JP7465157B2 - Method for producing orally disintegrating tablets containing rivaroxaban - Google Patents

Description

The present invention relates to an orally disintegrating tablet containing rivaroxaban and a method for producing the same.

Rivaroxaban (5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide) is a selective and direct factor Xa inhibitor. Rivaroxaban inhibits thrombin production and clot formation by inhibiting factor Xa in the intrinsic and extrinsic blood coagulation cascades. Rivaroxaban does not inhibit thrombin and has no direct effect on platelets. Oral anticoagulants containing rivaroxaban include, for example, Xarelto (registered trademark) tablets, which can be 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 deep vein thrombosis and pulmonary thromboembolism.

However, rivaroxaban is known to be poorly soluble, and in order to obtain good bioavailability, it is necessary to improve the solubility of rivaroxaban so that it can be sufficiently dissolved from the formulation. To achieve this, various pharmaceutical ideas have been devised. For example, Patent Document 1 discloses a method in which rivaroxaban is suspended in a granulation liquid in which hydroxypropyl methylcellulose and sodium lauryl sulfate are dissolved in water, and the suspension is added to a mixture of crystalline cellulose, lactose hydrate, and croscarmellose sodium, and wet granulation (stirred granulation and fluidized bed granulation) is performed, and the surface of rivaroxaban is specially treated with a hydrophilic binder to produce a granule that improves absorption behavior, and the granule is used to manufacture tablets. In addition, Patent Document 2 has found that crystalline cellulose in a granulated product containing rivaroxaban by stirring and granulation reduces the dissolution of rivaroxaban, and has disclosed a composition in which the content of crystalline cellulose is 5% by mass or less relative to the total mass of the granulated product and/or the water content of the granulation liquid used in preparing the granulated product is 25% by mass or less relative to the total mass of the solid components of the granulated product, aiming to improve the dissolution of rivaroxaban by sufficiently reducing the content of crystalline cellulose or reducing the water content in the granulation liquid used in preparing the granulated product. In addition, Patent Document 3 has found that the dissolution rate of rivaroxaban is improved when rivaroxaban is finely pulverized to reduce the particle size, and has disclosed a solid preparation containing rivaroxaban, characterized in that the cumulative 50% particle size (d50) based on volume is 12.0 μm or less.

On the other hand, for the purpose of improving the ease of administration, it is desirable to make rivaroxaban-containing formulations into an orally disintegrating tablet, which is an easy-to-take dosage form. In particular, since medication must be taken over a long period of time to prevent the onset of stroke or systemic embolism, it is expected that an orally disintegrating tablet that is easy to take will lead to patients' active participation in treatment and improved medication behavior. Orally disintegrating tablets are required to have the appropriate hardness as a tablet and to disintegrate quickly in the mouth.

Patent No. 4852423 Patent No. 6574041 JP 2020-29455 A

One of the objectives of the present invention is to provide an orally disintegrating tablet containing rivaroxaban that has a good dissolution rate and rapid disintegration in the oral cavity, and a method for producing the same.

According to one embodiment of the present invention, there is provided a method for producing an orally disintegrating tablet containing rivaroxaban, comprising: granulating a mixture containing rivaroxaban as a front-additive to produce a rivaroxaban-containing granulated powder; and compressing a mixture containing the rivaroxaban-containing granulated powder and a mixture containing a water-soluble polymer as a back-additive to tablet.

The water-soluble polymer may be at least one selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, and polyvinylpyrrolidone.

The water-soluble polymer may have a viscosity of less than 150 mPa·s in a 2% aqueous solution at 20°C.

The present invention provides an orally disintegrating tablet containing rivaroxaban that has a good dissolution rate and rapid disintegration in the oral cavity, and a method for producing the same.

FIG. 2 is a graph showing the dissolution rate of an orally disintegrating tablet containing rivaroxaban according to one embodiment of the present invention. FIG. 2 is a graph showing the dissolution rate of an orally disintegrating tablet containing rivaroxaban according to one embodiment of the present invention. FIG. 2 is a graph showing the dissolution rate of an orally disintegrating tablet containing rivaroxaban according to one embodiment of the present invention. FIG. 2 is a graph showing the dissolution rate of an orally disintegrating tablet containing rivaroxaban according to one embodiment of the present invention.

The rivaroxaban-containing orally disintegrating tablet and its manufacturing method according to the present invention will be described in detail below. However, the rivaroxaban-containing orally disintegrating tablet and its manufacturing method according to the present invention should not be interpreted as being limited to the description of the embodiments and examples shown below. In this specification, the "pre-addition part" refers to a mixture before granulation of the rivaroxaban-containing granulated powder by the stirring granulation method. In addition, the "post-addition part" refers to a mixture added to the rivaroxaban-containing granulated powder before tableting to form the rivaroxaban-containing orally disintegrating tablet.

As a result of the inventors' investigations, when an orally disintegrating tablet containing rivaroxaban was produced by the stirring granulation method, it was found that the dissolution rate of rivaroxaban was greatly improved by adding a water-soluble polymer to the front-addition section, but the oral disintegration time was significantly delayed. When an orally disintegrating tablet containing rivaroxaban was produced by producing a granulated powder containing rivaroxaban and then tableting a mixture containing the granulated powder containing rivaroxaban and a water-soluble polymer, it was found that the dissolution rate and disintegration property of rivaroxaban were improved by adding a water-soluble polymer to the rear-addition section.

The rivaroxaban of this embodiment is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide. The rivaroxaban-containing orally disintegrating tablet of the present invention contains, for example, 10 mg or 15 mg of rivaroxaban. The particle size of the rivaroxaban drug substance is not particularly limited. In order to improve the dissolution rate of rivaroxaban, the particle size of the rivaroxaban drug substance (D50 by laser diffraction scattering method) is preferably 15 μm or less, more preferably 10 μm or less.

The rivaroxaban-containing orally disintegrating tablet of this embodiment contains additives necessary for forming the tablet into an orally disintegrating tablet. Examples of additives include excipients, binders, disintegrants, stabilizers, and flavoring agents. The additives may be used alone or in combination of two or more. When there are two or more additives, the tablet may contain a so-called premix additive in which multiple additives are mixed and granulated in advance.

In the present embodiment, the orally disintegrating tablet containing rivaroxaban is produced by first producing a granulated powder containing rivaroxaban by agitation granulation, and then tableting a mixture containing the granulated powder containing rivaroxaban and a water-soluble polymer. Additives other than the water-soluble polymer may be added to the front-addition portion or the rear-addition portion. The orally disintegrating tablet containing rivaroxaban in the present embodiment may be produced from a mixture containing rivaroxaban in the front-addition portion and a water-soluble polymer in the rear-addition portion. After preparing the granulated powder containing rivaroxaban, the water-soluble polymer and, if necessary, other additives are mixed with the granulated powder, and the mixture is tableted to produce an orally disintegrating tablet containing rivaroxaban, which can have improved dissolution rate and disintegration properties.

In this embodiment, additives added to the front-end portion include, for example, excipients, binders, disintegrants, wetting agents, etc.

Excipients and binders include, for example, low-substituted hydroxypropylcellulose (L-HPC), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or hydrated, e.g., as the monohydrate), dextrose, maltose, sucrose, glucose, fructose, or maltodextrin.

Examples of disintegrants include carboxymethylcellulose, croscarmellose (crosslinked carboxymethylcellulose), crospovidone (crosslinked polyvinylpyrrolidone), low-substituted hydroxypropylcellulose (L-HPC), sodium carboxymethyl starch, sodium glycolate of potato starch, partial starch hydrolysates, wheat starch, corn starch, rice starch or potato starch, partially pregelatinized starch, etc.

Examples of wetting agents (surfactants) include sodium salts of fatty alcohol sulfates such as sodium lauryl sulfate, sulfosuccinates such as sodium dioctyl sulfosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylene sorbitan such as monolaurates, monostearates or monooleates of polyethylene glycol sorbitan, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers, or ethoxylated triglycerides.

Preferable additives to be added to the pre-addition portion include, for example, D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose (L-HPC), crospovidone, sodium lauryl sulfate (SLS), etc. The additives may be granulated in advance. The orally disintegrating tablet containing rivaroxaban according to the present invention can improve the dissolution rate of rivaroxaban by including sodium lauryl sulfate in the rivaroxaban-containing granulated powder.

In this embodiment, a water-soluble polymer is added to the post-addition portion. The water-soluble polymer added to the post-addition portion may be a cellulose derivative (cellulose-based polymer) or polyvinylpyrrolidone. The cellulose derivative may be selected from hypromellose, hydroxypropyl cellulose, methyl cellulose, and the like. In this embodiment, the water-soluble polymer added to the post-addition portion preferably has a viscosity of less than 150 mPa·s in a 2% aqueous solution at 20°C, more preferably 100 mPa·s or less. In this embodiment, the rivaroxaban-containing orally disintegrating tablet preferably contains 0.1% by weight or more and 5% by weight or less of a water-soluble polymer per tablet. The rivaroxaban-containing orally disintegrating tablet according to the present invention can be produced by tableting a mixture containing a rivaroxaban-containing granulated powder and a mixture containing a water-soluble polymer in the post-addition portion, thereby improving the dissolution rate and disintegrability.

In this embodiment, examples of additives that can be added to the rear-addition portion include excipients, binders, disintegrants, and lubricants. The excipients, binders, and disintegrants may be the same as those used in the front-addition portion.

Examples of lubricants include fumaric acid, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, high molecular weight fatty alcohols, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate or calcium silicate. A preferred example of a lubricant added later is magnesium stearate.

(Production method)
The rivaroxaban-containing orally disintegrating tablet according to the present invention can be produced by a known wet granulation method. As a wet granulation method, for example, agitation granulation method is preferable. The agitation granulation method is a method in which a granulation liquid is added to a homogenous mixture of an active ingredient and an additive, the mixture is kneaded, and the water is dried to produce a granule.

In one embodiment of the present invention, the rivaroxaban-containing granulated powder can be produced by mixing rivaroxaban and necessary additives as a pre-addition part in a commonly used mixer to prepare a homogeneous powder mixture, adding purified water to the mixture, kneading the mixture, drying the water, and then sizing the mixture in a sizing machine. There is no particular limit to the number of mixing steps, and the mixture may be mixed in several batches.

In one embodiment of the present invention, the rivaroxaban-containing orally disintegrating tablet can be produced by mixing the rivaroxaban-containing granulated powder with a mixture of a water-soluble polymer and necessary additives as a post-additional part using a commonly used mixer to obtain a homogeneous mixture, and compressing and molding the mixture using a commonly used tablet press. Any shape can be adopted as the shape of the tablet, and it can be molded into, for example, a tablet type, an oval shape, a sphere shape, or a rod shape.

An example of a method for producing an orally disintegrating tablet containing rivaroxaban according to the present invention is shown below, but this description is merely an example and is not intended to be limiting.

(Manufacture of premix additives)
In this example, a premix additive was prepared by mixing and granulating a plurality of additives as additives to be added to the front-addition portion. 405 g of D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.), 50 g of crystalline cellulose (PH-101, Asahi Kasei Corporation), 25 g of L-HPC (NBD-022, Shin-Etsu Chemical Co., Ltd.), 10 g of crospovidone (Kollidon CL-F, BASF Corporation) and 10 g of crospovidone (Kollidon CL-M, BASF Corporation) were mixed in a fluidized bed granulator (model: MP-01, manufactured by Powrex Corporation) to obtain a mixture. Fluidized bed granulation was performed while spraying purified water onto the obtained mixture. The obtained granules were sized using a sieve No. 22 to obtain a premix additive. The composition of the premix additive was 81% D-mannitol, 10% microcrystalline cellulose, 5% L-HPC, 2% crospovidone CL-F, and 2% crospovidone CL-M.

Example 1
Rivaroxaban (15 mg), premix additive (68.2 mg), and sodium lauryl sulfate (EMAL OS, Kao Indonesia Chemical) (0.5 mg) were added and mixed per tablet, and purified water was added to the mixture in an amount of 15% solid-liquid ratio, and kneaded using a mortar. The wet granules were sieved through a No. 8 sieve, dried to remove moisture, and sized through a No. 22 sieve to produce the rivaroxaban-containing granulated powder of Example 1. The obtained rivaroxaban-containing granulated powder was added with 0.3 mg of hypromellose (TC-5E, Shin-Etsu Chemical) and 1.0 mg of magnesium stearate (Plant, Taihei Chemical Industry), and mixed thoroughly, and then molded using a single-shot tablet press (No. 2B type, Kikusui Seisakusho Co., Ltd.) to obtain rivaroxaban-containing orally disintegrating tablets with a mass of 85.1 mg (n = 10) and a thickness of 2.79 mm (n = 5).

Example 2
Orally disintegrating tablets containing rivaroxaban with a mass of 85.3 mg (n=10) and a thickness of 2.80 mm (n=5) were obtained in the same manner as in Example 1, except that the amount of hypromellose in the rear addition portion was changed to 0.5 mg.

Example 3
Orally disintegrating tablets containing rivaroxaban with a mass of 85.7 mg (n=10) and a thickness of 2.80 mm (n=5) were obtained in the same manner as in Example 1, except that the amount of hypromellose in the rear addition portion was changed to 1.0 mg.

(Comparative Example 1)
Orally disintegrating tablets containing rivaroxaban with a mass of 87.8 mg (n=10) and a thickness of 2.86 mm (n=5) were obtained in the same manner as in Example 1, except that the amount of premix in the front-addition part was changed to 68.5 mg, the amount of hypromellose in the back-addition part was changed to 0 mg, and no hypromellose was added.

(Comparative Example 2)
Orally disintegrating tablets containing rivaroxaban with a mass of 84.3 mg (n=10) and a thickness of 2.80 mm (n=5) were obtained in the same manner as in Example 2, except that the amount of premix in the front-addition section was changed to 68.0 mg and the hypromellose added in the rear-addition section was changed to be added in the front-addition section (hypromellose was not included in the rear-addition section).

(Comparative Example 3)
Orally disintegrating tablets containing rivaroxaban with a mass of 84.5 mg (n=10) and a thickness of 2.81 mm (n=5) were obtained in the same manner as in Example 3, except that the amount of premix in the front-addition section was changed to 67.5 mg and the hypromellose added in the rear-addition section was changed to be added in the front-addition section (hypromellose was not included in the rear-addition section).

(Dissolution test)
Using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), a dissolution test was performed on the rivaroxaban-containing orally disintegrating tablets of Examples 1 to 3 and Comparative Examples 1 to 3, using 900 ml of the dissolution test liquid 1 (pH 1.2) of the Japanese Pharmacopoeia, 17th Edition, in accordance with the dissolution test method 2 (paddle method, 50 revolutions per minute) of the Japanese Pharmacopoeia, 17th Edition, as the test liquid. The dissolution test was performed three times using one tablet of each rivaroxaban-containing orally disintegrating tablet as a sample, and the average value was taken as the dissolution rate of the rivaroxaban-containing orally disintegrating tablets of Examples 1 to 3 and Comparative Examples 1 to 3. The dissolution rates of the rivaroxaban-containing orally disintegrating tablets of Examples 1 to 3 and Comparative Example 1 are shown in FIG. 1. The dissolution rates of the rivaroxaban-containing orally disintegrating tablets of Comparative Examples 1 to 3 are shown in FIG. 2.

As shown in Figures 1 and 2, the rivaroxaban-containing orally disintegrating tablets of Examples 1 to 3 and Comparative Examples 2 to 3, which contain hypromellose, all showed a significantly improved dissolution rate compared to the rivaroxaban-containing orally disintegrating tablet of Comparative Example 1, which does not contain hypromellose. There was no significant difference in dissolution rate between the rivaroxaban-containing orally disintegrating tablets of Examples 1 to 3, which contain hypromellose in the rear addition portion, and the rivaroxaban-containing orally disintegrating tablets of Comparative Examples 2 to 3, which contain hypromellose in the front addition portion.

(Physical properties of orally disintegrating tablets containing rivaroxaban)
The above-mentioned rivaroxaban-containing orally disintegrating tablets were evaluated for their formulation properties by measuring their hardness and disintegration time. The hardness of the tablets was measured using a tablet hardness tester (DC-50, Okada Seiko Co., Ltd.), and the average value of the measurements for three tablets was calculated. The disintegration time was measured in the oral cavity by a sensory test, and the average value of the measurements for two tablets was calculated. The hardness and disintegration time of Examples 1 to 3 and Comparative Examples 1 to 3 are shown in Table 1.

Table 1 shows the hardness and disintegration time of the rivaroxaban-containing tablets in Examples 1 to 3 and Comparative Examples 1 to 3. As shown in Table 1, the rivaroxaban-containing orally disintegrating tablets in Examples 1 to 3, in which hypromellose was added to the rear additive portion, all had good hardness and disintegration time. On the other hand, the rivaroxaban-containing orally disintegrating tablets in Comparative Examples 2 to 3, in which hypromellose was added to the front additive portion, had a significantly delayed disintegration time.

Example 4
Orally disintegrating tablets containing rivaroxaban with a mass of 85.1 mg (n=10) and a thickness of 2.79 mm (n=5) were obtained in the same manner as in Example 1, except that the amount of premix in the front-addition part was changed to 68.0 mg, the amount of hypromellose in the back-addition part was changed to 0.5 mg, and purified water was changed to a solid-liquid ratio of 20%.

Example 5
Orally disintegrating tablets containing rivaroxaban with a mass of 84.5 mg (n=10) and a thickness of 2.78 mm (n=5) were obtained in the same manner as in Example 4, except that the hypromellose (TC-5E, Shin-Etsu Chemical) in the post-addition portion was changed to hypromellose (TC-5R, Shin-Etsu Chemical).

Example 6
Orally disintegrating tablets containing rivaroxaban with a mass of 85.8 mg (n=10) and a thickness of 2.79 mm (n=5) were obtained in the same manner as in Example 4, except that the hypromellose (TC-5E, Shin-Etsu Chemical) in the post-addition portion was changed to hydroxypropyl cellulose (HPC SSL, Nippon Soda Co., Ltd.).

(Example 7)
Orally disintegrating tablets containing rivaroxaban with a mass of 84.3 mg (n=10) and a thickness of 2.79 mm (n=5) were obtained in the same manner as in Example 4, except that the hypromellose (TC-5E, Shin-Etsu Chemical) in the post-addition portion was changed to hypromellose (METOLOSE SR (90SH-100SR), Shin-Etsu Chemical).

(Example 8)
Orally disintegrating tablets containing rivaroxaban with a mass of 84.1 mg (n=10) and a thickness of 2.79 mm (n=5) were obtained in the same manner as in Example 4, except that the hypromellose (TC-5E, Shin-Etsu Chemical) in the post-addition portion was changed to methylcellulose (SM-4, Shin-Etsu Chemical).

Example 9
Orally disintegrating tablets containing rivaroxaban with a mass of 84.2 mg (n=10) and a thickness of 2.79 mm (n=5) were obtained in the same manner as in Example 4, except that the hypromellose (TC-5E, Shin-Etsu Chemical) in the post-addition portion was changed to polyvinylpyrrolidone (K30, Dai-ichi Kogyo Seiyaku Co., Ltd.) and purified water was changed to a solid-liquid ratio of 15%.

(Comparative Example 4)
Orally disintegrating tablets containing rivaroxaban with a mass of 85.3 mg (n=10) and a thickness of 2.79 mm (n=5) were obtained in the same manner as in Example 4, except that hypromellose (TC-5E, Shin-Etsu Chemical) in the post-addition portion was changed to hydroxypropyl cellulose (HPC M, Nippon Soda Co., Ltd.).

(Comparative Example 5)
Orally disintegrating tablets containing rivaroxaban with a mass of 85.1 mg (n=10) and a thickness of 2.79 mm (n=5) were obtained in the same manner as in Example 4, except that the hypromellose (TC-5E, Shin-Etsu Chemical) in the post-addition portion was changed to a polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat (registered trademark) IR, BASF Japan Ltd.).

Example 10
Rivaroxaban 15 mg, D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.) 55.0 mg, crystalline cellulose (PH-101, Asahi Kasei Corporation) 6.8 mg, L-HPC (NBD-022, Shin-Etsu Chemical Co., Ltd.) 3.4 mg, crospovidone (Kollidon CL-F, BASF) 1.4 mg, crospovidone (Kollidon CL-M, BASF) 1.4 mg and sodium lauryl sulfate (Emeral OS, Kao Indonesia Chemical) 0.5 mg were added and mixed, and purified water was added to the mixture in a solid-liquid ratio of 20% and kneaded using a mortar. The wet granules were sieved through a No. 8 sieve, the moisture was dried, and then the granules were sized through a No. 22 sieve to produce the rivaroxaban-containing granulated powder according to Example 10. The obtained rivaroxaban-containing granulated powder was added with 0.5 mg of hypromellose (TC-5E, Shin-Etsu Chemical) and 1.0 mg of magnesium stearate (plant, Taihei Chemical Industry), and mixed thoroughly. The mixture was then molded using a single-punch tablet press (No. 2B, Kikusui Seisakusho Co., Ltd.) to obtain orally disintegrating tablets containing rivaroxaban with a mass of 84.6 mg (n=10) and a thickness of 2.80 mm (n=5).

(Comparative Example 6)
Rivaroxaban 15 mg, D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.) 55.485 mg, crystalline cellulose (PH-101, Asahi Kasei Corporation) 6.85 mg, L-HPC (NBD-022, Shin-Etsu Chemical Co., Ltd.) 3.425 mg, crospovidone (Kollidon CL-F, BASF) 1.37 mg, crospovidone (Kollidon CL-M, BASF) 1.37 mg and sodium lauryl sulfate (Emeral OS, Kao Indonesia Chemical) 0.5 mg were added and mixed, and purified water was added to the mixture in a solid-liquid ratio of 15% and kneaded using a mortar. The wet granules were sieved through a No. 8 sieve, the moisture was dried, and then granulated with a No. 22 sieve to produce a rivaroxaban-containing granulated powder according to Comparative Example 6. The obtained rivaroxaban-containing granulated powder and 1.0 mg of magnesium stearate (plant, Taihei Chemical Industry) were added and thoroughly mixed, and then molded using a single-punch tablet press (No. 2B type, Kikusui Seisakusho Co., Ltd.) to obtain orally disintegrating tablets containing rivaroxaban with a mass of 85.0 mg (n = 10) and a thickness of 2.81 mm (n = 5).

The viscosities of the water-soluble polymers used in Examples 1 to 10 and Comparative Examples 1 to 6 are shown in Table 2. For Kollicoat IR, the viscosity is that of a 10% aqueous solution at 20° C., and for the others, the viscosity is that of a 2% aqueous solution at 20° C.

(Dissolution test)
Using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), a dissolution test was performed on the rivaroxaban-containing orally disintegrating tablets of Examples 4 to 10 and Comparative Examples 1, 4, 5, and 6, in accordance with the dissolution test method 2 (paddle method, 50 revolutions per minute) of the 17th Revised Japanese Pharmacopoeia, using 900 ml of the dissolution test solution 1 (pH 1.2) of the 17th Revised Japanese Pharmacopoeia. The dissolution test was performed three times using one tablet of each rivaroxaban-containing orally disintegrating tablet as a sample, and the average value was taken as the dissolution rate of the rivaroxaban-containing orally disintegrating tablets of Examples 4 to 10 and Comparative Examples 1, 4, 5, and 6. The dissolution rates of the rivaroxaban-containing orally disintegrating tablets of Examples 4 to 9 and Comparative Examples 1, 4, and 5 are shown in FIG. 3. The dissolution rates of the rivaroxaban-containing orally disintegrating tablets of Examples 2 and 10 and Comparative Examples 1 and 6 are shown in FIG. 4.

As shown in FIG. 3, the rivaroxaban-containing orally disintegrating tablets according to Examples 4 to 9, which contain hypromellose (TC-5E) or hypromellose (TC-5R), hydroxypropyl cellulose (HPC SSL) or hydroxypropyl cellulose (METOLOSE SR (90SH-100SR)), methylcellulose (SM-4), and polyvinylpyrrolidone (K30), all showed a significant improvement in dissolution rate, compared to the rivaroxaban-containing orally disintegrating tablet according to Comparative Example 1, which does not contain a water-soluble polymer. On the other hand, the rivaroxaban-containing orally disintegrating tablets according to Comparative Examples 4 and 5, which contain hydroxypropyl cellulose (M) or polyvinyl alcohol-polyethylene glycol graft copolymer, did not show a sufficient improvement in dissolution rate. Although not compared in the figure, there is no difference in dissolution rate between Examples 2 and 4, which indicates that the amount of purified water added to the pre-addition portion does not affect the dissolution rate of the rivaroxaban-containing orally disintegrating tablet.

As shown in Figure 4, the rivaroxaban-containing orally disintegrating tablets according to Example 2 and Comparative Example 1, which contain premixed additives prepared by granulating the additives to be added to the front-addition portion, showed dissolution rates comparable to those of the rivaroxaban-containing orally disintegrating tablets according to Example 10 and Comparative Example 6, which contain additives of the same composition added without granulating.

(Physical properties of orally disintegrating tablets containing rivaroxaban)
The above-mentioned rivaroxaban-containing orally disintegrating tablets were evaluated for their preparation properties by measuring their hardness and disintegration time.

Table 3 shows the hardness and disintegration time of the rivaroxaban-containing tablets in Examples 4 to 9 and Comparative Examples 4 and 5. Table 4 shows the hardness and disintegration time of the rivaroxaban-containing tablets in Examples 2 and 10 and Comparative Examples 1 and 6. As shown in Tables 2 and 3, all of the rivaroxaban-containing orally disintegrating tablets had good hardness and disintegration time.

Even if there are other effects and advantages different from those brought about by the aspects of each of the above-mentioned embodiments, those which are clear from the description in this specification or which can be easily predicted by a person skilled in the art are naturally understood to be brought about by the present invention.

Claims (1)

A mixture containing rivaroxaban as a pre-additive is granulated to produce a rivaroxaban-containing granulated powder.
A method for producing an orally disintegrating tablet containing rivaroxaban, comprising compressing a mixture containing the rivaroxaban-containing granulated powder and a mixture containing at least one water-soluble polymer selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, and polyvinylpyrrolidone, each of which has a viscosity of less than 150 mPa·s in a 2% aqueous solution at 20°C, as a post-addition component.

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