JP7752487B2 - Apixaban-containing solid dispersion - Google Patents

Description

The present invention relates to a solid dispersion containing apixaban and a tablet containing the solid dispersion.

Apixaban is known as 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperazinyl)phenyl]-4-5-6-7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (IUPAC name), and acts as a thrombin inhibitor at the X-terminal end, which is the convergence point of the extrinsic and intrinsic blood coagulation pathways. By inhibiting factor _a , it suppresses the downstream conversion of prothrombin to thrombin, making it useful as a drug that exhibits direct anticoagulant action and indirect antiplatelet action, and is provided to medical settings as "Eliquis (registered trademark) Tablets 2.5 mg" and "Eliquis (registered trademark) Tablets 5 mg" (Non-Patent Document 1).

Apixaban is poorly water-soluble, and formulation techniques to improve solubility are required.

Since the solubility of a drug is significantly affected by the drug's dissolution or oral absorbability, various solubilization techniques have been adopted to improve the solubility of poorly water-soluble drugs, including methods of refining crystals, encapsulating the drug in cyclodextrin, adding surfactants, and forming a solid dispersion of the drug with a solubilizing agent, such as a polymer. Furthermore, when the drug is a basic substance, a method of converting it into a soluble salt by adding an acid such as citric acid or tartaric acid has also been adopted.

Under these circumstances, formulation techniques for reducing crystalline apixaban to a specific particle size or less, and solid dispersion techniques comprising amorphous apixaban and a carrier are known (Patent Documents 1, 2, and 3). The former uses crystalline apixaban with a particle size of 89 μm or less (Patent Documents 4, 5, and 6), while the latter uses a controlled-release formulation containing a solid dispersion comprising amorphous apixaban and a specific carrier (Patent Document 7). Both of these techniques achieve good solubility and oral absorbability.

International Publication No. 2011/106478 International Publication No. 2010/147978 International Publication No. 2017/088841 Patent No. 5846647 Patent No. 6033945 Patent No. 6192078 Patent No. 5775071

Package insert for "Eliquis Tablets 2.5 mg/5 mg," revised January 2020 (1st edition)

An object of the present invention is to provide a solubilization technology for apixaban that exhibits higher solubility than crystalline apixaban and is expected to have good oral absorbability, and to provide a tablet containing an apixaban solid dispersion to which said technology is applied.

The inventors of the present invention have conducted studies focusing on the combination of solvents in the solvent method from the viewpoint of the solubility of apixaban, and have found that a specific combination of solvents results in good solubility of an apixaban solid dispersion, thereby completing the present invention.

That is, the present invention provides:
(1) Apixaban solid dispersion comprising apixaban and one or more carriers selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl pyrrolidone, copolyvidone, hypromellose phthalate, hypromellose, and hypromellose acetate succinate;
(2) The apixaban solid dispersion according to (1), wherein the carrier is one or more carriers selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl pyrrolidone, copolyvidone, and hypromellose phthalate.
(3) The apixaban solid dispersion according to (1) or (2), wherein the carrier is hypromellose phthalate.
(4) The apixaban solid dispersion according to any one of (1) to (3), wherein the blending ratio of apixaban to the carrier is 1:1 to 1:3.
(5) The apixaban solid dispersion according to any one of (1) to (4), which is produced by a production method including a step of using a mixed solution of methylene chloride and ethanol.
(6) An apixaban-containing tablet containing the apixaban solid dispersion according to any one of (1) to (5).
(7) The apixaban-containing tablet according to (6), which is a film-coated tablet.
(8) Use of a mixed solution of methylene chloride and ethanol to prepare apixaban solid dispersion.
(9) The use according to (8), wherein the mixing ratio of the mixed solution consisting of methylene chloride and ethanol is 90:10 to 30:70.
Regarding.

According to the present invention, it is possible to provide an apixaban-containing solid dispersion having better dissolution properties than apixaban alone, and an apixaban-containing tablet containing the solid dispersion.

FIG. 1 is a diagram showing the relationship between the blending ratio of methylene chloride/ethanol mixed solution and the solubility of apixaban. FIG. 1 shows the results of powder X-ray diffraction measurements of the solid dispersions obtained in Examples 1, 4, 7, 10, 13, and 16, and apixaban alone. FIG. 1 shows the results of powder X-ray diffraction measurements of the solid dispersions obtained in Examples 3, 6, 9, 12, 15, and 18, and apixaban alone. FIG. 1 shows the results of powder X-ray diffraction measurements of the solid dispersions obtained in Examples 20 and 22 to 26, and apixaban alone. FIG. 1 shows the dissolution profiles of apixaban over time for the solid dispersions obtained in Examples 20 and 22 to 26 and Comparative Example 1. FIG. 1 shows the dissolution profiles of apixaban over time for the solid dispersions obtained in Examples 19 to 21 and Comparative Example 1. FIG. 1 shows the dissolution profiles of apixaban over time for the tablets obtained in Examples 28 and 30 to 33 and Comparative Example 2. FIG. 1 shows the dissolution profiles of apixaban over time for the tablets obtained in Examples 27 to 29 and Comparative Example 2.

As used herein, "amorphous" refers to an "amorphous state" that has been qualitatively or quantitatively confirmed by powder X-ray diffraction, solid-state NMR, or near-infrared analysis. "Substantially amorphous" refers to, in one embodiment, the amount of apixaban in a crystalline state not exceeding about 25% by weight. In one embodiment, apixaban in the amorphous solid dispersion is "almost completely amorphous," meaning that the amount of apixaban in a crystalline state is not exceeding about 10% by weight.

As used herein, "amorphous apixaban" means that apixaban is present in a substantially amorphous state in the solid dispersion of the present invention or in a tablet containing an apixaban-containing solid dispersion. "Substantially amorphous" indicates that 90% or more, and in some embodiments, 95 to 100%, of the apixaban present in the solid dispersion or in the solid dispersion in the tablet is in an amorphous state. "Amorphous" apixaban refers to an apixaban-containing composition that does not contain a significant amount, or does not contain a significant amount, of crystalline apixaban, as determined, for example, by powder X-ray diffraction analysis.

As used herein, the term "solid dispersion" refers to a dispersion in which at least a portion of the amorphous drug (apixaban) is dispersed at the molecular level in a carrier such as a polymer. For example, amorphous apixaban can be confirmed as an amorphous apixaban (halo peak) in a composition comprising the amorphous drug and a carrier by powder X-ray diffraction or the like. The degree of amorphization is defined as the range in which solubility and/or oral absorbability are improved.

The physical properties of solid dispersions can be determined using thermal analysis (e.g., cooling curves, thawing/melting, thermal microscopy and DTA methods), X-ray diffraction, microscopy, spectroscopy, dissolution rate, thermodynamic methods, etc.

The solid dispersion containing apixaban and the tablet containing the solid dispersion of the present invention will be described below.

Apixaban for use in the present invention can be chemically synthesized by the methods described in WO 2006/13542 and WO 2007/001385. The form of apixaban used to prepare the solid dispersion may be any form that does not interfere with the formulation of the solid dispersion, including a crystalline state. The particle size is also not particularly limited as long as it does not interfere with the formulation of the solid dispersion. For example, (Group A) the D90 (meaning the particle size measured by laser light scattering and corresponding to a 90% cumulative percentage on a volume basis) is 0.1 μm to 250 μm in some embodiments, 1 μm to 200 μm in some embodiments, 1 μm to 89 μm in some embodiments, and 1 μm to 60 μm in some embodiments; (Group B) 90 μm or more in some embodiments, 100 μm to 200 μm in some embodiments, and 120 μm to 180 μm in some embodiments.

The carrier used in the present invention is pharmaceutically acceptable, and examples thereof include polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., product name Soluplus (registered trademark); BASF Japan Ltd.), polyvinyl alcohol-polyethylene glycol graft copolymer (e.g., product name Kollicoat (registered trademark) IR; BASF Japan Ltd.), polyvinylpyrrolidone (PVP K30), copolyvidone (e.g., product name Kollidon (registered trademark) VA64; BASF Japan Ltd.), and hypromellose phthalate (e.g., product name HPMCP (registered trademark) HP-50; Shin-Etsu Chemical Co., Ltd.), hypromellose (e.g., HPMC2910 (product name TC-5 (registered trademark) E; Shin-Etsu Chemical Co., Ltd.)), hypromellose acetate succinate (HPMCAS, product name Shin-Etsu Chemical Co., Ltd.), and hypromellose acetate succinate (HPMCAS, product name Shin-Etsu Chemical Co., Ltd.). Examples of suitable carriers include one or more polymers selected from the group consisting of hypromellose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and polyvinylpyrrolidone. In one embodiment, the carrier is hypromellose phthalate. These carriers can be used alone or in appropriate combination of two or more. In the present invention, apixaban is supported on a carrier in an amorphous state to form a solid dispersion.
The amount of the carrier used in the present invention may be any amount that achieves the object of the present invention, and when expressed as the ratio of apixaban to carrier, it is 1:1 to 1:3 in one embodiment, or 1:1 to 1:2 in another embodiment. It can also be expressed as the amount per tablet, and when expressed as the amount per tablet, it is 1 to 8% in one embodiment, or 2 to 6% in another embodiment.

For tablets containing the apixaban-containing solid dispersion of the present invention, various pharmaceutical additives may be appropriately used within the range in which the desired effects of the present invention are achieved, such as excipients, disintegrants, surfactants, binders, coating agents, acidulants, effervescent agents, sweeteners, flavorings, colorants, buffers, antioxidants, lubricants, etc.

Examples of excipients include D-mannitol, corn starch, crystalline cellulose, trehalose, anhydrous calcium hydrogen phosphate, D-sorbitol, lactose, sucrose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

Examples of disintegrants include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and crospovidone.

Examples of surfactants include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

Examples of binders include polyvinyl alcohol, hypromellose, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone.

Examples of coating agents include hypromellose, hydroxypropyl cellulose, methyl cellulose, macrogol, talc, and titanium oxide.

Examples of acidulants include citric acid, tartaric acid, malic acid, etc.

Examples of the foaming agent include bilayer foam.

Examples of sweeteners include sucralose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

Examples of flavorings include lemon, lemon-lime, orange, and menthol.

Examples of coloring agents include iron sesquioxide, yellow iron sesquioxide, black iron oxide, titanium oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, Food Blue No. 3, and the like.

Examples of buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or salts thereof, and the like.

Examples of antioxidants include ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

Examples of lubricants include sodium stearyl fumarate, stearic acid, sodium stearate, talc, magnesium stearate, calcium stearate, hydrogenated oil, and sucrose fatty acid ester.

Various pharmaceutical additives to be incorporated into the apixaban-containing tablet of the present invention can be appropriately combined. The amount of additives to be incorporated is not particularly limited as long as it does not affect the achievement of the desired effects of the present invention.

The solid dispersion containing apixaban and the tablet containing the solid dispersion of the present invention will be described below.

First, an apixaban-containing solid dispersion is produced. The production method of the solid dispersion includes a solvent method.

In the solvent method, apixaban and a carrier are dissolved and/or suspended in a suitable solvent, and the solvent is removed from the solution to prepare a solid dispersion. The solvent may be removed by distillation under atmospheric pressure or under reduced pressure. Alternatively, the solvent may be removed by spray drying. Conditions can be appropriately set taking into consideration the stability of apixaban and the carrier. The solvent can be removed by a method known per se. For example, the solvent can be removed by filtration or evaporation, or by a combination of evaporation and filtration.

The solvent used in the solvent method is not particularly limited, as long as it is pharmaceutically acceptable and capable of dissolving (and/or suspending) apixaban (at least partially or entirely) and the carrier. Specific examples include water, methanol, ethanol, isopropanol, propanol, methyl acetate, ethyl acetate, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, and methylene chloride. In some embodiments, one or more solvents selected from the group consisting of water, methanol, ethanol, and methylene chloride are used. Examples of combinations of two or more solvents include a water-ethanol mixture, a methylene chloride-ethanol mixture, and a methylene chloride-ethanol mixture.

For example, when two solvents are used in combination, the blending ratio is 90:10 to 10:90 in one embodiment, 80:20 to 20:80 in one embodiment, or 75:25 to 25:75 in one embodiment. In the case of combinations, the blending ratio of a methylene chloride/ethanol mixture is 90:10 to 30:70 in one embodiment, 90:10 to 50:50 in one embodiment, or 70:30 in one embodiment. The blending ratio of a water/ethanol mixture is 90:10 to 10:90 in one embodiment, 80:20 to 20:80 in one embodiment, or 25:75 in one embodiment.

The solid dispersion and tablet containing apixaban of the present invention can be produced by a method known per se.

(Method for producing solid dispersion)
For example, apixaban and a carrier (e.g., Soluplus, HPMC2910 (TC-5E), HPMCAS (AS-MG), HPMCAS (AS-HG), or PVP (K-30)) are placed in the same container or in separate containers, and a methylene chloride:ethanol mixed solution is added to dissolve and/or suspend them. Next, the solvent is distilled off (for example, by evaporating, spray drying, freeze-drying, etc.) from this solution or suspension (or, if placed in separate containers, from this solution or suspension after transferring to the same container) to obtain an apixaban solid dispersion.

(Tablet manufacturing method)
Tablets containing apixaban solid dispersions are produced by employing processes known per se. For example, apixaban solid dispersions can be mixed with excipients, disintegrants, surfactants, binders, coating agents, acidulants, effervescent agents, sweeteners, flavorings, colorants, buffers, antioxidants, lubricants, etc., and then produced by a method known per se.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to the following examples in any way.

<Dissolution tests using various solvents>
Apixaban (125 mg in a THF/water mixture, 100 mg in an ethanol/water mixture, and 250 mg in a methylene chloride/ethanol mixture) was added to 5 mL of each solvent and shaken for at least 12 hours. The resulting solution was centrifuged (3,000 rpm, 10 minutes), and the supernatant was filtered through a 0.45 μm filter. 1 mL of the filtered sample was weighed into a 250 mL volumetric flask and diluted with a dilution solvent (acetonitrile/water mixture (3:7) for the THF/water mixture and ethanol/water mixture, and acetonitrile for the methylene chloride/ethanol mixture) to prepare the sample solution for measurement. The sample solution was analyzed using high-performance liquid chromatography, and the amount of dissolved apixaban was calculated. The results of the dissolution test using a THF/water mixture, Table 1, the results of the dissolution test using an ethanol/water mixture, and Table 3 and Figure 1 show the results of the dissolution test using a methylene chloride/ethanol mixture.

<Dissolution tests using various carrier solutions>
300 mg of apixaban was added to 5 mL of each carrier solution (the carrier concentration was adjusted to give apixaban/carrier ratios of 1:1, 1:2, or 1:3) and shaken for at least 12 hours. The resulting solution was centrifuged (3,000 rpm, 10 minutes), and the supernatant was filtered through a 0.45 μm filter. 1 mL of the filtered sample was weighed into a 250 mL volumetric flask and made up to volume with acetonitrile to prepare the measurement sample. The sample solution was analyzed using high-performance liquid chromatography, and the amount of dissolved apixaban was calculated. The test results are shown in Table 4.

Examples 1 to 3 (Carrier: Soluplus)
1.6 g, 3.2 g, and 4.8 g of Soluplus (product name) were each dissolved in 50 mL of a mixed solution of methylene chloride:ethanol in a ratio of 7:3. 1.6 g of apixaban was added and dissolved in this solution. The solvent was removed using an evaporator to obtain the apixaban solid dispersions of Example 1 (apixaban/carrier = 1:1), Example 2 (apixaban/carrier = 1:2), and Example 3 (apixaban/carrier = 1:3) of the present invention.

Examples 4 to 6 (Carrier: HPMC2910)
1.6 g, 3.2 g, and 4.8 g of HPMC2910 (TC-5E) (product name) were each dissolved in 50 mL of a mixed solution of methylene chloride:ethanol in a ratio of 7:3. 1.6 g of apixaban was added to this solution and dissolved. The solvent was removed using an evaporator to obtain the apixaban solid dispersions of the present invention of Example 4 (apixaban/carrier=1:1), Example 5 (apixaban/carrier=1:2), and Example 6 (apixaban/carrier=1:3).

Examples 7 to 9 (Carrier: Hypromellose Phthalate)
1.6 g, 3.2 g, and 4.8 g of hypromellose phthalate (HPMCP, HP-50) (product name) were each dissolved in 50 mL of a mixed solution of methylene chloride:ethanol in a ratio of 7:3. 1.6 g of apixaban was added to this solution and dissolved. The solvent was removed using an evaporator to obtain the apixaban solid dispersions of the present invention of Example 7 (apixaban/carrier=1:1), Example 8 (apixaban/carrier=1:2), and Example 9 (apixaban/carrier=1:3).

Examples 10 to 12 (Carrier: HPMCAS (AS-MG))
1.6 g, 3.2 g, and 4.8 g of HPMCAS (AS-MG) (product name) were each dissolved in 50 mL of a mixed solution of methylene chloride:ethanol in a ratio of 7:3. 1.6 g of apixaban was added to this solution and dissolved. The solvent was removed using an evaporator to obtain apixaban solid dispersions of the present invention in Example 10 (apixaban/carrier=1:1), Example 11 (apixaban/carrier=1:2), and Example 12 (apixaban/carrier=1:3).

Examples 13 to 15 (Carrier: HPMCAS (AS-HG))
1.6 g, 3.2 g, and 4.8 g of HPMCAS (AS-HG) (product name) were each dissolved in 50 mL of a mixed solution of methylene chloride:ethanol in a ratio of 7:3. 1.6 g of apixaban was added to this solution and dissolved. The solvent was removed using an evaporator to obtain apixaban solid dispersions of the present invention in Example 13 (apixaban/carrier=1:1), Example 14 (apixaban/carrier=1:2), and Example 15 (apixaban/carrier=1:3).

Examples 16 to 18 (Carrier: PVP)
1.6 g, 3.2 g, and 4.8 g of PVP (K-30) were each dissolved in 50 mL of a mixed solution of methylene chloride:ethanol in a ratio of 7:3. 1.6 g of apixaban was added to this solution and dissolved. The solvent was removed using an evaporator to obtain apixaban solid dispersions of the present invention in Example 16 (apixaban/carrier=1:1), Example 17 (apixaban/carrier=1:2), and Example 18 (apixaban/carrier=1:3).

The apixaban solid dispersions obtained in Examples 1, 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, and 18 were pulverized in a mortar, and the crystal form was confirmed using a powder X-ray diffractometer. The measurement results are shown in Figures 2 and 3.

Examples 19 to 21 (Carrier: Hypromellose Phthalate)
4.8 g, 9.6 g, and 14.4 g of hypromellose phthalate (HPMCP, HP-50) were each added to 150 mL of a mixed solution of methylene chloride:ethanol in a ratio of 7:3 and dissolved. 4.8 g of apixaban was added to this solution and dissolved. The solvent was removed using an evaporator to obtain apixaban solid dispersions of the present invention in Example 19 (apixaban/carrier=1:1), Example 20 (apixaban/carrier=1:2), and Example 21 (apixaban/carrier=1:3).

Example 22 (Carrier: Soluplus)
9.6 g of Soluplus (product name) was dissolved in 150 mL of a mixed solution of methylene chloride and ethanol in a ratio of 7:3. 4.8 g of apixaban was dissolved in this solution. The solvent was removed using an evaporator to obtain the apixaban solid dispersion of the present invention.

Example 23 (Carrier: HPMC2910)
9.6 g of HPMC2910 (TC-5E) (product name) was dissolved in 150 mL of a mixed solution of methylene chloride and ethanol in a ratio of 7:3. 4.8 g of apixaban was dissolved in this solution. The solvent was removed using an evaporator to obtain the apixaban solid dispersion of the present invention.

Example 24 (Carrier: HPMCAS (AS-MG))
9.6 g of HPMCAS (AS-MG) (product name) was dissolved in 150 mL of a mixed solution of methylene chloride and ethanol in a ratio of 7:3. 4.8 g of apixaban was dissolved in this solution. The solvent was removed using an evaporator to obtain the apixaban solid dispersion of the present invention.

Example 25 (Carrier: HPMCAS (AS-HG))
9.6 g of HPMCAS (AS-HG) (product name) was dissolved in 150 mL of a mixed solution of methylene chloride and ethanol in a ratio of 7:3. 4.8 g of apixaban was dissolved in this solution. The solvent was removed using an evaporator to obtain the apixaban solid dispersion of the present invention.

Example 26 (Carrier: PVP)
9.6 g of PVP (K-30) was dissolved in 150 mL of a mixed solution of methylene chloride and ethanol in a ratio of 7:3. 4.8 g of apixaban was dissolved in this solution. The solvent was removed using an evaporator to obtain the apixaban solid dispersion of the present invention.

The apixaban solid dispersions obtained in Examples 20 and 22 to 26 were pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800), and the crystal form was confirmed using a powder X-ray diffraction measurement device. The measurement results are shown in Figure 4.

The dissolution properties of the apixaban solid dispersions (Examples 19 to 26) were evaluated by the dissolution test method (paddle method, 50 rpm, test solution pH 6.8) of the Japanese Pharmacopoeia, 17th Edition, using the unpulverized apixaban product as Comparative Example 1. The test results are shown in Table 5 and Figures 5 and 6.

Example 27: Tablets
The apixaban solid dispersion prepared in Example 19 was pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800). 49.25 g of lactose hydrate, 39.5 g of microcrystalline cellulose, 4 g of croscarmellose sodium, and 1 g of sodium lauryl sulfate were added to 5 g of the resulting pulverized product and mixed for 3 minutes, followed by addition of 1.25 g of magnesium stearate and mixing for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets of the present invention. 50.93 g of hypromellose, 10.19 g of macrogol 6000, 17.82 g of talc, and 5.09 g of titanium oxide were dissolved and dispersed in 643.5 g of purified water to prepare a coating solution. Using a coating device (PRC-1.5GTX, manufactured by Powrex), the coating liquid is sprayed onto the tablets until a predetermined mass is reached, thereby carrying out film coating, and the film-coated tablets of the present invention are obtained.

Example 28: Tablets
The apixaban solid dispersion prepared in Example 20 was pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800). To 7.5 g of the resulting pulverized product, 46.75 g of lactose hydrate, 39.5 g of microcrystalline cellulose, 4 g of croscarmellose sodium, and 1 g of sodium lauryl sulfate were added and mixed for 3 minutes, and 1.25 g of magnesium stearate was further added and mixed for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets of the present invention. 50.93 g of hypromellose, 10.19 g of macrogol 6000, 17.82 g of talc, and 5.09 g of titanium oxide were dissolved and dispersed in 643.5 g of purified water to prepare a coating solution. Using a coating device (PRC-1.5GTX, manufactured by Powrex), the coating liquid is sprayed onto the tablets until a predetermined mass is reached, thereby carrying out film coating, and the film-coated tablets of the present invention are obtained.

Example 29: Tablets
The apixaban solid dispersion prepared in Example 21 was pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800). To 20 g of the resulting pulverized product, 88.5 g of lactose hydrate, 79 g of microcrystalline cellulose, 8 g of croscarmellose sodium, and 2 g of sodium lauryl sulfate were added and mixed for 3 minutes, and 2.5 g of magnesium stearate was then added and mixed for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets of the present invention. 77 g of hypromellose, 15.4 g of macrogol 6000, 26.95 g of talc, and 7.7 g of titanium oxide were dissolved and dispersed in 972.95 g of purified water to obtain a coating solution. Using a coating device (Powrex Corporation, PRC-1.5GTX), the coating solution was sprayed onto the tablets until a predetermined mass was reached, followed by film coating to obtain film-coated tablets of the present invention.

Example 30: Tablets
The apixaban solid dispersion prepared in Example 22 was pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800). To 7.5 g of the resulting pulverized product, 46.75 g of lactose hydrate, 39.5 g of microcrystalline cellulose, 4 g of croscarmellose sodium, and 1 g of sodium lauryl sulfate were added and mixed for 3 minutes, and 1.25 g of magnesium stearate was then added and mixed for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets of the present invention. A coating solution was prepared by dissolving and dispersing 127.31 g of hypromellose, 25.46 g of macrogol 6000, 44.56 g of talc, and 12.73 g of titanium oxide in 1608.64 g of purified water. Using a coating device (PRC-1.5GTX, manufactured by Powrex), the coating liquid is sprayed onto the tablets until a predetermined mass is reached, thereby carrying out film coating, and the film-coated tablets of the present invention are obtained.

Example 31: Tablets
The apixaban solid dispersion prepared in Example 23 was pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800). To 7.5 g of the resulting pulverized product, 46.75 g of lactose hydrate, 39.5 g of microcrystalline cellulose, 4 g of croscarmellose sodium, and 1 g of sodium lauryl sulfate were added and mixed for 3 minutes, and 1.25 g of magnesium stearate was further added and mixed for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets of the present invention. A coating solution was prepared by dissolving and dispersing 127.31 g of hypromellose, 25.46 g of macrogol 6000, 44.56 g of talc, and 12.73 g of titanium oxide in 1608.64 g of purified water. Using a coating device (PRC-1.5GTX, manufactured by Powrex), the coating liquid is sprayed onto the tablets until a predetermined mass is reached, thereby carrying out film coating, and the film-coated tablets of the present invention are obtained.

Example 32: Tablets
The apixaban solid dispersion prepared in Example 25 was pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800). To 7.5 g of the resulting pulverized product, 46.75 g of lactose hydrate, 39.5 g of microcrystalline cellulose, 4 g of croscarmellose sodium, and 1 g of sodium lauryl sulfate were added and mixed for 3 minutes, and 1.25 g of magnesium stearate was further added and mixed for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets of the present invention. A coating solution was prepared by dissolving and dispersing 127.31 g of hypromellose, 25.46 g of macrogol 6000, 44.56 g of talc, and 12.73 g of titanium oxide in 1608.64 g of purified water. Using a coating device (PRC-1.5GTX, manufactured by Powrex), the coating liquid is sprayed onto the tablets until a predetermined mass is reached, thereby carrying out film coating, and the film-coated tablets of the present invention are obtained.

Example 33: Tablets
The apixaban solid dispersion prepared in Example 26 was pulverized using a small pulverizer (Iwatani Corporation, Iwatani Millser, IFM-800). To 7.5 g of the resulting pulverized product, 46.75 g of lactose hydrate, 39.5 g of microcrystalline cellulose, 4 g of croscarmellose sodium, and 1 g of sodium lauryl sulfate were added and mixed for 3 minutes, and 1.25 g of magnesium stearate was then added and mixed for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets of the present invention. A coating solution was prepared by dissolving and dispersing 127.31 g of hypromellose, 25.46 g of macrogol 6000, 44.56 g of talc, and 12.73 g of titanium oxide in 1608.64 g of purified water. Using a coating device (PRC-1.5GTX, manufactured by Powrex), the coating liquid is sprayed onto the tablets until a predetermined mass is reached, thereby carrying out film coating, and the film-coated tablets of the present invention are obtained.

Comparative Example 2: Tablets
5 g of apixaban was mixed with 103.5 g of lactose hydrate, 79 g of microcrystalline cellulose, 8 g of croscarmellose sodium, and 2 g of sodium lauryl sulfate for 3 minutes, and then 2.5 g of magnesium stearate was added and mixed for 1 minute. The resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho, VEL-5) to obtain tablets. 77 g of hypromellose, 15.4 g of macrogol 6000, 26.95 g of talc, and 7.7 g of titanium oxide were dissolved and dispersed in 972.95 g of purified water to obtain a coating solution. Using a coating device (Powrex, PRC-1.5GTX), the coating solution was sprayed onto the tablets until the desired mass was reached, followed by film coating to obtain film-coated tablets of the comparative example.

The ingredients and amounts per tablet of Examples 27 to 29 and Comparative Example 2 are shown in Table 6.

The ingredients and amounts per tablet of Examples 30 to 33 and Comparative Example 2 are shown in Table 7.

The dissolution properties of the tablets containing apixaban solid dispersion (Examples 27 to 33) and the tablet not containing apixaban solid dispersion (Comparative Example 2) were evaluated by the dissolution test method (paddle method, 50 rpm, test solution pH 6.8) of the Japanese Pharmacopoeia, 17th Edition. The test results are shown in Table 8 and Figures 7 and 8.

Claims (5)

Apixaban solid dispersion containing apixaban and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The apixaban solid dispersion according to claim 1, wherein the ratio of the mass of apixaban to the mass of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1:1 to 1:3. An apixaban-containing tablet containing the apixaban solid dispersion according to claim 1 or 2. The apixaban-containing tablet according to claim 3, which is a film-coated tablet. A method for producing an apixaban solid dispersion, comprising dissolving polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and apixaban in a mixed solution of methylene chloride and ethanol,
The method wherein the ratio of the mass of methylene chloride to the mass of ethanol in the mixed solution is 9:1 to 6:4.