JP7641098B2 - Rivaroxaban-containing tablets - Google Patents

Description

The present invention relates to a pharmaceutical tablet containing rivaroxaban, which has improved dissolution properties and oral absorbability.

Rivaroxaban is a selective direct-acting factor Xa inhibitor and is useful for the prevention and treatment of thromboembolic diseases.

The active ingredient is rivaroxaban, and the drug is sold as a pharmaceutical formulation called "Xarelto (registered trademark) tablets" and "Xarelto (registered trademark) fine granule sachets" (Bayer Yakuhin, Ltd.). The pharmaceutical package insert for the tablets states that the tablets are film-coated tablets containing hypromellose (Non-Patent Document 1).

On the other hand, Patent Document 1, which may be related to "Xarelto (registered trademark) tablets" and "Xarelto (registered trademark) fine granules sachets" as preparations containing rivaroxaban as an active ingredient, describes an invention relating to a pharmaceutical composition containing rivaroxaban in which BA is improved by adopting a wet granulation method (fluidized bed granulation) in the formulation process, since rivaroxaban has relatively poor water solubility (about 7 mg/L), low oral bioavailability (hereinafter referred to as BA) and increased biological variability in absorption rate. In addition, as for the specific formulation, a pharmaceutical composition manufactured by fluidized bed granulation or high-speed stirring granulation is described.

The pharmaceutical package insert states that the tablet is a film-coated tablet containing crystalline cellulose, croscarmellose sodium, hypromellose, lactose hydrate, magnesium stearate, sodium lauryl sulfate, ferric oxide, macrogol 4000, and titanium oxide (Non-Patent Document 1).

Patent Document 2 describes an invention relating to a rivaroxaban-containing tablet produced by high-speed stirring granulation or fluidized bed granulation using a specific formulation with ingredients almost identical to those in Patent Document 1.

Patent Document 3 describes an invention relating to a pharmaceutical composition having improved dissolution and high oral BA. It describes the discovery that microcrystalline cellulose reduces the dissolution of rivaroxaban (problem) in the tablet specifically disclosed in the examples, and describes a means for solving the problem, relating to a pharmaceutical composition containing 5% or less crystalline cellulose.

However, there is a need for the development of new technologies that can improve the solubility of rivaroxaban and result in good bioavailability.

Japanese Patent No. 4852423 International Publication No. 2017/146709 JP 2019-108324 A

Package insert "Xarelto Tablets 10 mg/15 mg", revised June 2019 (1st edition)

Rivaroxaban is a poorly water-soluble drug, and therefore it is necessary to improve its dissolution and oral absorbability when it is orally administered. The present invention provides a pharmaceutical composition containing rivaroxaban as an active ingredient, which has improved dissolution and excellent oral bioavailability.

Therefore, an object of the present invention is to provide a pharmaceutical tablet containing rivaroxaban having improved dissolution properties and oral absorbability.

The inventors of the present invention have confirmed that, with respect to various polymers, a specific cellulose-based polymer has the effects of the present invention from the viewpoint of the ability to maintain a supersaturated state of rivaroxaban in a solution, and have thus completed the present invention.

That is, the present invention is as follows:
(1) A tablet comprising rivaroxaban and one or more cellulose polymers selected from the group consisting of hypromellose, hydroxypropyl cellulose, and methylcellulose.
(2) The tablet according to (1), wherein the viscosity of the cellulose-based polymer is 1 to 10 mPa s.
(3) The tablet according to any one of (1) to (2), further comprising a pharmaceutical additive.
(4) The tablet according to any one of (1) to (3), wherein the pharmaceutical additive comprises one or more selected from the group consisting of an excipient, a disintegrant, a lubricant, and a surfactant.
(5) The tablet according to any one of (1) to (4), wherein the excipient comprises one or more selected from the group consisting of D-mannitol, lactose hydrate, D-sorbitol, sucrose, starch, alpha-starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate;
(6) The tablet according to any one of (1) to (5), wherein the disintegrant comprises one or more selected from the group consisting of corn starch, potato starch, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and crospovidone.
(7) The tablet according to any one of (1) to (6), wherein the lubricant comprises one or more selected from the group consisting of sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, calcium stearate, hardened oil, and sucrose fatty acid ester.
(8) The tablet according to any one of (1) to (7), wherein the surfactant comprises one or more selected from the group consisting of polysorbate 80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil.
(9) The tablet according to any one of (1) to (8), wherein the amount of the cellulose polymer is 0.1 to 10% by weight based on the total weight of the tablet.
(10) A method for producing a tablet comprising adding a solvent containing a cellulose-based polymer to a mixture containing rivaroxaban and carrying out stirring granulation to produce a granulated product containing rivaroxaban.

By adopting the configuration of the present invention, when rivaroxaban is in a supersaturated state in a solution, the supersaturated state can be maintained (see Test Example 1 described below), and the solubility of rivaroxaban can be improved, thereby increasing the dissolution rate of rivaroxaban, and as a result, the oral bioavailability of rivaroxaban can be expected to be improved.

A drug substance solution in which rivaroxaban was dissolved was dropped into a test solution in which various binders were dissolved in water, and the amount of rivaroxaban dissolved was calculated over time from the start of the test using a UV measurement method to evaluate the precipitation of rivaroxaban. FIG. 1 shows the dissolution profiles of rivaroxaban over time from the formulations of Examples 1-6 and Comparative Examples 1-2.

The rivaroxaban-containing pharmaceutical composition of the present invention will be described below.

The rivaroxaban used in the present invention has the generic name 5-chloro-N-([{5S}-2-oxo-3-[4-(3-oxomorpholin-4-yl)-phenyl]-1,3-oxazolidin-5-yl]methyl)thiophene-2-carboxamide, and medicines containing this active ingredient are already in clinical use, so rivaroxaban is easily available. Rivaroxaban can be used in either a crystalline or amorphous form.

The efficacy and effects are to suppress the onset of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, and to treat and suppress recurrence of deep vein thrombosis and pulmonary thromboembolism. Regarding the dosage and administration, in the former case, 15 mg of rivaroxaban is orally administered once a day after a meal to adults. For patients with renal impairment, the dosage is reduced to 10 mg once a day depending on the degree of renal function. In the latter case, 15 mg of rivaroxaban is orally administered twice a day after a meal to adults for the first three weeks after the onset of deep vein thrombosis or pulmonary thromboembolism, and thereafter 15 mg is orally administered once a day after a meal.

The amount of rivaroxaban blended is not particularly limited as long as it is the amount of rivaroxaban in the formulation that constitutes the dosage of the pharmaceutical formulation, for example, 1 to 20% by weight in one embodiment, and 5 to 15% by weight in another embodiment.

The cellulose-based polymer used in the present invention is not particularly limited as long as it improves the solubility of rivaroxaban, such as one that can maintain a supersaturated state of rivaroxaban in a solution. The cellulose-based polymer is not particularly limited as long as it is pharma- ceutical acceptable and has a viscosity of 1 to 10 mPa·s. Specific examples include hypromellose, hydroxypropyl cellulose, methyl cellulose, and the like. In one embodiment, hypromellose includes a grade with a viscosity of 1 to 10 mPa·s (about 4.5 mPa·s), such as TC-5M (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.); hydroxypropyl cellulose includes a grade with a viscosity of 1 to 10 mPa·s (about 3 to 5.9 mPa·s), such as HPC-SL (trade name, manufactured by Nippon Soda Co., Ltd.); and methyl cellulose includes a grade with a viscosity of 1 to 10 mPa·s (about 4 mPa·s), such as SM-4 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.). The viscosity value means a 2% aqueous solution concentration at 20° C. (Japanese Pharmacopoeia). The viscosity is measured according to the viscosity measurement method of the Japanese Pharmacopoeia, 17th Edition. Specifically, for example, the Ubbelohde capillary viscometer method can be used.

The amount of the cellulose-based polymer is not particularly limited as long as it is an amount that improves the solubility of rivaroxaban, such as maintaining a supersaturated state of rivaroxaban in the solution. Specifically, for example, it is 0.1% by weight or more, in one embodiment, 0.5% by weight or more, and 10% by weight or less, in one embodiment, 5% or less (equivalent to 3% by weight in the embodiment). The lower limit and/or upper limit can be combined with an appropriate numerical value. Specifically, for example, it can be 0.1 to 10% by weight, 0.5 to 5% by weight, 0.5 to 10% by weight, 0.1 to 5% by weight, etc. A part of the cellulose-based polymer may be coated as a coating agent, and is interpreted as the amount contained in the tablet.

The incorporation of the cellulose-based polymer is not particularly limited as long as it is contained in the tablet of the present invention. Specifically, the incorporation of the cellulose-based polymer includes, for example, an embodiment in which the cellulose-based polymer is contained as an excipient, a binder, a coating agent, or the like.

In this specification, the term "tablets" refers to tablets including plain tablets, OD tablets, and film-coated tablets.

The rivaroxaban-containing tablet of the present invention contains one or more pharmaceutical additives selected from the group consisting of excipients, disintegrants, lubricants, and surfactants.

Examples of excipients include D-mannitol, D-sorbitol, lactose hydrate, sucrose, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, 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 sodium, low-substituted hydroxypropyl cellulose, crospovidone, and the like.

Examples of lubricants include sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, calcium stearate, hardened oil, sucrose fatty acid esters, and the like.

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

The tablet containing rivaroxaban of the present invention is formulated by appropriately using various other pharmaceutical additives within the scope of achieving the desired effect of the present invention. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutical and pharmacologically acceptable. For example, binders, coating agents, acidulants, effervescent agents, sweeteners, flavorings, colorants, buffers, antioxidants, etc. may be used.

Examples of binders include gum arabic, hydroxyethyl cellulose, polyvinylpyrrolidone, and the like.

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

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

The foaming agent may, for example, be sodium bicarbonate.

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

Examples of the flavoring include lemon, lemon-lime, orange, menthol, and the like.

Examples of coloring agents include ferric oxide, yellow ferric oxide, black ferric 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 the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or a salt thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or a salt thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or a salt thereof, and the like.

Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

The tablet of the present invention can be produced by a method known per se, including steps of pulverization, mixing, granulation, drying, molding (tabletting), coating, etc. In detail, the tablet of the present invention is produced by mixing rivaroxaban (which may be pre-pulverized), an excipient (e.g., D-mannitol, crystalline cellulose, etc.), and a disintegrant (e.g., carmellose, etc.), stirring and granulating the mixture with a solution of a cellulose-based polymer (e.g., hypromellose, hydroxypropyl cellulose, methylcellulose, etc.) and a surfactant (e.g., sodium lauryl sulfate, etc.) dissolved and/or suspended in a solvent (e.g., water, etc.) as a binding liquid, drying and sieving the granulated product, mixing a disintegrant (e.g., crospovidone, etc.) and a lubricant (e.g., sodium stearyl fumarate, etc.) with the granulated product, and compression-molding (e.g., tableting) the mixture to produce plain tablets (the tablet of the present invention). Furthermore, the uncoated tablet is coated with a coating agent (e.g., hypromellose, macrogol 6000, titanium oxide, talc, etc.) to produce a film-coated tablet (the tablet of the present invention). The step of blending rivaroxaban may be any step in the granulation process, such as a mixing step, a step of preparing a binder solution, or a step of adding a disintegrant and a lubricant to the granules and mixing them.

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

Test Example 1: Examination of maintaining supersaturation
We searched for a binder that exhibits high supersaturation maintenance properties for rivaroxaban. The binders used in this study are shown in Table 1 below.

A test solution was prepared by dissolving 3 mg of binder in 900 ml of purified water, and 1.5 ml of a drug substance solution prepared by dissolving 2 g of rivaroxaban in 30 ml of dimethyl sulfoxide was dropped into the test solution, and a dissolution test was performed using the paddle method at 200 rpm. 10 mL of samples were taken over time from the start of the test until 30 minutes after the start of the test, and filtered through a membrane filter with a pore size of 0.45 μm. For the solution in which 4 mL of acetonitrile was added to 1 mL of the filtrate, the dissolution rate was calculated from the absorbance at a wavelength of 248.0 nm by UV measurement. The measurement results are shown in Figure 1.

The results shown in FIG. 1 reveal that TC-5M, SM-4, and HPC-SL have superior supersaturation maintenance properties compared to other binders.

(Binder: TC-5M)
20 g of rivaroxaban, 135 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into an agitation granulator (Powrex: VG-01) and agitated, and then a binder solution in which 6 g of hydroxypropylmethylcellulose (hypromellose; Shin-Etsu Chemical: TC-5M) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water is sprayed and granulated. After completion of granulation, the mixture is sieved through a sieve with a mesh size of 1.7 mm, dried using a fluidized bed granulation dryer (Powrex: MP-01), and sieved again through a sieve with a mesh size of 1.0 mm to obtain a sized powder. 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) is added to the obtained sized powder and mixed, and then 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain a tablet powder. Using a rotary tablet press (VEL5, manufactured by Kikusui Seisakusho), the tablet is made into a circular tablet having a tablet mass of 100 mg and a diameter of 6.5 mm, and tableted at a final pressure of 11 kg to obtain the tablet of the present invention (Tablet 1).

(Binder: HPC-SL)
20 g of rivaroxaban, 135 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into a stirring granulator (Powrex: VG-01) and stirred, and then a binder solution in which 6 g of hydroxypropyl cellulose (Nippon Soda: HPC-SL) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water is sprayed and granulated. After completion of granulation, the mixture is sieved through a sieve with a mesh size of 1.7 mm, dried using a fluidized bed granulation dryer (Powrex: MP-01), and sieved again through a sieve with a mesh size of 1.0 mm to obtain a sized powder. The resulting sized powder was mixed with 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan), and then mixed with 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) to obtain a tablet powder. Using a rotary tablet press (VEL5, manufactured by Kikusui Seisakusho), the tablet mass was made into a circular tablet with a diameter of 100 mg and a diameter of 6.5 mm, and the tablet was compressed at a pressure of 10 kg to obtain the tablet (tablet 2) of the present invention.

(Binder: SM-4)
20 g of rivaroxaban, 135 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into an agitation granulator (Powrex: VG-01) and agitated, and then a binder solution in which 6 g of methylcellulose (Shin-Etsu Chemical: SM-4) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water is sprayed and granulated. After completion of granulation, the mixture is sieved through a sieve with a mesh size of 1.7 mm, dried using a fluidized bed granulation dryer (Powrex: MP-01), and sieved again through a sieve with a mesh size of 1.0 mm to obtain a sized powder. 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) is added to the obtained sized powder and mixed, and then 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain a tablet powder. Using a rotary tablet press (VEL5, manufactured by Kikusui Seisakusho), the tablet is made into a circular tablet having a tablet mass of 100 mg and a diameter of 6.5 mm, and compressed at a main pressure of 11 kg to obtain the tablet of the present invention (Tablet 3).

Comparative Example 1 (Binder: PD-1)
20 g of rivaroxaban, 135 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into a stirring granulator (Powrex: VG-01) and stirred, and then a binder solution in which 6 g of pregelatinized starch (Asahi Kasei: PD-1) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water is sprayed and granulated. After completion of granulation, the mixture is sieved through a sieve with 1.7 mm openings, dried using a fluidized bed granulation dryer (Powrex: MP-01), and sieved again through a sieve with 1.0 mm openings to obtain a sized powder. The resulting sized powder was mixed with 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan), and then mixed with 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) to obtain a tablet powder. Using a rotary tablet press (VEL5, manufactured by Kikusui Seisakusho), the tablet mass was made into a circular tablet with a diameter of 6.5 mm and a tableting pressure of 10 kg to obtain a comparative tablet (Tablet 4).

<<Comparative Example 3>>
(Binder: TC-5M)
135 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into a stirring granulator (Powrex: VG-01) and stirred to prepare a mixture for granulation. 6 g of hydroxypropyl methylcellulose (hypromellose; Shin-Etsu Chemical: TC-5M) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water, and 20 g of rivaroxaban is further suspended in this solution to obtain a binder solution. The binder solution is added dropwise while stirring the mixture for granulation to granulate it. After the granulation is completed, the mixture is sieved through a sieve with a mesh size of 1.7 mm, dried using a fluidized bed granulation dryer (Powrex: MP-01), and then sieved again through a sieve with a mesh size of 1.0 mm to obtain a sized powder. 3 g of crospovidone (BASF Japan: Kollidon CL-F) is added to the obtained sized powder and mixed, and then 3 g of sodium stearyl fumarate (JRS Pharma: PRUV) is added and mixed to obtain a tablet powder. Using a rotary tablet press (Kikusui Seisakusho: VEL5), the mixture is made into a circular tablet with a tablet mass of 100 mg and a diameter of 6.5 mm, and tableted to obtain the tablet (Tablet 5) of Comparative Example 3 .

<<Comparative Example 4>>
(Binder: HPC-SL)
135 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into an agitation granulator (Powrex: VG-01) and agitated to obtain a mixture for granulation. 6 g of hydroxypropyl cellulose (Nippon Soda: HPC-SL) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water, and 20 g of rivaroxaban is suspended in this solution to obtain a binder solution. The binder solution is dropped while stirring the mixture for granulation to granulate. After completion of granulation, the mixture is sieved through a sieve with 1.7 mm openings, dried using a fluidized bed granulation dryer (Powrex: MP-01), and sieved again through a sieve with 1.0 mm openings to obtain a sized powder. 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) was added to the obtained sized powder and mixed, and then 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) was added and mixed to obtain a tablet powder. Using a rotary tablet press (VEL5, manufactured by Kikusui Seisakusho), the tablet mass was 100 mg and the tablet was compressed into a circular tablet having a diameter of 6.5 mm to obtain the tablet of Comparative Example 4 (Tablet 6).

<<Comparative Example 5>>
(Binder: SM-4) 135 g of D-mannitol (Mitsubishi Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into a stirring granulator (Powrex: VG-01) and stirred to prepare a mixture for granulation. 6 g of methylcellulose (Shin-Etsu Chemical: SM-4) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water, and 20 g of rivaroxaban is further suspended in this solution to obtain a binder solution. The binder solution is added dropwise while stirring the mixture for granulation to granulate. After the granulation is completed, the mixture is sieved through a sieve with a mesh size of 1.7 mm, dried using a fluidized bed granulation dryer (Powrex: MP-01), and then sieved again through a sieve with a mesh size of 1.0 mm to obtain a sized powder. 3 g of crospovidone (BASF Japan: Kollidon CL-F) is added to the obtained sized powder and mixed, and then 3 g of sodium stearyl fumarate (JRS Pharma: PRUV) is added and mixed to obtain a tablet powder. Using a rotary tablet press (Kikusui Seisakusho: VEL5), the mixture is made into a circular tablet with a tablet mass of 100 mg and a diameter of 6.5 mm, and tableted to obtain the tablet of Comparative Example 5 (Tablet 7).

Comparative Example 2 (Binder: PD-1)
135 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannit P), 20 g of carmellose (Godo Pharmaceutical: NS300), and 12 g of crystalline cellulose (Asahi Kasei: PH-101) are charged into an agitation granulator (Powrex: VG-01) and agitated to obtain a mixture for granulation. 6 g of pregelatinized starch (Asahi Kasei: PD-1) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) are dissolved in 43 g of purified water, and 20 g of rivaroxaban is suspended in this solution to obtain a binder solution. The binder solution is dropped while stirring the mixture for granulation to granulate. After completion of granulation, the mixture is sieved through a sieve with 1.7 mm openings, dried using a fluidized bed granulation dryer (Powrex: MP-01), and sieved again through a sieve with 1.0 mm openings to obtain a sized powder. 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) is added to the obtained sized powder and mixed, and then 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain a tablet powder. Using a rotary tablet press (VEL5, manufactured by Kikusui Seisakusho), the tablet is made into a circular tablet having a tablet mass of 100 mg and a diameter of 6.5 mm, and tableted to obtain the tablet of the present invention (tablet 8).

Test Example 2: Dissolution test
Dissolution tests were conducted using the tablets obtained in Examples 1 to 3 and Comparative Examples 1 to 5. Dissolution of the tablets was conducted in 900 ml of acetic acid/sodium acetate buffer solution of pH 4.5 containing 0.2% sodium lauryl sulfate in a dissolution tester (manufactured by Toyama Sangyo) by the paddle method at 75 rpm. 10 ml of sample was withdrawn over time from the start of the test until 30 minutes later, filtered through a membrane filter with a pore size of 0.45 μm, and the filtrate was diluted 2-fold with acetonitrile. The dissolution rate of this solution was calculated from the absorbance at a wavelength of 248.0 nm by UV measurement. The measurement results are shown in Table 2 and FIG. 2.

From the results in Table 2 and Figure 2, the dissolution profile clearly demonstrates that tablets prepared according to the present invention enhance the solubility of the drug.

Claims (10)

A compressed tablet comprising a granulated material containing rivaroxaban and one or more cellulose polymers selected from the group consisting of hypromellose, hydroxypropyl cellulose, and methylcellulose,
The granules are formed from a granulation mixture and a granulation liquid,
The tablet is characterized in that the granulation mixture contains rivaroxaban together with D-mannitol in an amount more than twice the weight of the rivaroxaban, and does not contain lactose hydrate . The tablet according to claim 1, wherein the viscosity of the cellulose polymer is 1 to 10 mPa·s. The tablet according to any one of claims 1 to 2, further comprising a pharmaceutical additive. The tablet according to any one of claims 1 to 3, wherein the pharmaceutical additive comprises one or more selected from the group consisting of an excipient, a disintegrant, a lubricant, and a surfactant. The tablet according to any one of claims 1 to 4, wherein the excipient further comprises, in addition to D-mannitol, one or more selected from the group consisting of D-sorbitol, white sugar, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. The tablet according to any one of claims 1 to 5, wherein the disintegrant comprises one or more selected from the group consisting of corn starch, potato starch, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and crospovidone. The tablet according to any one of claims 1 to 6, wherein the lubricant comprises one or more selected from the group consisting of sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, calcium stearate, hydrogenated oil, and sucrose fatty acid ester. The tablet according to any one of claims 1 to 7, wherein the surfactant comprises one or more selected from the group consisting of polysorbate 80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil. The tablet according to any one of claims 1 to 8, wherein the amount of the cellulose polymer is 0.1 to 10% by weight based on the total weight of the tablet. A method for producing a compressed tablet, comprising the steps of adding a binder solution containing a cellulose polymer to a granulation mixture containing rivaroxaban and more than twice the weight of D-mannitol and not containing lactose hydrate , and compressing the granulated product containing rivaroxaban produced by stirring granulation into tablets.