dextrin, etc. Examples of celluloses include crystalline cellulose and low-substituted hydroxypropyl cellulose. Examples of carmelloses include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, etc. Examples of phosphates include calcium hydrogen phosphate, etc. Examples of carbonates include calcium carbonate and magnesium carbonate, etc. Examples of sulfates include calcium sulfate, etc. These excipients can be used alone or in combination of two or more.

[0024] The binder can be selected from, for example, celluloses such as crystalline cellulose, hydroxypropyl cellulose, hypromellose, hydroxyethylmethylcellulose, ethyl cellulose, and methyl cellulose; vinyl polymers such as povidone, polyvinyl acetal diethylaminoacetate, fully saponified polyvinyl alcohol, partially saponified polyvinyl alcohol, carboxyvinyl polymer, and polyvinyl chloride; acrylic polymers such as aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), and ethyl acrylate-methyl methacrylate copolymer dispersions; stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogol, starch, and the like.

[0025] The disintegrant can be selected from, for example, celluloses such as carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium and methylcellulose; starches such as partially pregelatinized starch and corn starch; crospovidone; and the like.

[0026] The stabilizer can be selected from, for example, ascorbic acid, sodium ascorbate, aspartic acid, sodium aspartate, arginine, sodium edetate, anhydrous citric acid, citric acid hydrate, sodium citrate hydrate, sodium hydroxide, magnesium hydroxide, stearic acid, potassium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, and the like.

[0027] The flavoring agent can be selected from, for example, ascorbic acid, aspartic acid, sodium aspartate, aspartame, caramel, reduced maltose syrup, glycyrrhizic acid, saccharin, saccharin sodium, sucralose, purified stevia extract, refined white sugar, menthol, and the like.

[0028] The lubricant can be selected from, for example, hydrous silicon dioxide, light anhydrous silicic acid, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, talc, leucine, and the like.

[0029] The apixaban-containing pharmaceutical composition according to this embodiment contains apixaban-containing particles that are adsorbates in which amorphous apixaban is adsorbed on the surface and / or inside the pores of porous silicate, thereby maintaining the amorphous state of apixaban. Such an apixaban-containing pharmaceutical composition using an adsorbate of apixaban has not been known until now, and is realized for the first time in the present application.

[0030] [Method of manufacturing apixaban-containing particles] The apixaban-containing particles according to this embodiment are particles in which amorphous apixaban is adsorbed on the surface and / or inside the pores of a porous silicate. For example, a solution is prepared by dissolving apixaban in a solvent containing acetic acid. The solution is added to the porous silicate, and the solvent is removed. In this embodiment, the apixaban used as a raw material for producing the apixaban-containing particles may be amorphous apixaban or crystalline apixaban, as long as the amorphous nature of the apixaban-containing particles is maintained.

[0031] When adsorbing a drug substance onto a porous material, the solvent is likely to remain in the adsorbate, so purified water or the like is usually used as the solvent. However, since apixaban is a poorly soluble drug, a large amount of solvent is required to dissolve it in such a solvent, exceeding the adsorption limit of the porous material, making purified water or the like an inappropriate solvent. In this embodiment, apixaban can be dissolved in acetic acid and adsorbed onto the porous silicate. Furthermore, by using a solvent containing acetic acid, apixaban can be dissolved and amorphous apixaban can be adsorbed onto the porous silicate, maintaining the amorphous state of apixaban.

[0032] In one embodiment, particles containing amorphous apixaban and a porous silicate carrier are prepared so that the porous silicate carrier is 100% by weight or more relative to the weight of the amorphous apixaban contained in the apixaban-containing particles. In one embodiment, particles containing amorphous apixaban and a porous silicate carrier may be prepared so that the porous silicate carrier is 900% by weight or less relative to the weight of the amorphous apixaban contained in the apixaban-containing particles. If the porous silicate content is less than 100% by weight relative to the amorphous apixaban contained in the apixaban-containing particles, it is difficult to obtain apixaban-containing particles. While it is possible to increase the porous silicate content to 1000% by weight or more relative to the amorphous apixaban contained in the apixaban-containing particles, this is not preferred because the silicate content per tablet increases, resulting in a lower hardness of the resulting pharmaceutical composition and causing tableting problems.

[0033] By removing the solvent from the solution, particles containing amorphous apixaban and a porous silicate carrier can be obtained. The solvent can be removed by a known method, such as a tray dryer.

[0034] As described above, in the production method of this embodiment, a pharmaceutical composition containing apixaban-containing particles can be produced by a simpler method without using a spray dryer.

[0035] [Method of manufacturing apixaban-containing pharmaceutical composition] The apixaban-containing pharmaceutical composition of this embodiment can be produced by mixing apixaban-containing particles with one or more of the above-mentioned pharmaceutically acceptable additives and compressing the mixture into tablets. Alternatively, a premixed additive comprising two or more additives may be used.

[0036] In this embodiment, the apixaban-containing particles are adsorbents in which amorphous apixaban is adsorbed on the surface and / or inside the pores of porous silicate, thereby enabling the amorphous state of apixaban to be maintained in the apixaban-containing pharmaceutical composition.

[0037] [Amorphous evaluation] The amorphous state of apixaban can be evaluated by powder X-ray diffraction measurement. As used herein, "amorphous" means that no peaks derived from crystalline components are detected in the diffraction pattern obtained by powder X-ray diffraction measurement. "No peaks detected" means that a broad halo pattern relative to the baseline is observed in the diffraction pattern, and no significant peaks derived from crystalline components are observed. [Example]

[0038] [Study on porous silicates] Porous silicates were investigated for use in apixaban-containing particles.

[0039] [Example 1] Hydrous silicon dioxide was used as the porous silicate. 4 g of apixaban crystals were dissolved in 25 g of acetic acid. The resulting solution was added to 16 g of hydrous silicon dioxide (SYLOPURE (registered trademark) P100, Fuji Silysia Chemical Ltd.) using a mortar, allowing apixaban to be adsorbed onto the hydrous silicon dioxide. The hydrous silicon dioxide with apixaban adsorbed thereon was then dried in a tray dryer to remove the solvent, yielding apixaban-containing particles of Example 1 containing 400 wt% hydrous silicon dioxide relative to the amorphous apixaban.

[0040] [Example 2] Apixaban-containing particles of Example 2 containing 400% by weight of hydrous silicon dioxide relative to amorphous apixaban were obtained by the same production method as in Example 1, except that the porous silicate was changed to hydrous silicon dioxide (Fujisil (registered trademark), Fuji Chemical Industry Co., Ltd.).

[0041] [Example 3] Apixaban-containing particles of Example 3 containing 400% by weight of hydrous silicon dioxide relative to amorphous apixaban were obtained by the same production method as in Example 1, except that the porous silicate was changed to hydrous silicon dioxide (Parteck (registered trademark) SLC, Merck Millipore).

[0042] [Example 4] Apixaban-containing particles of Example 4 containing 400% by weight of light anhydrous silicic acid relative to amorphous apixaban were obtained by the same production method as in Example 1, except that the porous silicate was changed to light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation).

[0043] [Example 5] Apixaban-containing particles of Example 5 containing 400 wt % magnesium aluminometasilicate relative to amorphous apixaban were obtained by the same production method as in Example 1, except that the porous silicate was changed to magnesium aluminometasilicate (Neusilin (registered trademark) UFL2, Fuji Chemical Industry Co., Ltd.).

[0044] [Amorphous evaluation] The apixaban-containing particles of Examples 1 to 5 were confirmed to be amorphous by powder X-ray diffraction measurement. Each apixaban-containing particle was stored for one month under open conditions at 25°C and 75% relative humidity, and the amorphous state was confirmed by powder X-ray diffraction measurement. Amorphous apixaban alone was also evaluated as Comparative Example 1. A Bruker D8 ADVANCE powder X-ray diffractometer was used for the measurement, with Cu-Ka radiation, a tube voltage of 40 kV, a tube current of 40 mA, a measurement range of 2θ = 10.0 to 25.0°, a scan speed of 1 sec / step, and a step size of 0.015°.

[0045] The evaluation results of the amorphous state are shown in Table 1. [Table 1]

[0046] The results in Table 1 demonstrate that apixaban maintained its amorphous state even after one month of storage in the apixaban-containing particles of Examples 1 to 3, which used hydrous silicon dioxide as the porous silicate, Example 4, which used light anhydrous silicic acid as the porous silicate, and Example 5, which used magnesium aluminometasilicate as the porous silicate. On the other hand, in Comparative Example 1, which contained amorphous apixaban alone, the amorphous state of apixaban could not be maintained, and it was revealed that adsorption onto the porous silicate carrier was necessary. These results demonstrate that the apixaban-containing particles according to the present invention can maintain the amorphous state of apixaban by including a porous silicate carrier, regardless of the type of porous silicate.

[0047] Apixaban-containing pharmaceutical compositions were produced using the apixaban-containing particles of Examples 1 to 5. In addition, as Comparative Example 2, an apixaban-containing pharmaceutical composition was produced using D-mannitol instead of the porous silicate.

[0048] [Example 6] 6.25 g of the apixaban-containing particles of Example 1, 0.5 g of sodium lauryl sulfate (Emar OS, Kao Corporation), 34.6275 g of D-mannitol (Mannit-P, Mitsubishi Corporation Life Sciences), 4.275 g of crystalline cellulose (CEOLUS® PH-101, Asahi Kasei Corporation), 2.1375 g of low-substituted hydroxypropyl cellulose (L-HPC® NBD-022, Shin-Etsu Chemical Co., Ltd.), 0.855 g of crospovidone (Kollidon® CL-F, BASF Japan), 0.855 g of crospovidone (Kollidon® CL-M, BASF Japan), and magnesium stearate (vegetable-based, Taihei Chemical Industry Co., Ltd.) 0.5 g of each compound was mixed in a vinyl bag and compressed into tablets using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain 100 mg of the apixaban-containing pharmaceutical composition of Example 6.

[0049] [Example 7] The apixaban-containing pharmaceutical composition of Example 7 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 2 were used.

[0050] [Example 8] The apixaban-containing pharmaceutical composition of Example 8 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 3 were used.

[0051] [Example 9] The apixaban-containing pharmaceutical composition of Example 9 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 4 were used.

[0052] [Example 10] The apixaban-containing pharmaceutical composition of Example 10 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 5 were used.

[0053] Comparative Example 2 D-mannitol was used instead of porous silicate. The mixture consisted of 1.25 g of amorphous apixaban, 5 g of D-mannitol (Granutol F, Freund Corporation), 0.5 g of sodium lauryl sulfate (Emal OS, Kao Corporation), 34.6275 g of D-mannitol (Mannit-P, Mitsubishi Corporation Life Sciences), 4.275 g of crystalline cellulose (CEOLUS® PH-101, Asahi Kasei Corporation), 2.1375 g of low-substituted hydroxypropyl cellulose (L-HPC® NBD-022, Shin-Etsu Chemical Co., Ltd.), 0.855 g of crospovidone (Kollidon® CL-F, BASF Japan), 0.855 g of crospovidone (Kollidon® CL-M, BASF Japan), and magnesium stearate (vegetable-based, Taihei Chemical Industry Co., Ltd.). 0.5 g of each compound was mixed in a vinyl bag and compressed into tablets using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain 100 mg of the apixaban-containing pharmaceutical composition of Comparative Example 2.

[0054] [Amorphous evaluation] Powder X-ray diffraction analysis confirmed that the apixaban-containing pharmaceutical compositions of Examples 6 to 10 and Comparative Example 2 were amorphous. Furthermore, each apixaban-containing particle was stored for one month under open conditions at 25°C and 75% relative humidity, and the amorphous state was confirmed by powder X-ray diffraction analysis. Measurements were performed using a Bruker D8 ADVANCE powder X-ray diffractometer under the following conditions: Cu-Ka radiation, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0°, scan speed: 1 sec / step, step size: 0.015°.

[0055] The evaluation results of the amorphous state are shown in Table 2. [Table 2]

[0056] The results in Table 2 demonstrate that apixaban maintained its amorphous state even after one month of storage in the apixaban-containing pharmaceutical compositions of Examples 6 to 8, which contained apixaban-containing particles in which amorphous apixaban was adsorbed onto porous silicate hydrous silicon dioxide; Example 9, which contained apixaban-containing particles in which amorphous apixaban was adsorbed onto light anhydrous silicic acid; and Example 10, which contained apixaban-containing particles in which amorphous apixaban was adsorbed onto magnesium aluminometasilicate. On the other hand, it was revealed that apixaban in the apixaban-containing pharmaceutical composition of Comparative Example 2, which contained amorphous apixaban alone, was unable to maintain its amorphous state after one month of storage.

[0057] [Example 11] The relationship between the ratio of porous silicate to amorphous apixaban and the maintenance of the amorphous state of apixaban was further investigated. As an example, hydrous silicon dioxide (Fujisil®, Fuji Chemical Industry Co., Ltd.) was used. The apixaban-containing particles of Example 11, containing 100% by weight of hydrous silicon dioxide relative to amorphous apixaban, were obtained by the same manufacturing method as in Example 1, except that 7.50 g of apixaban crystals were dissolved in 15.8 g of acetic acid and the amount of hydrous silicon dioxide (Fujisil®, Fuji Chemical Industry Co., Ltd.) was changed to 7.50 g.

[0058] [Example 12] Apixaban-containing particles of Example 12 containing 150% by weight of hydrous silicon dioxide relative to amorphous apixaban were obtained by the same production method as in Example 1, except that 7.50 g of apixaban crystals were dissolved in 23.4 g of acetic acid and the amount of hydrous silicon dioxide (Fujisil (registered trademark), Fuji Chemical Industry Co., Ltd.) was changed to 11.25 g.

[0059] [Example 13] Apixaban-containing particles of Example 13 containing 232% by weight of hydrous silicon dioxide relative to amorphous apixaban were obtained by the same production method as in Example 1, except that 5 g of apixaban crystals was dissolved in 20 g of acetic acid and the amount of hydrous silicon dioxide (Fujisil (registered trademark), Fuji Chemical Industry Co., Ltd.) was changed to 11.6 g.

[0060] [Example 14] Apixaban-containing particles of Example 14 containing 900% by weight of hydrous silicon dioxide relative to amorphous apixaban were obtained by the same production method as in Example 1, except that 2 g of apixaban crystals was dissolved in 25 g of acetic acid and the amount of hydrous silicon dioxide (Fujisil (registered trademark), Fuji Chemical Industry Co., Ltd.) was changed to 18 g.

[0061] [Amorphous evaluation] Powder X-ray diffraction analysis confirmed that the apixaban-containing particles of Examples 11 to 14 were amorphous. Each apixaban-containing particle was stored for one month under open conditions at 25°C and 75% relative humidity, and the amorphous state was confirmed by powder X-ray diffraction analysis. Measurements were performed using a Bruker D8 ADVANCE powder X-ray diffractometer under the following conditions: Cu-Ka radiation, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0°, scan speed: 1 sec / step, step size: 0.015°.

[0062] The evaluation results of the amorphous state are shown in Table 3. The evaluation results of Example 2 and Comparative Example 1 are also shown below. [Table 3]

[0063] The results in Table 3 show that the apixaban-containing particles of Examples 2 and 11 to 14, which contain 100% to 900% by weight of porous silicate relative to amorphous apixaban, maintain the amorphous state of apixaban even after storage for one month.

[0064] Apixaban-containing pharmaceutical compositions were prepared using the apixaban-containing particles of Examples 2 and 11 to 14 above.

[0065] [Example 15] The apixaban-containing pharmaceutical composition of Example 15 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 11 were used.

[0066] [Example 16] The apixaban-containing pharmaceutical composition of Example 16 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 12 were used.

[0067] [Example 17] The apixaban-containing pharmaceutical composition of Example 17 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 13 were used.

[0068] [Example 18] The apixaban-containing pharmaceutical composition of Example 18 was obtained by the same production method as in Example 6, except that the apixaban-containing particles of Example 14 were used.

[0069] [Amorphous evaluation] Powder X-ray diffraction analysis confirmed that the apixaban-containing pharmaceutical compositions of Examples 15 to 18 were amorphous. Furthermore, each apixaban-containing particle was stored for one month under open conditions at 25°C and 75% relative humidity, and the amorphous state was confirmed by powder X-ray diffraction analysis. Measurements were performed using a Bruker D8 ADVANCE powder X-ray diffractometer under the following conditions: Cu-Ka radiation, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0°, scan speed: 1 sec / step, step size: 0.015°.

[0070] The evaluation results of the amorphous state are shown in Table 4. The evaluation results of Example 7 and Comparative Example 2 are also shown below. [Table 4]

[0071] The results in Table 4 indicate that the apixaban-containing pharmaceutical compositions of Examples 7 and 15 to 18, which used apixaban-containing particles containing 100% to 900% by weight of porous silicate relative to amorphous apixaban, maintained the amorphous state of apixaban even after storage for one month.

Claims

1. Apixaban-containing particles comprising amorphous apixaban and a porous silicate as a carrier.

2. The apixaban-containing particles according to claim 1, comprising 100% by weight or more of the porous silicate as a carrier based on the weight of the amorphous apixaban.

3. The porous silicate is one or more porous silicates selected from the group consisting of hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate. The apixaban-containing particles according to claim 1.

4. An apixaban-containing pharmaceutical composition comprising the apixaban-containing particles according to any one of claims 1 to 3 and one or more pharmaceutically acceptable additives.

5. Dissolve apixaban in a solvent containing acetic acid to prepare a solution, Add the solution to the porous silicate and remove the solvent, A method for producing apixaban-containing particles, comprising obtaining particles comprising amorphous apixaban and the porous silicate.

6. The porous silicate is one or more porous silicates selected from the group consisting of hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate. The method for producing apixaban-containing particles according to claim 5.

7. A method for producing an apixaban-containing pharmaceutical composition, comprising mixing the apixaban-containing particles produced by the method for producing apixaban-containing particles according to claim 5 or 6 with one or more pharmaceutically acceptable additives and tableting.