Apixaban solid amorphous dispersion

Abstract

To provide an apixaban solid amorphous dispersion with superior stability that exhibits inhibited crystallization and impurity formation under heated and humidified storage conditions in a formulation with improved apixaban dissolution, as well as a pharmaceutical preparation comprising the apixaban solid amorphous dispersion.SOLUTION: An apixaban solid amorphous dispersion is prepared by dispersing apixaban in a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and / or polyvinyl alcohol at a predetermined mass ratio.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a solid amorphous dispersion containing apixaban and having excellent storage stability. The present invention further relates to a pharmaceutical preparation containing the solid amorphous dispersion and having excellent dissolution property. [Background technology]

[0002] Apixaban is an oral anticoagulant that reversibly inhibits blood coagulation activation factor X (FXa). FXa is a type of serine protease produced by the activation of factor X, and is an enzyme that produces thrombin (FIIa), which plays a role in converting fibrinogen to fibrin, and plays a central role in blood coagulation. Apixaban has high affinity and selectivity for FXa, and exerts a direct anticoagulant effect and an indirect antiplatelet effect by suppressing thrombin production through the inhibition of FXa, thereby exerting an antithrombotic effect. In Japan, it is used to prevent the onset of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, and to treat and prevent recurrence of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism).

[0003] Apixaban is poorly soluble in water. In order to ensure stable dissolution of apixaban from a formulation, a technology for a solid formulation using crystalline apixaban having a D90 of 89 μm or less (Patent Document 1) and a technology for improving dissolution in the stomach by coating apixaban with an aminoalkyl methacrylate copolymer (Patent Document 2) have been disclosed.

[0004] In addition, a technique for obtaining good dissolution properties by amorphizing apixaban is also known. For example, a technique for improving solubility by dispersing apixaban in a monomolecular form and supporting it in a specific polymer, so-called a solid amorphous dispersion (Patent Documents 3 to 5). A technique for improving solubility by amorphizing a mixture of apixaban and a polymer through mechanochemical action such as impact, compression, shear, etc. (Patent Document 6), and a technique for improving solubility by adsorbing apixaban at the molecular level to a porous material to amorphize it (Patent Document 7). Furthermore, a technique for maintaining the amorphous state by using a specific additive that suppresses the crystallization of amorphized apixaban (Patent Document 8), etc. are disclosed.

[0005] On the other hand, it is known that amorphous substances are thermodynamically unstable and recrystallize due to the temperature and humidity during storage, resulting in a decrease in solubility (Non-Patent Document 1). Therefore, it is required for solid amorphous dispersions to maintain a stable amorphous state even during storage.

[0006] However, for the amorphization techniques in the above-mentioned patent documents, no data on stability during storage is provided except for Patent Document 8. Even in Patent Document 8, only data on storage stability under mild conditions of 25° C. and a relative humidity of 75% is provided. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 6192078 [Patent Document 2] Patent Publication No. 2022-112698 [Patent Document 3] Patent No. 5775071 [Patent Document 4] Patent Publication 2021-152005 [Patent Document 5] Patent Publication No. 2022-32772 [Patent Document 6] Patent Publication No. 2023-7915 [Patent Document 7] Patent Publication No. 2023-54766 [Patent Document 8] Patent Publication No. 2023-8994 [Non-patent literature]

[0008] [Non-Patent Document 1] Importance of solid state physical property evaluation in formulation development of amorphous drugs Pharmacia Vol.52, No.5, 392-396 (2016) Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a solid amorphous dispersion of apixaban having good stability, in which the dissolution properties of apixaban are improved and crystallization and generation of impurities during storage at high temperature or high humidity are suppressed, and a pharmaceutical formulation containing the same. [Means for solving the problem]

[0010] As a result of intensive research, the present inventors have found that the above problems can be solved by preparing a solid amorphous dispersion of apixaban with a specific polymer. More specifically, a solid amorphous dispersion of apixaban can be obtained by adding a water / ethanol mixture to a mixed powder of apixaban and a specific polymer, dissolving the mixture, and evaporating the solvent of the solution by any method to obtain a powder, or by subjecting a mixed powder of apixaban and a specific polymer to a thermal melting and cooling method, and adjusting the size and powdering the mixture. It has been found that this solid amorphous dispersion of apixaban maintains an amorphous state and high purity even when stored for 4 weeks under conditions of 60°C and 25°C and a relative humidity of 75%. Furthermore, it has been found that a pharmaceutical preparation prepared by adding any additive to this solid amorphous dispersion of apixaban exhibits good dissolution properties, and the present invention has been completed.

[0011] The present invention includes the following inventions: (1) A solid amorphous dispersion of apixaban in which apixaban is dispersed in polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and / or polyvinyl alcohol in a mass ratio of 2 or 3 times or more relative to the mass of apixaban. (2) The solid amorphous dispersion of apixaban according to (1), wherein apixaban remains amorphous and the amount of each impurity is 0.2% or less when stored for 4 weeks in an environment at 60°C or in an environment at 25°C and 75% relative humidity. (3) A pharmaceutical formulation containing the solid amorphous dispersion of apixaban according to (1) or (2) and any additive. (4) A pharmaceutical formulation containing the solid amorphous dispersion of apixaban according to (3), which has a dissolution rate of 80% or more after 30 minutes when the pharmaceutical formulation containing the solid amorphous dispersion of apixaban is subjected to a dissolution test in water at 50 rotations by the paddle method according to the Japanese Pharmacopoeia dissolution test. (5) A method for producing the solid amorphous dispersion of apixaban according to (1), comprising the steps of dissolving apixaban and polyvinyl alcohol, or apixaban and a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in a water / ethanol mixture, and distilling off the solvent from the solution. (6) A method for producing the solid amorphous dispersion of apixaban according to (1), comprising a step of granulating apixaban and polyvinyl alcohol, or apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer by a hot melt cooling method.

[0012] The solid amorphous dispersion of apixaban of the present invention can be obtained by a simple and inexpensive method, and has excellent stability, such as maintaining the amorphous state of apixaban even when stored in a high temperature or high humidity environment, and having high purity, etc. In addition, a pharmaceutical preparation containing the solid amorphous dispersion of apixaban of the present invention exhibits good dissolution properties. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern of Comparative Example 1 (apixaban crystalline powder). [Diagram 2] FIG. 2 is a diagram showing powder X-ray diffraction patterns of the mixed powders obtained in Examples 1 and 2, and Comparative Examples 2 and 3. [Diagram 3] FIG. 2 is a diagram showing powder X-ray diffraction patterns of the mixed powders obtained in Examples 3 to 5 and Comparative Example 4. [Figure 4] FIG. 2 shows powder X-ray diffraction patterns of the solid amorphous dispersion of Example 2 at the start of storage and after 4 weeks of storage. [Diagram 5] FIG. 1 shows powder X-ray diffraction patterns of the solid amorphous dispersion of Example 4 at the start of storage and after 4 weeks of storage. [Figure 6] FIG. 1 shows powder X-ray diffraction patterns of the mixed powders obtained in Examples 6 to 11. [Figure 7] FIG. 1 shows the results of the dissolution test of the tablets obtained in Example 12 and Comparative Example 5. [Figure 8] FIG. 13 shows the results of a dissolution test of the tablets obtained in Example 13. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The solid amorphous dispersion of apixaban according to the present invention and a pharmaceutical formulation containing the same will be described below. However, the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0015] In the present invention, the solid amorphous dispersion of apixaban is a dispersion of apixaban in a solid, inactive polymer, in which individual molecules of apixaban are randomly present in the polymer, and when the solid amorphous dispersion of apixaban is measured with a powder X-ray diffractometer, it does not substantially exhibit diffraction peaks specific to crystalline apixaban, but instead exhibits a halo pattern specific to amorphous materials.

[0016] The polymer in the apixaban solid amorphous dispersion of the present invention is selected from polyvinyl alcohol and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0017] The polyvinyl alcohol in the present invention is a polymer obtained by saponifying polyvinyl acetate, and may be either a completely saponified product represented by -(CH2CHOH)n- and having a degree of saponification of 97 mol% or more, or a partially saponified product represented by -(CH2CHOH)n-(CH2CHOCOCH3)m- and having a degree of saponification of 78 to 96 mol%. In the present invention, however, a partially saponified product is preferred, and one having a viscosity of 4.6 to 6.0 mPa s when made into a 4% aqueous solution is particularly suitable.

[0018] The polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in the present invention is a copolymer of polyvinyl alcohol (partially saponified), acrylic acid, and methyl methacrylate in a mass ratio of 32:1:7, and has an average molecular weight of about 4000. The viscosity of a 5% aqueous solution of the copolymer is 4.6 to 5.5 mPa s.

[0019] The mass ratio of apixaban to polyvinyl alcohol in the solid amorphous dispersion of apixaban of the present invention is not particularly limited, but it is preferable to use 3 times or more, and more preferably 5 times or more, of polyvinyl alcohol relative to the mass of apixaban.

[0020] The mass ratio of apixaban to polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in the solid amorphous dispersion of apixaban of the present invention is not particularly limited, but it is preferable to use polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in an amount that is at least twice as large as the mass of apixaban, and more preferably at least three times as large.

[0021] The method for producing the solid amorphous dispersion of apixaban in the present invention is not particularly limited, and any method can be used, such as a method in which a mixture of apixaban and polyvinyl alcohol or a mixture of apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is dissolved in a solvent and the solvent is removed by means of spray drying, spray granulation, or the like to obtain a solid amorphous dispersion (solvent removal method), a method in which a mixture of apixaban and polyvinyl alcohol or a mixture of apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is heated and melted to obtain a solid amorphous dispersion (thermal melting and cooling method), or a method in which a mixture of apixaban and polyvinyl alcohol or a mixture of apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is mixed and ground by mechanochemical action such as impact, shear, compression, etc. to obtain a solid amorphous dispersion (mixed and ground method). Preferred production methods are the solvent distillation method and the hot melt cooling method. In the case of the solvent distillation method, the solvent is preferably a water / ethanol mixture, and particularly preferably a 75% aqueous ethanol solution.

[0022] In addition, in the preparation of the solid amorphous dispersion of apixaban in the present invention, it is also possible to contain pharma- ceutical acceptable additives in addition to apixaban, polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0023] The solid amorphous dispersion of apixaban of the present invention can be further prepared into pharmaceutical preparations such as granules, fine granules, dry syrups, and tablets, including plain tablets and film-coated tablets, by adding pharma- ceutical acceptable additives.

[0024] The method for producing the pharmaceutical formulation containing the solid amorphous dispersion of apixaban in the present invention is not particularly limited, and the formulation can be produced by any method, such as direct compression, dry granulation, wet stirring granulation, fluidized bed granulation, and melt granulation, but in the present invention, the fluidized bed granulation is preferred.

[0025] The types of pharma- ceutically acceptable additives used in the pharmaceutical formulation containing the solid amorphous dispersion of apixaban of the present invention are not particularly limited, and excipients, disintegrants, binders, solubilizers, lubricants, film coating agents, colorants, gloss agents, etc. may be added.

[0026] (Excipients) Examples of excipients used in the pharmaceutical formulation of the solid amorphous dispersion of apixaban of the present invention include sugars such as lactose hydrate, anhydrous lactose, crystalline cellulose, white sugar, trehalose, sucrose, etc.; sugar alcohols such as mannitol, erythritol, sorbitol, xylitol, etc.; starches such as partially pregelatinized starch, corn starch, potato starch, etc., which can be used alone or in appropriate combination.

[0027] (Disintegrant) Disintegrants used in the pharmaceutical preparation of the solid amorphous dispersion of apixaban according to the present invention include, for example, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, sodium starch glycolate, etc., which can be used alone or in appropriate combination.

[0028] (Binding Agent) The binder used in the pharmaceutical preparation of the solid amorphous dispersion of apixaban according to the present invention can be selected from, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, macrogol, and the compounds listed above as excipients, etc. These binders can be used alone or in appropriate combination.

[0029] (Solubilizer) The solubilizer used in the pharmaceutical preparation of the solid amorphous dispersion of apixaban according to the present invention can be selected from, for example, sodium benzoate, polyoxyethylene hydrogenated castor oil, polysorbate 80, sodium lauryl sulfate, etc. These solubilizers can be used alone or in appropriate combination.

[0030] (lubricant) The lubricant used in the pharmaceutical formulation of the solid amorphous dispersion of apixaban according to the present invention can be selected from, for example, magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol, etc. These lubricants can be used alone or in appropriate combination.

[0031] (Film coating agent) The film coating agent used in the pharmaceutical preparation of the solid amorphous dispersion of apixaban according to the present invention may be any agent that can be used for pharmaceutical purposes, and examples of such agents include hypromellose, polyvinyl alcohol, ethyl cellulose, lactose hydrate, carboxymethylethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, PVA copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, Opadry, carnauba wax, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, etc. Also, components such as light-shielding agents and colorants, such as titanium oxide and ferric oxide, may be added.

[0032] (Plasticizer) The plasticizer used in the pharmaceutical preparation of the solid amorphous dispersion of apixaban according to the present invention may be any plasticizer that can be used for pharmaceutical purposes, and examples of such plasticizers include triethyl citrate, triacetin, diethyl phthalate, propylene glycol, polysorbate 80, macrogol 400, and macrogol 6000. These plasticizers may be used alone or in appropriate combination.

[0033] When a pharmaceutical formulation containing the solid amorphous dispersion of apixaban according to the present invention is stored at 60°C (tightly sealed) for 4 weeks or at 25°C and 75% relative humidity (open) for 4 weeks and impurities in the tablet are determined by liquid chromatography, the amount of impurities formed is small, and the amount of each impurity formed is 0.5% or less, more preferably 0.2% or less.

[0034] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0035] [Examples 1 to 11, Comparative Examples 2 to 4] A mixed powder of apixaban and a polymer was produced using the polymers, mass ratios, and production methods shown in Table 1. <Production by solvent distillation method> A mixture of apixaban and a polymer in a mass ratio of equal to 5 times was dissolved in a 75% aqueous ethanol solution, and the solution was heated to distill off the solvent, thereby obtaining mixed powders of Examples 1 to 5 and Comparative Examples 2 to 4. <Manufactured by the thermal melting and cooling method> A mixture of apixaban and a polymer in a mass ratio of 3 to 10 times was granulated using a hot melt granulator (ZE-9 type extruder, Three-Tec Corporation), and the granulated material was cooled and pulverized to obtain the mixed powders of Examples 6 to 11.

[0036] Table 1. Mixed powders prepared in the Examples and Comparative Examples [Table 1]

[0037] (Experimental Example 1: Measurement of the Crystalline State of Apixaban) The mixed powders of Examples 1 to 11 and Comparative Examples 2 to 4, as well as the apixaban crystalline powder (Comparative Example 1), were measured using a powder X-ray diffractometer (Rigaku Electric MiniFkex 600). The apixaban crystalline powder of Comparative Example 1 was from the same lot as the apixaban used in Examples 1 to 5 and Comparative Examples 2 to 4. Powder X-ray diffraction charts are shown in Figures 1 to 3 and 6. A list of the crystalline states of apixaban is shown in Table 2.

[0038] Table 2 Crystalline state of apixaban [Table 2] Crystalline state: Diffraction peaks mainly due to apixaban crystals were detected. Mixed state: Both diffraction peaks based on apixaban crystals and a halo pattern characteristic of amorphous materials were observed. Amorphous state: No diffraction peaks due to apixaban crystals were detected, and only a halo pattern specific to amorphous materials was confirmed.

[0039] As shown in Figure 1, the apixaban crystalline powder of Comparative Example 1 was a crystal exhibiting a specific X-ray diffraction pattern. In addition, as shown in Figure 2, in the mixed powder of apixaban and polyvinyl alcohol prepared by the solvent distillation method, diffraction peaks due to apixaban crystals were confirmed in Comparative Examples 2 and 3, but in Examples 1 and 2, which were prepared with a mass ratio of polyvinyl alcohol to apixaban of 3 times or more, the diffraction peaks of apixaban crystals disappeared and only a halo pattern specific to amorphous substances was confirmed, confirming that a solid amorphous dispersion of apixaban and polyvinyl alcohol was formed.

[0040] As shown in Figure 3, in the combination of apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, diffraction peaks due to apixaban crystals were detected in Comparative Example 4, where the mass ratio of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer to apixaban was equal. On the other hand, in Examples 3 to 5, where the mass ratio of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer to apixaban was more than twice the mass of apixaban, diffraction peaks due to apixaban crystals were not detected and only a halo pattern specific to amorphous substances was observed, confirming that a solid amorphous dispersion consisting of apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer was formed.

[0041] As shown in Figure 6, in Examples 6 to 11, which were prepared so that the mass ratio of polyvinyl alcohol or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer to the mass of apixaban was 3 times or more, no diffraction peaks of apixaban crystals were detected and only a halo pattern specific to amorphous substances was observed, confirming that a solid amorphous dispersion consisting of apixaban and polyvinyl alcohol or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer was formed.

[0042] (Experimental Example 2: Evaluation of storage stability of solid amorphous dispersion) The solid amorphous dispersions of Example 2 and Example 4 were stored at 60°C (sealed) for 4 weeks, or at 25°C and 75% relative humidity (open) for 4 weeks, and then the change in the crystalline state of each sample was measured using a powder X-ray diffractometer, and the increase in the amount of impurities was measured using liquid chromatography. The results of the powder X-ray diffraction are shown in Figures 4 and 5. The results are also listed in Table 3.

[0043] Table 3 Storage stability of solid amorphous dispersion in Experimental Example 2 [Table 3] Amorphous state: No diffraction peaks due to apixaban crystals were detected, and only a halo pattern specific to amorphous materials was confirmed.

[0044] As a result of the stability test of the apixaban solid amorphous dispersion of Experimental Example 2, no crystals of apixaban were detected even after storage for 4 weeks at 60°C or at 25°C and 75% relative humidity, confirming that the amorphous state was stably maintained. In addition, the maximum amount of each decomposition product was 0.2% or less, and the total amount of the decomposition products was also small, being 0.5% or less, confirming that the dispersion was stable.

[0045] [Example 12] A mixture of 75.6 g of lactose hydrate, 82 g of microcrystalline cellulose, and 1.0 g of sodium lauryl sulfate was placed in a fluidized bed granulator (MP01, Powrex Corporation) and fluidized. A solution of 5 g of apixaban and 15 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in 1000 mL of 75% ethanol solution was added and heated to 70°C to dissolve the mixture. The resulting granules were granulated using a granulator (Comil 197S, Powrex Corporation), and 8 g of croscarmellose sodium and 2.4 g of magnesium stearate were added and mixed to obtain tablet powder. The tablet powder was compressed using a rotary tablet press (HT-AP18, Hata Iron Works, Ltd.) to obtain circular tablets with a diameter of 6 mm containing 2.5 mg of apixaban per 95 mg of mass.

[0046] [Comparative Example 5] A powder mixture consisting of 2.5 g of apixaban (90% particle size: 110 μm), 41 g of crystalline cellulose, 50.25 g of anhydrous lactose, 4 g of croscarmellose sodium, 1 g of sodium lauryl sulfate, and 1.25 g of magnesium stearate was compressed and molded using a rotary tablet press (HT-AP18, Hata Iron Works) to obtain tablets with a diameter of 6 mm containing 2.5 mg of apixaban per 100 mg of mass.

[0047] [Example 13] Apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer were mixed in a ratio of 1:3, and 126.95 g of this mixed powder was fed into a melt granulator (ZE-9 type extruder, Three-Tec Co., Ltd.) at a powder feed rate of 3 g / min and a screw rotation speed of 300 min -1 The resulting granules were granulated at a barrel temperature of 150 to 230°C. The granules were then sieved in a sample mill (SAMT Nara Machinery Works, Ltd.) equipped with a 0.5 mm screen at a rotation speed of 16,000 min -1The granulation was carried out under the following conditions. 5 g of this granulation was mixed with 31.9 g of lactose hydrate, 10 g of crystalline cellulose, 2 g of croscarmellose sodium, and 0.5 g of sodium lauryl sulfate, and mixed by hand for 3 minutes, and then 0.6 g of magnesium stearate was added and mixed by hand for another minute. This tablet powder was compressed using a rotary tablet press (HT-AP18 type, Hata Iron Works) to obtain tablets with a diameter of 6 mm containing 5 mg of apixaban per 200 mg of tablet. A coating solution was sprayed onto these tablets using a coating device (HCT-MINI, Freund Corporation), and film-coated tablets with an average mass of 208 mg were obtained. The coating solution was prepared by dissolving 32.6 g of hydroxypropylmethylcellulose 2910 and 3.8 g of macrogol 6000 in 220 g of purified water, adding to this solution a dispersion of 9.6 g of titanium dioxide and 1.9 g of yellow ferric oxide in 100 g of purified water, stirring and mixing, and then sieving the resulting solution through a 140M sieve.

[0048] (Experimental Example 3: Dissolution test) The tablets obtained in Example 12, Example 13, and Comparative Example 5 were subjected to a dissolution test in accordance with the 18th Edition of the Japanese Pharmacopoeia using the paddle method at 50 rotations in water. The results are shown in Figures 7 and 8.

[0049] The dissolution rate of the tablet of Comparative Example 5 was 50% or less after 30 minutes, whereas the tablets of Examples 12 and 13 were approximately 80% or more dissolved after 30 minutes, demonstrating that the solid amorphous dispersion of apixaban exhibits high solubility. [Industrial Applicability]

[0050] According to the present invention, a solid amorphous dispersion of apixaban and a pharmaceutical formulation containing a solid amorphous dispersion of apixaban, which have excellent stability and dissolution property, can be obtained by an inexpensive and simple method.

Claims

1. A solid amorphous dispersion of apixaban, in which apixaban is dispersed in polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and / or polyvinyl alcohol in a mass ratio of 2 or 3 times or more relative to the mass of apixaban.

2. 2. The solid amorphous dispersion of apixaban according to claim 1, wherein apixaban remains amorphous and the amount of each impurity is 0.2% or less when stored in an environment at 60°C for 4 weeks or when stored in an environment at 25°C and a relative humidity of 75% for 4 weeks.

3. A pharmaceutical formulation containing a solid amorphous dispersion of apixaban, comprising the solid amorphous dispersion of apixaban according to claim 1 or 2 and any additive.

4. 4. The pharmaceutical formulation containing the solid amorphous dispersion of apixaban according to claim 3, wherein when a dissolution test is performed in water at 50 rotations using the paddle method according to the Japanese Pharmacopoeia dissolution test, the dissolution rate after 30 minutes is 80% or more.

5. 2. A method for producing the solid amorphous dispersion of apixaban according to claim 1, comprising the steps of dissolving apixaban and polyvinyl alcohol, or apixaban and a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in a water / ethanol mixture, and distilling off the solvent from the solution.

6. 2. A method for producing the solid amorphous dispersion of apixaban according to claim 1, comprising a step of granulating apixaban and polyvinyl alcohol, or apixaban and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer by a hot melt cooling method.

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